IL34816A - 7-acyl-5-phenyl-benzodiazepine derivatives,their preparation and pharmaceutical compositions containing them - Google Patents

Description

RAN 4008/157* The present invention relates to 7-lower alkanoyl-benzodiazepines of the formula wherein B represents methylene (-CH"2-) or carbonyl ( X ) ; Rx represents hydrogen or lower alkyl; R, represents hydrogen or halogen and and R^ represent hydrogen or lower alkyl.

By the term "lower alkyl" as utilized herein, there is intended both straight and branched chain C^-C^, preferably C^-C^ hydrocarbon groups such as methyl, ethyl, propyl, iso-propyl, butyl and the like. By the term "halogen" as utilized herein there is intended all four forms thereof, i.e. chlorine, bromine, fluorine and iodine. By the term "lower alkanoyl", as utilized herein, the acyl moiety of a lower alkanoic aoid is intended, e.g., acetyl, propionyl, butyryl, pentylcarbonyl, isopropionyl, caproyl, and the like. When R2 is halogen, it is preferably joined in the 2-position of the 5-phenyl Also when R^ and in formula I above represents lower alkyl, a lower alkyl group containing up to four oarbon atoms is preferred, most preferentially when the lower alkyl group is methyl. As is evident from the above, preferred are compounds which contain a methyl group as R^, a methyl group as and/or R2 as hydrogen or fluorine Joined in the 2-position of the 5-Pbenyl ring. Preferably R^ is hydrogen.

This invention also relates to a prooess for the manufacture of compounds of general formula I which process oomprises a) treating a compound of the general formula wherein B, R^ R2 and R^ have the meaning indicated above, with nitrous acid to form a dlazonlum salt and then converting the resulting dlazonlum salt into the desired compound of the formula I above or cyclyzing a compound of the general formula wherein B, R^, R^* Rj nave tne meaning indicated above, or c) treating a compound of the general formula wherein B, R , R≥ and R^ have the meaning indicated lower alkyl above, except that B is methylene in case is hydrogen, with a lower alkyl lithium, yielding a compound of formula I wherein R, is lower alkyl, or d) converting a compound of the general formula V wherein B, R1, R2, and have the meaning indicated above, into a compound of formula I by oxidation of the ^-methylene group in the 7-position, preferably by treatment with a eerie salt, or ·) N- lower alkylating a compound of formula I wherein is hydrogen, yielding a compound of formula I wherein R^ is lower alk l, or f) oxidizing a compound of formula I wherein B is methylene into the corresponding compound of formula I wherein B is carbonyl.

The formation of the diazonium salt of a compound of formula II above in process aspect a) is effected by first preparing a solution of a compound of the formula II above in a dilute mineral acid such as aqueous sulfuric acid, aqueous hydrochloric acid and the like and then treating the so-prepared solution with nitrous acid. Conveniently, the nitrous acid is provided by adding to the said solution, \ sodium nitrite. The nitrous acid treatment is preferably-carried out at or below room temperature to avoid the reaction proceeding too energetically. Thus, temperatures between -5 to 25°C are preferred.

The so-obtained diazonium salt is then treated with a lower alkanoyl group providing agent, preferably after neutralizing the reaction medium with a buffering agent such as sodium acetate, sodium carbonateand the like whereby to render the reaction medium less acidic. Any substance which is capable of reacting with the diazonium salt to subsequently permit the corresponding compound of the formula I above to be generated is suitable for the purposes of the present invention. Representative of such substances are formaldehyde semicarbazone, lower alkyl aldehyde semicarbazones such as acetaldehyde semicarbazone., proplonaldehyde semicarbonazones and the like, oximes and derivatives thereof of the formula wherein R,_ and Rc are hydrogen or lower alkyl such as formaldoxime, propionaldoxime, the methyl ether of the latter and the like. However, preferred for this purpose is acetaldehyde semicarbazone.

The reaction of the lower alkanoyl group providing agent with the diazonium salt is effected preferably in the presence of finely divided oopper or a cupric salt, e.g., CuSO^, and results in an intermediate product of the formula wherein X represents -OR^ or - HC0NH2 and B, R^, R^, R^, R^ and have the meaning indicated above.

The resulting intermediate is hydrolized with any-suitable reagent to remove the grouping X to thereby effect the preparation of the corresponding compound of the formula I. This is conveniently done by treating the intermediate with a dilute acid such as aqueous hydrochloric acid, aqueous sulfuric acid, aqueous nitric acid and the like.

The reaction scheme in a preferred embodiment involves conversion of a compound of the formula II above by diazotizat-ion into the diazonium salt thereof, treating the resulting diazonium salt with acetaldehyde semicarbazone, preferably in the presence of cupric sulfate, and then hydrollzing the resulting product with a dilute acid.

With respect to prooess aspect b) the compound of formula III can easily be oyolized, for instance by adding methanol, ethanol and the like. By permitting the resultant solution to stand and/or by the application of heat, cyclizat-ion to the corresponding compound of the formula I occurs.

As is evident from process aspect c) above, an important aspect of this invention is the finding that a lower alkyl lithium can be utilized to treat a nitrile of the formula IV above whereby to selectively effect the preparation of the desired compound of the formula I above. As will be recognized, there are many reactive sites on a compound of the formula IV above which possess the capability of being affected when in the presence of a substance such as a lower alkyl lithium.

However, it is entirely surprising to find that when treating a compound of the formula IV above with lower alkyl lithium, there can selectively occur the conversion of a nitrile group into a lower alkanoyl grouping without such other reactive sites on the molecule being affected. It is to be understood that process aspect c) provides compounds of formula I except that B is methylene in case is hydrogen.

The above is particularly true since temperature and pressure are not critical to a successful performance of the process aspect c) discussed above. Thus, it should be understood that the manner of bringing together the reaction partners (the lower alkyl lithium and the compound of the formula IV above) is not of primary importance insofar as effecting a successful performance of the process of the present invention and thus, the particular mode for carrying out the reaction is largely a matter of convenience.

In a preferred embodiment, the reaction is carried out in the presence of an inert reaction medium, i.e., an inert solvent. It will be appreciated that the use of a solvent will ordinarly allow the reaction to proceed in a relatively simple manner which avoids the use of extraordinary conditions, extensive equipment and the like.

Inert solvents capable of providing the inert reaction medium suitable include hexamethyl phosphoramide; ethers, such as tetrahydrofuran, methyl ethyl ether, ether and the like; dioxane and similar type solvents or mixtures thereof. An ether such as tetrahydrofuran or ether itself is employed in the most efficacious embodiment.

While as indicated above, temperature is not critical to a successful performance of this process aspeot, it is preferred to effect the reaction at temperatures below room temperature, i.e., temperature from about -70°C to about 20°C.

In performing the novel process aspect c) of the present invention, in a preferred aspect, the reaction is effected in a nitrogen atmosphere, although the atmosphere of nitrogen may be replaced by any other atmosphere of an inert gas such as argon, helium or the atmosphere may be dispensed with and still the desired compound of the formula I above may be obtained, provided the atmosphere contains no, substance which would effect the reaction route.

After the treatment of a compound of the formula IV \ which contains a complex salt is subjected to hydrolyzing conditions utilizing any conveniently available hydrolyzing agent according to conventional procedures. After the hydrolysis is completed, the reaction mixture can be treated according to conventional manipulation techniques to isolate the desired compound of the formula I above.

As hydrolyzing agents, there can be utilized a basic hydrolyzing agent or an aoidic hydrolyzing agent or a neutral hydrolyzing agent suoh as water. In a preferred embodiment, there is utilized as the hydrolyzing agent, a dilute mineral acid, e.g., dilute hydrochloric acid, dilute hydrobromic acid, dilute sulfuric acid and the like or an aqueous organic acid such as aqueous acetic acid or a base suoh as an alkali metal hydroxide such as sodium hydroxide.

