IL38420A - 7-(1-hydroxyalkyl)-5-phenyl-1,4-benzodiazepine derivatives,their preparation and pharmaceutical compositions containing them - Google Patents

Description

38420/2 ηικ o^'aon nmpin 7-(l-Bgrroxyailcyl)-5-phenyl^l,4- benaodiaaepine derivatives, their preparation and pharmaceutical compositions containing them SPARAMEDICA AG C:36526 4008/180 k The present invention relates to benzodiazepine deriva' of the general formula wherein B represents methylene (-CIL,-) or carbonyl- (-CO-); ^, It,, and represent hydrogen or lower alkyl, R,_ represents hydrogen or halogen and Rg and R,-, represent hydrogen or taken together an additional C-N- bond, and pharmaceutically acceptable acid addition salts thereof.

As used herein the term "lower alkyl" connotes both straight and branched chain hydrocarbon groups with 1-6, preferably 1-4, carbon atoms such as methyl, ethyl, propyl, iso-propyl, butyl, pentyl, hexyl and the like. The term "halogen" connotes the four forms fluorine, chlorine, bromine and iodine, unless otherwise specified.

Preferred compounds are those wherein R-. is halogen, pre y lhen R is other than hydrogen, it is preferably joined to the 5-phenyl ring at the 2-position thereof. is preferably hydrogen. The most preferred member of the lower alkyl grouping recited therein is the lower alkyl grouping methyl. Thus, as is evi-dent from the above, in formula I R^,' Rg and are all preferentially hydrogen or methyl, R^ is preferentially hydrogen and R^ is preferentially hydrogen or fluorine and when fluorine is joined to the 5-phenyl ring at the 2-position thereof. Most preferred is a compound of the formula I above wherein ^ is hydrogen, ^ is methyl, R^ is hydrogen or methyl, ^ is hydrogen and R-. is fluorine. Also preferred are compounds wherein B is carbonyl.

In accordance with the present invention compounds of the formula I and pharmaceutically acceptable acid additions salts thereof can be prepared b a process which comprises'. a) for preparing compounds of the formula I wherein ^ represents hydrogen reducing a compound of the general formula b) for preparing compounds of the formula I wherein represents lower alkyl with the proviso that when B is carbonyl . is hydrogen, treating a compound of the formula II above with the proviso that when B is carbonyl, is hydrogen, with a lower alkyl lithium compound, or c) for preparing compounds of the formula I wherein B represents carbonyl and Rg and R^ taken together represent an additional C-N-bond cyclizing a compound of the general formula. wherein R1 , R» , R, , R . and R^. are as above , or d) for preparing compounds of the formula I wherein R^ represents lower alkyl appropriately 1-alkylating a compound of the general formula la wherein B, R, , R0, R, , R--, Rr and R7 are as above, e) for preparing compounds of the formula I wherein Rg and R7 taken together represent an additional C-N-bond oxidizing a compound of the general formula wherein B, R, , R , R, , R. and R^ are as above, or f) for preparing compounds of the formula lb above reducing a compound of the general formula Ic or g) for preparing compounds of the formula I wherein B represents methylene and R, and R„ represent hydrogen reducing b. I a compound of the general formula wherein R_ , R~ , R, , R . and R^ are as above and h) if desired, converting a compound obtained into a pharmaceutically acceptable acid addition salt.

A compound of the formula I above wherein R^ is hydrogen can be prepared by treating a compound of the formula II above with a mild reducing agent such as a metal borohydride. Representative of metal borohydride usable for this purpose include, preferentially, alkali metal borohydrides such as sodium boro-hydride, potassium borohydride and the like. Alkaline earth metal borohydrides such as, magnesium borohydride can also be efficaciously utilized. By the use of a mild reductant such as posi ion-7 of the compound of the formula I occurs without substantially effecting the other reducible moieties present in the molecule under the reaction conditions employed.

The reduction with metal borohydride preferably proceeds in an inert organic solvent. Among the many inert organic solvents that may be advantageously utilized, there can be included lower alkanols such as methanol, ethanol, propanol and the like, ethers such as tetrahydrofuran and the like, dimethylsulfoxide, dimethylfonaamide and/or any other suitable inert organic solvent.. Preferably, the reduction is effected at a temperature from about -20° to about 80°. In the most preferred process aspect, this reduction is effected at about a temperature range of from about 0°C. to about 25°C, most preferably at about room temperature.

Compounds of the formula I above wherein R^ is hydrogen and Rg and represent hydrogen can also be prepared directly from a compound of the formula II above wherein Rg and ^ taken together represent an 'additional C-N-bond by catalytic reduction, preferably using platinum as catalyst. In this manner, the R2-CO grouping and the 4,5-double bond in the formula II above are, grouping and the radical compound of the formula I is obtained. Suitably about two mole equivalents of platinum are employed in this reduction step.

Conveniently, the reduction is effected in the presence of an suitable inert or anic solvent. Amon the man solvents and the like, ethers such as diethylether and tetrahydrofuran and similar solvents .Temperature is not critical to a successful performance of the reduction step and so the reduction can be conducted at room temperature or above or below room temperature.

Compounds of the formula II above wherein is hydrogen and B is C=0 or when is hydrogen or lower alkyl and B is CEL, can be treated with. a lower alkyl lithium (R^ Li) in the manner described more fully hereinafter to obtain a corresponding compound of the formula I wherein is lower alkyl. The most advantageous of the lower alkyl lithiums for the purposes of the present invention is methyl lithium. However, other lower alkyl lithiums can also be utilized such as ethyl lithium, propyl lithium, butyl lithium, pentyl lithium, and the like.

In a preferred embodiment, the reaction utilizing a lower alkyl lithium is carried out in the presence of an inert solvent. It will be appreciated that the use of such type solvent will ordinarily allow the reaction to proceed in a relatively simple manner, thereby avoiding the use of extraordinary conditions, extensive equipment and the like. Inert solvents capable of functioning efficaciously in this process step include benzene, e ralrydrofuran, dioxane and the like or any other appropriate inert solvent. Suitably, the reaction proceeds at temperatures much below room temperature. A preferred reaction temperature range is from about -100° to about 0°, most preferably between -80° to -50°.

A com ound of the formula III above either in crude corresponding compound of the formula I by dissolving the compound of the formula III in an inert organic solvent such as a lower alkanol, for example, methanol, ethanol and the like and by permitting the resultant solution to stand. The cyclisation can be accelerated by heating.

Compounds of the formula I above wherein ^ is hydrogen, i.e. compounds of the formula la, above, can be converted into the corresponding compounds wherein is lower alkyl be first forming the sodio derivative of a compound of the formula la above with an alkali metal alkoxide, e.g., sodium methoxide, potassium .t-butoxide and the like or an alkali metal hydride, such as sodium hydride and the like and treating the said sodio derivative with an alkylating agent such as a lower alkyl halide, e.g., methyl iodide or ethyl iodide, a dilower alkyl sulfate, such as dimethylsulfate and the like whereby alk lation of the nitrogen atom in the 1-posi ion of the benzodiasepine of the formula la results.

Compounds of the formula lb above can be converted into the corresponding compound of the formula I above wherein R^ and taken together resprent an additional C- -bond, i.e. compounds of the formula Ic above, by treating the compound of the formula lb above with any suitable oxidising system capable of causing selective oxidation whereby the double bond at the ,5-position of the compound of the formula Ic above results.

L preferred oxidizing agent for the purpose of this solvent such as aromatic hydrocarbons, e.g. benzene, toluene and the like, halogenated hydrocarbons, e.g. carbon tetrachloride ethers, e.g. dioxane, tetrahydrofuran and the like, and advantageously at a temperature between about room temperature and the reflux temperature of the solvent.

Compounds of the formula Ic can be converted into the corresponding compounds of the formula lb above by reducing the former by any conveniently available technique. For example, the reduction of a compound of the formula Ic above to a compound of the formula lb above can be effected catalytically by hydrogenation in the presence of a platinum catalyst. Also, the reduction can be effected utilizing Raney nickel.

Conveniently, the reduction is effected in the presence of any suitable inert organic solvent. Among the many solvents there can be included lower alkanols such as methanol, ethanol and the like, ethers such as diethyl ether and tetrahydrofuran and similar solvents. Temperature is not critical to a successful performance of the reduction step and so the reduction can be conducted at room temperature or above or below room temperature.

Compounds of the formula Id above can be converted into the corresponding compounds of the formula I above, wherein B represents methylene and Rg and R^ represent hydrogen, by treating the compound of the formula Id with lithium aluminum hydride. Conveniently ,the treatment is effected in the presence of an inert organic solvent such as ethers, e.g. tetrahydrofuran, and the like and under anhydrous conditions. Preferably, this should he noted that the treatment of the compounds of the formula Id with lithium aluminum hydride yields a mixture of the corresponding ethylenic tetrahydro and dihydro compounds, i.e. a mixture of compounds of formula I with B "being CH^ where in Rg and are hydrogen and taken together represent an additional C-N-bond, respectively. It has "been found that the application of heat or the presence of a substituent in the 1-position favors the formation of the corresponding ethylenic tetrahydro compounds.

