IL34760A - 1,4-benzodiazepin-2-one derivatives,their preparation and pharmaceutical compositions containing them - Google Patents

Description

"he prsoent invention relates to 1-oarboxyalkyl substituteft-l ,4~benzodi'a¾e in-~2~one3 correoponding to the following general formula Y-C OH wherein Y represents a s ra ght or branched alkylwne or an 1 lkenylone g ou hav ng from 2 to 10 carben atoms, R 2 represents halogen, hydrogen, or nitro, and B represents an optionally hal gen or lotfor alkyl-aubstituted phenyl group, or a pyridyl group, and salts? thereof, and also to the 4,5-dihydro and 4,5-dihydro-4-»lower alicyl derivatives thereof and to salts of such compounds.

In a preferred aspect of the present invention Y is a s raig or branched alkylene group having 2 to 6 carbon 1 atoms, H is nitro or halogen, most preferably chloro, iodo 2 or brono, and R is phenyl, phenyl substituted with halogen, most preferably chlorine or fluorine, or pyridyl. In the case where S2 ia phenyl .substituted with halogen, it is moat desirable that the halogen be substituted &*o the ortho or '-position. V'hen E s pyridyl, it is preferred that the pyridyl group be bonded to the liorzodiasepine nucleus through the 2-position of the pyridyl ring. The ,5-dehydro derivatives corresponding to formula I, i.e. those bearing a ,5-double bond are also preferre The term "halogen" as used herein is meant to denote all four forms thereof, i.e., chlorine, fluorine, bromine and iodine unless otherwise specified. "Lower alkyl" includes straight and branched chain saturated hydrocarbon groups having from 1 to 7» preferably 1 to 4, carbon atoms including, for example methyl, isobutyl, ethyl, propyl, butyl and the like. -A-rpprpRPntati lower alkanoyloxy group ic an aootoxy group.

The term straight and branched chain saturated hydrocarbon groups having from 2 to 10, preferably 2 to 6 carbon atoms. Likewise, the term straight and branched chain olefinic unsaturated hydrocarbon groups having from 2 to 10, preferably 2 to 6 carbon atoms.

The compounds of formula I above form pharmaceutically acceptable acid addition salts with pharmaceutically acceptable organic and inorganic acids such as hydrochloric acid, hydro-bromic acid, sulfonic acid, phosphoric acid, nitric acid, tartaric acid, citric acid, camphorsulfonic acid, ethane-sulfonic acid, ascorbic acid, salicylic acid, maleic acid and the like. In addition, compounds of formula I in the form of the pharmaceutically unacceptable acid addition salts may be converted to the desired pharmaceutically acceptable acid addition salt form by treatment of the pharmaceutically unacceptable acid addition salt with a pharmaceutically acceptable acid under ion exchange conditions. An alternative method for effecting substitution of the acid salt forms is to the free base followed by formation of the desired pharmaceutically acceptable acid form therefrom by means known in the art .

In a further aspect of the present invention there is encompassed within the scope of formula I above the basic salts of the carboxylic acid group. Such salts are formed by exchanging the hydrogen ion of the carboxyl group with a cation such as an alkali or alkaline earth metal cation, e.g., sodium ion, potassium ion, calcium ion, etc. or a complex cation such as an ammonium ion or a substituted ammonium ion such as a mono-, di- or trialkylammonium ion or a mono-, di- or trihydroxy-alkylammonium ion. Base salt forms of the compounds of formula I are readily prepared from the free acid by treating said acid with a desired base compound using techniques now well known in the art. Examples of preferred base compounds for this purpose include sodium hydroxide, sodium carbonate, ethylenediamine, diethanolamine, triethanolamine or tris-(hydroxymethyl )aminomethane .

The resulting salt solutions will range in pH slightly on the alkaline side depending on the concentrations desired.

The base compound content is usually one mole equivalent with the exception of the weaker bases such as tris- (hydroxy-methyl) -aminomethane which require somewhat more than one mole equivalent. The pH range of these solutions may be from 7 to but generally is from 8 to 9.

The compounds of formula I, in one process aspect •wherein R and R have the meaning indicated above, or a 4,5-dihydro or 4,5-dihydro-4-lov:er alkyl derivative thereof with a compound of the following general fornula - 1 - ' III -wherein Y has the meaning indicated above, ∑ represents ohloi-ine, iodine of bromin© (brorains is preferred), and Z represents car xyl or a srou convertible into carboxyl by hydrolysis, oxidation, nitrosatiGn, halogenation etc., e.g. carbalkoxy (-CC0 alkyl) or carbaroxy (-COO aryl), carbamoyl (-CCIH.,). hydroxyme h l (~CH2G∑S), formyl (-0Π0}8 cyano, methylcarbon/l (-OOCK^), anhydride, etc. (preferably 2 is carbox 1 or carbalkoxy, sost preferably earbomothoxy or c rboethoxy) , and ¾here Z is other than carboxy1 converting said carboxy precursor into & carboxy ^roup.

In order to facilitate? the reaction between compounds of formulae 11 nnd III above, it is most desirable that the compound of formula II be Initially converted to the sodium salt form. This may most conveniently be accomplished by treating the compound of formula II with a reactive sodium agent such as sodium hydride. It is the sodium form of the compound of formula II which, in this preferred aspect of the invention reacts with the compounds of formula III above to produce the compounds of the present invention, e.g., compounds of formula I or immediate precursors thereto.