Thus, in a preferred aspect, the 7-cyano compound of the formula IV above is added to an appropriate inert organic solvent, which preferably is tetrahydrofuran. Then, while maintaining the temperature below room temperature, e.g., at temperatures below 0°, there is added to the resultant solution, a lower alkyl lithium contained in an appropriate solvent which may be the same solvent which was utilized to dissolve the 7-cyano compound of the formula IV above or another appropriate solvent. Preferably, as indicated above, an ether such as tetrahydrofuran or ether is utilized as the solvent mediums for both reactants. The resultant crude is then sub ected to h drol zin conditions utilizing any suitable \ chloric acid), capable of effecting hydrolysis in accordance with prior art techniques as noted above. The product of the formula I above is then isolated in accordance with usual purification procedures.

In a particularly preferred embodiment, the lower alkyl lithium utilized is methyl lithium so that there is obtained the 7-acetyl benzodiazepine. However, other lower alkyl lithiums can also be utilized such as ethyl lithium, propyl lithium, butyl lithium, pentyl lithium and the like whereby the corresponding lower alkanoyl radical can be obtained.

It is to be understood that by utilizing process aspect c) only compounds of formula I can be obtained wherein is lower alkyl.

In the process aspect d) set forth above, a compound of the formula V above is oxidized to the corresponding 7-acyl derivative thereof. In case a compound of formula I is used wherein B is methylene, oxidation with a eerie salt may result in concurrent oxidation of the methylene group in the 2-position yielding a compound of formula I wherein B is carbonyl. Preferably the compound of formula V is added to any appropriate inert reaction medium and to the resultant medium, there is added a eerie salt. As a suitable inert reaction medium, there can be utilized an inert organic solvent such as a saturated fatty acid, e.g., formic acid, acetic acid, propionic acid and the like, or a dilute aqueous mineral acid such as dilute nitric acid. It should be evident that all that is re and the starting material of the formula V above be soluble therein. Thus, the artisan will readily recognize the myriad of solvents suitable for the purposes of this process aspect.

Ceric salts, for use in the process of process aspect d), may be represented by ceric ammonium nitrate, cerio nitrate, ceric sulfate or any other suitable ceric salt.

While temperature is not critical to a successful performance of process aspect d), it is preferred to perform the reaction at a temperature range of from between about o o 0 C to about 50 C, most preferably at room temperature.

From the above, it should be evident that the manner of bringing together the reaction partners (i.e., a ceric salt and a compound of the formula V above) is not of primary importance to a successful performance of the disclosed processes and hence, the particular manner of carrying out the reaction is largely a matter of convenience.

In a preferred embodiment, the reaction is carried out in the presence of an inert organic solvent of the type set forth above. It should be appreciated that the use of a solvent will ordinarily allow the reaction to prooeed in a relatively simple manner, which avoids the use of extraordinary conditions, extensive equipment and the like.

In a preferred process aspect, either a compound of the s which is preferably a lower fatty aoid such as aoetlo acid. To the resultant solution there is added a eerie salt, most preferably, oeric ammonium nitrate dissolved in water, The resultant reaction mixture is then permitted to stand at room temperature. The product of the formula I above which results is thereafter isolated.

In an especially preferred embodiment, the eerie salt utilized is eerie ammonium nitrate and the R-,-CH2-group present on the compound of the formula V above is an ethyl group so that there can be obtained respectively a 7-aoetyl-benzodiazepine. However, other lower alley1 group-containing compounds such as a 7-propyl, 7-butyl, 7-isobutyl, 7-pentyl benzodiazepine of the formula V above may also be utilized with equal efficaciousness so as to obtain the corresponding compound of the formula I above.

Compounds of the formula I above wherein is hydrogen, can be converted - aocording to process aspect e) above -into the corresponding compound of the formula I above wherein R1 is lower alkyl by conventional procedures. For example, compounds of the formula I above wherein R1 is hydrogen can be converted into its 1-sodio derivative with sodium methoxide, sodium hydride and the like and the resulting 1-sodio compound can then be alkylated utilizing conventional alkylating agents such as methyl iodide, ethyl iodide, dimethylsulfate and the like. Suitably, the alkylation is effected in the presence of any conveniently available inert organic solvent methanol, ethanol, dimethylformamide, benzene, toluene and N-methylpyrrolidine or the like.

According to process aspect f) above, compounds of the formula I wherein B is a methylene group, can be oxidized with ruthenium tetroxide into the corresponding compound of the formula I above wherein B is carbonyl. In a preferred aspect, ruthenium tetroxide is in a molar excess to the reaction zone containing a compound of the formula I wherein B is methylene. Preferably, the oxidation is effeoted at below room temperature, e.g., at a temperature range of from about -20°C to about 15°C, most preferably from about 0°C to about 10°C. The reaction proceeds most suitably in the presence of an inert organic solvent and among the many solvents suitable for the purposes of the present invention there may be included halogenated aliphatic hydrocarbons such as chloroform, carbontetraohloride, dichloromethane and the like.

Advantageously, after the oxidation reaction is permitted to proceed for the time necessary to effect the desired end, any suitable reagent may be added to the reaction medium to destroy any excess ruthenium tetroxide present therein. A preferred reagent for this purpose is a lower alkanol such as 2-propanol.

Compounds of formula III can be obtained by a variety of rocedures all startin with the corres ondin 2-Amino- lower alkanoyl wherein R.^ and have the meaning indicated above.

Compounds of formula A may be prepared by a four stage process outlined below.

In the first stage of this process for the preparation of compounds of formula A, a p-lower alkyl aniline or a N-lower alkyl derivative thereof is reacted with a benzoyl halide or a halo-benzoyl halide, preferably, having the halo group in the ortho position in the presence of a catalyst such as zinc chloride whereby to obtain a compound of the general formula wherein R1 and R2 have the meaning indicated above and R-j is lower alkyl.

Preferred benzoyl groupsinclude benzoyl chloride, o-chloro-benzoyl. chloride, o-fluorobenzoyl chloride and the like. The reaction of the benzoyl halide with the lower alkyl aniline in the presence of zinc chloride is suitably effected at elevated temperatures. It is especially preferred to conduot the reaction at a temperature of above about 130°C. The reaction should be performed in an anhydrous medium. Thus, it can be conducted in the absence of any solvent outside of the reaotants themselves or alternatively, it can be conducted in the presence of an inert organic solvent such as benzene and the like. Suitably, the reaction is effected utilizing the benzoyl halide as the reaction medium.

In the second stage for the preparation of benzophenone of formula A the so-obtained compound of formula B above is converted into the corresponding compound bearing a suitable nitrogen protecting group at the aniline nitrogen. This group functions to prevent the nitrogen atom on the 2-amino function from participating in further reactions until it is desired.

Nitrogen protecting groups are well known and can be represented by a lower alkanoyl group provided by acetic anhydride, acetyl chloride and the like. Suitably, this reaction is effected in the presence of an inert organic solvent such as benzene, ether, a halogenated hydrocarbon such as methylene ohloride and the like. Temperature and pressure are not critical to a successful performance of this process step.

Thus, the reaotion can be effected at room temperature or at reaction is conducted under reflux conditions.

The third stage for the preparation of compounds of formula A, the protected compound obtained from the second stage is oxidized. In a preferred embodiment, the oxidation is effected utilizing a buffered solution of potassium permanganate as the reagent for oxidation. Of course, any oxidating reagent which is suitable for the purposes of converting the lower alkyl moiety in the 5-position into a lower alkanoyl moiety can also be conveniently employed. The oxidation with potassium permanganate occurs upon treatment with dilute aqueous solution (0.1-5$) of potassium permanganate. Suitably, for every one mole of the compound to be oxidized, there is present from about 1 to about moles of permanganate in the reaction medium. The reaction is effected at a temperature of from about 0° to about 8o°, most preferably from about 50° to about 70°. As is evident, this stage is effected in an excess of water provided by the dilute aqueous solution of permanganate and this excess can serve as the solvent medium. However, other suitable solvents can also be utilized as the medium in which the reaction may be conducted. While potassium permanganate is described as being the preferred oxidizing reagent, it is, of course, to be understood that other permanganates suoh as lithium, sodium, calcium and magnesium can similarly be utilized with equal efficaciousness for the purposes of the present invention.

In the fourth stage for the preparation of compounds of subjected to hydrolyzlng conditions wherein to obtain a 2-amino group containing oompound. Standard hydrolyzation procedures can be used, e.g., water miscible solvents such as dioxane, tetrahydrofuran, ethanol and the like in the presenoe of an acid such as hydrochloric acid or a base such as an alkali metal hydroxide (preferably sodium hydroxide).

