IL32100A - 2-(7-halo-5-halophenyl-2,3-dihydro-2-oxo-1h-1,4-benzodiazepin-1-yl)alkyl esters and process for the manufacture thereof - Google Patents

Description

«1»>T1M 0» ¾08 C?*K~1-t 'BTK'Tl T 33-4,1 halo 2- (7-halo-5Vphenyl-2 , 3-dihydro-2-oxo-1 H-1 , 4- benzodiazepin-1 -yl)alkyl esters and process for the manufacture thereof.

SPARAi'lSDICA A.G.

C : 30422 - 2 - 32100/2 The present invention relates to benzodiazepine derivatives of the general formula wherein R^ and Rg are halogen and R is halo lower alkanoyl, lower alkoxy lower alkanoyl, aryl-CO- where aryl stands for phenyl or pyridyl optionally substituted with at most 3 lower alkoxy group or halogen atoms, the monoacyl moiety of a lower alkanoic or lower alkenoic dibasic acid and their salts, a carbamate moiety, a sulfate moiety or a phosphate moiety, the group -CO-lower alk lene- N J or the group -cmH2m0H» R,_ and g are each hydrogen ^-or lower alkyl and n and m are whole integers from 2-7; and salts thereof.

By the term "lower alkyl" as utilized herein, both straight and branched chain C-^-O^, preferably C^-C^-hydrocarbon groups are intended such as methyl, ethyl, isobutyl, isopropyl and the like. By the term lower alkoxy? there is similarly intended both straight and branched chain C^-C.-,, preferably C^-C^, hydrocarbonoxy groups such as methoxy, ethoxy and the like. The term "halogen" or "halide" as found herein is intended to connote all four forms thereof, i.e. chlorine, bromine, fluorine and iodine, unless otherwise specified. The term "lower alkanoyl" connotes a moiety containing 1-7 carbon atoms, either in a branched or straight chain such as methyl carbonyl, ethyl carbonyl, isopropyl carbonyl and the like. The term "lower alkenoic acid" connotes an acid containing both 4-7 carbon atoms, and an ethylenic double bond.

The radical -^^-^rT may be a straight or branched chain lower alkylene grouping such as ethylene, propylene, ethyl-ethylene, pentamethylene and the like.

Illustrative of the groupings encompassed by the character R of formula I are substituted (e.g. with halo, lower alkyl or lower alkoxy), lower alkanoyl moieties such as haloacetyl, halopropionyl, e.g. 3-°hloro-propionyl, halo-butyryl, e.g. ' -chlorobutyryl, lower alkoxy lower alkanoyl such as methoxyacetyl, ethoxyacetyl and the like. •—co- An ar^yl/moiety may be represented preferably, by benzoyl or substituted benzoyl such as lower alkyl benzoyl (p-lower alkyl benaoyl), dilower alkoxy benzoyl such as di-methoxy benzoyl, tri-lower alkoxy benzoyl such as trimethoxy r l-co- carboxylic acyl moiety of heterocyclic/acids such as picolinic acid, iso-nicotinic acid, nicotinic acid and the like which may be un-substituted or substituted with such groupings as lower alkoxy, halo, lowor allyl and the liko. Representative of substituted carboxylic heterocyclic/acids suitable for the purposes of the present invention are lower alkoxy nicotinic acid, e.g. 2-methoxy-nicotinic acid, halo-nicotinic acid, e.g. 2,4 or 5-bromonico-tinic acid, 3-.lower alkyl isoniootinio aoid and the like.

Ar-lower alkanoyl its Illustrated b phenyl acetyl. By the carboxylic expression, a monoacyl moiety of dibasic/acid as utilized herein, there is intended the monoacyl moiet of a lower alka-noic dibasic acid such as acid succinyl and the like and the monoacyl moiety of a lower -alkenoic dibasic acid such as acid maleyl, acid glutaconoyl and the like. Salts of the latter can be formed with any suitable base such as an alkali metal alkoxide, e.g. sodium methoxide. A carbamate moiety, i.e., -CONH-lower alkyl, can be provided by the utilization of a lower alkyl isocyanate such as methyl isocyanate when esteri-fying the compound of the formula II . R as the phosphate grouping or a sulfate group can be conveniently provided by esterifying with polyphosphoric acid, phosphorus oxychloride, ethylthiophosphate, cone, sulfuric acid and the like.

In formula I R-^ is preferably nitro or halogen, most and . suitably, chlorine. - f ≥ ¾g , other than hydrogen, it is preferably halogen, mo8 suitably, fluorine or chlorine and is situated in the 2-position of the 5-Phenyl ring. 32100/2 preferred embodiment R^ is chlorine, R2 fluorine in 2'- u position, n is 2 and or a carbamate moiety or the moiety of a dibasic carboxylic acid and salts thereof.

The process of the present invention comprises treating compound of the general formula ' wherein R1* Rg and n are as above, with an acid agent containing a halo lower alkanoyl, lower alkoxy lower alkanoyl, aryl-CO- where aryl stands for phenyl or pyridyl optionally substituted with at most 3 lower alkoxy groups or halogen' atoms, the monoacyl moiety of a lower alkanoic or lower alkenoic dibasic acid, a carbamate, sulfate or phosphate moiety, or with a diol of the general formula HOC III wherein m has the meaning indicated above, if desired, treating a compound obtained wherein R represents . a halo lower alkanoyl moiety with an amine of the general formula wherein Rr and have the meaning incidated above, o and, if desired, transforming a product obtained into a salt .