Compounds of the formula II can be obtained by a wide, variety of procedures. Λ process for the preparation of compounds of formula II wherein B is carbonyl and R-. is hydrogen or halogen in the ortho position is illustrated diagrammatically in the following flow sheet. In the reaction schemes depicted in this flow sheet, R^, ^, ^ and ^. are as described above. Rg and ^ represent a moiety capable of being removed by hydrolyzation and X signifies a group that can be transformed into an amino group, for example, an azido group or a phthalimido group, or alternatively, a leaving group, for example, halogen such as chloro, bromo or iodo, alkyl- or arylsulfonyloxy groups, i.e., mesyloxy, benzenesulfonyloxy and tosyloxy.

Compounds of the formula IV above can be prepared in the manner set forth in Gisvold et al. , J, Pharm. Sci, 7, 784 (1968).

In the first process step, depicted in the Plow Sheet a compound of the formula IV is reacted with a compound of the formula V to yield a compound of the formula VI. This reaction proceeds, preferably, in the presence of an inert organic solvent. Representative of such solvents are alcohols, for example, lower alkanols such as ethanol and methanol, dimethylsulfoxide and dimethylformamide. Preferred are lower alkanols, particularly, methanol, It is essential that a base be present during this atep and any suitable base may be employed. However, an alkali metal hydroxide such as sodium hydroxide is advantageously utilized during the reaction between compounds of formula IV and V. to yield a compound of formula VI, For this reaction, it is preferable that the temperature be maintained in the range of from about room temperature to about 100°C, most preferably, from about room temperature to about 60°C. The product of the formula VI need not be isolated prior to conversion to a compound of the formula VII, but, in a preferred aspect, it is preferably isolated from the reaction mass.

In the second process step, depicted in the Plo Sheet i.e., the formation of a compound of the formula VII from a compound of the formula VI above, a compound of the formula VI is hydrogenated catalytically. Catalysts suitable for this purpose include palladium on carbon, platinum, nickel, and cobalt, with f y presence of any suitable inert organic solvent medium.

Representative of such inert organic solvent mediums are tetra-bydrofuran, dimethylformamide, and lower alkanols such as, methyl alcohol, ethyl alcohol and the like. It is preferable when proceeding from a compound of the formula VI to a compound of the formula VII, that the reaction be ended when the theoretical amount of hydrogen is absorbed. If the amount of hydrogen employed exceeds the theoretical amount, it is conceivable that competing side reactions can occur. Hence, in order to avoid this event and assure the highest yields possible, the preference to the use of theoretical amounts of hydrogen should become quite clear.

A compound of the formula VII above can be converted int the corresponding compound of the formula X above by a wide variety of preparative techniques.

For example, as shown in the Plow Sheet, a compound of the formula VII can be treated with a compound of the formula acetic anhydride, mesyloxyacetic anhydride, tosyloxyacetic anhydride and benzene sulfonylacetic anhydride.

Suitable halo-lower alkanoyl halides, i.e., wherein Y chloride and the like. Prom the above, it should be evident that the halogen moieties of the above-identified halo-lower alkanoyl halide compound or the above-mentioned anhydrides are preferably selected from the group consisting of chlorine and bromine. It is advantageous that his step in the reaction sequence 13 effected in the presence of an acid acceptor, such as an inorganic or organic base. Suitably, bases which contain hydroxide ions such as an alkali hydroxide, e.g., sodium hydroxide, potassium hydroxide, can be used. Other bases are illustrated by sodium carbonate, trlethylamine, pyridine and the like. i 4 Representative of compounds of the formula Y-CH-CO-halide wherein Y is a lower alkyl sulfonyloxy or aryl-sulfonyl-oxy group are mesyloxyacetyl chloride and tosyloxyacetyl chloride.

Suitably this ..process aspect, i.e., the preparation of a compound of the formula VIII wherein X is halogen, a lower alkyl sulfonyloxy or an aryl-sulfonyloxy group, is effected in the presence of an inert organic solvent such as benzene, ether, methylene chloride and the like. Temperature and pressure are not critical to a successful performance of this process step. However, in a preferred aspect, this step is conducted below room temperature, e.g., at a temperature from about 0° to about 20°C.

It is important to bear in mind in the performance of this process propensity t should be avoided along the. reaction path in accordance with good scientific practices.

Following preparation of the compounds of formula VIII wherein X is halogen,., a lower alky1 sulfonyloxy or an aryl-sulfonyloxy group, the so-obtained compound may be treated with ammonia and the resulting compound of the formula IX cy-clized to the corresponding l,4-benzodiazepin-2-one of the formula X.

The compound of the formula IX need not be isolated prior to cyclizin same but the ring closure thereof to the compound of the formula X can be effected in the reaction medium in which the compound of the formula IX.was prepared, without isolating same, or interrupting the reaction sequence before the desired compound of the formula X is obtained, For example, the haloacylamido compound of the formula VIII above or a tosyloxyacylamido compound of the formula VIII above or a mesyloxyacylamido compound of the formula VIII above can be placed in a lower alkanol solution of ammonia such as ethanolic ammonia or methanolic animonia and, subsequently, after a period of serveral hours, for example, overnight , the corresponding l,4-benzodiazepin-2-one represented by the formula X (e.g., wherein Rg and together represent an ethylene group, a 7-(2-P.2-l,3-dioxolan-2-yl)benzodiazepin-2-one) can be recovered. The cyclization can be accelerated by heating.

In another embodiment, in lieu of methanolic ammonia, the in an inert organic solvent such as methylene chloride, carbon tetrachloride, ethers such as tetrahydrofuran, dioxane and ethyl' ether, dimethylsulfoxide, dimethyIforma ide and the like and e resultant solutio can be treated with liquid ammonia whereby a compound of the formula IX results. The so-obtained compound of the formula IX, either in crude or a more purified form, can be added to an inert organic solvent such as a lower alkan-ol, e.g., methanol, ethanol and the like. By permitting the resultant solution to stand and/or by the application of heat, cyclization to the corresponding compound of the formula X occurs.

In another preparative approach, compounds of the formula VIII above wherein X is halogen other than iodine and bromine or lower alkylsulfonyloxy or aryl-sulfonyloxy can be converted into the corresponding compound of the formula VIII above wherein X is iodo. This is particularly efficacious when X is other than iodine or bromine. Suitably,, this can be effected by treating the compound of the formula VIII above wherein X is halogen other than iodine or bromine, or lower alkylsulfonyloxy or aryl-sulfonyloxy with an alkali metal iodide in an inert organic solvent. While sodium iodide is illustrated as the pre^ ferred iodine providing agent, it is, of course, to be understood that other suitable agents would be readily recognized by those skilled in the art as usable for this purpose. Preferably, the iodo compound is then treated with ammonia in the manner described above to obtain the desired compound of the formula X ab ve In a further process aspect, compounds of the formula VIII above wherein X is a phthaliraido group can "be obtained by treating a compomd of the formula VII above with a compound of the formula wher halogen, in the pres ensation is carried out in a suitable inert solvent such as a halogenated hydrocarbon, e.g., chloroform and methylene chloride pyridine and the like. It is preferred to effect this reaction at room temperature.

A compound of the formula VIII above wherein X. is phthalimido can also be obtained by treating the corresponding compound of the formula VIII wherein X is halogen, lower alkyl sulfonylo:cy and aryl sulfonyloxy, in a preferred aspect with an alkali metal salt of phthaliinide (phthalimide potassium) .

The so-obtained compound of the formula VIII above wherein X is phthalimido can be converted into the corresponding compound of the formula IX by treating the former with hydrazine solvent. Preferably, one or more molar equivalents of hydrazine hydrate is present in the reaction zone for every one molar equivalent of a compound of the .formula VIII wherein X is' phthali-mido. Temperature and pressure are not critical to a successful performance of this process step. However, elevated temperature is preferred. Also, for good yields it has been found that the reaction should be conducted in an inert organic solvent such as a lower alkanol, e.g., ethanol. In proceeding accordingly, the compound of the formula IX is obtained and it can be converted directly to the corresponding compound of the formula X without isolation of the said compound of the formula IX or interrupting the reaction before the desired benzodiazepin-2-one of the formula X is obtained.

In an alternate process step, a compound of the formula VIII above wherein X is halogen, a lower alky1 sulfonyloxy or an aryl sulfonyloxy group is treated with an azido-introducing reagent. Representative of azide group-providing agents are alkali metal azides such as sodium azide, potassium azide, D.ithium azide and alkaline earth metal azides such as calcium azide, ammonia azide and the like. Preferred io sodium azide whereby to obtain the corresponding azide of the formula VIII compound. In this process step, a compound of the formula VIII is added to an appropriate organic solvent such as an alkanol, e.g., methanol, an ether. such as dioxane and tetrahydrofuran and the like. The resultant solution is then gently heated whereby to obtain the azide compound. The so-obtained compound is then noble metal catalysts such, as palladium, platinum, and the like, whereby to obtain the corresponding compound of the formula IX, The catalytic hydrogenation is suitably effected in the presence of an inert organic solvent such as an ether, e.g., tetrahydro-furan. In a preferred aspect the resulting compound of the formula IX is dissolved, without isolation from the reactio medium in which it is prepared, in an appropriate inert organic solvent such as ethanol, methanol and the like, and then cycli-zed to the corresponding compound of the formula X as described above.