As is evident from the above the four stage process Just desoribed for the preparation of compounds of formula A yields only such compounds wherein the lower alkanoyl moiety has 2 and more carbon atoms. Corresponding 5-formyl derivatives can be obtained by oxidizing a 5-methyl-benzophenone with a eerie salt as described below in greater detail.

As indicated above, the so- btained 2-amino-5-lower alkanoyl benzophenone of the formula A can be converted into the corresponding compound of the formula III by a wide variety of procedures.

For example, the so-obtained 2-amino-5-lower alkanoyl benzophenone of the formula A can be treated with a halo-lower alkanoyl leaving group containing compound of the formula Y-?H-CO-halide wherein Y is halogen, phthalimido, lower alkyl sulfonyloxy, e.g., mesyloxy or a phenyl sulfonyloxy group, e.g., benzene sulfonyloxy, or tosyloxy, whereby to obtain a compound of the general formula lower wherein R^, , R^ and Y have the meaning indicated above.

Suitable halo-lower alkanoyl halides (i.e., wherein Y is halogen, most suitably chlorine, bromine and iodine) are preferably represented by chloroacetyl chloride, broraoacetyl bromide, bromoacetyl chloride, bromopropionyl chloride and the like. From the above, it should be evident that the halogen moieties of the above-identified halo-lower alkanoyl halide compounds are preferably selected from the group consisting of chlorine and bromine. Representative of compounds of the formula Y-CH-CO-halide wherein Y is lower alkyl sulfonyloxy or a phenyl sulfonyloxy are mesyloxyacetyl chloride and tosyloxyacetyl chloride. Suitably, this process aspect is effected in the presence of an inert organic solvent suoh as benzene, ether, methylene chloride and the like. Temperature and pressure are not critical to a successful performance of this step. However, in a preferred aspect, this step is conducted at elevated temperatures, e.g., at about the reflux temperature of the reaction medium.

V The so-obtained compound of the formula C wherein Y is halogen, lower alkyl sulfonyloxy, and a phenyl sulfonyloxy group is treated with ammonia and the resulting compound of the formula III is cyclized without isolation to the corresponding 7-lower alkanoyl benzodiazepine of the formula I above. The compound of the formula III above need not be isolated prior to cyclizing same but the ring closure thereof to the compound of the formula I can be effected in the reaction medium in which the compound of the formula III was prepared without isolating same or interrupting the reaction sequence before the desired compound of the formula I is obtained. For example, the haloacylamido compound of the formula C above or a mesyloxyacylamido compound of the formula C or a tosyloxyaoylamido compound of the formula C can be placed in a lower alkanol suspension of ammonia such as ethanolic ammonia or methanolic ammonia and, subsequently after a period of several hours, for example, overnight, the corresponding 7-lower alkanoyl benzodiazepine represented by the formula I can be recovered. The cyclization can be accelerated by heating. In another embodiment, in lieu of methanolic ammonia, the compound of the formula C wherein Y is halogen, a lower alkyl sulfonyloxy group or a phenyl sulfonyloxy group can be dissolved in an inert organic solvent such as methylene chloride, carbon tetrachloride, ethers such as tetrahydrofuran, dioxane and ethyl ether, dimethylsulfoxide, dimethylformamide and the like and the resultant solution can be treated with liquid ammonia whereby a compound of the formula III results. The so-obtained compound of the formula III, \ a compound of formula I In the manner described above.

Compounds of the formula C wherein Y is a carbobenzoxy amino grouping can be obtained by reacting a compound of the formula A above with a oarbobenzoxy-glycylating agent such as oarbobenzoxy glycine, carbobenzoxy-glycine anhydride and carbo-benzoxy-glycyl halide. The carbobenzoxy-glycylation can be conducted at room temperature or at temperatures above or below room temperature. In one preferred embodiment, the carbobenzoxy-glycylation is effected by condensing carbo-benzoxy-glycine with a compound of the ormula A above in . the presence of an Ν,Ν'-disubstituted carbodiimide. The reaction can, for example, be carried out at a temperature o o between about 0 C and about 50 C preferably, at a temperature slightly below room temperature. Advantageously, a solvent is present during the reaction. Among the solvents which can be used for this purpose, there can be included organic solvents, such as methylene chloride, chloroform, dioxane, tetrahydrofuran, dimethylformamide, acetonitrile and the like, as well as water and mixtures of the above.

The so-obtained compound of the formula C above wherein Y is carbobenzoxyamino (e.g., a carbobenzoxy-glycyl-amino- -acetylbenzophenone ) can be converted into the corresponding compound of the formula III via the treatment thereof with a hydrohalic acid in the presence of acetic acid. This reaction step results in the selective splitting of one of the amide linkages of the carbobenzoxy-glycylamino chain so as to used as the hydrohalio acid, in this process step, hydrobromic acid. However, other hydrohalic acids such as hydrochloric acid can also be used. The reaotlon can be performed either in aqueous or anhydrous media. It can be conducted at room temperature or temperatures above or below room temperature. The so-obtained compound of the formula III can then be converted into the corresponding compound of the formula I in the manner described above.

A further embodiment of this process aspect relates to a process for the preparation of a compound of the formula I which comprises the steps of treating a 2-carbobenzoxy-glycyl-aminobenzophenone with hydrohalic aoid, e.g., hydrobromic acid, in the presence of acetic acid and alkalizing the. crude reaction product to a pH of at least 7* e.g., to at least neutrality. Thus, a compound of the formula C wherein Y is carbobenzoxyamino can be directly converted into compounds of the formula I without isolating an intermediate of the formula III. As the alkalizing agent, either strong or weak bases can be used, for example, ammonia, sodium carbonate, alkali metal hydroxides such as potassium hydroxides, sodium hydroxides and the like.

In a further aspect, compounds of the formula C above wherein Y is phthalimido can be obtained by treating a compound of the formula A above with a phthalimido acetyl halide (preferably bromide or chloride) or an o lower alkyl derivative thereof, in the presence or in the absence of an alkaline halo inert solvent such as a halogenated hydrocarbon, e.g., chloroform and methylene chloride, pyridine and the like.

A preferred temperature range for effecting this process aspeot is from about room temperature to about the reflux temperature of the solvent utilized.

A compound of the formula C above wherein Y is phthal-imido can also be obtained by treating the corresponding compound of the formula C wherein Y is halogen, lower alkyl, sulfonyloxy and aryl sulfonyloxy in a preferred aspeot with an alkali metal salt of phthalimide (phthalimide potassium).

The so-obtained oompound of the formula C above wherein Y is phthalimido can be converted into the corresponding compound of the formula III by treating the former with hydrazine hydrate. Suitably this prooess is effected in an inert organic solvent. Preferably, one or more molar equivalents of hydrazine hydrate is present in the reaction zone for every one molar equivalent of compound of the formula C wherein Y is phthalimido. Temperature and pressure are not critical to a successful performance of this process step. However, elevated temperatures, preferably at about the reflux temperature of the reaction mixture are preferred. Also, for good yields it has been found that the reaction should be conduoted in an inert organic solvent such as a lower alkanol, e.g., ethanol. In proceeding accordingly, the compound of the formula III is obtained and it can be converted directly to the corres ondin com ound of the formula I without isolation reaction before the desired benzodiazepin-2-one of the formula I is obtained.

In an alternate process step, a compound of the formula C above wherein Y is halogen or lower alkyl sulfonyloxy or an aryl sulfonyloxy group is treated with an azide-generating reagent. Representative of azide group-providing agents are alkali metal azides such as sodium azide, potassium azide, lithium azide and alkaline earth metal azides such as caloium azide, ammonium azide and the like, preferably sodium azide, whereby to obtain the corresponding azide. In this process step, a compound of the formula C is added to an appropriate organic solvent such as an alkanol, e.g., methanol, an ether such as dioxane and tetrahydrofuran and the like. To the resultant solution there is added the azide-generating agent, and the reaction mixture is then heated at temperatures from slightly above room temperature to about the reflux temperature of the reaction medium, The so-obtained azide is then selectively reduced by catalytic hydrogenation utilizing any conveniently available reducing system which may include catalysts, Raney-Nickel, and noble metal catalysts such as palladium, platinum and the like, whereby to obtain the corresponding compound of the formula III. The catalytic hydrogenation is suitably effected in the presence of an inert organic solvent such as an ether, e.g., tetrahydrofuran. In a preferred aspect the resulting compound of the formula III is dissolved, without isolation from the reaotion medium in which it is prepared, in an appropriate inert organic solvent such as In still another alternative process embodiment, the azide Just discussed can be prepared directly from a compouhd of the formula C by reacting such compound with a compound of the formula N3CHCOCI (e.g., azidoacetyl chloride) at a o o temperature of from about 10 C to about 50 C in the presence of an inert organic solvent such as chloroform.