Conversion of carboxy precursors into carboxyl may be accomplished by procedures well known in the art.

Thus, for example, when compounds of formula III having Z as a carboxyalley1 group are employed in the above reaction, it is necessary to hydrolyze the reaction product to yield the desired compounds of formula I. Such hydrolysis is readily conducted in the presence of alkali using conventional conditions. The desired free acid is obtained after acidification with an acid, e.g., a mineral acid or organic acid such as hydrochloric acid or acetic acid. Similar methods can be used in case Y being a carboxy-aryl group or anhydride. A oarboxy-amine group may be converted into a carboxy group by treatment with nitrous acid. For the oxidation of a hydroxymethyl or a formyl group, treatment with a permanganate, an organic peracid such as perbenzoic acids, perphthalic acid, etc. or with silver oxide or similar agents affords the corresponding carboxy derivative. A cyano group can be hydro-lyzed by treatment with acid such as diluted hydrochloric acid, to yield the corresponding amide which is in turn transformed into the carboxy derivative as described above. A methyl- treatment with a halogen, e.g. bromo, chloro or iodo followed by alkaline hydrolysis, e.g. with sodium hydroxide.

The reaction between compounds of formula III and the sodio derivative of compounds of formula II may be carried out in the presence of an inert organic solvent such as, for example, benzene, toluene, Ν,Ν-dimethylformamide, hexa-methylphosphoramide, dimethylsul oxide and the like. The latter three solvents are preferred. The reaction is conducted at a temperature in the range of from -10 to the reflux temperature of the reaction medium, most preferably in the range of from about 0 to 80eC.

The compounds of formula I as well as the pharmaceutically acceptable salts thereof are useful as pharmaceuticals and are characterized by activity as anticonvulsant agents, sedatives and muscle relaxants. These compounds can be used in the form of conventional pharmaceutical preparations; for example, the aforesaid compounds can be mixed with conventional organic or inorganic, inert pharmaceutical carriers suitable for parenteral or enteral administration such as, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gums, polyalkylene glycols, Vaseline or the like. They can be administered in conventional pharmaceutical forms, e.g., solid forms, for example, tablets, dragees, capsules, suppositories or the like; or in liquid forms, for example, injectable solutions, suspensions or emulsions. Moreover, the pharmaceutical compositions con ventional pharmaceutical expedients such as sterilization and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for the adjustment of osmotic pressure or buffers. The compositions can also contain other therapeutically active materials.

A suitable pharmaceutical dosage unit can contain from about 2 to 200 mg of the aforesaid compounds of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof. Suitable oral dosage regimens in mammals comprise from about 0.05 mg/kg per day to about 4 mg/kg per day. Suitable parenteral dosage regimens in mammals comprise from about 0.05 mg/kg Per day to about 6 mgAg Per day. However, for any particular subject, the specific dosage regimen should be adjusted according to individual needs and the professional judgment of the person administering or supervising the administration of the aforesaid compound.

It is to be understood that the dosages set forth herein are exemplary only.

The following examples are illustrative of this invention. All temperatures are in degrees Centigrade.

Example 1 A solution of 20 g (0.0692 mol) of 7-chloro-5- ( 2-fluoro-phenyl)-l, 3-dihydro-2H-l, -benzodiazepin-2-one in 100 ml of 8,4 g (0. 206 mole) of a 60 percent dispersion of sodium hydride in mineral oil. After 0 minutes, the reaction mixture was cooled in an ice bath and treated with 12,6 g (0, 83 mole) of 3-bromopropionic acid. The reaction was heated for 3 hours at 60° and then the solvent was removed under reduced pressure. The residue was dissolved in 150 ml of dichloro-methane and dilute hydrochloric acid. The aqueous layer was made hasic with ammonium hydroxide and the layers were separated. The aqueous layer was extracted with dichloro-methane, acidified with acetic acid and the product was obtained by filtration. Recrystallization twice from a mixture of methanol and ether gave 11 g (44 ) of 3- ( 7*·οίι1θΓθ-5-( 2-fluorophenyl ) -1 , 3-dihydro-2-oxo-2H-l * 4-benzocfi azepin-1-yl]propionic acid as pale yellow prisms, m.p. 184-188° .

Example 2 A solution of 10 g (0.0346 mole) of 7-chloro-5-(2-fluorophenyl )-l, 3-dihydro-2H-l,4-benzodiazepin-2-one in 80 ml of dry Ν,Ν-dimethylformamide under nitrogen was treated with 1,7 g (0,04l5 mole) of a 57 percent dispersion of sodium hydride in mineral oil. After 0 minutes, «S-bromobutyric acid ethyl ester was added with stirring and allowed to stand for 5 hours at room temperature. Solvent was removed under reduced pressure and the residue was dissolved in 100 ml of dichloro-methane. The solution was washed with 100 ml of water, 75 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness.

The residual oil was dissolved in 50 ml of benzene and chromatographed over an alumina column (150 g) using 500 ml of benzene which was discarded. Elution with 1 1. of ether and 1,5 1 of ethyl acetate gave 11 g of product, which was crystallized from ethanolic hydrogen chloride and ether.

Recrystallization from ethanol and ether gave 9,8 g (64 #) of 7-chloro-5- (2-fluoropheny1)-1,5-dihydro-2-oxo-2H-lA-benzodiazepine-l-butyric acid ethyl ester hydrochloride as pale yellow needles, m.p. 196-198° (sealed tube).