In still another alternative process embodiment, the azide of the compound of formula VIII can be prepared directly from a compound of the formula VII by reacting such compound g., azidoacetyl chloride) at a temperature from about 10°C to about 50°C in the presence of an inert organic solvent such as chloroform.

Compounds of the formula VIII or of the formula X above can be converted into the corresponding compounds bearing an N-lower alkyl substituent by any suitable technique, Por example, compounds of the formula VIII or X can be treated with an alkali netal hydride, e.g., sodium hydride, or potassium t-butoxide and the like to form the corresponding !T-alkali metal salt. The resulting alkali metal salt derivative can be thereafter treated with an alkylating agent suchas methyl halide, e.g., methyl iodide, ethyl iodide, propyl iodide and the like or a dilower alkyl sulfate, e.g., dimethyl sulfate or diethylsulfate to form pound of the formula XI ' hearing a lower alkyl substituent in the 1-position in the manner disclosed above for the corresponding IT-unsubstituted compounds.

Compounds of the formula XI can he reduced catalytically to the corresponding tetrahydro derivative thereof of the formula XII above, with a suitable reducing 3ystem, e.g., hydro-genation in the presence of platinum, Raney nickel and the like. Suitably, this reaction is effected in the presence of an inert organic solvent such as alkanols, e.g. ethanol, methanol and the like, ethers such as diethyl ether, tetrahydrofura nd the like in accordance with usual procedures.

Compounds of the formula XI and XII above are converted readily into the corresponding compounds of the formula II above by any suitable readily available hydrolyzing technique conducted at a pH of below 7. As indicated above, RQ and R^ represent a jr readily removable moiety capable of being removed by suitable hydrolyzing techniques. Preferably, Rg and individually signify lower alkyl and when taken together connote a -CK^CK^ -grouping or a -CH2CH2CH2- ro pi . It is of course to be recognized that the character of the groups designated by R^ and ^ is not critical to the successful performance of the instant process as long as they can be readily hydrolyzed. R0 and Rn com- o y bine to function as a protecting group, and insure the preparation of the compounds of the. formula II above in high yields. Most preferred for the purposes of the present invention is the grouping when RQ and ^ represent together -CH2CH2-, i.e., the A compound of the formula XI or XII can he dissolved, in an r.queous medium such as an aqueous lower alkanoic acid, an aqueous lower alkanol medium, e.g., aqueous methanol, aqueous ethanol and the like. By heating the so-obtained medium at a temperature of from 40 to 100° the respective conversion of. a compound of the formula. I or XII into the corresponding compound of the formula II may he' suitably effected.

In the most preferred embodiment , the hydrolysis of the compound of the formula XI or XII to the corresponding compound of the formula II is effected by simple solution in aqueous mineral acid. Inert organic solvents such as dimethylformamide, lower alkanols such as methanol, dimeth lsulfoxide, ethers such as tetrahydrofuran and dioxane may be added as solubilizing agents. Temperature and pressure are not critical to a successful performance of this process step, but it is preferred to effect the reaction at a temperature range from about -10° to about 100°, most preferably, at about 10 to 30°, most advante- ously at about room temperature. Suitably, in a most preferred embodiment as is noted above, the hydrolysis is effected in an aqueous solution of an acid, preferably a 3N to 12ϊΓ acid. The acid agent can be provided by any suitable conveniently available technique such as the addition of the acid agent to a medium containing a compound of the formula XI or XII. Acid agents can be represented by mineral acids such as nitric acid, h drochloric acid, aqueous hydrobromic acid, sulfuric acid and the like or an organic acid such as sulfonic acids, e.g., toluenesul- as oxalic acid. The particular acid agent utilized is not critical and can be selected by the artisan from the many he will readily recognize are suitable for the purposes of the present invention.

Alternatively, the compounds of the formula II wherein and R^ taken together represent an additional C-N-bond can be prepared according to the following reaction scheme. In this reaction scheme, I^, ^, R^, and X have the meaning indicated above and P represents any suitable nitrogen protecting system vrtaich is removable by hydrolyzation procedures* In the first stage of this process aspect a p-lower alkyl aniline or a. H-lower alk l derivative thereof is reacted with a benzoyl halide or a halo-benzoyl halide in the presence of a catalyst sich as zinc chloride whereby to obtain a compound of 5 the formula 3VI.

Preferred benzoyl groups include 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 Q temperatures. It is especially preferred to conduct the reaction at a temperature of above about 130°C. The reaction should be performed in an anhydrous medium. Thus, it can be conducted in1 the absence of any solvent outside of the reactants themselves or alternatively, it can be conducted in the presence of an _5 inert organic solvent suc¾ as benzene and the like. Suitably, the reaction is effected utilizing the benzoyl halide as the reaction medium..

In the second process step the so-obtained compound of formula XVI above is converted into the corresponding compound 0 of formula XVII bearing a suitable nitrogen protecting group at the aniline nitrogen. This group functions to prevent the nitrogen atom on the 2-araino 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 5 provided by acetic anhydride, acetyl chloride and the like.

However, the literature describes a multitude of nitrogen protectin rou s which would be readil reco nizable b the ar an this reaction, is effected in the presence of an inert organic solvent such as benzene, ether, a halogenated hydrocarbon such as methylene chloride and the like. Temperature and pressure are not critical to a. successful performance of this process step. Thus, the reaction can be effected at room temperature or at elevated temperatures. However, in a preferred aspect, the reaction is conducted under reflux conditions.

In the third process step a compound of the formula XVII wherein is lower alkyi 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 allcyl moiety in the 5-position into a lower alkoiaoyl moiety ca also bo 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 4 moles of permanganate in the reaction medium. The reaction is effected at a temperature of from about 0° to about 80°, 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. VJhile potassium permanganate is described as being the prepferred oxidizing reagent, it is, of course to be understood that other erman anates such as with equal efficaciousness for the purposes of the present invention.

Alternatively a compound of the formula XVIII can be obtained by oxidizing a compound of the formula XVII with a eerie salt. Preferably the compound of formula XVII 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 C^-C^ 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 required of the inert organic solvent utilized is that the eerie ions formed be stable therein and also that both the eerie salt and the starting material of the formula XVII 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 this process aspect, may be represented by ceric ammonium nitrate, ceric nitrate, ceric sulfate or an other suitable ceric salt.

While temperature is not critical to a successful performance of this process aspect, it is preferred to perform the reaction at a temperature range of from between about 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 hence, the particular manner of carrying out the reaction is largely a matter of convenience.

In this connection it should be noted that 5-foriayl-derivatives of the formula XVill can only be obtained by the above eerie salt method.

In the fourth stage a compound of the formula XVIII is subjected to hydrolyzing conditions wherein to obtain a 2-amino-group containing compound. Standard hydrolyzation procedures can be ised, e.g. , water miscible solvents such as dioxane, tetrahydrofuran, ethanol and the like in the presence of an acid such as hydrochloric acid or a base such as an alkali metal hydroxide (preferably sodium hydroxide) . Λ compound of the formula XIX above can be converted into the corresponding compound of the formula lie above wherein B is carbonyl via the reaction of the formula XIX compound with a compound of the formula halo-CO CH-Y I wherein and Y have the meaning indicated above in the same manner as described above in connection with the conversion of a compound of the formula VII into a compound of the formula .

In a further process aspect, compounds of the formula XX wherein B is carbonyl and X is a carbobenzoxy amino grouping can be obtained by reacting a compound of the formula XIX above with carbobenzoxy-glycine anhydride and carbobenzoxy-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 carbobenzoxy-glycine with a compound of the formula XIX above in the presence of an Ν,Ν'-disubstituted car-bodiimide. The reaction can, for example, be carried out at a temperature between about 0°C and about 50°G,preferabljr at a temperature slightly below room temperature. Advantageously, a solvent is present- during. he .reaction. Among the solvents which can be used for this purpose, there can be included organic solvents, such as methylene chloride, chloroform, dioxane, tetra-hydrofuran, dimethylformamide, acetonitrile and the like, as well as water and mixtures of the above.

The so-obtained compound of the formula XX above wherein X is carbobenzoxyamino (e.g., a carbobenzoxy-glycyl-amino-5-acetylbenzophenone) can be converted into the corresponding compound of the formula XXI 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 yield a compound of the formula XXI. Preferably, there is used as the hydrohalic acid, in this process step, hydrobromic acid. However, other hydrohalic acids such as hydrochloric acid can also be used. The reaction can be performed either in aqueous or anhydrous media. It .can be conducted at room temperature or tempera 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 H which comprises the steps of treating a 2-carbobenzoxy-glycyl-aminobenaophenone. with hydrohalic acid, 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 XX wherein X is carbobenzoxy-amino can be directly, converted ;into compounds of the formula I without isolating an intermediate of the formula XXI. As the alkalizing agent, either strong or weak bases can be used, for example, ammonia,' sodium carbonate, alkali metal hydroxides such as potassium hydroxide , sodium hydroxide and the like.