Compounds of formula III wherein B is methylene can be obtained by treatment of the benzophenone of formula A with an ethylene dihalide and subsequently with ammonia in analogy to the process described above with respect to the corresponding compounds of formula III wherein B is carbonyl.

Furthermore, benzophenones of the formula A above can be reacted with a phthalimidoethyl halide to produce the corresponding 2-(phthalimidoethylamino)-benzophenone which in turn is treated with hydrazine hydrate yielding a compound of formula III wherein B is methylene.

Still a further method consists in reacting a compound of formula A above with a benzamidoethyl halide and treating the 2- (benzamidoethylamino) -benzophenone obtained with hydrochloric acid whereby to give a compound of formula III wherein B is methylene.

As is evident from the foregoing, compounds of formula III wherein B is methylene need not be isolated before cyclisation to compounds of formula I is effected similarly as discussed in detail with respect to compounds of formula III wherein B is carbonyl.

Process aspect d) discussed above can also be used to prepare S-acyl-benzophenones of the general formula wherein R , R2 and R^ have the meaning indicated above and P represents any suitable nitrogen atom protecting system, by treatment of the corresponding 5-lower alkyl-benzophenone with a eerie salt as discussed above with respect to the conversion of compounds of formula V into compounds of formula I.

In the formula D above, there is illustrated a grouping identified as P. This grouping is defined as a suitable nitrogen protecting group. This group functions to prevent the nitrogen atom on the 2-amino function of a compound of the formula D from participating in the reaction with the cerio salt whereby the formation of undesired side products can be avoided. Nitrogen-protecting groups are well known and can be represented by a lower alkanoyl group provided by acetic anhydride, acetyl chloride and the like. However, the literature describes a multitude of nitrogen protecting groups which would be readily recognizable by the artisan as suitable for the purposes of the present invention.

The compounds of the formula D can be converted into 7-lower alkanoyl benzodiazepine as is indicated above.

The compounds of the formula I are useful as anticonvulsants, muscle relaxants and sedatives. Such compounds can be formulated into pharmaceutical preparations in admixture with a compatible pharmaceutical carrier and can be administered enterally or parenterally with dosages fitted to suit the exigencies of a pharmacological situation.

For example, a compound of the formula I wherein B is carbonyl, R1 and are both methyl and and are both hydrogen have demonstrated properties in the metrazole test properties in the metrazole test with dosage levels about 25 mg/kg.

As oontemplated by this invention, the novel compounds of the formula I can be embodied in pharmacological dosage formulations containing from about 0.5 mg to about 200 mg of active substance, with dosage adjusted to species and individual requirements. (Parenteral formulations would ordinarily contain less of the active substance than composit ions intended for oral administration). The novel compounds of this invention can be administered alone or in combination with pharmaceutically acceptable carriers as indicated above in a wide variety of dosage forms.

For example, solid preparations for oral administration can inolude tablets, capsules, powders, granules, emulsions, suspensions and the like. The solid preparation may comprise ' an inorganic carrier, e.g., talc, or an organic carrier, e.g. lactose ,starch. Additives such as magnesium stearate (a lubri cant) can also be included. Liquid preparations such as solutions, suspensions or emulsions may comprise the usual diluents such as water, petroleum jelly and the like, a suspension media such as polyoxyethylene glycols, vegetable oils and the like. They may also contain other additional ingredients such as preserving agents, stabilizing agents, Q wetting agents, salts for varying the psmotic pressure or buffers. They may also contain, in combination, other therapeutically useful substances.

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

Example 1 51.4 g (0.2 m) of 7-amino-2,3-dihydro-l-methyl-5-phenyl-lH-l, 4-benzodiazepinedihydrochloride was treated with 40 g (ca. 0.4 m) of concentrated H2S04 in 2( 0 ml of water with ice salt bath cooling. A cooled aqueous soltuion containing 14 g (0.202 m) sodium nitrite in 30 ml of water was added dropwise (stirring) over a period of 10 minutes. (Reaction temperature rose from -3° to 5° ) · Stirring was continued with cooling for 30 minutes after completion of addition of the sodium nitrite solution. A solution of l8 g anhydrous NaOAc in 50 ml H20 was then added. To the ice cold resulting reaction mixture there was carefully added with vigorous stirring a suspension prepared utilizing 93 g (0.93 m) acetaldehyde semicarbazone, 65 g anhydrous NaOAc, 10 g CuS04.5H20 and 900 ml H20. The reaction temperature was maintained at 22-25° throughout the addition. Time of addition was 2 1/2 hours. Ether was added from time to time to help control foaming which occurred.

After addition of the suspension, it was stirred for an additional 2 1/2 hours.

The reaction mixture was made strongly basic with 40 aqueous NaOH and extracted with CH2C12. The organic phase was washed with H20, dried over anhydrous Na2S04 and evaporated to dryness leaving a residue containing 2,3-dihydro-l-methyl-7 of concentrated HCl was added to the residue and the mixture was refluxed for one hour, cooled, basified with 40# aqueous NaOH and extracted with CH2C12. The organic phase was dried over anhydrous Na2S04 and concentrated. The residue was redissolved in a small amount of CH2C12 and poured onto a sintered glass funnel containing silica gel suspended in CH2C12. It was then washed through with 2 liters of EtOAc. Concentration of the EtOAc washing afforded a thick dark residue. A column was prepared using 425 8 silica gel (0.05-0.2 mm Merck for column chromatograph ) . The silica gel was slurried in EtOAc. The residue in a small amount of CH2C12 was placed on the column and washed through with EtOAc. (300 ml fractions were collected). The fractions were concentrated and oombined, yielding 7-acetyl-2, 3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepine in the residue (as determined by TLC ) . Recrystallization from CH2C12-Pet. Et20 gave 2 crops, which were dried at 63°/high vacuum overnight, m.p. 109-113°.

Example 2 The ice-cold solution containing 7 ·7 ml (0.0048 m) of Ο.Ο63 N Ru04 in CHCI3 was added dropwise over a period of 40 minutes to the solution of 1.23 g (0.0044 m) 7-acetyl-2, 3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepine in 25 ml CC14 with ice-bath cooling. The reaction mixture was stirred for 45 minutes after the completion of addition. 10 ml of H20 was then added and the mixture was filtered through a Celite pad. The upper H20 phase was pipetted off and the organic phase yellow viscous residue. The residue was dissolved in ether and yielding a precipitate. Reorystallization from CH2Cl2.Et20 (pulling through Celite again to remove traces of Ru04 ) afforded off-white prisms of 7-aoetyl-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one, m.p. 120-125°.

Example 3 In a similar manner to the procedures found in Example 1, 7-propionyl-2,3-dihydro-l-methyl-5-phenyl-lH-l, -benzodiazepine can be prepared via the reaction of 7-amino-2,3-dihydro-l-methyl-5-phanyl-lH-l,4-benzodiazepine dihydrochloride and propionaldehyde semicarbazone to obtain 2,3-dihydro-l-methyl-7-propionyl-5-phenyl-lH-l,4-benzodiazepine semicarbazone which can be hydrolized to 7-propionyl-2,3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepine. The last-mentioned compound can then be oxidized by the procedure described in Example 2 to 7-propionyl-l,3-dihydro-l-methyl-5-phenyl-2H-l, -benzo-diazepin-2-one .

Example 4 In a similar manner to that described in Example 1 starting with 7-amino-2,3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepine dihydrochloride and butyraldehyde semicarbazone, there can be prepared 2,3-dihydro-l-methyl-7-butyryl-5-phenyl-lH-l,4-benzodiazepine semicarbazone which can be converted by the procedures described in Example 1 to 7-butyryl-2,3- last-mentioned compound can be oxidized with Ru04 as described in Example 2 to 7-butyryl-l,3-dihydro-l-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one .