A solution of 4,5 g (0.0105 mole) of 7-chloro-5- (2-fluoro-phenyl )-1,5-dihydro-2-oxo-2H-l ,4-benzodiazepine-l-butyric acid ethyl ester hydrochloride in 50 ml of methanol was treated with 25 ml of 5N sodium hydroxide and 75 ml of water. After 1 hour, the solution was acidified with concentrated hydro-chloric acid, made basic with ammonium hydroxide and the methanol was distilled. The solution was washed with dichloro-methane (2 x 0 ml), acidified with acetic acid and cooled in an ice bath. The water was decanted and the residue was dissolved in 75 ml °? dichloromethane, which was washed with 75 ml of water, 0 ml of saturated brine, dried and evaporated. The product was crystallized from a mixture of methanol, ether and petroleum ether to give 5,4 g (87 ) of 7-chloro-5- (2-fluoropheny1)-1,5-dihydro-2-oxo-2H-l ,4-benzo-diazepine-l-butyric acid as white rods, m.p. 175-178°.

Example 3 A solution of 10 g (0,03 6 mole) of 7-chloro-5-(2-fluoro-phenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one in 70 ml of dry Ν,Ν-dimethylformamide under nitrogen was treated with 1,7 g (0,04l5 mole) of a 57 percent dispersion of sodium hydride in mineral oil. After 30 minutes, the solution was cooled to °, 10,8 g (O.O519 mole) of ethyl 5-bromovalerate was added with stirring and the solution was allowed to stir at room temperature for 18 hours. Solvent was removed under reduced pressure. The residue was dissolved in 100 ml of dichloro-methane which was washed with 100 ml of water, 75 ml of saturated brine, dried and evaporated to dryness. The oil was converted to the salt by crystallization from ethanolic hydrogen chloride and ether. The salt was recrystallized from a mixture of ethanol and ether to give 7 6 (45 ) of 7-chloro-5- (2-fluorophenyl ) -1 , 3-dihydro-2-oxo-2H-l , 4-benzodiazepine-1-valeric acid ethyl ester hydrochloride as pale yellow prisms, m.p. 137-1 7° (sealed tube).

A solution of 5.0 g (0.011 mole) of 7-chloro-5-(2-fluorophenyl) -l,3-dihydro-2-oxo-2H-l,4-benzodiazepine-l-va-leric acid ethyl ester hydrochloride in 250 ml of methanol was treated with ml (0,025 mole) of IN sodium hydroxide and 100 ml of water and after 18 hours, the solution was acidified with 3N hydrochloric acid, made basic with ammonium hydroxide and methanol was removed by distillation. The solution was washed with 125 ml of dichloromethane, acidified with acetic of water, 75 ml of saturated brine, dried and evaporated. The oil was converted to the hydrogen sulfate salt by adding an equivalent amount of concentrated sulfuric acid to an acetone solution of the product and then adding ether until precipitation occurred. The precipitate was recrystallized from a mixture of acetone and ether to give 3* S (65 ) of the salt as white prisms, m.p. 205-209°.

The free acid was liberated from the pure salt and was recrystallized from a mixture of dlchloromethane, ether and hexane to ive 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-lH-1, 4-benzodiazepine-l-valeric acid as white prisms, m.p. 115-118°.

Example 4 A solution of 10 g (0.03 6 mole) of 7-chloro-5-(2-fluoro-phenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one in 75 ml of dry Ν,Ν-dimethylformamide was treated with 3»8 g (0,0795 mole) of a 50 percent sodium hydride dispersion in mineral oil. The solution was stirred under nitrogen for 1 hour, cooled in an ice bath and treated with 10,8 g (0,04l5 mole) of«»* -bromodecanoic acid. The mixture was stirred for 18 hours at room temperature, at 50° for 8 hours and at 80° for 2 hours. Solvent was removed under reduced pressure. The residue was dissolved in 100 ml of dilute ammonium hydroxide,washed with 100 ml of ether and acidified with acetic acid. After cooling in an ice bath, the water was decanted and the residual oil remaining water, dried over anhydrous sodium sulfate, treated with charcoal and evaporated to dryness. The residue was dissolved in 50 ml of benzene and chromatographed over 250 g of silica gel using as eluant 2,5 1 of benzene. Evaporation of benzene afforded 3,8 g of 7-chloro-5-(2-fluorophenyl)-l,3-dihydro-2-oxo-2H-l, -benzodiazepine-l-decanoic acid product as a non-crystalline oil.

Example 5 A solution of 10 g (0.0355 mole) of l,3-dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one in 75 ml of dry N,N-dimethylformamide under nitrogen was treated with >,b g (0,08l6 mole) of a 57 percent dispersion of sodium hydride in mineral oil. After 0,5 hour, the solution was cooled to 10° and treated with 6,5 g (0,042 mole) of 3-bromopropionic acid. The mixture was heated to 55° for 5 hours, then solvent was removed under reduced pressure. The residue was treated with 100 ml of dilute ammonium hydroxide, which was then washed with 100 ml of dichloromethane. The basic layer was acidified with acetic acid, , cooled and the solution was decanted. The residue was dissolved in dichloromethane, which was dried and concentrated to a small volume. The product was obtained by filtration and was recrystallized from methanol to give 3,7 g (30 ) of 7-nitro-5-phenyl-l,3-dihydro-2-oxo-2H-l, -benzo-diazepine-l-propionic acid as white prisms, m.p. 198-206° (sealed tube).