Compounds of formula XXI wherein B is methylene can be obtained by treatment of the benzophenone of formula XIX with' an ethylene dihalide and subsequently, with ammonia in analogy to the process described above with respect to the corresponding compounds of formula IX.

Furthermore, benaophenones of the formula XIX above can be reacted with a phthalimidoethyl halide to produce the corresponding 2-(phthalimidoethylamino)-benzophenone which in turn is treated with' ydrazine hydrate yielding a compound of formula XXI wherein B is methylene.

Still a further. method consists in reacting a compound of formula XIX above with a benzamidoethyl halide and treating the results in an intermediate product of the formula.

XXIII wherein X .represents -ΟΙΐ^ or; -MICOM2 and 3, R^, R^f R^, and have the meaning indicated ahove.

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 II.

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 in a preferred embodiment involves conversion of a compound of the formula XXII above by diazotization into the diazonium salt thereof, treating the resulting diazonium salt with acetaldehyde semicarbazone, preferably in the presence of cupric sulfate, and then hydrolizing the resulting product with a dilute acid.

Compounds of the formula He wherein B is methylene can be converted into corresponding ketals, e.g. by treatment with hydrolyzation the corresponding compotmds of formula II wherein 13 is methylene and and II,-, represent hydrogen can "be obtained.

A compound of the formula III above can be prepared via wherein '-R- is as above yielding a compound of .the formula XXV preparation of a compound of the formula VI.

Compounds of the formula XXV -above are converted readily' into the corresponding compounds of the formula \ wherein and are as above, in the same manner as. described above in connection with the conversion of a compound of the formula XI or XII into the corresponding compound of the formula II, Compounds of the formula XXVI above can be converted into the corresponding compound of the formula XXVII wherein an<3- are as above, XXVIII wherein ^, li^ and are as above, by the treatment of a compound of the formula XXVI above with an R^.Li wherein ^ is as above. The treatment of a compound of the formula XXVI with an alkali metal borohydride or an ^ Li is effected in the same manner as described above in connection with the conversion of a compound of the formula II into the corresponding compound of the formula I.

A compound of the formula XXVII or XXVIil above can converted into the corresponding compound of the general formula wherein ^, ^ and R^ are as above, in the same manner as described, above in connection with the A compound of the formula XXIX above can "be treated with a . compound of the formula T-CH-CO-halide (halide preferably representing the chloride or the bromide grouping) or the corresponding anhydride of the formula wherein Y ' is halogen or any other suitable leaving group such as lower alk lsulfonylox , e.g., mesyloxy or a. phenyl sulfonyloxy group, e.g., benzene sulfonyloxy, tosyloxy and the like, whereby to obtain the corresponding compound of the formula wherein Y', R^, R4 an( ^5 are as above.

Suitable halo lower alkanoyl halides, or corresponding anhydrides are preferably represented by chloroacetyl chloride, bromoacetyl bromide, bromoacetyl chloride, bromopropionyl halogenj it is preferably selected from the group consisting of chlorine and bromine.

Representative of compounds of the formula Y'-CH-CO-halide or the corresponding anhydride thereof wherein Y* is lower alk l sulfonyloxy or a phenyl sulfonyloxy are mesyloxy acetyl chloridet tosyloxy acetyl chloride, mesyloxyacetic anhydride, tosyloxy-acetic anhydride and phenylsulfonyl acetic anhydride.

It should be noted that in order to insure the best yields of. the desired compound, no more than one or a little more than one equivalent of the acylating agent should be used. Due to the greater reactivity of the amino group, selective acylations can be achieved by proper practices well known in the art.

Suitabl this process aspect is effected in the presence of an inert organic solvent such 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 room temperature or elevated temperatures, e.g., at about the reflux temperature of the reaction mixture.

A compound of the formula XXX above can be N-alkylated in the same manner as described above in connection with the conversion of a compound of the formula X into a compound of the formula AI ound- of the formula wherein IL^, R^t ^'» an<^ ^5 are as a"bove , can be ring closed to the corresponding compound of the formula I above. The ring closure 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 above is obtained.

The compounds of the formula I above 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 suited to fit the emergen cies of a pharmacological situation. As contemplated by this invention, the novel compounds of the formula I can be embodied in- a pharmaceutical dosage formulation 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' compositions intended for oral administration). The novel compounds of this invention can be administered alone or in combination a wide variety of dosage forms. Suitably, the dosage regimen consist of four tablets of 50 mg each give daily.

In addition to compounds of the formula I above, there is also encompassed within the invention, the pharmaceutically acceptable salts of said compounds and the compounds of the formula I above can be administered in the form of such salts. The compounds of the formula I above form acid addition salts with pharmaceutically acceptable acids, for example, with orgar. or inorganic acids such as hydrochloric acid, hydrobroraic acid, sulfuric acid, phosphoric acid, nitric acid, citric acid, tarta> ric acid, salic clic acid, ascorbic acid, maleic acid, formic acid and the like.

Solid preparations of compounds of the formula I above or salts thereof for oral administration can include tablets, capsules, powders, granules, emulsions, suspensions and the lik The solid preparations may comprise an inorganic carrier, e.g. , talc, or an organic carrier, e.g., lactose, starch. Additives such as magnesium stearate (a lubricant) can also be included. Liquid preparations containing a compound of the formula I abov or salts thereof such as solutions, suspensions or emulsions ma comprise the usual diluents such as water, petroleum jelly and the like, a suspension media such as polyox ethylene glycols, vegetable oils and the like. They may also contain other additional ingredients such as preserving agents, stabilizing agents, wetting agents, salts for varying the osmotic pressure The following examples are illustrative "out not limitative of the .present invention. temperatures are stated in degrees Centigrade.

Example 1 Λ solution of 3.0 g (10.8 mmoles) of 7-acetyl-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one and 570 mg (15.0 mmoles) of sodium borohydride in 100 ml of ethanol was stirred at room temperature for 2 hours. The solution was poured into a mixture of 400 ml of water and 800 ml of methylene chloride and stirred for 15 minutes. The methylene chloride layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated to dryness.- The residue on crystallization from ether ielded 1,3-dih dro-7- (1-h droxyeth l)-5-phenyl-2H-l,4-benzodia-zepin-2-one of a light yellow solid, mp 214-216°.

The starting material may he prepared either according to method A) or B) below: Λ) To a solution of 330 g (2,0 moles) of p-nitroaceto-phenone in ;2.5 1 of benzene was added 160.0 g (2.5 moles) of ethylene glycol and 5.0 g of p-toluenesulfonic acid. The clear solution was heated to a reflux for 3 hrs . with a Dean-Stark trap until no more water separates. On coolin the cloudy benzene solution was decanted away from a small alcoholic layer d dried over anhydrous sodium sulfate. The solution was concen trated to about 11 and poured into 4 1 of hexane. Colorless flakes were collected, washed with hexane yielding 2-methyl-2-(4 nitrophenyl)-l,3-dioxolane, m.p. 71-73°.

Analytical sample was obtained as colorless flakes after To a room temperature solution of 100 g (2.5 moles) of sodium hydroxide in 500 ml of methanol was added 58.6 g (0.50 mole) of phenyl acetonitrile, followed by 104 g (0.50 mole) of 2-methyl-2-(4-nitrophenyl)-l,3-dioxolajie. The reaction temperature rose to about 55° in the first 0.5 hr of stirring. After 16. rs of vigorous stirring, 5-(2-meth l-l,3-dioxolo.n-2-yl)-3-phenyl-2,l-benzisoxazole was collected on a filter, and was washed thoroughly with water followed by small portions of cold methanol. The product was collected as a light yellow powder and was found to have a in.p. 137-138°.

A solution of 2.81 g (10 mmoles) of 5-(2-meth l-l, 3-dioxolan-2-yl)-3-phenyl-2,l-benzisoxazole in 35 ml of tetrahy-drofuran containing 200 mg of palladium on carbon was hydro-genated at 1 atmosphere and room temperature for 2 hrs. The catalyst was removed by filtration. The filtrate was evaporated to dryness. The residual oil was crystallized from benzene/ hexane to yield crude 2-amino-5-(2-methyl-l,3-dioxolan-2-yl) benzophenone as light yellow needles m.p. 97-99°.

The crude material was further purified by chromatography on 50 g of alumina (neutral oelm activity I). Elution with 20o ether/methylene chloride yielded 2-amino-5-(2-methyl~l, 3-dioxolan-2-yl)benzophenone, m.p. 112-114° as yellow prisms (methylene chloride/hexane) .