Example 5 To a solution of 41.7 g (Ο.36 moles) of zinc chloride in 175 ml (I.52 moles) of benzoyl chloride maintained at l40°C, 29.I g ( 0.24 moles) of p-ethylaniline was added portionwise (from a beaker) with stirring. The mixture was heated under reflux at 210-220°c for 1 hour. The temperature was then lowered to l40°C, and the excess benzoyl chloride was removed by distillation at water aspirator pressure.

Without letting the mixture cool, 100 ml of 6 N hydrochloric acid was added carefully at about l40°C and the reaction mixture was stirred and heated under reflux at l40-l6o°C for 20 hours. The mixture was partially cooled. Methylene chloride (about 300 ml) was added followed by about 300 ml of water. The mixture was stirred until all solids dissolved. The aqueous layer was extracted two more times with methylene chloride. The combined methylene chloride layers were washed thoroughly with 3 N hydrochloric acid, 3 N sodium hydroxide and water in this sequence. After drying over anhydrous sodium sulfate and evaporation of methylene chloride a dark gum of 2-amino-5-ethylbenzophenone was obtained.

The gum was chromatographed on a column of 500 g of activity I alumina. Elution with 10% ether in benzene gave Crystallization from petroleum ether gave pale yellow plates, m.p. 5 -56° .

To a solution of 90.0 g (0.4 moles) of 2-amino-5-ethyl-benzophenone in 400 ml of benzene was added 84 ml ( 91.0 g, 0.8 moles) of acetic anhydride and the reaction mixture was heated under reflux for 5 minutes.

On oooling the reaction mixture was concentrated in vacuo, to yield a semi-solid. Repeated solution in ethyl acetate followed by evaporation of the solvent gave a deep brown solid. After one recrystallization from ethanol, 2-acetamido-5-ethyl-benzophenone in a pale brown amorphous form, was obtained, m.p. IO9-IIO.5° · Repeated recrystallization from ethanol gave colorless needles, m.p. 112-113.5°.

A three-necked 3 liter flask was charged with 5.0 g ( 125 nnioles ) of magnesium oxide, 170 ml ( 250 mmoles) of concentrated nitric acid and 2 liters of water. To this solution was added 13 ·3 g ( 50 mmoles) of 2-acetamido-5-ethyl-benzophenone and 19.5 g ( 125 mmoles) of potassium permanganate. The reaction mixture was heated with stirring at 60° - 2°C for 5 hours.

The reaction mixture was chilled in ice. Manganese dioxide was dissolved by reduction with a stream of gaseous sulfur dioxide. The remaining pale yellow solid was collected and washed with water. After two recrystallizations from ethanol, needles, m.p. 115-116°.

To a solution of 5.6 g (20 mmoles) of 2-acetamido-5-acetylbenzophenone in 100 ml of ethanol was added 100 ml (0.2 mole) of 2 N sodium hydroxide and the mixture was heated under reflux for 3 hours. On oooling, pale yellow crystals of 5-a°etyl-2-aminobenzophenone precipitated. The crystals were collected and washed with ethanol. After recrystallizatlon from benzene-petroleum ether, 5-&cetyl-2-aminobenzophenone . o was obtained as yellow prisms, m.p. 153-154.5 C.

To a solution of 7.2 g (30 mmoles) of 2-amino-5-acetyl-benzophenone in 100 ml of benzene was added 12.06 g (60 mmoles) of bromoacetyl bromide and the mixture was heated under reflux for 3 hours. On cooling, the reaction mixture was washed with ice cold dilute alkali, and water, dried over anhydrous sodium sulfate and evaporated in vacuo to yield a buff colored solid. On recrystallizatlon from benzene-petroleum ether, 5-acetyl-2- (2-bromoacetamido)benzophenone was obtained as a buff colored amorphous acid, m.p. ll8-120°C. A portion of this material on further recrystallizatlon yielded red hexagonal prisms .

In a similar manner by reacting 2-amino-5-acetylbenzo-phenone with mesyloxyacetyl chloride, there can be obtained 5-acetyl-2- (2-mesyloxyacetamido )benzophenone .

Also, in a similar manner by reacting 2-amino-5-acetyl- obtained 5-acetyl-2- (2-tosyloxyacetamido)benzophenone.

To a solution of 3.0 g (8Λ mmoles) of 5-acetyl-2- (2-bromoacetamido)benzophenone in 120 ml of methanol, was added I.08 g (I6.8 mmoles) of sodium azide in one portion.

The reaction mixture was heated on a steam bath for 15 minutes. On cooling, 5-aoetyl-2-(2-azidoacetamido) benzophenone precipitated as pale pink micro-prisms. Upon recrystallization from ethanol, pink microprlsms were obtained, m.p. 144-145°C.

In a similar manner upon the treatment of 5-acetyl-2-(2-tosyloxyacetamido)benzophenone or 5-a-cetyl-2-(2-mesyloxy-acetamido)benzophenone with sodium azide, there can be obtained 5-acetyl-2- (2-azidoacetamido )benzophenone .

To a solution of 2.0 g (6.2 mmoles) of 5-acetyl-2- (2-azidoacetamido)benzophenone in 125 ml of tetrahydrofuran was added 350 g of 10 palladium on carbon. The mixture was hydrogenated at one atmosphere for 2 hours and yielded 5-acetyl-2-glycylaminobenzophenone. The catalyst was removed by filtration through a pad of Celite, and the solution was evaporated to dryness. The pale yellow solid obtained was dissolved in 125 ml of ethanol and heated to a reflux for 2 hours. Evaporation of ethanol gave an oil. Upon treatment of the oil with benzene-petroleum ether, 7-acetyl-l,3-dihydro-5-phenyl-2H-l, -benzodiazepin-2-one, precipitated as pale yellow powder, m.p. l8 -l86.5°.

Example 6 A solution of 2.4 g (6.8 mmoles ) of 5-acetyl-2- (2-bromo-aoetamido)benzophenone in 10 ml of methylene chloride was added to 25 ml of liquid ammonia at -78°C, chilled in a dry ice-aoetone bath giving 5-acetyl-2-glycylaminobenzophenone.

After stirring for 2 hours, the dry ice bath was removed, and the liquid ammonia allowed to evaporate. The methylene chloride layer was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The oily residue, which contained 5-acetyl-2-glycylaminobenzophenone, was dissolved in 40 ml of ethanol and heated to reflux for 1 hour. Evaporation of ethanol and repeated recrystallization of the residue from benzene-petroleum ether gave 7-acetyl-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, as a yellow powder.

Example 7 Starting with p-fluorobenzoyl chloride and p-ethylaniline, there was obtained 5-acetyl-2-amino-2f-fluorobenzophenbne in the manner described in the first four paragraphs of Example 5· To a solution of 30 mmoles of 2-amino-5-acetyl-2'-fluoro-benzophenone in 100 ml of benzene was added 60 mmoles of bromoacetyl bromide and the mixture was heated under reflux for 3 hours. On cooling, the reaction mixture was washed with ice-cold dilute alkali, and water, dried over anhydrous sodium On reorystallization from benzene-petroleum ether, 5-acetyl-2- ( 2-bromoacetamido)-2'-fluorobenzophenone was obtained.

A solution of 2.4 g 6.8 mmoles of 5-acetyl-2- ( 2-bromo-aoetamido)-2'-fluorobenzophenone in 10 ml of methylene chloride was added to 25 ml of liquid ammonia at -78°c, chilled in a dry ice-acetone bath giving 5-acetyl-2-glycylamino-2 '-fluoro-benzophenone. After stirring for 2 hours, the dry ice bath was removed, and the liquid ammonia allowed to evaporate.