Examples of acid agents suitable of effecting the esterification of compounds of the formula II, there can be efficaciously utilized isonicotinoyl chloride, benzoyl chloride, 4, "methyl bonsoyl ohlor-i-de, 3,4,5-trimethoxybenzoyl chloride, succinic anhydride, isonicotinic p-< A^HT-H ,·> ,«ρ·>^ maleic anhydride, glutaconic acid anhydride, methyl isocyanate, ethyl isocyanate, strong inorganic acids such as acid phosphates, e.g. polyphosphoric acid, ethylthio phosphate, phosphorus oxychlorlc acid and acid sulfates such as concentrated sulfuric acid and the like.

As is evident from the above, also suitable as acid agents are organic acids which are substituted with halogen, lower a ky or lower alkoxy. Representative of these ar© halo-acetic acid such as chloroacetlc acid, lower alkoxy acetio anhydride such as methoxy acetic anhydride, ethoxy acetic anhydride and the like, Ί "lower alkyl bonaoyl chloride such uu Hiio hyl bonaoyl ohlorldo, 2,4,5-trimethoxy benzoyl chloride, 2,4 or 5-halonicotinic acid such as 5-bromonlcotinic acid, 2,4, or 5 lower alkoxy nicotinic acid such as 2-methoxynico-tinic acid and the like.

The esterification with any of the acid agents specified above is conducted in accordance with procedures conventional in the art and well documented in the literature . a carboxylic For example, with an acid agent such as/acid anhydride, or with aEaac iyhalide, e.g. a benzoyl halide such as 3,4,5- trimethoxy benzoyl chloride, or nicotinoyl halide, the reaction can proceed to the desired este by permitting the reaction medium to stand at room temperature, particularly, if pyridine or the like is utilized as the solvent medium.

As is evident from the above, the particular reaction conditions for esterifying a compound of the formula II are not critical and can be selected by one of ordinary skill in the art depending upon the acid agent utilized, particularly when viewing the esterification desired in the light of the prior art on the subject. By a cursory perusal of the literature, one can readily ascertain a myriad of suitable reagents capable of functioning efficaciously in the formation of the esters of the formula I.

If a terminal free acid group is present in position-1 in a compound of the formula I (when a dibasic acid or a derivative thereof is utilized as the acyl group providing agent), it can be converted by treatment with a suitable base such as sodium hydroxide or potassium hydroxide, potassium carbonate, alkali metal alkoxides such as sodium methoxide, into the corresponding benzodiazepine of the formula I bearing wherein A is the cation of the base utilized. Preferably, A connotes sodium, potassium or the like.

The esterification as is evident from the above, can be conducted in any conventional organic solvent such as dimethyl-formamide, pyridine, a hydrocarbon such as toluene and the like. However, it is preferred to effect the esterification where possible in the presence of pyridine. Moreover, it has been found that in the case where an acid anhydride is used as the acyl group providing agent, such acid anhydride can itself serve as the reaction medium in addition to being a reaction participant. The reaction is preferably conducted at room temperature but it can also proceed to the desired product efficaciously at above or below room temperature depending upon the acid agent utilized.

Especially preferred esters are those which evidence particularly high water solubility. Those esters which contain as the R group in formula I nicotinoyl, succinoyl or the phosphate radical have been found to be particularly useful because of their high solubility in water, when in pharma-ceutically acceptable salt forms. Thus, particularly desirable esters are those which are formed from compounds of the formula II utilizing as the esterification agent an acid substance containing a nicotinoyl moiety, a succinoyl moiety or a phosphate moiety.

The reaction of a compound of the formula I wherein l X wherein n, R, and R are as above and X is halogen, preferably, chlorine or bromine, with an amine of the formula IV is preferably conducted in an inert organic solvent medium utilizing one or more inert organic solvents such as acetone, methyl ethyl ketone, lower alkanols such as methanol, ethanol and the like, dimethyl-formamide, benzene, nitromethane and N-methyl-pyrrolidone and the like. Temperature and pressure are not critical and thus, the reaction can be carried out at or below room temperature and at atmospheric pressure, or at elevated temperatures and/or elevated pressures. However, elevated temperatures, e.g. about the reflux temperature of the reaction mixture, are preferred. If desired, the reaction can proceed in the presence of an alkali halide, e.g. sodium iodide.

Any primary or secondary amine of the formula IV can be suitably employed. If a secondary amine is utilized, the two carbon atoms joined to the nitrogen atom of the amine pendently of the other group. Therefore, such carbon atoms can individually comprise a part of a straight or branched chain lower alkyl radical such as methyl, ethyl, propyl, iso propyl or the like.

Compounds of formula I wherein R represents the group •C OH can be prepared by reacting the alcohols of the m cm _ , formula II with a diol of formula III. In aIpreferred aspect the invention is effected utilizing the diol as the solvent medium. Thus, by the convenient expedient of utilizing the diol in excess, there can be provided to the reaction zone, a* reaction participant as well as the medium 'in which the reaction may be effected. Temperature is not a critical aspe of this process aspect and thus the reaction can be effected at room temperature or elevated temperatures. However, it is preferred to utilize elevated temperatures, e.g. from abou 70° to about 180°, more preferably from about 130° to about 180°, most suitably at about the reflux temperature of the. reaction mixture. Conveniently, a promoter may be present in the reaction system. Illustrative of these are concentrated hydrochloric acid, polyphosphoric acid, thionyl chloride and the like. ·.

. Illustrative of suitable diols are ethylene glycol, 1,5-propyiene glycol, 1, -butyleneglycol, l,j5-dihydroxy butane, 1,2-dihydroxy propane and the like.