A mixture of 14.2 g (50 mmol) of 2-amino-5-(2-methy1-1,3-dioxolan-2-yl)-benzophenone, 10.4 g (50 mmol) of chloroacetic anhydride and 150 ml of benzene was kept at 5°C overnight. The dried, evaporated to dryness, and the residue was crystallized from ethanol to yield 2 '-benzoyl-2-chloro-4'-(2-meth 1-1,3-dioxolan-2-yl)acetanilide, ra.p. 131-133° as colorless needles.

In a similar manner by reacting 2-amino-5-(2-meth 1-1,3-dioxolari-2-yl)benzophenone with mesyloxyacetyl chloride, there can be obtained 2 '-benzoyl-2-mesyloxy-4 '~(2-methyl-l,3-dioxolan -2-yl)acetanilide« A.lso, in. a similar manner by reacting 2-amino-5-(2-methy1 -l,3-dioxolan-2-yl)benzophenone with tosyloxyacetyl chloride, there can be obtained 2 '-benzoyl-2-tosyloxy-4 '-(2-methy1-1,3-dioxolan-2-yl)acetanilide.

A mixture, of 2.0 g (5.6 mmol) of 2 '-benzoyl-2-Chloro-4 (2-methy1-1,3-dioxolan-2-yl)acetanilide, 1.68 g (11.2 mmole) of sodium iodide, and 100 ml of. acetone was heated to reflux for 0.5 hr. On cooling the insoluble inorganic salts were filtered. The filtrate was evaporated to dryness. The residue was then partitioned between methylene chloride and water and the organic layer was dried, evaporated to dryness and the residue obtained was crystallized from methanol to 2*-benzoyl- 2-iodo- '-(2-methyl-lj3-dioxolan-2-yl)acetanilide, m.p. 117- 119° as colorless prisms.

The prisms were dissolved in 150 ml of tetrahydrofuran. The so-obtained solution was added to a 1000 ml three-necked flask equipped with a stirrer, a dry ice condenser and containing 400 ml of liquid ammonia. The mixture was stirred under tration. The tetrahydrofuran was evaporated in vacuo. The residual oil was dissolved in 200 ml of ethanol and heated under reflux for two hours. On. cooling l,3-dihydro-7-(2-methyl- 1.3-dioxolan-2-yl)-5-phenyl-2H-l,4-benzodiazepin-2-one crystallized, m.p. 250-252° as colorless prisms. Λ solution of 161 mg (0.50 mmole) of l,3-di dro-7-(2-methyl-1, 3-dioxolan-2-yl)-5-phenyl-2H-l-, 4-benzodiazepin-2-one in 1.5 ml of 6lT hydrochloric acid was allowed to stand at room temperature for about 3 rain. The solution was dilute with 10 ml of water and neutralized to pH 7-8 with aqueous potassium hydroxide. Extraction with methylene chloride gave, after crystallization from ether, 7-acet l-l,3-dihydro-5-phenyl-2H- 1.4-benzodiazepin-2-one as colorless prisms, m.p. 192-193°.

In a similar manner as described above, l,3-dihydro-5-phenyl-7-propionyl-2H-l,4-benzodiazepin-2-one (pale yellow prisms from ether, m.p. 172-174,5°) can be prepared from 1,3-dihydro-7-(2-ethyl-l,3-dioxolan-2-yl)-5-phenyl-2H-l,4-benzodia-zepin-2-one and; 7-butyry1-1,3-dihydro-5-phenyl-2H-l,4-benzodia-zepin-2-one can be prepared from l,3-dihydro-7-(2-propyl-l,3- ': dioxolan-2-yl)-5-phenyl-2II-l,4-benzodiazepin-2-one and; 1,3- dihydro-7-pentanoyl-5-phenyl-2H-l,4-benzodiazepin-2-one (m.p. 111-112,5° from ether/pentane as pale yellow prisms) can be prepared from l,3-dihydro-7-(2-butyl-l,3-dioxolan-2-yl)-5-phenyl- 2Ii-l,4-benzodiazepin-2-one.

B) To a solution of 41.7 g (0.36 moles) of zinc chloride ° (from a beaker) with- stirring. The mixture was heated under reflux at 210-220°C for l'hour. The temperature was then lowered to 140°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 140°C and the reaction mixture was stirred and heated under reflux at 140-160°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 IT 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 lOo ether in benzene gave 2-amino-5-ethylbenzophenone as a gum (single spot on tic).

Crystallization from petroleum ether gave pale yellow plates, m. . 54-56°.

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 45 minutes.

On cooling the reaction mixture was concentrated in vacuo, to yield a semi-solid. Repeated solution in ethyl acetate After one recrystallization from ethanol, 2-acetamido^5-ethyl-benzophenone in a pale brown aiaorphous form, was obtained, m.p. 109-110.5°. Repeated recrystallization from ethanol gave colorless needles, m.p. 112-113.5°. Λ three-necked 3 liter flask was charged with 5.0 g (125 mmoles) 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-benzo-phenone 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 recrystallization3 from ethanol, 2-acetamido-5-acetylbenzophenone was obtained as colorless needles, m.p. 115-116°.

To a solution of 5.6 g (20 mmoles) of 2-acetainido-5- acetylbenzophenone in 100 ml of ethanol was added 100 ml (Θ.2 mole) of 2 N sodium hydroxide and the mixture was heated under reflux for 3 hours. On cooling, pale yellow crystals of 5- acetyl-2-aminobenzophenone precipitated. The crystals were collected and washed with ethanol. After recrystallization from benzene-petroleum ether, 5-acetyl-2-aminobenzophenone was obtained as yellow prisms, m.p. 153-154.5°C. 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 recrystallization from benzene-petroleum ether, 5-acetyl-2-(2-bromoacetamido)benzophenone was obtained as a buff colored amorphous solid, m.p. 118-120°C. A portion of this material on further recrystallization yielded red hexagonal prims.

• In a similar manner by reacting 2-3jnino-5-acetylbenzo-phenone with nesyioxyacetyH. chloride, there can be obtained 5-acet l-2-(2-raesyloxyacetamido)benzophenone.

Also, in a similar manner by reacting 2-amino-5-acetyl-benzophenone with tosyloxyacetyl chloride, there can be obtained 5-acetyl-2-(2-tosyloxyapetamido)benzophenone.

To a solution of 3.0 g (8.4 mmoles) of 5-acetyl-2-(2-bromoacetamido)benzophenone in 120 ml of methanol, was added 1.08 g (16.8 mmoles) of sodium azide in one portion. The reaction mixture was heated on a steam bath for 15 minutes. On cooling, 5-acetyl-2-(2-azidoacetamido)benzophenone precipitated as pale pink micro-prisms. Upon recrystallization from ethanol, pink microprisms were obtained, m.p. 144-145°C.

In a similar manner upon the treatment of 5-acetyl-2^-(2- tosyloxyacetamido)benzophenone or 5-acetyl-2-(2-mesyloxyacetamido) 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 etrahydrofuran was added 350 rag of ICfi palladium on carbon. The mixture was hy-drogenated at one atmosphere for 2 hour3 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,4- . benzodiazepin-2-one, precipitated as pale yellow powder, m.p. 184-186,5°.

This compound can also be obtained as follows: A solution of 2,4 g (6.8 mmoles) of 5-acet l-2-(2-bromo-acetamido)benzophenone 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-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 re,flux 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.

A solution of 2.96 g (10 mmoles) of 7-acetyl-5-(2-fluoro-phenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one and 570 mg (15.0 mmoles) of sodium borohydride in a mixture of 100 ml of ethanol and 100 ml of tetrahydrof ran was stirred at room temperature for 2 hours. The mixture was partitioned between 800 ml of water and 800 ml of methylene chloride. The methylene chloride layer was separated, washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue on crystallization from ether yielded 5-(2-fluoro-pheny1)-1,3-dihydro-7-(1-hydroxyethyl)-2H--1,4-benzodiazepin-2-o e, a light yellow solid, mp 222-224°.

The starting material may be prepared as follows: Starting with p-fluorobenzoyl chloride and p-ethylaniline, there was obtained '-fluorobenzophenone in the manner described in Example 1, method B, To a solution of 30 mmoles of 2-amino-5-acet 1-2 '-fluorobenzophenone in 100 ml of benzene was added 60 mmoles of broino-acetyj. 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 recrystsJLlization from benzene-petroleum ether, 5-acetyl-2- (2-bromoacetamido )-2 '-fluorobenzophenone was obtained.

A solution of 2.4 g(6.8 mmoles) -acet l-2-(2-bromoacet- added to 25 ml of liquid ammonia at -78°C, chilled in a dry ice-acetone bath giving 5-acetyl-2-glycylamino-2 '-fluorobenzo- phenone. 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~glycylamirio-2 '-fluorobenzophenone was dissolved in 40 ml of ethanol and heated to. reflux for 1 hour. Evaporation of ethanol and repeated recrystallization of the residue from ether-petroleum ether gave 7-acet l-l,3-dihydro- 5-(2-fluorophenyl)~2H-l,4-benzodiazepin-2-one as light yellow prisms, m.p. 211-213°.