The methylene chloride layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The oily residue which contained 5-a°etyl-2-glycylamino-2,-fluoro-benzophenone was dissolved in 40 ml of ethanol and heated to reflux for 1 hour. Evaporation of ethanol and repeated reorystallization of the residue from ether petroleum ether gave 7-acetyl-l,3-dihydro-5- (2-fluorophenyl)-2H-l,4-benzo-diazepin-2-one as light yellow prisms, m.p. 211-213°, To a solution of 8.4 mmoles of 5-acetyl-2- ( 2-bromo-acetamido)-2 '-fluorobenzophenone in 120 ml of methanol, was added 16.8 mmoles of sodium azide in one portion. The reaction mixture was heated on a steam bath for 15 minutes. On cooling and concentration, 5-acety 1-2- (2-azidoacetamido) -2 ' -fluorobenzophenone precipitated, which can be converted into 7-acetyl-l,3-dihydro-5- (2-fluorophenyl)-2H-l,4-benzodiazepin-2-one in analogous manner as described in the last paragraph of Example .

Example 8 To a solution of 2.3 g of 5-acetyl-2-aminobenzophenone and 2.1 g of oar obenzoxyglyclne in 25 ml of tetrahydrofuran, 2.2 g of N,N!-dicyclohexyloarbodiimide was added. After stirring for several minutes, dicyclohexylurea began to crystallize. Stirring was continued fbr two hours and dicyclohexylurea was then filtered off. The filtrate was then treated with 2 ml of acetic acid to decompose any excess Ν,Ν'-dicyclo-hexylcarbodiimide. After fifteen minutes additional solid was removed by filtration. The filtrate was taken to dryness in vacuo and the residue was dissolved in benzene and washed successively with 1 N hydrochloric acid, water and 5$ sodium bicarbonate and then dried over sodium sulfate. The benzene layer was concentrated and hexane added to turbidity. On seeding (4-acetyl-2-benzoylphenylcarbamoylmethyl)carbamic acid benzyl ester crystallized.

A solution of 4 .5 g of ( 4-acetyl-2-benzoylphenyl-carbamoylmethyl )carbamic acid benzyl ester in 4 ml of $ hydrobromic acid in acetic acid was stirred for thirty minutes at room temperature. Anhydrous ether ( 175 ml) was then carefully added. After pouring off the supernatant, the residue was stirred with water and ether, cooled in an ice bath and made slightly alkaline with ammonia. The ether layer was dried over sodium sulfate, filtered, some benzene added and the resulting solution concentrated in vacuo to small volume. On addition of hexane to the residue 5-acetyl- obtained compound to ethanol and refluxing, it was cyclized to 5-acetyl-l,3-dihydro-5-phenyl-2H-l, -benzodiazepin-2-one.

Example 9 A solution of >.1 g of (4-acetyl-2-benzoylcarbamoyl-methyl)carbamic acid benzyl ester in 30 ml of 20% hydrobromic acid in glacial acetic acid was stirred for 45 minutes at room temperature. To the resultant solution, 175 ml of anhydrous ether was added. After several minutes the ether solution was decanted. The resultant 5-acetyl-2-glycylaminobenzophenone was not isolated but about 155 ml of ether was added to the residue and after chilling in an ice bath, 10% sodium hydroxide was added until the mixture was made alkaline. The ether layer was then separated, washed twice with water and dried over sodium sulfate. After filtration, the ether solution was concentrated to dryness in vacuo. The residue was crystallized from benzene to yield 7-acetyl-l,3-dihydro-5-phenyl-2H-l, 4-benzodiazepin-2-one .

Example 10 To 125 ml of a chloroform solution of phthalimidoacetyl chloride, there was added 5 g of 5-a°etyl-2-aminobenzophenone. After refluxing for 3 hours the reaction mixture was allowed to stand for 48 hours at room temperature. Removal of the solvent in vacuo left crystalline 2-phthalimidoacetamido-5-acetyl benzophenone.

A solution of 2-phthalimidoacetamido-5-acetylbenzophenone ( 0.5 mg) in 95^ ethanol ( 25 ml) containing hydrazine hydrate (CUT g) was heated under reflux for two hours. About 10 ml of ethanol was then distilled off. The so-obtained reaction mixture which contained 5-acetyl-2-glycylaminobenzophenone was cooled to room temperature and filtered. The filtrate was acidified by addition of $ hydrochloric acid. The mixture was then warmed to about 8o° . After so warming, the mixture was cooled so that the temperature was brought to about room temperature. The so-obtained mixture was made alkaline with dilute sodium hydroxide and exhaustively extracted with methylene chloride. The extract was washed with water, the solvent removed by distillation and the remaining 7-acetyl-l, 3-dihydro-5-phenyl-2H-l, -benzodiazepin-2-one was recrystal-lized from benzene-petroleum ether as a pale yellow powder.

Example 11 A 500 ml three necked flask was charged with a solution of 41.0 g ( 0.3 moles) of zinc chloride in 175 ml ( 1.25 moles) of benzoyl chloride. The solution was heated up to 150°C, and 29.8 g ( 0.2 moles) of p-n-butylaniline was added portion-wise with vigorous stirring, the temperature being maintained at 150°C. The temperature was then raised to ( 210-220°C) and the reaction mixture was heated under reflux for 0.75 hour, till most of the gaseous HC1 was expelled.

The reaction mixture was cooled to ΐ4θ , the excess without letting the mixture cool, 100 ml of 6 N hydrochloric acid was added carefully and the mixture was heated under reflux for 20 hours.

The hot resinous materials were partitioned between water and methylene chloride till all the solids dissolved. The aqueous phase was extracted twice more with methylene chloride, the combined organic layers were washed twice with 250 ml portions of 3N HC1, 3N NaOH, and water in this sequence, dried over anhydrous sodium sulfate, evaporated in vacuo to yield a greenish yellow oil. The oil was essentially 2-amino-5-butylbenzophenone .

To 2.53 g ( 0.01 mole) of 2-amino-5-butylbenzophenone as the oil obtained in the preceding example in 15 ml of benzene, was added 3 · 0 ml ( 0.03 moles) of acetic anhydride, and the reaction mixture was stirred at room temperature for 2 hours.

The solvent was then evaporated in vacuo, the dark solid obtained was dissolved in 10 ml of dimethylformamide, and treated with water to yield a light brown solid (76-77°C).

After recrystallization from ether-pentane, 2-acetamido-5-butylbenzophenone was obtained in a light yellow amorphous form, m.p. 79·5-8ΐ ·5° .

A 250 ml 3-neclced flask was charged with a solution of 290 mg (7.2 mmoles) of magnesium oxide in 150 ml of water, 1.0 ml ( 15 mmoles) of concentrated nitric acid, 1.00 g (7 ·2 mmoles) of potassium permanganate. The reaotion mixture was heated with stirring for 8 hours at 60 - 2°C. On cooling, gaseous sulfur was passed through the dark brown mixture to dissolve the manganese dioxide. The remaining pale yellow solid was collected and washed with water. This solid was dissolved in methylene chloride and washed with aqueous sodium bicarbonate. The methylene chloride layer was dried over anhydrous sodium sulfate and evaporated to dryness.

Trituration of the residual solid followed by chilling gave 2-acetamido-5-butyrylbenzophenone as colorless needles, m.p. 125-126.5°.

The so-obtained 2-acetamido-5-butyrylbenzophenone can be converted in the manner described in the fourth and fifth paragraph of Example 5 and in Example 6, into 7-butyryl-l, 3-dihydro-5-phenyl-2H-l,4-benzodlazepin-2-one by conversion to 2-amino-5-butyrylbenzophenone which is then converted to 2- ( 2-bromoacetamido)-5-butyrylbenzophenone which, upon treatment with ammonia, is then converted into 5-Dutyryl-2-glycylamino-benzophenone which in turn cyclizes to the desired 7-butyryl-benzodiazepin-2-one.

Example 12 A solution of 52 mg ( 0.20 mmole) of 7-cyano-2,3-dihydro-l-methyl-5-phenyl-lH-l, -benzodiazepine in ml of dry tetra-hydrofuran under nitrogen, was chilled in powdered dry ice. Through a serum stopper, O.50 ml ( 0.8 mmole) of a 1.55 M The mixture was stirred for 10 minutes at the dry ice temperature, then decomposed by pouring with stirring into 40 ml of 0.1 N hydrochloric acid. After 5 minutes at room temperature, the aqueous solution was basified to pH of about 9 with 1 N sodium hydroxide and the product isolated by extraction with methylene chloride. Evaporation of methylene chloride gave a yellow oil, which crystallized from methylene chloride-hexane, giving 7-acetyl-2, 3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepine as yellow prisms, m.p. 90-110°.