The compounds of formula I are useful as sedatives in view of their capability of inducing sleep. Said compounds and " their pharmaceutically acceptable salts can be- administered with dosage adjusted to individual requirements and fitted to the pharmaceutical exigencies of a situation. For example, they can be administered internally, i .e .enterally or parenter- ally in the form of tablets, suspensions, solutions, capsules, dragees and the like according to conventional pharmaceutical procedures. They exhibit superior pharmacological properties than the structurally moot, related known compound 7-chlo.ro-l , 3- dihydro-l-( 2-hydroxyethyl ) -5-pheny1-211-1 , 4-benzodiazepine-one .

The compounds of the formula I form pharmaceutically acceptable salts (depending of course, on the nature of the substituent in position-1) with both inorganic and organic pharmaceutically acceptable acids and bases such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, succinic acid, methanesulfonic acid, para-toluenesulforiic acid; ammonia; amines such as tertiary amines, e.g. triethylamine; alkali alkali metal alkoxides such as sodium methoxide and the like. Such salts can be formed quite readily by those skilled in the art, with the prior art and the nature of the compound to be placed in salt form, in view.

The following examples are illustrative of the present invention. All temperatures are stated in degrees centigrade.

Example 1 A solution of 5 g (0.0151 M) of 7-chloro-5- (2-fluoro-phenyl)-l- (2-hydroxyethyl)-l, 3-dihydro-2H-l, -benzodiazepin-2-one in 60 ml of dry toluene was treated with 2.95 S (0.0502 M) of maleic anhydride and the resulting mixture was refluxed with stirring for 5 hours. The reaction mixture was cooled and poured into 0 ml of ether and 100 ml of dilute ammonium hydroxide. The layers were separated and the basic layer was acidified with acetic acid. The crude product was extracted with 2 x 100 ml of dichloromethane and evaporated to dryness. The residual oil was dissolved in 100 ml of dichloromethane which was washed with 2 x 100 ml of water, 100 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness .

The product was crystallized from isopropanol and then recrystallized twice from a mixture of dichloromethane and hexane to give 2- (7-chloro-5- (2-fluorophenyl) -2 , j5-<iihydro-2-oxo-lH-l, 4-benzodiazepin-l-yl Jethyl maleate as pale yellow The starting material may be prepared as follows: A) A solution of 10 g (0.0346 m) of 7-chloro-5- (2- luoro-phenyl )-l , -dihydro-2H-l,4-benzodiazepin-2-one hydrochloride in 25 ml of N,N-dimethyl ormamide was treated with 10.6 ml of a solution containing 0.0415 m of sodium methoxide in methanol. The solution was stirred at room temperature for minutes and 8.7 g (0.0692 m) of 2-bromoethanol was added. The reaction mixture was heated at 80° for 2 hours and then poured into 200 ml of water. The reaction products were removed by filtration, dissolved in 100 ml of dichloromethane which was then washed with water (2 x 100 ml), saturated brine, dried over sodium sulfate and evaporated. The residual oil (IO.5 g) was crystallized from ether and the ether medium was filtered. The mother liquors were evaporated, dissolved in benzene and filtered over 200 g of silica. The silica was eluted with ether until all impurities had been removed and 7-chloro-5-(2-fluorophenyl)-l-(2-hydroxyethyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one was then obtained by using methanol as the eluant .

Removal of the solvent gave the product as an oil. An excess of ethanolic hydrogen chloride was added, followed by ether to precipitate the salt. Three recrystallizations of the salt from a mixture of methanol and ether gave 7-chloro-1- (2-hydroxyethyl )-5-(2-fluorophenyl ) -1,3-dihydro-2H-l , 4-benzodiazepin-2-one hydrochloride as pale yellow prisms, m. p.194-196° dec.

B) A solution of 1 g (0.003 6 m) of 7-chloro-5- (2-fluoro-phenyl)-;3H-l,4-benzodiazepin-2(lH)-one in 15 ml o dry N,N-dimethylformamide was treated with 0.9 ml (0.004l5 m) of a 4.69 N solution of sodium methoxide in methanol. The mixture was stirred for 0.5 hour, when a solution of 0.45 g (0.0105 m) of ethylene oxide in 5 ml of dry Ν,Ν-dimethyl ormamide was added. The reaction mixture was stirred at room temperature for 2 hours, and at 60° for 1 hour. Solvent was removed under reduced pressure and the residue was treated with 1.5 g (0.015 m) of succinic anhydride, and ml of toluene. The solution was heated under reflux for j5 hours, then cooled in an ice bath, made basic (pH 9 ) with ammonium hydroxide and the layers were separated. The aqueous layer was treated with 5 nil of sodium hydroxide solution and after 30 minutes, the mixture was first acidified with concentrated hydrochloric acid and then made basic with ammonium hydroxide. The product was extracted into 100 ml of dichloromethane, which was then washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness.

The residual oil was dissolved in 1 ml of benzene, and filtered through 50 g of silica gel. The silica gel was eluted with 200 ml of benzene and then with 250 ml of ethyl acetate. The ethyl acetate fraction was evaporated to dryness, dissolved in 5 nil of ethanol and treated with an excess of ethariolic hydrogen chloride. Ether was added and 7-chloro-l-(2-hydroxyethyl) - - (2-fluorophenyl )-1, 3-dihydro-2H-l, 4-benzo-diazepin-2-one hydrochloride was separated by filtration as Example 2 A solution of 1.6 g (0.00371 M) of crude 2- [7-chloro-5-(2-fluorophenyl)-2,;5-dihydro-2-oxo-lH-l,4-benzodiazepin-l-yl] -ethyl maleate in 10 ml of methanol was treated with 0.7 ml (Ο.ΟΟ528 W) of 4.69 N sodium methoxide in methanol and the solution was evaporated to dryness. The residual oil was triturated with ether and the residue was crystallized from a mixture of ethanol and ether. Recrystallization from a mixture of methanol and ether gave 2-[7-chloro-5(2-fluorophenyl)-2,3-dihydro-2-oxo-lH-l,4-benzodiazepin-l-yl] ethyl maleate sodium salt as pale yellow prisms, melting at 143-7°. It was found that this sample retained methanol at 100°, but on recrystallization from a mixture of methanol and acetone, the product was obtained methanol free as pale yellow prisms, melting at 220-2°.