Example 6 A solution of 10 g (0,0317 mole) of 5-(2-chlorophenyl)-l,3-dihydro-7-nitro-2H-l,4-benzodiazepin-2-one in 75 ml of dry Ν,Ν-dimethylformamide under nitrogen was treated with 3#05 g (0,0729 mole) of 57 percent sodium hydride dispersion in mineral oil and after 30 minutes, the mixture was cooled to 10° when 5*8 g (0,038 mole) of 3-bromopropionic acid was added with stirring. The solution was warmed at 55° for 5 hours. Solvents were removed under reduced pressure and the residue was dissolved in 100 ml of dichloromethane. The solution was extracted with 100 ml of dilute ammonium hydroxide. The basic layer was acidified with acetic acid, cooled and the solution decanted from the acid. This was then dissolved in 100 ml of dichloromethane, which was washed with 100 ml of water, 75 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The product was recrystallized twice from methanol to give 1,2 g (10 ) of 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-2-oxo-2H-l ,4-benzodiazepine-l-propionic acid as pale yellow prisms, m.p. 188-191° (sealed tube).

Example 7 A solution of 10 g (0,0333 mole) of l,3-dihydro-5-(2-fluorophenyl)-7-nitro-2H-l, -benzodiazepin-2-one in 75 ml of dry Ν,Ν-dimethylformamide under nitrogen was treated with 3*2 g (0,0765 mole) of a 57 percent sodium hydride dispersion in mineral oil. After 30 minutes, the reaction was cooled to propionic acid. The solution was warmed to 5° for 6 hours and then solvent was removed under reduced pressure. The residue was dissolved in a mixture of 100 ml of dichloromethane and 100 ml of dilute ammonium hydroxide. The basic layer was separated, acidified with acetic acid, cooled and the water layer was decanted. The precipitate was recrystallized from methanol to give 2,3 g (19 ) of 5-(2-fluorophenyl)-7-nitro-l,3-dihydro-2-oxo-2H-l, -benzodiazepine-l-propionic acid as white prisms, m.p. 188-192°.

Example 8 A solution of 10 g (0.0316 mole) of 7-bromo-l,3-dihydro-5-(2-pyridyl)-2H-l, -benzodiazepin-2-one in 75 ml of dry Ν,Ν-dimethylformamide was treated with 3,1 g (0,0726 mole) of a 57 percent sodium hydride dispersion under nitrogen.

After 0 minutes, the solution was cooled to 10°and treated with 5#8 g (0,0378 mole) of 3-bromopropionic acid. The mixture was allowed to stand at room temperature for 5 days. Hydrochloric acid (3N) was added to pH 9 and solvents were removed under reduced pressure. The residue was dissolved in 300 ml of dichloromethane and 200 ml of dilute ammonium hydroxide was added. The layers were separated and the basic layer was acidified with acetic acid. The mixture was cooled and the water was decanted. The residue was dissolved in 100 ml of dichloromethane, washed with 100 ml of water, 75 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The product was crystallized from methanol 2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-l-propionic acid as pale yellow rods, m.p. 102-109°.

Example 9 To a solution of 7,6 g (20 mmole) of 5- (2-fluorophenyl ) -l,3-dihydro-7-iodo-2H-l,4-benzodiazepin-2-one in 250 ml of dry tetrahydrofuran was added ,3 g (30 mmole) of potassium t-butoxide and 8 g (40 mmole) of ethyl 4-bromobutyrate.

The mixture was stirred overnight at room temperature (24 hours), filtered through Celite and concentrated in vacuo. The re-sidue was dissolved in ether and filtered through 40 g of alumina. The first 150 ml of eluate were collected. The residue left on removal of the solvent in vacuo were dissolved in ether and treated with 5 nil of ION ethanolic hydrogen chloride to give 5,6 g (50%) of 5- (2-fluorophenyl)-l,3-dihydro-7-iodo-2H-l,4-benzodiazepin-2-one-l-butyric acid ethyl ester hydrochloride, m.p. 183-187°. Recrystallization from ethanol/ ether gave yellow prisms, m.p. 187-189°.

A solution of 3,5 g (66 mmole) of 5- (2-fluorophenyl)-l,3-dihydro-7-iodo-2H-l,4-benzodiazepin-2-one-l-butyric acid ethyl ester hydrochloride in 100 ml of methanol was treated with 13*2 ml of IN sodium hydroxide, heated on a steambath for 1 hour and then diluted with 100 ml of water. The methanol was removed in vacuo and the product precipitated by the addition of acetic acid. The precipitate was collected and crystallized from benzene to give 1,7 g (55$) of 5- (2- 1-butyric acid, m.p. 190-192°. Recrystallization from chloro-form/hexane gave colorless prisms, m.p. 190-192°.

The starting material may be prepared as follows A solution of 10,75 g (50 mmole) of 2-amino-2 ' -fluoro-benzophenone in 100 ml of glacial acetic acid was heated to 80°, and a solution of 8, 2 g (50 mmole) of iodine monochloride in 25 ml of acetic acid was added. This mixture was allowed to stand at room temperature for 2 days and then poured onto ice. The product was extracted with methylene chloride, and the methylene chloride solution washed with sodium bicarbonate solution until neutral. The residue left on concentration of the dry (sodium sulfate) methylene chloride solution was crystallized from ethanol to give 4,8 g (28$ ) , m.p. 90-102° of crude 2-amino-2'-fluoro-5-iodobenzophenone. Recrystalliza-tion from hexane and then ethanol/water gave orange needles, m.p. 102-105°.