This compound can also be obtained as follows: To a solution .'of 8.4 mmoles of 5-acetyl-2-(2-bromoacet- amido)-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-acetyl-2-(2-azidoacetamido)-2 '-fluorobeiizo- phenone precipitated, which can be converted into 7-acet l-l, »- dihydro-5-(2-fluorophenyl)-2H-l,4-"benzodiazepin-2-one in analogous manner as described in Example 1, method B.

Examples 3 A solution of 30 mg (1.7 mmole) of 7-acetyl-5-(2-fluoro-phenyl)-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2-one and 100 mg at room temperature for 2 lirs. The mixture was poured into 200 ml of water and extracted with 4 portions of 50 ml of methylene chloride. The combined methylene chloride layers were washed twice' with water, dried over anhydrous sodium sulfate, then evaporated to dryness. The residual oil crystallized from ether/pentane to yield 5-(2-fluorophenyl)-l,3-^dihydro-7-(l-hydroxyethyl)-l-methyl-2H-l,4-benzodiazepin-2-one of light yellow prisra3, m.p. 133-135°.

The starting material may he prepared as follows: To a solution of 2.96 g (10 mmoles) of 7-acet l-l, 3-di-hydro-5-(2-fliiorophenyl)-2H-l,4-henzodiazepin-2-one in 50 ml of dimeth lformamide was added 540 mg (11 mmoles) of a 5Tf° dispersion in oil of sodium hydride. The mixture was stirred in an ice bath for 15-20 minutes under nitrogen until a clear solution was obtained. To this solution was added 1.85g (0.013 moles) of methyl iodide and the mixture was kept in the refrigerator at -5° to -10°C for 15 hrs.

The reaction mixture was partitioned between water and benzene. The organic layer was dried over anhydrous sodium sulfate, then evaporated to dryness. The residual oil crystallized from methylene chloride-petroleum ether to yield a pale yellow amorphous solid, melting at 106-108.5°. After recrystallizations from the same solvent, yellow prisms of 7-Acetyl-5-(^-fluorophenyl)-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2-one were obtained; mp 117-119.5° .

Example 4 To a solution of 1.50 g (5.05 mmole) of 5-(2-fluorophenyl) -l,3-dihydro-7-(l-hydroxyethyl)-2H-l,4-benzodiazepin-2-one in' 30 ml of di ethylformaiaide chilled in an ice-bath under nitrogen, was added 255 mg (5.5 mmole) of a 57 dispersion in oil of sodium hydride. After stirring for 20 min., 850 mg (6.0 mmoles) of methyl iodide vras added and the mixture was kept at 0°0 for 15 hours. The reaction mixture was poured into 150 ml of ice water, and was extracted twice with 150 ml portions of. methylene chloride.. The combined methylene chloride layers were dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from ether/pentane to yield 5-(2-fluoro-pheny1)-1,3-dihydro-7-(1-h d oxyethyl)-1-methy1-2H-1, -benzo-diazepin-2-one, m.p. 133-135.5°.

Example 5 A solution of 2.92 g (10 mmoles) of 1, -dihydro-5-pnenyl-7-propionyl-2H-l,4-benzodiazepin-2-one and 570 mg (15 mmole) of sodium borohydride in 100 ml of ethanol was stirred at room temperature for 2 hrs. The solution was poured into a mixture of 500 ml of water and 500 ml of methylene chloride and stirred for 15 min. The methylene chloride layer was separated, washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from ether to yield 1,3-dihydro-7-(1-hydroxypropyl)-5-phenyl-2S-l, -benzodia- Example 6 A solution of 3.2 g (10 mmoles) of l, 3-dihydro-7-pentanoyl -5-phenyl-2H-l,4-benzodiazepin-2-one and 570 mg (15.0 mmole) of sodium borohydride in 100 ml of ethanol was stirred at room temperature for 2 lars. The mixture was poured into a mixture of 11 of water and 800 ml of methylene chloride and stirred for 15-20 min. The methylene chloride layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness. The oily residue crystallized from ether/pentane to yield 1, 3-di-hydro~7-(l-hydroxypentyl)~5-phenyl-2H-l,4-'enzodiazepin-2-or-e as mushroom shaped clusters of yellow solid, m.p. 172-174°.

Example 7 Λ solution of 1.92 g (6.5 mmole) of 7-acetyl-5-(2-fluoro-phenyl)^2, 3-dihydro-l-methyl-lH-l,4-benzodiazepine and 340 mg (9.0 mmole) of sodium borohydride in 60 ml of ethanol was stirred for 2 hrs. The mixture was poured into 300 ml of water, and extracted with 300 ml of methylene chloride. The methylene chloride layer was separated, dried over anhydrous sodium sulfate, and evaporated to dryness. The residual oil crystallized from ethane/pentane to yield 5-(2-fluorophenyl)-2, 3-dihydro-7-(l-hy-droxyethyl)-l-methyl-UI-l,4-benzodiazepine as light yellow prisms, m.p. 125-127°.

The starting material may be prepared as follows: A solution of 105 g (0.7 mole) of lT-methyl-N-(2-aminoethyl) chloride in 3 1 of benzene at 25°.. The mixture was then stirred under reflux for 3 hr , cooled to 15°, treated with 380 ml of 2 IT sodium hydroxide and stirred at room temperature, for 0.5 hr. The benzene layer was separated, dried over magnesium sulfate, and concentrated in vacuo. The residue was crystallized from cold hexane to give 2-fluoro-N- 2-(methylphenylamino)etl¾'-lJ benzamide, m.p. 43-48°. Recrystallization from ether/petroleum ether gave colorless prisms, m.p. 52-54°.

To a solution of 54.4 g (0.2 mole) of 2-fluoro-IT- [2-(methylphenylamino) ethyl] benzamide in 400 ml of phosphorus oxychloride was added 42.6 g (0.3 mole) of phosphorus pentoxide and the mixture was stirred and heated under reflux for 3 hr. From the solution 360 ml of phosphorus oxychloride was distilled at 63-66°/220 Torr. The residue was cooled and treated with 500 ml of methylene chloride, 400 ml of 6 N sodium hydroxide and 1 kg of ice. After standing for 1 hr. the liquid phases were separated from the solid. The solid was treated with sodium bicarbonate solution and allowed to stand for 1.5 hr. This mixture was extracted with methylene chloride.

The methylene chloride extracts were combined, dried over sodium sulfate and concentrated in vacuo to give 5-(2-fluoro-phenyl)-2,3-dihydro-l-met¾^l-lH-l,4-henzodiazepine as yellow prisms, m.p. 105-110°. Recrystallization of the product from ethyl acetate/petroleum ether gave off-white prisms, m.p. 114-117°.

A solution of 137.5 g (0.54 mole) of 5-(2-fluorophenyl) sulfuric acid vras cooled to 15° in an ice bath and treated drop-wise over a period of 0.5 to 0.7 hr. with a solution of 195 g (1.2 mole) of iodine monochloride in 500 ml of acetic acid.

This mixture was stirred in the ice hath for 1 hr after the addition was complete. The precipitated red solid was collected. Recrystallization from ethanol give3 red needles, m.p. 164-165°.

The crude red solid was suspended in 1.5 1 of methylene chloride and stirred with 1.2 1 of saturated sodium bis.ilfite solution. The mixture was cooled and the pH adjusted to S-9 with concentrated ammonium hydroxide. The organic phase was separated, dried over sodium sulfate and filtered through 1,3 kg of alumina using 3 1 of methylene chloride for wash. The filtrate was concentrated in vacuo to a thick oil which was dissolved in 1 1 of boiling hexane. The hot solution was filtered and cooled to give 5-(2-fluorophenyl)-2,3-dihydro-7-iodo-l-methyl-lH-l,4-benzodiazepine, m.p. 102-105°.

A mixture of 22.8 g (60 mmoles) of 5-(2-fluorophenyl)-2,3-dihydro-7-iodo-l-methyl-lE-l,4-benzodiazepine and 10.8 g (120 mmoles) of cuprous cyanide in 200 ml of dimeth lformamide was heated to reflux under a nitrogen atmosphere for 2 hrs. The reaction mixture, was poured, while hot, into 1000 ml of ice and water. The yellow precipitate formed was collected o --a filter, then stirred with 800 ml of methylene chloride and 800 ml of water containing 30.0 g (0.61 mole) of sodium cyanide for 2 hrs.. (until almost all solids dissolved). The methylene chloride layer was separated, washed with two portions of 500 ml of -( 2-fluorophenyl)-2 , 3-dihydro-l-methyl-lH-l, -benzodiazepine D.s colorless crystalline · needles, m.p. 155-137°.

To a solution of 2.79 g (10 moles) of 7-cyano-5-(2-fluoro-plienyl)-2,3-(iihydro-l-methyl-lIi--l,4-' enzodiasepine in 100 ml of dry tetrahydrofuran, clilled.:in a solid CO^ bath to -70°C, was added 25 ml (50 mraoles) of 2.0 I-I solution of methyl lithium in ether under a nitrogen atmosphere. The reaction mixture vras stirred at -70°C for 2 hrs , then poured into 1000 ml of 1 N lid and was stirred at room temperature for twenty minutes.