Example j? A solution of 4 g (0.0121 M) of 7-chloro-5- (2-fluoro-phenyl)-l- (2-hydroxyethyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one in 40 ml of dry pyridine was treated with 8.2 g (0.0362 M) of 3*4,5-trimethoxybenzoyl chloride, and the mixture was allowed to stand at room temperature for l6 hours. Solvent was removed by distillation and the residue was dissolved in 100 ml of dichloromethane. The solution was washed with 100 ml of 5 er cent potassium carbonate solution, 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to then from a mixture of dichloromethane and hexane gave 2- [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-lH-l, 4-benzodiaze-pin-l-yl] ethyl 3,4,5-trimethoxy-benzoate as white prisms, melting at l6l-3° .

Example 4 A solution of 4 g (0.012 M) of 7-chloro-5- (2-fluoro-phenyl )-1- (2-hydroxyethyl )-1,3-dihydro-2H-l,4-benzodiazepin-2-one in 15 ml of dry pyridine was treated with 20 ml of methyl isocyanate and the reaction mixture was warmed on the steam bath for 2 hours. Solvents were removed under reduced pressure and the residue was dissolved in 0 ml of dichloromethane . The solution was washed with 0 ml of dilute ammonium hydroxid 25 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness giving N-methyl-2-[7-chloro-5-(2-fluorophenyl)-2,j5-dihydro-2-oxo-lH-l, 4-benzodiazepin-l-yl ] -ethyl carbamate as an oil.

The resulting oil was dissolved in 10 ml of ethanol, and an excess of ethanolic hydrogen chloride was added. The solution was evaporated to dryness and the residue was crystallized first from a mixture of isopropanol and ether, and then from a mixture of methanol and ether to give the hydrochloride as pale yellow prisms, melting at I75-8O0 in a sealed tube.

Example 5 reflux condenser, drying tube, nitrogen inlet tube, and a dropping funnel was added 100 g (0-5 6 M) of 7-chloro-5- (2-fluorophenyl)-l,3-dihydro-2H-l, 4-benzodiazepin-2-one hydrochloride and 400 ml of dry Ν,Ν-dimethylformamide . The' solution was stirred under a slow stream of nitrogen and 33 - 2 g (0.692 M ) of a 50 per cent dispersion of sodium hydride in mineral oil was added. After 30 minutes the solution was cooled in an ice bath to 5°C, and 150 g ( 1.04 M) of 2-bromoethanol in lOO ml of dry Ν,Ν-dimethylformamide was added dropwise over a 20 minute period. he nitrogen was turned off, and the reaction mixture was heated to 100°C for 5 hours, and then it was rinsed into a 3 liter flask with benzene and distilled to dryness under reduced pressure. The so-obtained 7-chloro-5- (2-fluorophenyl ) -1- (2-hydroxyeth l ) -1 , 3-dihydro-2H-l, 4-benzodiazepin-2-one was transferred to a 3 liter 3-necked flask with 750 ml of benzene, then 100 ml (0.719 M) of triethylamine and 100 g (1.0 M) of succinic anhydride were added, and the reaction was stirred for l6 hours at room temperature. The reaction mixture was rinsed into a 3 liter flask with benzene, and evaporated to dryness under vacuum. The dark oil was dissolved in 750 ml of benzene which was then treated with 4 0 ml of water with shaking or stirring, and then with a mixture of 550 ml of ice and water to bring the temperature down to approximately 10°C. The solution was made basic (about pH 8.5 ) with 175 ml of a 50 per cent (w/v) potassium carbonate solution with stirring to avoid foaming over. After transferring to a separatory funnel the layers were separated, and the water layer was extracted with x 600 ml of benzene. The benzene solutions solution, dried over anhydrous sodium sulfate, and evaporated to dryness under vacuum to give an oil containing 2- [ 7-chloro-5- (2- luorophenyl )- , 3-dihydro-2-oxo-lH-l, 4-benzodiazepin-l-yl] ethylsuccinate potassium salt.

Example 6 A solution of 5 g (0.0151 M) of 7-chloro-l- ^-hydrox -eth l^S-^-fluorophenyl)-l,;5-dihydro-2H-l, 4-benzodiazepin-2-one hydrochloride in 60 ml of pyridine was treated with 8 g (0.044 ) of nicotinoyl chloride hydrochloride, and the solution was heated on the steam bath, with stirring, for 2 hours. Pyridine was removed under vacuum. The residue was dissolved in 100 ml of dichloromethane, washed with 10 percent potassium carbonate solution (2 x 75 ml), 75 ml of a saturated brine solution, dried over anhydrous sodium sulfate and evaporated to dryness.

The oil was crystallized from ether, and then recrystallize from methanol to give l-(2-nicotinoyloxyethyl) -7-chloro-5-(2-fluorophenyl)-l, 3-dihydro-2H-l,4-benzodiazepin-2-one as white prisms, melting at 138-40°.