As in this Example, if ethyl lithium is utilized 7-pro-pionyl-2, 3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepine can be obtained.

Also, if propyl lithium is reacted with 7-cyano-2, 3-dihydro-5-Phenyl-lH-l, -benzodiazepine as in this Example, 7-butyryl-2, 3-dihydro-5-phenyl-lH-l, -benzodiazepine can be obtained.

Example 13 A solution of 130.6 mg ( 0.50 mmoles) of 7-oyano-l, 3-dihydro-5-phenyl-2H-l, -benzodiazepin-2-one in 20 ml of dry tetrahydrofuran under nitrogen, was chilled in powdered dry ice. Through a serum stopper, 1.00 ml ( 1.5 mmoles) of a I.55 M solution of methyl lithium in ether was injected in one portion. The mixture was stirred for 0.5 hour at the dry ice temperature, then decomposed by pouring with stirring room temperature, the mirky solution was basified to about pH 8 with 1 N sodium hydroxide and the product isolated by extractions with methylene chloride. Upon crystallization from ether 7-acetyl-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one was obtained in a yellow amorphous form, m.p. l86-l87°.

As in this Example, if ethyl lithium is utilized, 7-propionyl-l,3-dihydro-5-phenyl-2H-l, -benzodiazepin-2-one can be obtained.

Also, as in this Example, if propyl lithium is utilized 7-butyryl-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one can be obtained.

Example 14 Using 417 m (1.5 mmoles) of 7-oyano-l,3-dihydro-5- (2-fluorophenyl)-2H-l,4-benzodiazepin-2-one, 4.00 ml (6.0 mmoles) of 1.55 methyl lithium solution in ether and 30 ml of dry tetrahydrofuran, an analogous procedure to that described in Example 2 was followed yielding 7-acetyl-l,3-dihydro-5÷ (2-fluorophenyl)-2H-l,4-benzodiazepin-2-one which, upon crystallization from ether-petroleum ether, was obtained as light yellow prisms having a m.p. 211-213°..

Example 15 A solution of 132 mg ( 0.50 mmole) of 7-ethyl-l,3-dihydro 5-phenyl-2H-l, 4-benzodiazepin-2-one in 4 ml of glacial acetic acid was mixed with a solution of 1.10 g ( 2.0 mmoles) of eerie ammonium nitrate in 4 ml of water. The mixture, a clear solution, was allowed to stand at room temperature. After one day, the mixture was diluted with 50 ml of water and extracted twice with equal volumes of methylene chloride.

The combined methylene chloride layer was washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residual yellow gum was separated by preparative thin-layer chromatography (silica gel, Brinkmann PF 254 , 2 mm, thick, 2 plates measuring 20 cm x 20 cm; ether used as eluent). 7-Acetyl-l,3-dihydro-5-phenyl-2H-l, 4-benzo-dlazepin-2-one was isolated as a gum which crystallized from a small volume of acetonitrile as light yellow prisms, m.p. I87-I890.

In a similar manner l,3-dihydro-7-ethyl-5- ( 2-fluoro-phenyl)-2H-l,4-benzodiazepin-2-one can be treated with eerie ammonium nitrate to give 7-acetyl-l, 3-dihydro-5- ( 2-fluoro-phenyl)-2H-l,4-benzodiazepin-2-one as yellow prisms, m.p. 211-213°.

Also, in a similar manner, l,3-dihydro-5-phenyl-7-propyl 2H-l,4-benzodiazepin-2-one can be treated with eerie ammonium nitrite to give 7-propionyl-l, 3-dihydro-5-phenyl-2H-l,4- As in this Example, 7-butyl-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one can be treated with eerie ammonium nitrate to give 7-butyryl-l,3-dihydro-5-phenyl-2H-l,4-benzo-diazepin-2-one .

Example 16 A solution of 0.50 mmole of 2-acetamido-5-ethylbenzo-phenone in 4 ml of glacial acetic acid was mixed with a solution of 2.0 mmoles of eerie ammonium nitrate in 4 ml of water. The mixture, a clear solution, was allowed to stand at room temperature. After 1 day, the mixture was diluted with 0 ml f water and extracted twice with equal volumes of methylene chloride. The combined methylene chloride layer was washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residual yellow solid was washed with water. After recrystallization from ethanol, 2-acetamido-5-acetylbenzophenone was obtained as colorless needles, m.p. II5-II0 .

In a similar manner, 2-acetamido-5-butylbenzophenone can be treated with eerie ammonium nitrate to give 2-acetamido-5-butyrylbenzophenone, m.p. 125-126.5°.

Example 1 A tablet formulation containing the following ingredients Ingredients mg/Tablet 7-Acetyl-l,3-dihydro-l-methyl-5-phenyl-2H- l,4-benzodiazepin-2-one 25.0 Lactose 98.0 Corn Starch 6l.O Corn Starch as 10% Paste 5.0 Talcum 4.5 Magnesium Stearate 1.5 Corn Starch 5.0 Tablet Weight 200.0 was prepared as follows: Mix the 7-acetyl-l,3-dihydro-l-methyl-5-phenyl-2H-l, -benzodiazepin-2-one, lactose and corn starch in a suitable mixing container and add the starch paste slowly to achieve a heavy moist mass. Pass this moist mass through a coarse screen. Place the moist granules on drying pans and dry at 43°C Pass the dried granules through a screen, place in a suitable mixing container and add the talcum magnesium stearate and second portion of corn starch. Mix well and compress into tablet on either a single or multiple tabletting machine to an individual tablet weight of 200 mg. A standard concave scored punch is suitable, yielding tablets with a thickness o approximately «35 mm* Example 18 A capsule formulation containing the following ingredients Ingredients Per Capsule 7-Acetyl-l,3-dihydro-l-methyl-5-phenyl- 2H-l,4-benzodiazepin-2-one 10 mg Lactose 165 mg Corn Starch 30 mg Talc 5 mg Total Weight 210 mg was prepared as follows: 7-Acetyl-l,3-dih dro-l-methyl-5-phenyl-2H-l, -benzo-diazepin-2-one, 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 19 A parenteral formulation containing the following ingredients Ingredients Per ml 7-Acet l-l, 3-dlhydro-l-methyl-5-phenyl- 2H-l,4-benzodiazepin-2-one 5.0 mg Propylene Glycol 0.4 ml Benzyl Alcohol (Benzaldehyde free) 0.015 ml Ethanol 9556 0.10 ml Sodium Benzoate 48.8 mg Benzoic Acid 1.2 mg Water for Injection q.s. 1.0 ml were prepared (for 10, 000 ml) as follows: 50 g of 7-Acetyl-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one were dissolved in 150 ml of benzyl alcohol 4, 000 ml of propylene glycol and 1, 000 ml of ethanol were added. 12 g of benzoic acid were dissolved in the above. The 48.8 g of sodium benzoate dissolved in 3 , 000 ml of Water for Injection were added. The solution was brought up to final volume of 10, 000 ml with Water for Injection. The solution was filtered through a candle filter, filled into suitable size ampuls, gassed with N2 and sealed. It was then auto-claved at 0.7 atmospheres for 30 minutes.

Claims (4)

Having now particularly described and ascertained the nature of our said invention and in what manner the same is to be performed,we declare that what we claim is:

1. Process for the manufacture of benzodiazepine derivative of the general formula wherein B represents methylene (-CH2-) or carbonyl (_§-). R represents hydrogen or lower alkyl; R2 represents hydrogen or halogen and R^ and R^ represent hydrogen or lower alkyl, which process comprises a) treating a compound of the general formula wherein B, R. , R0 and R. have the meaning indicated above, ηι with Introus acid to form a diazonium salt and thus converting the resulting diazonium salt into the desired compound of the formula I above or b) cyclyzing a compound of the general formula wherein B. R.^, R^, and R^ have the meaning indi above, or treating a compound of the general formula wherein B, R.. , and R. have the meaning indicated above, 1 2 4 lower alkyl except that B is methylene in c¾se R^^ is ydrogen, with a lower alkyl lithium, yielding a compound of formula I wherein ^ is lower alkyl, or \ wherein B, R.^, R^, R-^ and R^ have the meaning indicated above, into a compound of formula I by oxidation of the ©c-meth lene group in the 7-position, preferably by treatment with a eerie salt, or e) lower alkylating a compound of formula I wherein R^ is hydrogen, yielding a compound of formula I wherein R is lower alkyl, or f ) oxidizing a compound of formula I wherein B is methylene into the corresponding compound of formula I wherein B is ca bon l.