The mixture was basified to about pH 9 with 3 ST sodium hydroxide. The aqueous and tetrahydrofuran layers were separated. The aqueous layer was extracted with two portions of 250 ml of methylene chloride. The tetrahydrofuran layer was combined with the methylene chloride layers and was washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether/pentane to yield 7-acety1-5- (2-fluorophenyl)-2 , -dihydro-l-methyl- H-l, -benzo-diazepine as buff colored prisms, m.p. 112-114°.

Example 8 To a solution of 2.78 g (10 mmole) of 7-acetyl-5-phenyl -l,3-dihydro-2II-l,4-benzodiazepin-2-one in 100 ml of dry teti»a-hydrofuran chilled in a solid C02 bath to -70°C was added 30 ml (45 mmole) of 1.5 M solution of methyl lithium in ether under a nitrogen atmosphere. The reaction mixture was stirred was stirred at roora emperature for 20 minutes. The mixture w s then basified to about pH 9 with 3 H sodium hydroxide. The aqueous- and tetrahydrofuran layers were separated. The aqueous layer was extracted with two portions of 250 ml of methylene chloride. The tetrahydrofuran layer was combined with the methylene chloride layers, and was washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from ether yielding l,3-dihydro-7-(l-liydroxy-l-methylethyl)-5-phenyl-2H-l,4-benzodiazepin-2-one as light yellow amorphous powder, m.p. 227-229°.

Example 9 To a solution of 1.00 g (3.4 mmoles) of 7-acetyl-5-(2-fluorophenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one in 100 ml of dry tetrahydrofuran, chilled in a solid CO2 bath at -70°C, was added, under nitrogen, 10 ml (20 mmoles) of a 2 N solution of methyl lithium in ether. After stirring at -70°C for 90 min, the mixture was diluted with 150 ml of 1 Ή HC1, and was allowed to stir at room temperature for 20 min. The mixture was then neutralized to about pH 8 with 3 N NaOH (about 30 ml).

The aqueous and tetrahydrofuran layers were separated; the aqueous layer was extracted twice with 100 ml portions of methylene chloride,the tetrahydrofuran and methylene chloride layers were combined, washed with two 150 ml portions of water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue cr stallized from ether ieldin - 2-fluoro hen l 2-one as light yellow prisms, .in.p. 230-232°, Example 10 To a solution of 560 mg (2.0 mmole) of l,3~dihydro-7-(l-hydro^eth l rr5"-.plieBy3.--2H-l,4-benzodiazepin-2-or.e in 75 ml of tetrahydrofuran was added 200 mg of PtO, The mixture was hydrogenated at 1 atmosphere overnight (15 hrs ). The catalyst was removed hy filtration. The tetrahydrofuran solution was evaporated to dryness. The residue crystallized from ether/ pentane to yield 7-(l-hydroxyethyl)-5-phenyl-l,3#4,5-tetrahy-dro-2H-l,4- enzodiazepin-2-one as a colorless solid, m.p. 159-161°.

Example 11 A mixture of 12.4 g (39 mmoles) of 2 '-benzoyl-2-chloro -4 '-(l-hydroxyethyl)-acetanilide, 11.6 g (78 mmoles) of sodium iodide and 500 ml of acetone was heated under reflux for 0.5 hours. On cooling, the inorganic solids were filtered. Acetone was evaporated in vacuo. The residue was dissolved in 150 ml of tetrahydrofuran and added to a 113-necked flask equipped with a stirrer and a dry-ice condenser and containing 400 ml of liquid ammonia. The mixture was stirred under refluxing ammonia for 5 hours whereby 2 '-henzoyl-2-g,mino-4 '-(l-hydroxy- ethyl)acetanilide was formed. Excess ammonia was allowed to evaporate overnight. The inorganic solids were removed by filtration. The tetrabydrofuran was evaporated. The residual oil was dissolved in 200 ml of ethanol and was heated under reflux for 2 hours. On cooling and concentration of the solutio , 1,3-dihydro-7- ( 1-hydroxyethyl)-5-phenyl-2H-l, 4-benzodiazepin-2-one crystallized, m.p. 214-216°.

The starting material may be prepared as follows: To a hot solution of 28.2 g (0.10 mole) of 5-(2-methyl-l,3-dioxolan-2-yl)-3-phenyl-2,l-benzisoxazole in 125 ml of tetrabydrofuran on a steam bath, was added 50 ml of aqueous 3i hydrochloric acid. The mixture was maintained at near boiling for 0.5 hr. , then cooled, diluted with water and extracted with methylene chloride. Evaporation of methylene chloride followed by recrystallizatidn from methanol gave 5-acetyl-3-phenyl-2,l-benzisoxazole as yellow stout needles, m.p. 108-110°.

A solution of 18.8 g (78 mmoles) of 5-acetyl-3-phenyl-2 ,1-benzisoxazole and 5.90 g (156 mmoles) of sodium borohydrid in a mixture of 1 1 of ethanol and 400 ml of etrabydrofuran was allowed to stand at room temperature. After 18 hours, excess hydride was decomposed with acetic acid. The mixture was neutralized with sodium bicarbonate, then concentrated to a small volume. The residue was partitioned between methylene chloride and water. The methylene chloride layer was washed with water, dried and evaporated. Crystallization of the residue from methanol gave 5- (1-hydroxyethyl)-3-pbeny1-2,1-benziso xazole, m.p. 94-95°« A solution of 600 mg (2.5 mmoles) of 5-(l-hydroxyethyl)-3-phen l-2,l-benzisoxazole in 25 ml of tetrahydrofuran was hydrogenated at 1 atmosphere in the presence of 200 ing of 10 per cent pa3.1adium on carbon. Hydrogen uptake was complete within 40 minutes. Catalyst was removed by filtration. Evaporation of tetrahydrofuran gave an oil which after crystallization and recrystallization from ether-petroleum ether gave 2~amino-5-(l-hydroxyethyl)benzophenone as yellow needles, m.p. 107-109°.

A mixture of 12 «7 g (50 mmoles) of 2-amino-5-(l-hydroxy-ethyl)benzophenone, 10.4 g (50 mmoles) of chloroacetic anhydride ■and 150 ml of benzene was kept at 5° overnight. The benzene solution was washed with saturated NaHCO, and water, then dried and evaporated. Crystallization of the residue from ethanol gave 2 '-benzoyl-2-chloro-4 '-(l-hydroxyethyl)acetanilide.

Example 12 A capsule formulation containing the following ingredients Per capsule 1,3-dihydro-7-(1-hydroxyethyl)-5-»pheny1 2H-l,4-benzodiazepin 25 mg lactose 153 mg corn starch 30 mg magnesium stearate 2 mg can be prepared as follows : Blend 1, 3-dihydro-7- (l-hydroxyethyl)-5-phenyl-2H-l, 4-benzodlazepin-2-pne with lactose and corn starch in a suitable mixer. Pass the blended mixture through a comminuting machine to obtain a uniform mixture. Return the powders to the mixer, add talc and mix. Fill into empt hard shell capsules on a capsule filling machine.

Example 13 A tablet formulation containing the following ingredients l(3-diliydro-7-(l-hydi¾¾'ethyl)-5-phenyl, -2H-1, 4-benzodiazepin-2-one dicalcium, phosphate, dihydrate,' unmilled corn starch microcrystalline cellulose, calcium stearate Total weight can be prepared as follows: Blend the ingredients (except the calcium stearate) in a suitable mixer. Pass the mixture through a comminuting machine Return to mixer and add calcium stearate. Compress on a pellet machine.

Example 14 Λ parenteral formulation containing the following ingredients: Per ml 1, 3-dihydro-7-(.l-hydroxyethyl)-5-phenyl- 2H-l,4-benzodiazepin-2-one 1 mg "benzyl alcohol 0.015 ml propylene. lycol 0.5 ml ethyl alcohol 0.1 ml disodium edetate (disodium salt of ehtylene diamine tetraacetic acid) 0.1 mg sodium acetate 1.4 mg glacial acetic acid . . 0.6 m sodium hydroxyide to adjust pH to approximately 6 vrater for injection qs to 1 ml can he prepared as follows; Add l;3-dihydro-7-(l-hydrox ethyl)-5-phen 1-2H-1, 4-¾enzo-diazepin-2-one to a mixture of propylene glycol and "benzyl alcohol. Blend slightly with stirring to effect solution. Cool, then add ethyl alcohol, and disodium edetate, sodium acetate and glacial acetic acid dissolved in part of the water for infection. Adjust the pH with sodium hydroxide or acetic acid, and add the required volume of water for injection. Filter through sterile Qandle and fill into sterile 2 ml ampules. Gas with nitrogen and seal.