Example 7 A solution of 0.5 g (0. 00151 M) of 7-chloro-5- (2-fluorophenyl)-!- (2-hydroxyethyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one in 15 ml of ethylene glycol was treated with 2 drops of at l60° for hours with stirring, then it was cooled, poured into 100 ml of ice water, and filtered to remove tarry material. The filtrates were extracted with 100 ml of dichloromethane, which was then washed with 100 ml of water, dried over an-hydrous sodium sulfate and evaporated to dryness, yielding 7-chloro-5-(2-fluorophenyl)-l,3-dihydro-l-[2-(2-hydroxyethyl)-oxyethyl] -2H-l,4-benzodiazepin-2-one .' The residue was dissolved in 10 ml of ethanol, and 1 ml of 7.8N ethanolic hydrogen chloride was added and the solution was evaporated to dryness. The 7-chloro-5-(2-fluorophenyl)-l,3-dihydro-l-[2-(2-hydroxy-ethyl)oxyethyl] -2H-l,4-benzodiazepin-2-one hydrochloride was crystallized from a mixture of ethanol and ether, and re-crystallized from a mixture of methanol and ether to give the product as pale yellow prisms, m.p. l80-l85° decomp. (sealed tube).

Example 8 .

A solution of 10 g (0.03 M) of 7-chloro-5- (2-fluoro-phenyl )-1- (2-hydroxyethyl )-1,3-dihydro-2H-l,4-benzodiazepin-2-one in 100 ml of benzene was treated with g of succinic an-hydride and 4 ml of triethylamine. After 18 hours at room temperature, solvents were removed under reduced pressure. The residue was dissolved in 100 ml of dilute potassium carbonate solution, washed with 100 ml of ether and the aqueous layer was acidified with acetic acid. The liquid was decanted and the residual oil was dissolved in 100 ml of dichloromethane.

The solution was washed with 100 ml of water, dried over an - (2-fluorophenyl ) -2 ,3-dihydro-2-oxo-lH-l,4-benzodiazepin-l-yl ] ethyl succinate crystallized from ether. Upon recrystallization from a mixture of methanol and ether, the product was obtained as white prisms, m.p. 152-156° .

Example 9 A solution of 15 g (0.045 M) of 7-chloro-5- (2-fluoro-phenyl) -1- (2-hydroxyethyl) -1 , 3-dihydro-2H-l,4-benzodiazepin-2-one in 200 ml of xylene was treated with 12.8 g (0. 135 M) of chloroacetic acid and the solution was heated under reflux for 4 hours using a Dean-Stark trap. The reaction mixture was cooled, washed with 10$ potassium carbonate solution (3 x 75 ml water (3 x 75 ml), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was dissolved in dichloro-methane (50 ml), filtered over 100 g of Florisil* using 500 ml of ether as the eluant . The solvent was evaporated and the residue was recrystallized twice from a mixture of dichloro-methane and petroleum ether to give 7-chloro-l- (2-chloro-acetoxyethyl) -5- (2-fluorophenyl )-l,3-dihydro-2H-l, 4-benzo-diazepin-2-one as white prisms, m.p. 135-137° · Example 10 A solution of 3.0 g (0.00733 M) of 7-chloro-l- (2-chloro-acetoxyethyl) -5- (2-fluorophenyl ) -1 , 3-dihydro-2H-l,4-benzo-diazepin-2-one in 25 ml of benzene was treated with 5 ml of diethylamine, and the solution was heated under reflux for residue was triturated with a mixture of ether and petroleum ether. The precipitate was recrystallized from a mixture of dichloromethane, ether and petroleum ether to give 7-chloro-l-(2-diethylaminoacetoxyethyl)-5-(2-fluorophenyl)-l,5-dihydro-2H-1, -benzodiazepin-2-one as white prisms, m.p. 84.5-88°.

Example 11 A solution of 15 g (0.0½5 M) of 7-chloro-5- (2-fluoro-phenyl)-l-(2-hydroxyethyl)-l,5-dihydro-2H-l, -benzodiazepin-2-one in 170 ml of xylene was treated with 11.1 g (0.09 M) of isonicotinic acid, and the solution was heated under reflux for 56 hours using a Dean-Stark trap. The reaction mixture was cooled, washed with 100 ml of 10$ potassium carbonate solution, and then with 100 ml of water. The xylene solution was extracted with IN hydrochloric acid (2 x 75 ml). The acid layers were combined, washed with 100 ml of ether, and then made basic with ammonium hydroxide. The product was extracted into 100 ml of dichloromethane, which was then washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The oil was crystallized from ether and recrystallized from a mixture of dichloromethane and petroleum ether to give 7-chloro-5-(2-fluorophenyl)-l-(2~iso-nicotinoyloxyethyl )-1,3-dihydro-2H-l, -benzodiazepin-2-one as white plates, m.p. 158-1^2°.

Example 12 acetoxyethyl)-5- (2-fluorophenyl )-l,3-dihydro-2H-l, -benzodiaze-pin-2-one in 75 ml of benzene was treated with 1.8 g (O.Oj505 ). of propylamine, and heated under reflux for 20 hours. The mixture was cooled, treated with 75 ml of water and enough hydrochloric acid to adjust the pH to 5· The acid layer was separated, made basic with ammonium hydroxide, and extracted with 100 ml of dichloromethane . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness yielding 7-chloro-5- (2-fluorophenyl ) - 1- (2-propylamino-acetoxyethyl) -1, j5-dihydro-2H-l, 4-benzodlazepin- 2-one. A solution of 3 g of the residue in 10 ml of ethanol was treated with 1 equivalent of ethanolic hydrogen chloride (0.6 ml of a 7·8Ν solution) and the solution was evaporated to dryness. The monohydrochloride was crystallized from iso-propanol and recrystallized from a mixture of methanol and ether to give 7-chloro-5- (2-fluorophenyl)-l- (2-propylamino-acetoxyethyl )-l,3-dihydro-2H-l, 4 benzodiazepin-2-one hydrochloride as white prisms, m.p. 219-222° decomp. (sealed tube).