2. Process as claimed in Claim 1, wherein a compound of formula II wherein R^ is hydrogen is subjected to process step a) defined in Claim 1.

3. Process as claimed in Claim 1, wherein a compound of formula III wherein B is carbonyl and R≥ is hydrogen or halogen in the 2' -position is subjected to process step b)

4. Process as claimed in Claim 1, wherein a compound of formula IV wherein R2 is hydrogen or halogen in the 21 -position is subjected to process step c) defined in Claim 1, 5· Process as claimed in Claim 1, wherein a compound of formula V wherein B is carbonyl and is hydrogen or halogen in the 2' -position is subjected to process step d) defined in Claim 1.

6. Process as claimed in Claim 1, wherein a compound of formula I wherein and are hydrogen are N-^-lower alkylated.

7. Process as claimed in Claim 1, wherein a compound of formula I wherein B is methylene and is hydrogen is oxidized.

8. A process as claimed in Claim 1 or 5 wherein the eerie salt utilized is eerie ammonium nitrate, eerie nitrate or eerie sulfate.

9. A process as claimed in any one of Claims 1 to 7 wherein R^ is hydrogen.

10. A process as claimed in any one of Claims 1 to 9 wherein R≥ is halogen and is joined in the 2-position of the 5-Phenyl ring. fluorine.

12. A process as claimed in any one of Claims 1 to 11 wherein Rn is hydrogen.

13. A process as claimed in any one of Claims 1 to 11 wherein is methyl.

14. A process as claimed in any one of Claims 1 to 1 > wherein R-, is methyl. 15· A process as claimed in any one of Claims 1 to 14 wherein 7-acetyl-2, 3-dihydro-l-methyl-5-phenyl-lH-l,4-benzo-diazepine is prepared.

16. A process as claimed in any one of Claims 1 to 14 wherein 7-acetyl-l, 3-dihydro-l-methyl-5-phenyl-2H-l, 4-benzo-diazepin-2-one is prepared.

17. A process as claimed in any one of Claims 1 to 14 wherein 7-acetyl-l, 3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one is prepared.

18. A process as claimed in any one of Claims 1 to 14 wherein 7- cety 1-1 , J-dihydro-5- (2-fluoropheny 1 ) -2H-1 , 4-benzo-diazepin-2-one is prepared. as claimed in Claim 1

19. Process/for the preparation of benzodiazepine with reference to the foregoing Examples.

20. Process for the manufacture of preparations having anticonvulsant, muscle relaxant and sedative properties, characterized in that a benzodiazepine derivative of formula I herein defined is mixed, as active substance, with nontoxic, inert, therapeutically compatible solid or liquid carriers, commonly used in such preparations, and/or excipients.

21. Compositions having anticonvulsant, muscle relaxant and sedative properties, containing a benzodiazepine derivative of formula I herein defined and a carrier.

22. Benzodiazepine derivatives of the general formula wherein B represents methylene (-CHg-) or carbonyl {-$-) R1 represents hydrogen or lower alkylj R≥ represents hydrogen,of halogen and R^ and R^ represent hydrogen or lower alkyl, whenever prepared by the process of Claim 1, 8 or 19 or by an obvious chemical equivalent thereof. 2jJ. Benzodiazepine derivatives of formula I in Claim 22 wherein R^ is hydrogen, whenever prepared by the process of Claim 2 or by an obvious chemical equivalent thereof.

24. Benzodiazepine derivatives of formula I in Claim 22 wherein B is carbonyl and R2 is hydrogen or halogen in the 2 '-position, whenever prepared by the process of Claim 3 or by an obvious chemical equivalent thereof.

25. Benzodiazepine derivatives of formula I in Claim 22 wherein Rg is hydrogen or halogen in the 2' -position, whenever prepared by the process of Claim or by an obvious

26. Benzodiazepine derivatives of formula I in Claim 22 wherein B is carbonyl and R2 is hydrogen or halogen in the 2 ' -position, whenever prepared by the process of Claim 5 or 8 or by an obvious chemical equivalent thereof.

27. Benzodiazepine derivatives of formula I in Claim 22 wherein is hydrogen and is lower alkyl, whenever prepared by the process of Claim 6 or by an obvious chemical equivalent thereof.

28. Benzodiazepine derivatives of formula I in Claim 22 wherein B is carbonyl and R^ is hydrogen, whenever prepared by the process of Claim 7 or by an obvious chemical equivalent thereof.

29. Benzodiazepine derivatives of formula I in Claim 22 wherein R^ is hydrogen, whenever prepared by the process of Claim 9 or by an obvious chemical equivalent thereof. JO. Benzodiazepine derivatives of formula I in Claim 22 wherein R2 is halogen and is joined in the 2-position of the 5-phenyl ring, whenever prepared by the process of Claim 10 or by an obvious chemical equivalent thereof.

1. Benzodiazepine derivatives as claimed in Claim 0 wherein R^ Is fluorine, whenever prepared by the process of Claim 11 or by an obvious chemical equivalent thereof.

32. Benzodiazepine derivatives of formula I in Claim 22 wherein is hydrogen, whenever prepared by the process of Claim 12 or by an obvious chemical equivalent thereof. 33· Benzodiazepine derivatives of formula I in Claim 22 wherein is methyl, whenever prepared by the process of Claim 13 or by an obvious chemical equivalent thereof. 3^ . Benzodiazepine derivatives of formula I in Claim 22 wherein is methyl, whenever prepared by the process of Claim 14 or by an obvious chemical equivalent thereof. 35 · 7-Acetyl-2, 3-dihydro-l-methyl-5-pnenyl-lH-l, 4-benzo diazepine whenever prepared by the process of Claim 15 or by an obvious chemical equivalent thereof.

36. 7-Acetyl-l, 3-dihydro-l-methyl-5-phenyl-2H-l, 4-benzo diazepine-2-one, whenever prepared by the process of Claim l6 or by an obvious chemical equivalent thereof. 37 · 7-Acetyl-l, 3-dihydro-5-phenyl-2H-l, -benzodiazepin-2-one, whenever prepared by the process of Claim 17 or by an obvious chemical equivalent thereof.

38. 7-Acetyl-l, 3-dihydro-5-(2-fluorophenyl)-2H-l, -benz diazepin-2-one, whenever prepared by the process of Claim l8 or by an obvious chemical equivalent thereof.

39. Benzodiazepine derivatives of the general formula wherein B represents methylene (-CH2-) or carbonyl (-$-); represents hydrogen or lower alkyl; R2 represents hydrogen. or halogen and and R^ represent hydrogen or lower alkyl.

40. Benzodiazepine derivatives of formula I in Claim 3 wherein R^ is hydrogen.

41. Benzodiazepine derivatives of formula I in Claim 39 wherein Rg is halogen and is joined in the 2-position of the 5-phenyl ring.

42. Benzodiazepine derivatives as claimed in Claim 41 wherein R2 is fluorine. 4 . Benzodiazepine derivatives of formula I in Claim 39 wherein R^ is hydrogen.

44. Benzodiaze ine derivatives of formula I in Claim 54816/2

5. Benzodiazepine derivatives of formula I in Claim 59 wherein R, is methyl. . 46. 7-Acetyl-2,5-dihydro-l-methyl-5-phenyl-.lH-l,4-benzodiazepine.

47. 7-Acetyl-l,5-dihydro-l-methyl-5-phenyl-2H-l,4-benzo-diazepine-2-one .

48. 7-Acetyl-1 -dihydro-5-phenyl-2H-l,4-beriz diazepin- 2-one.

49. 7-Acetyl-l,5-dihydro-5-(2-fluorophenyl)-2H-l,4 benzodiazepin-2-one . /I. For the Applicants DR. REINHOLD COM AND PARTNERS By I