A mixture of 32, 1 g (9 , 3 mmole) of 2-amino-2 ' -fluoro-5-iodo-benzophenone, 40, 2 g (17 * 6 ml, 0, 2 mole) of bromo-acetyl bromide and 500 ml of benzene was heated under reflux for 2 hours, cooled, neutralized with dilute ammonium hydroxide, and diluted with methylene chloride. The organic phase was separated, washed with water,dried over sodium sulfate and concentrated in vacuo to ca. 200 ml. Addition of petroleum ether precipitated 30 g of 2-bromo-2 ' - (2-fluorobenzoyl)- ' -iodoacetanilide, m.p. 148-151°· Recrystallization from A mixture of 27 g (58,5 mmole) of 2-bromo-2'-(2-fluoro-benzoyl) - '-iodoacetanilide and 750 ml of anhydrous ammonia was stirred under a dry ice condenser for 5 hours and then the ammonia was allowed to evaporate overnight. A suspension of the residue in 1,2 1 of pyridine was stirred and heated under reflux for 2 hours. The solvent was evaporated in vacuo and the residue partitioned between methylene chloride and water. The organic phase was dried over sodium sulfate and concentrated in vacuo.

Crystallization of the residue from ether gave 17*2 g (77#) of 5-(2-fluorophenyl)-l,3-dihydro-7-iodo-2H-l, 4-benzo-diazepin-2-one, m.p. 221-22j5°. Recrystallization from ethanol gave white needles, m.p. 222-224° .

Example 10 To a solution of 22, 8 g (60 mmoles) of 5-(2-fluoro-pheny1)-1 , 3-dihydro-7-iodo-2H-l , 4-benzodiazepin-2-one , in 300 ml of dry tetrahydrofuran was added 10,1 g (90 mmoles) of potassium t-butoxide and 25 g (120 mmoles) of ethyl 5-bromovalerate. The mixture was heated under reflux for hours, cooled, filtered through Celite to remove inorganic material and concentrated in vacuo. The residue was dissolved in ether and the product precipitated by bubbling in hydrogen chloride to give 17 # 6 g (53#) of crude 5- (2-fluorophenyl) -l,3-dihydro-7-iodo-2H-l, 4-benzodiazepin-2-one-l-valeric acid ethyl ester hydrochloride, m.p. 80-90°. Recrystallization A solution of 5,4 g (10 mmoles) of 5-(2-fluorophenyl)-l,3-dihydro-7-iodo-2H-l,4-benzodiazepin-2-one-l-valeric acid ethyl ester hydrochloride in 100 ml of methanol was treated with 20 ml of IN sodium hydroxide, heated on a steambath for 1 hour, and then diluted with 100 ml of water. The methanol was removed on a rotary evaporator. The cloudy solution was then filtered through Celite and the product precipitated by the addition of acetic acid to give 4,2 g of crude 5-(2-fluoro-phenyl-1,3-dihydro-7-iodo-2H-l ,4-benzodiazepin-2-one-l-valeric acid.

Example 11 A solution of 10 g (0.037 mole) of 7-chloro-l, 3-di-hydro-2-oxo-5-phenyl-2H-l,4-benzodiazepine and 70 ml of Ν,Ν-dimethylformamide was treated, at 0-5°, with a solution of 1,03 g (0.045 mole) of sodium in 10 ml of methanol. The mixture was then stirred for 15 minutes at room temperature and cooled to 5-10°. At that temperature, 9,5 g (0.053 mole) of y-bromo-crotonic acid methyl ester were added and stirring was continued overnight. After concentration under reduced pressure, the residue was partitioned between water and methylene chloride whereupon the organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated. The residual oil was chromatographed with benzene over alumina (150 g, neutral, activity III). The uniform fractions were combined, concentrated and crystallized from ether. Recrystallization from methanol yielded 5,5 g of 7-chloro-l, -dihydro-2-oxo-5-phenyl-2H-l, - benzodiazepine-l-crotonic acid methyl ester, m.p. 125-127°.

According to the method described above there was obtained, from 10 g of 7-chloro-l,3-dihydro-2-oxo-5-pheny1-2H-1, -benzodiazepine and 11,7 g of y-bromo-crotonic acid tert. butyl ester, 5,5 g of 7-chloro-l,3-dihydro-2-oxo-5-phenyl-2H-l,4-benzodiazepine-l-crotonic acid tert. butyl ester; m.p. 164-166° after recrystallization from acetonitril.

A solution of 10 g of the tert. butyl ester thus obtained in 350 ml of xylene was refluxed for 1 hour with 4,6 g of p-toluenesulfonic acid monohydrate. After cooling, the yellow precipitate was sucked off, washed with ether, dissolved in 400 ml of hot methanol, and after addition of 800 ml of ether, cooled on ice. There was obtained 10,5 g of 7-chloro-1,3-dihydro-2-oxo-5-phenyl-2H-l,4-benzodiazepine-l-crotonic acid p-toluenesulfonate » m.p. 268-270° (dec).

The same substance was obtained by saponification of the 7-chloro-l ,3-dihydro-2-oxo-5-pheny1-2H-1 , 4-benzodiazepine-1-crotonic acid methyl ester described above.