Example l^ 4 g (12.0 mmol) of 7-chloro-5- (2-fluorophenyl ) -1- (2-hydroxyethyl)-1,3-dihydro-2H-l, 4-benzodiazepin-2-one is dissolved in 21 ml of anhydrous pyridine and 150 ml of dry ether and the solution is cooled to -10°. A second solution of 1.2 ml of phosphorous oxychloride in 75 ml of ether is added, from a pressure-equilibrated dropping funnel, over a half-hour period, with stirring. The temperature is kept below After one additional hour, 300 ml of ice slush and 150 ml of ether are added, and after one hour, the layers are separated.

The aqueous portion is concentrated in vacuo at j50° and the pH adjusted downward to 3.2. The organic derivative is adsorbed into 100 ml of a J>0 aqueous suspension of acid-washed NORITE. The liquid. phase is removed, and the charcoal is washed with four bed volumes of water adjusted to the mildly acid pH of the original solution. The phosphate is then de-sorbed with a 1:1 mixture of ethanol-water containing O.> concentrate H^ in 5 x 100 ml batches.

The combined filtrates are concentrated to a highly hygroscopic oil, reconcentrated once with absolute ethanol and finally triturated with several batches of ethyl ether. The resultant powder is kept in a vacuum desiccator, yielding 7-chloro-l- (2-hydroxyethyl)-5- (2-fluorophenyl )-1,3-dihydro-2H-l,4-benzodiazepin-2-one o-phosphate diammonium salt.

Example 14 A solution containing 4.4 g (O.OljJl M) of 7-chloro-5-(2-fluorophenyl) -1- (2-hydroxyethyl)-1,3-dihydro-2H-l, 4-benzo-diazepin-2-one and 2.0 g (0.0 51 M) of 2-methoxynicotinic acid in 100 ml of xylene was heated under reflux for 58 hours using a Dean-Stark trap. The reaction mixture was cooled and washed with 75 ml of IN hydrochloric acid, which was then extracted with 0 ml of ether. The ether was combined with the xylene 50 ml of saturated brine, dried over anhydrous sodium sulfate and distilled to dryness under vacuum giving 7-chloro-l, 3-dihydro-5- (2-fluorophenyl) -1- (2-methoxynicotinoyloxyethyl)-2H- l, 4-benzodiazepin-2-one. The oil was dissolved in 100 ml of benzene and 5 ml (0.039 ) of a 7-8N ethanolic hydrogen chloride solution was added and the solution was distilled to dryness under vacuum. The residue was crystallized from a mixture of acetone and ether, and then recrystallized from a mixture of methanol and ether to give 7-chloro-l,3-dihydro-5- (2-fluorophenyl) -1- (2-methoxynicotinoyloxyethyl)-2H-1, 4-benzodiazepin-2-one dihydrochloride as pale yellow prisms, m.p. 154-158° (sealed tube).

Example 15 A solution of 3.3 g (Ο.ΌΙ M) of 7-chloro-5- (2-fluorophenyl )-l-(2-hydroxyethyl)-l, 3-dihydro-2H-l,4-benzodiazepin-2-one and 2.0 g (0.01 M) of 5-bromonicotinic acid in 100 ml of xylene was heated under reflux for 48 hours using a Dean-Stark trap. The reaction mixture was cooled and washed with 75 ml of IN hydrochloric acid to remove unreacted starting material. The aqueous layer was extracted with 50 ml of ether which was combined with the xylene solution and washed with 100 ml of dilute ammonium hydroxide, 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was crystallized from ether and recrystallized from a mixture of dichloromethane and hexane to give 7-chloro-l- (5-bromonicotinoyloxyethyl)-l, 3-dihydro- m.p. 140-143°.

Example 16 A solution of 10 g (0.030 M) of 7-chloro-5- (2-fluoro-phenyl )-1- (2-hydroxyeth l ) -1,3-dihydro-2H<-l,4-benzodiazepin-2-one in 100 ml of dry benzene was treated with 6 ml (0.0428 M) of triethylamine, and 6.3 g (0.0^3 M) of ethoxyacetic anhydride. After 18 hours at room temperature, the solvents were removed under vacuum and the residue was dissolved in 100 ml of di-chloromethane which was washed with 100 ml of 10^ ^CO^ solution, 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness yielding 7-chloro-l,3-dihydro- 1- (2-ethoxyacetoxyethyl ) -5- (2-fluorophenyl ) -2H-1,4-benzodiazepin- 2-one as an oil. The oil was dissolved in 100 ml of benzene which was treated with 6 ml (0.0468 M) of a solution of 7.8N ethanolic hydrogen chloride, and then evaporated to dryness. The residue was recrystallized from a mixture of acetone and ether to give 7-chloro-l,j-dihydro-l- (2-ethoxyacetoxyethyl) -5- (2-fluorophenyl )-2H-l,4-benzodiazepin-2-one hydrochloride as pale yellow prisms, m.p. 154-158° (sealed tube) .

Example 17 7-Chloro-5- (2-fluorophenyl ) -1- (2-hydroxyethyl ) -1,3-dihydro-2H-l,4- benzodiazepin-2-one, 4 g (12.0 mMol) is dissolved in 21 ml of anhydrous pyridine and 1 0 ml of dry of 1.2 ml of phosphorous oxychlorlde in 75 nil of ether is added, from a pressure-equilibrated dropping funnel, over a half-hour period, with stirring. The temperature is kept below 0° for another two hours, and then allowed to rise to ambient. After one additional hour, 300 ml of ice slush and 150 ml of ether are added, and after one hour, the layers are separated.