Example 12 A solution of 10 g (0,037 mole) of 7-chloro-l, -dihydro 2-oxo-5-phenyl-2H-l, 4-benzodiazepine in 125 ml of N,N-di-methylformamide was treated, at room temperature and under nitrogen, with 2^5 g (0,045 mole) of a 50$ suspension of and cooling to 0°, a solution of 11,1 g (0.053 mole) of 4-bromo-2,2-dimethyl-butyric acid methyl ester in 30 ml of N,N-dimethyl-formamide was added to the mixture,which was then heated to 50° for 15 hours. The solution obtained was con-centrated under reduced pressure, the residue was partitioned between methylen chloride and water, whereupon the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The residual oil was chromatographed with benzene on 200 g of aluminum oxide (neutral, activity III). After recrystallization from methanol, the uniform fractions yield 98 g of 7-chloro-l,3-dihydro-2-oxo-5-phenyl-2H-l, -benzo-diazepine-lT ,a-dimethyl-butyric acid methyl ester of m.p. 130-132°.

A stirred suspension of 6,0 g (0.015 mole) of the ester thus obtained in 30 ml of ethanol was treated with 70 ml of 10 N sodium hydroxide and refluxed for 1 hour, a clear yellow solution being obtained. The ethanol was then evaporated in vacuo, the aqueous solution was washed with acetic acid ethyl ester and the pH was fixed to -6 with dilute acetic acid ethyl ester. The precipitate was sucked off, washed with water and dried at 80°/l0 mm in a drying oven. 5,5 g of a crude product were obtained; m.p. about 150°. Crystallization from iso-propyl ether yields a light yellow crystalline powder which melts at about 120° with evolution of gas; since this product was very difficult to fr*ee from the isopropyl ether, the powder was dissolved in 2N hydrochloric acid and reprecipitated in phenyl-2H-l,4-benzodiazepine-l-o<,o^-dimethyl-butyric acid is obtained; m.p. 176-I780.

Example 13 A solution of 15 g (0,0515 M) of 7-ohloro- ,5-dihydro-5-(2-fluorophenyl)-3H-l,4-benzodiazepin-2(lH)-one in 50 ml of N,N-dlmethylformamide was treated with 2.7 g (O.0567 M) of 50 percent sodium hydride in mineral oil under nitrogen.

The mixture was cooled in an ice bath and 11.8 g (Ο.Ο567 M) of ethyl 5-bromo-valerate was added dropwise with stirring. After 68 hours at room temperature, the solution was evaporated to dryness. The residue was dissolved in 100 ml of dichloromethane, washed with 0 ml of a saturated brine solution, dried over anhydrous sodium sulfate, and evaporated to dryness.

The residue was dissolved in 50 ml of ethanol and a percent excess of a solution of hydrogen chloride in ethanol was added. The solution was evaporated to dryness and the salt was recrystallized from a mixture of ethanol and ether to give 7-ohloro-5-(2-fluorophenyl)-l,3,4,5-tetra-hydro-2-oxo-2H-l,4-benzodiazepine-l-valeric acid ethyl ester hydrochloride as white rods, melting at l62-l6 ° (sealed tube).

Example 14 Method A: A solution of 7 g (0.0154 M) of 7-chloro-5- zepine-l-valeric aoid ethyl ester hydrochloride in 100 ml of methanol was treated with 46.6 ml ( 0.0466 M) of IN sodium hydroxide, and then 140 ml of water was added with stirring. After l8 hours at room temperature, the mixture was acidified with 3N hydrochloric acid, made basic with ammonium hydroxide and methanol was removed under vacuum. The solution was extracted with 100 ml of dichloromethane, and the water layer was acidified with acetic aoid. The supernatant liquid was decanted. The residual oil was dissolved in 75 ml of dichloro-me hane and washed with 50 ml of a saturated brine solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from methanol to give 7-chloro-5- ( 2- luorophenyl) -1, 3, 4 , 5-tetrahydro-2-oxo-2H-l, 4-benzo-diazepine-l-valeric acid as white prisms, m.p. 1 9-1 °.

Method B; A solution of .7 g ( 0.0147 M) of 7-chloro-5- (2-fluorophenyl)-l,3-dihydro-2-oxo-2H-l,4-benzodiazepine-1-valeric acid in 100 ml of acetic acid was treated with 25 ml of water and 0.4 g of platinum oxide. The mixture was hydro-genated at atmospheric pressure until the theoretical amount of hydrogen had been absorbed. The catalyst was removed by filtration through celite. The solution was made basic with ammonium hydroxide, acidified with acetic acid and the oil obtained was recovered by decanting the supernatant liquid. The oil was next dissolved in 50 ml of dichloromethane, washed with 50 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized and re-crystallized from methanol, to give 7-chloro-5- ( 2-fluoro valeric acid as white prisms, ra.p. and mmp with a sample prepared as in Method A above, 149-155°.

Example 15 A solution of 4 .7 g ( 0.01 M) of 7-chloro-5- (2-fluoro-phenyl ) -4-methy 1- 1,3 *4 , 5-tetrahydro-2-oxo-2H- 1 , 4-benzodiazepine 1-valerio acid ethyl ester hydrochloride in 60 ml of methanol was treated with 25 ml ( 0.025 M) of IN sodium hydroxide with stirring, and then 70 ml of water was added. The reaction mixture was stirred at room temperature for 20 hours. After first acidifying with 3N hydrochloric acid, the solution was made basic with ammonia and metanol was removed under vacuum. The solution was extracted with dichloromethane (50 ml), and the aqueous layer was aoidified with acetic acid. The precipitate was recovered by filtration, washed with water and recrystallized from methanol to give 7-chloro-5- (2-fluoro-phenyl)-4-me hyl-l,3 ,4 ,5-tetrahydro-2-oxo-2H-l, 4-benzodiazepine' 1-valeric acid as white prisms, m.p. 167-174°.