The aqueous portion is concentrated in vacuo at 30° (careful! avoid splashing) and the pH adjusted downward to 3.2 . The organic derivative is adsorbed into 100 ml of a 30 percent aqueous suspension of acid-washed NORITE. The liquid phase is removed, and the charcoal is washed with four bed volumes of water adjusted to the mildly acid pH of the original solution. The phosphate is then desorbed with 1: 1 mixture of ethanol-water containing 0.3 percent concentrated H^ i x 100 ml batches. The combined filtrates are concentrated to highly hygroscopic oil, reconcentrated once with absolute ethanol and finally triturated with several batches of ethyl ether. The resultant powder is kept in a vacuum desiccator yielding 7-chloro-l- (2-hydroxyethyl) -5- (2-fluorophenyl)-l,3-dihydro-2H-l, 4-benzodiazepin-2-one O-phosphoric acid diammonium salt (MW 447.1 ) - 2.7 mM.

Example 18 A solution of 0.332 g (1 mM) of 7-chloro-5- (2-fluoro-phenyl ) -1- (2-hydroxyethyl) -1 ,3-dihydro-2H-l, 4-benzodiazepin-2-one in 6 ml of dry pyridine was mixed with 0.795 g (5mM) temperature overnight. The residue left after removal of the solvent in vacuo at 25°C was dissolved in water, and adjusted to pH 7 with saturated Ba(OH)2 solution. An equal volume of ethanol was added, and the BaSO^ removed by centrlfugation.

The supernatant and a 50 percent ethanol wash of the precipitate were combined, concentrated in vacuo to dryness, and the" residue dissolved in 95 percent ethanol. After centrlfugation to remove some insoluble material, the ethanol solution was evaporated and the residue dissolved in 1 ml of water. Chroma-tography was carried out on a DEAE-cellulose (bicarbonate) column, 2 x 20 cm, using a linear gradient of H20-0.j5M pH 7 TEABIC (triethylammoniumbicarbonate)of 1500 ml totalvolume.Fractions 161-235 contained 7-chloro-5-(2-fluorophenyl)-2 , 3-dihydro-2-oxo-lH-l, -benzo-diazepin-l-ethyl hydrogen sulfate triethylamine salt, and fractions 201-235 were evaporated to give the product as a EtOH yellow glass, with a = 311 πιμ; Ε^-,η = 400 O.D., corres- max - J-ponding to 0. l8 m (based on E2200 ) * Example 19 A quantity of 300 mg (2 mMoles) of dilithium S-(ethyl). phosphorothioate was converted to its pyridinium salt by passage over Dowex-50 (pyridinium). The pyridinium salt was rendered anhydrous with frequent high vacuum concentration, using anhydrous pyridine. To the dry residue was added 3 2 mg (1 m ole)of 7-chloro-5- (2-fluorophenyl)-l- (2-hydroxyethyl)-l, 3-dihydro-2H-l, -benzodiazepin-2-one, 800 mg (½ mM) of di-cyclohexylcarbodiimide and 10 ml of anhydrous pyridine. The 3 ml, was added and the reaction left standing overnight. The dicyclohexylurea was filtered and washed with aqueous pyridine. The filtrate was concentrated to remove the pyridine and the residue dissolved in water (2 ml) and the pH adjusted to 8 with dilute ammonium hydroxide. The solution was applied to a 4 x 40 cm column of DEAE-cellulose DE-2J (bicarbonate form) and the column washed with a linear gradient consisting of 2 liters of triethylammonium bicarbonate in the reservoir (0.2 M, pH 7.2) and 2 liters of water in the mixing vessel.

Fractions of 20 ml were collected at a flow rate of 3 ml/ in. , Fraction 100-220 contained the product as shown by paper chromatography (70 parts acetonitrile, 30 parts 0.1 N ammonium chloride pH 9, ascending). The fractions were pooled and concentrated to an oily residue and dissolved in 10 ml of water. A solution containing 1.2 g I≥ in acetone (10 ml) was added and the mixture left standing for J hours. The solution was extracted with 6 x JO ml of ether and the aqueous portion concentrated and the pH adjusted to J.2. Activated Norite (70 ml of a JO percent suspension) was added and the mixture left at 0° for 15 minutes. The charcoal was filtered and washed with water. The product was desorbed twice with a mixture of 100 ml of water, 100 ml of ethanol and 0.6 ml concentrated NH-,. The filtrate was concentrated and reconcentrated with ethanol to an oil. 7-Chloro-l-(2-hydroxyethyl) ^-^-fluorophenyl )-l,j5-dihydro-2H-l,4-benzodiazepin-2-one 0-phosphoric acid diammonium salt as a yellowish powder was obtained upon triturating with ether.

Example 20 A tablet formulation containing the following ingredients Per Tablet 2- [ 7-Chloro-5- (2-fluorophenyl) 2,5-dihydro-2-oxo-lH-l, 4-benzo diazepin-l-yl] ethyl succinate 25 - 00 mg Dicalcium Phosphate Dihydrate, Unmilled I75.OO mg Corn Starch 24.00 mg Magnesium Stearate 1 . 00 mg Total Weight 225.ΟΟ mg was prepared as follows: 2- [ 7-Chloro-5- (2-fluorophenyl ) -2, dihydro-2-oxo-lH-1, 4-benzodiazepin-l-yl] ethyl succinate and corn starch were mixed together and passed through a screen with hammers forward.

This premix was then mixed with dicalcium phosphate and one-half of the magnesium stearate, passed through a screen with knives forward, and slugged.