The starting material used above may be prepared as follows : To 9.6 g ( 0.0229 M) of 7-chloro-5- (2-fluorophenyl)-l,3 , 4 , -tetranydro- 2-oxo-2H- 1 , 4-benzodiaze ine- 1-valeric acid ethyl ester in 100 ml of N,N-dimethylformamide was treated with ,9 g ( 0.0274 M) of methyl iodide. The reaction was heated at 45° for 2 hours when an additional 2 g ( 0,014 M) of methyl iodide was added. The reaction mixture was then vacuum, and the residue was dissolved in 75 ml of dichloro-methane. The solution was washed with 50 ml of dilute ammonium hydroxide, 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in 25 ml of ethanol and 10 ml (0.084 ) of 8.4N ethanolic hydrogen chloride was added. The solution of the salt was evaporated to dryness and the product crystallized from a mixture of ethanol and ether to give 7-chloro-5-(2- luorophenyl )-4-methy1-1,3,4,5-tetrahydro-2-oxo-2H-l,4-benzodiazepine-l-valerio acid ethyl ester as white prisms, m.p. I58-I670 (sealed tube).

Example l6 The pharmacological activity of a series of compounds of the present invention was determined in standard screening tests. Compounds of the present invention which were employed in these experiments were as follows: 3- [7-chloro-5- (2-fluorophenyl ) -1,;5-dihydro-2-o o-2H-l,il·-benzodiazepin-l-yl] propionic acid (Compound A) 7-chlor0-5- (2-fluorophenyl ) -1,j5-dihydro-2-oxo-2H-l, -benzodiazepine-l-butyric acid (Compound B) 7-chloro-5- (2-fluorophenyl) -2, j5-dihydro-2-oxo-lH-l, -benzodiazepine-l-valeric acid (Compound C) 7-nitro-5-phenyl-l , j5-dihydro-2-oxo-2H-l , 4-benzodiazepine-l-propionic acid (Compound D) - (2-chloropheny1 )-7-nitro-l , 3-dihydro-2-oxo-2H-l, -benzodiazepine-l-propionic acid (Compound E) - (2-fluorophen l )-7-nitro-l , 3-dihydro-2-oxo-2H-l, -benzodiazepine-l-propionic acid (Compound F) 7-bromo-5-(2-pyridyl)-2, -dihydro-2-oxo-lH-1, -benzodiazepine-l-propionic acid (Compound G).

For the purposes of demonstrating the critical nature of the selection the value of the alkyl group's carbon chain lenght within the range defining the compounds of the present invention, e.g., 2-10, a further comparison was run in this experiment utilizing a compound where the alkyl group carbon chain was 1. This compound is 2- (7-chloro-5- (2-fluoro-phenyl)-l,' -dihydro-2-one-l, -benzodiazepin-l-yl] acetic acid and is designated Compound H in the following tests. This compound has a representative configuration with respect to substltuents as the compounds of the present invention employed in the tests.

The tests employed in this experiment were the following: Inclined Screen The test is useful in determining muscle relaxant activity. Groups of 6 male mice are given the test drug (maximum dose of 500 mg/kg) and then are left on the inclined screen at least four hours for observation of paralyzing effects severe enough to cause them to slide off the screen.

This activity is observed, additional doses are tested until at least two are reached at which some, but not all, the animals slide off the screen. Doses at which mice fall off the screen due to toxicity or excitation are not included in the calculation of POcn» The PD.-_ is determined from a graph on which dose is plotted against percent of mice paralyzed.

This PD.__ value is defined as the dose in mg/kg which can 50 be expected to cause 50 percent of the mice to slide off the screen.

Foot Shock This test is a screen for compounds having muscle relaxant activity. A pair of mice is confined under a 1 liter beaker placed on a grid which presents shock to the feet. period. Pairs of mice are marked and pre-treated by oral dosage one hour prior to a second shocking. Logarithmic-dose intervals are utilized up to a maximum of 100 mg/kg. At the 100 percent blocking dose, three out of three pairs must be blocked from fighting.

Unanaesthetized Cat Cats are treated orally and observed for minimum symptoms usually ataxia. One cat is used at a dose of 50 mg/kg. If activity is present, up to three cats/dose are used.

Results are given as minimum effective dose. This test is useful in determining muscle relaxant activity.

Antlmetrazole This test determines anticonvulsant activity of compounds In mice. The test compound is administered orally to groups of four mice at various dose levels. One hour later, metrazole (at a dose level previously determined to be sufficient to induce convulsive seizures in all test animals ~ 12 mg kg) is administered subcutaneously and the animals are observed for protection from convulsive seizures. Results are recorded as the number of animals protected against convulsions. The dose at which 50 percent of the animals are protected from convulsive seizures is expressed as the ED-._. 50 Maximum Shock When 30 mA of current is delivered to mice for 0, 2 se-conds through corneal electrodes, a maximal tonic-clonic seizure is induced. The components of the maximal seizure in mice are: phase of body clonus. Mice are screened twenty-four hours prior to an assay to make sure that they respond normally. In the general screen, a compound is administered orally to groups with four mice at various dose levels. One hour after administration of drug, the 30 mA shock is applied. This appearance of the hind leg extensor component is the criterion of activity. When activity is observed, the compound is administered to additional groups until the extensor phase reappears. The dose in mg/kg which prevents hind limb extension in two of four animals is reported as the effective dose (ED^Q) . On active compounds, eight animals are employed per dose group.

Minimum Shock Seizures are induced by the application of a current to the eyes of the mice through corneal electrodes. A drop of physiological salt solution is placed on each eye of the mouse and the eyes are brought into direct contact with the electrodes. All mice are initially shocked at 6,0 mA for 0,2 seconds. Only those animals which have a minimal seizure are utilized in an assay. After a twenty-four hour period has elapsed, the compound to be assayed is administered to groups of four animals at various dose levels. Following a 1-hour interval, the animals are again shocked at 6,0 mA. The criterion of activity is protection against a minimal seizure induced with this intensity of current. ED-- values are po determined for active compounds using eight animals per dose group.

The test results from the above test using indicated compounds including those of the present invention are summarized below in Table 1.

TABLE I Inclined Foot Shock 100 Anti- Screen Percent Blocking Unanaesthetized metraz Compound PD50 mg/kg Dose Level mg/kg Cat MED mg/kg ED50 m Compound A 30 40 4 6.74 Compound B 40 20 1 4 Compound C 20 10 - 5 Compound D 200 100 - 102 Compound E 40 10 >5 1.4 Compound F 100 40 20 6.3 Compound G 350 >100 - 50 Compound H 400 >100 — 455 She comparison of results between Compound H and the correspondingly substituted Compounds Α» B and 0 indicates that superior activity is exhibited for the latter ^roup of com-pouv da v.-hcre the '.lkyl 'jroup carbon chain is greater than 1 , i.e., 29 3 and 4S respectively. l*his is qui e an unexpected result in view of the state of the benzodiazepine art where it has previously been observed that the activity duo to a subs itusnt is decreased as the length of the alkylene chain bearing the substituent is increased.

In testing compounds of this invention in conparison with related com runds lr.own from Israel Patent No. 21557 it could be shown by the first thref tests mentioned above that the former compounds are more active n :ruscle relaxants than the prior art compounds.

E ample 17 Λ representative formulation solution for parenteral use is aa follows: 7»chlo 0-5-(2-fluo ©phenyl)-2,3- dihydro-2~oxo-2II=1 ,4-benzodiazepine- 1 "butyric acid 51 mg Diethanolaoin© 21 mg Benzyl alcohol 10 mg Water for Injection .s. e above solution had a p.'I of about 3.9. n storage at one month at 55°Ct this solution exhibited obout 3 percent decomposition which demonstrates a useful stability in terras of a reasonable shelf life. - 33 34760/2

Claims (1)

1. CLAIMS of the general formula wherein Y or branched or an group from to 10 carbon 1 2 or represents an optionally or or a and alkyl derivatives of the compounds formula I in and salts of such Benzodiazepines of formula 1 in Claim w Y a straight or branched alkylene formula in wherein Y is a straight or branched group having 2 to carbon derivatives of formul I in Claim 1 is or is halophenyl or derivatives according to Glaim is bromine or 34 Benzodiazepine derivatives according to Claim 2 wherein is or Fluorophenyl 35 1 Com ounds of formula 1 in Claim 1 and salts substantially as described herein with reference to Examples 1 to 10 and or reference to Compounds according to Claim substantially as described herein with to 13 to process for the manufacture of benzodiazepine derivatives of formula in Claim 1 and salts reacting a compound of the general formula Y XXX wherein represents iodine Z represents a carboxyl or a group convertible into carboxyl by and Y has the same meaning as in Claim 1 with a compound of the general formula wherein E have meaning as in Claim and where Z is other than converting the precursor into a if converting the product thus obtained into a salt A process for the preparation of vatives and alley1 derivatives according to of salts of such compounds which comprises reacting a compound of formula in Claim 22 with a dihydro or derivative of a compound of formula in in which and have 1 sane as in 22 and have meanings as in and is other than converting the precursor into if converting product thus obtained into a salt process claimed in Claim wherein a compound of formula ΣΙΙ in which Y is straight or branched group and 4 derivative of formula II are used as starting in Glcim 22 or wherein a starting of formula in which Z represents carbamoyl or the radical of an is used in Claim 24 or wherein starting of which is a straight or branched group having 2 to carbon is process as claimed in any of Claims 22 and 24 to s 37 a d 2 or is hal or A process as in Claim wherein in the formula ΪΙ bromine or process claimed Claim wherein in the starting material of formula II is or A process for the preparation of benzodiazepine derivatives of formula I in Claim 1 in which Y is a straight or branched group substantially as herein described with reference to 1 to 10 and process for the preparation of benzodiazepine derivatives of formula I in Claim 1 in which Y is an ene group substantially as described heroin with reference to A process for preparation of compounds according tc Claim substantially as described herein with reference to Examples 13 to Pharmaceutical having sedative and muscle relaxant containing a diazepine derivative of 1 in 1 in which Y is straight or branched group of 2 to 10 carbon or a salt of such compounds and a Pharmaceutical anticonvulsan sedative and muscle relaxant containing a diazepine derivative of formula I in Claim 1 in which I is an group of 2 to 10 atoms or a salt of such and compositions sedative and relaxant containing a compound according to 2 a insufficientOCRQuality