The slugs were passed through a plate at slow speed with knives forward, and the remaining magnesium stearate was added.

The mixture was mixed and compressed.

Example 21 Per Capsule 2- [ 7-Chloro-5- (2-fluorophenyl)- 2 ,3-dihydro-2-oxo-lH-l, -benzo- diazepin-l-yl] ethyl succinate 10 mg Lactose 165 mg Corn Starch 30 mg Talc 5 mg Total Weight 210 mg was prepared as follows: 2- [7-Chloro-5- (2-fluorophenyl) -2, 3-dihydro-2-oxo-lH-l, -benzodiazepin-l-yl] ethyl succinate, lactose and corn starch were mixed in a suitable mixer.

The mixture was further blended by passing through a Comminuting Machine with a screen with knives forward.

The blended powder was returned to the mixer, the talc added and blended thoroughly.

The mixture was filled into hard shell gelatin capsules on a capsulating machine.

Example 22 A parenteral formulation containing the following ingredients. Per ml 2- [ 7-Chloro-5- (2-fluorophenyl ) - 2,3-dihydro-2-oxo-lH-l> -benzodiazepin-l- yl] ethyl succinate 10.2 mg Diethanolamine 2.904 m Benzyl Alcohol 0.01 ml i were prepared (for 10 liters) as follows: The 29-04 g of diethanolamine and 100 ml of benzyl alcohol were dissolved in 8 liters of water for injection.

The 102 g of 2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-lH-l,4-benzodiazepin-l-yl] ethyl succinate were added and the mixture was stirred until the drug was completely dissolved A IN preparation of HC1 was added slowly, dropwise, with constant stirring to a pH of 7.3. The solution was brought up to final volume of 10 liters with water for injection.

The solution was filtered through a Selas candle, filled into suitable size amber ampuls, gassed with and sealed. The sealed ampuls were then autoclaved at 0.7 atm. for JO minutes.

Claims (1)

1. CLAIMS Benzodiazepine derivatives of the general f la wherein and are halogen and R is halo lower lower alkoxy lower where stands for phenyl or pyridyl optionally substituted at most 3 lower alkoxy groups or halogen the moiety of a lower alkanoic or lower alkenolo dibaelo acid and their a carbamate a sulfate moiety or a phosphate the group alk or the group and are each hydrogen or and n and m are whole integers from and salts Benzodiazepine derivatives according to Claim wherein is Benzodiazepine derivatives according to Claim wherein is in of the ring and represents fluorine or Benzodiazepine derivatives according to any of 1 to wherein n is Benzodiazepine derivatives according to Claims 2 to wherein is chlorine and is fluorine 33 Benzodiazepine derivatives according to Claim represents where aryl has the same meaning as in Claim the monoacyl moiety of a basic or alkenoic and salts or a carbamate Benzodiazepine derivatives according to Claim wherein the moiety is Benzodiazepine derivatives according to Claim wherein R is a in whic represent hydrogent lower or Benzodiazepine derivatives according to Claim wherein are Benzodiazepine derivatives according to Claims 1 to wherein R represents a nicotinoyl or succinoyl Benzodiazepine derivative according to Claims 1 to wherein R is a phosphate maleate or the maleate sodium salt 34 Benzodiazepine derivatives of formula I in Claim substantially as described herein with reference to the A process for the manufacture of benzodiazepine derivatives of the formula I in Claim and salts which comprises treating a compound of the general formula with an acid a gent containing a halo lower lower alkoxy lower where aryl stands for phenyl or pyridyl optionally substituted with at most 3 lower alkoxy groups or halogen the moiety of a lower alkanoic or lower alkenoic dibasic a sulfate phosphate or with a of the general formula HOC OH in which formulae and m have the same meaning aa in Claim if treating a compound obtained wherein R represents a halo lower alkanoyl moiety with an amine of the general formula wherein and have the same meaning as in Claim if transforming a product obtained into a A process according to 21 wherein a compound of formula II in represents chlorine is used as starting A process according to any of Claims 21 or wherein a compound of formula II in which is fluorine or chlorine in the of the ring used as starting A process according to any of Claims 21 to wherein a compound of formula II in which n is 2 is used as starting 36 A process according to any of Claims 21 to 24 wherein a compound of formula II in which is chlorine and is fluorine in the is used as starting A process according to Claim 25 wherein is treated with an acid agent containing an moiety ary is as in Claim 1 or a moiety or the moiety of a dibasic alkanoic or alkenoic if a product obtained is transformed into a A process according to Claim wherein the moiety is A process according to Claim wherein the compound of formula II reacted an acid agent containing an moiet in which are lower alkoxy or A process according to Claim and are A process according to any one of Claims 21 to wherein the R moiety introduced into the compound XX is a 37 A process according to any one of Claims 21 to 25 wherein the R moiety introduced into the compound is a phosphate A process according to any of Claims 21 to 26 wherein maleate or salt thereof is A process according to any of Claims 21 to 26 wherein carbamate is process according to any of Claims 21 to 27 and 30 wherein is process according to any of Claims 21 to 26 and 30 wherein is A process according to any of Claims 21 to 25 and 31 wherein acid is A process to any of Claims 21 to 25 wherein is A prooess according to any of Claims 21 to 25 wherein is 38 process according to any of Claims 21 to 25 is A according to Claim 21 for the preparation of benzodiazepine derivatives of formtala I in Claim 1 as hereinbefore described with to the derivatives of the general I in Claim 1 and salts thereof when preparedly a process according to any of Claims 21 to Compositions sedative properties containing a benzodiazepine derivative of formula I in Claim 1 in mixture with a pharmaceutically acceptable the Applicants S insufficientOCRQuality