Claims (1)

1. Having now particularly described and ascertained the nature of our said invention and in what manner the sane is to be performed, we declare that what -we claim is: 1. A process for the manufacture of benzodiazepine derivatives of the general formula R, 3 wherein B represents methylene (-GEL,-) or . carbonyl (-GO-); ^, Rgi lj and R^ represent hydrogen or lower alkyl, represents hydrogen or halogen and Rg and R^' represent hydrogen or taken together an additional C-I^ bond, and pharmaceutically acceptable acid addition salts thereof, whic process comprises a) for preparing compounds of the formula I wherein ^ represents hydrogen reducing a compound of the general formula wherein B, R , R,, . , P-C., ^ and R„ are as above, or b) for preparing compounds of the formula I wherein R£ represents lower alkyl with the proviso that when B is carbonyl is hydrogen, treating a compound of the formula II above with the proviso that when B is carbonyl, is hydrogen, with a lower alkyl lithium compound, or c) for preparing compounds of the formula I, wherein B represents carbonyl and Rg and R^ taken together represent an additional C-N-bond cyclizing a compound of the general formula wherein ^, ^ ^, ^ and R-. are as above, ά) for preparing compounds of the formula I wherein ^, represents lower alkyl appropriately 1-alk lating · a compound of the general formula. H wherein B, It. , R?, R., Rj-, R,. and 7 are as above or e) for preparing compounds of the formula I wherein Rg and R7 taken together represent an additional C-U-ibond oxidizing a compound of the general formula wherein B, ^, R^, R^, ^_ and R-. are as above, or f) for preparing compounds of the formula lb ab wherein B, R_ ,'■ Rp, R_, R and R,- are as above, or g) for preparing compounds of the formula I wherein B. represents methylene and Rg and R^ represent hydrogen reducing a . compound of the general formula wherein ^, ^, R^» ^ and R^ are as above and h) if desired, converting a compound obtained into pharmaceutically acceptable acid addition salt. V 2. A process as claimed in Claim 1, wherein a compound of the formiilae III or Id in which formulae ^ is hydrogen and is joined to the 2 '-position or a compound of the formula lb wherein R^ is hydrogen, R,- is joined to the 2' -position and B is methylene or a compound of the formula Ic wherein is hydrogen, ^ is joined to the 2 '-position and B is carbonyl is used a starting material. 3. A process as claimed in Claim 1, wherein a compound of the formula II wherein g and R^ taken together represent an additional C-N-bond in case B is methylene is treated with, a mild reducing agent or with a lower alkyl lithium or a compound of the f.orm¾la II wherein Rg and R^ taken together represent an additional C-N-bond is catalytically hydrogenated or a compound of the formula la is used as the starting material or a compound of the formula lb wherein ^ is lower alkyl and/ or R^ is not joined to the 2 '-position and/or B is carbonyl or a compound of the formula Ic wherein R^ is lower alkyl and/or e- is not joined to the 2 '-position and/or B is methylene is used as the starting material. 4. A process as claimed in Claim 3, wherein the mild reducing agent is a metal borohydride. 5. A process as claimed in Claim 3» wherein the catalytic hydrogenation is effected in the presence of platinum. 6. A process as claimed in any one of Claim 1-3, wherein the oxidizing agent is diethylazodicarboxylate. 7. Λ process as claimed in any one of Claims 1-3, "wherein the reduction according to process step f) in Claim 1 is effected catalytically by hydrogenation. 8. A process as claimed in Claim 7, herein platinum or Raney nickel is used as the catalyst. 9. A process as claimed in Claim 1 or 2, wherein the reduction according to process step g) in Claim 1 is effected "by means of lithium aluminum, hydride. 10. A process as claimed in any one of Claims 1-9, wherein R^ is hydrogen. 11. A process as claimed in any one of Claims 1-10, wherein B is carbonyl. 12. A process as claimed in any one of Claims 1-11, wherein R-j is hydrogen or fluorine joined to the 2'-position. 13. A process as claimed in any one of Claims 1-12, wherein ^, ^ and are hydrogen or methyl. 14. Λ process as claimed in any one of Claims 1-13, wherein R^ is hydrogen, 2 is methyl, is hydrogen or methyl, ^ is hydrogen, ^ is fluorine joined to the 2'-position and B is carbonyl. 15. A process as claimed in Claim 12, herein 1,3-dihydro-7-(l-hydroxyethyl)-5-phenyl-2H-l,4-benzodiazepin-2-one is prepared. 16. A process as claimed in Claim 14,wherein 5-(2-fluoro-phen 1)-1,3-dihydro-7-(1- drox ethyl)-2H-1,4-benzodia epin-2-one is prepared. 17. A process as claimed in Claim 14, wherein^-^-fluorophenyl)-1,3-dihydro-7-(1-hydroxyeth l)-1-methy1-2K-1,4-benzodia-zepin-2-one is prepared. 18. A process as claimed in Claim 12, herein 1,3-dihydro-7-(l-hydroxypropyl)-5-phenyl-2H-l,4-henzodiazepin-2-one is prepared. ig. A process as claimed in Claim 12, herein 1,3-dihydro-7-r-(l-hydroxypentyl)-5-phenyl-2H-l,4-' enzodiazepin-2-one is prepared. 20. A process as claimed in Claim 10,wherei 5-(2-fluoro-pheny1)-2,3-.dihydro-7-(1-hydroxyeth l)-1-methy1- E-l,4-benzodia-zepine is prepared. 21. A process as claimed in Claim 13, wherein 1,3-dihydro-7-(1-h droxy-l-methylethyl)-5-phenyl-2H-l,4-benzodiazepin-2-one is prepared. 22. A process as claimed in Claim 13, wherein 5-(2-fluoro- phesy1)-1,3-dihydro-7-ί1-hydroxy-l-methylethyl)-2H-1,4-benzodia- zepin-2-one is prepared. 23. A process as claimed in Claim 13, wherein 7-(1-hydroxy- ethyl) -5-phen l-l, 3 » 4 * 5-tetrahydro-2H-l, -benzodiazepin-2-one is prepared. X 24. Process for the preparation of benzodiazepine derivatives as hereinbefore particularly described, especially with reference to the foregoing Examples. . 25. Process for the manufacture of preparations having anticonvulsive, muscle relaxant and sedative properties, characterized in that a benzodiazepine derivative of the formula I in Claim 1 or a pharmaceutically acceptable acid addition salt thereof, is mixed, as active substance, with nontoxic, inert, therapeutically compatible solid or liquid carriers, commonly used in such preparations, and/or excipients. 26. Compositions having anticonvulsive, muscle relaxant and sedative properties, containing a benzodiazepine derivative of the formula I in Claim 1 or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier. 1 27. Benzodiazepine derivatives of the general formula wherein B represents methylene (-CH^-) or carbonyl (-CO-); ^, Rg» ^ an(^ ^4 represent hydrogen or lower alkyl, represents hydrogen or halogen and g and ^ represent hydrogen or taken together an additional C-N- bond, and pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process of any one, >of Claims 1, 4 to 9 and_24 or:"by an obvious . chemica! . equivalent thereof. 28. Benzodiazepine derivatives of the formula I in Claim 27, wherein is hydrogen and R.- is joined fo the 2'-position, whenever prepared by the process of Claim 2 or;: . by an obvious chemical equivalent thereof. 29. Benzodiazepine derivatives- of the formula I in Claim 27, whenever prepared by the process of Claim 3..e£r - ::· -by an obvious chemical equivalent thereof. Claim 10 or "by an obvious chemical equivalent thereof. 31. Benzodiazepine derivatives of the formula I in Claim 27, wherein B is carbonyl, whenever prepared by the process of Claim 11 or by an obvious chemical, equivalent thereof. 32. Benzodiazepine derivatives of the formula I in Claim 27, wherein is hydrogen or fluorine joined to the 2 '-position whenever prepared by the process of Claim 12 or by an obvious chemical equivalent thereof. 33. Benzodiazepine derivatives of the formula I in Claim 27, wherein and are hydrogen or methyl, whenever pre-' pared by the process of Claim 13 or by an obvious chemical equivalent thereof. 34. Benzodiazepine derivatives of the formula I in Claim 27, wherein is hydrogen, It, is methyl, is hydrogen or methyl, is hydrogen, is fluorine joined to the 2*-position and B is carbonyl, whenever prepared by the process of Claim 14 or by an obvious chemical equivalent thereof. 35. 1,3-Dihydro-7-(1-hydroxyethyl)-5-phenyl-2H-l, -benzo-diazepin-2-one, whenever prepared by the process of Claim 15 or by an obvious chemical equivalent thereof. 36. 5-(2-Fluorophenyl)-1,3-dihydro-7-(1-hydroxyethyl)-2H-l,4-benzodiazepin-2-one, whenever prepared by the process of · Claim 16 or by an obvious chemical equivalent thereof. 37. 5- ( 2-Fluorophenyl)-l, 3-dihydro-7-( 1-hydrox ethyl )-1-ir,ethyl-2H-l,4-benzodiazepin-2-one, whenever prepared by the process of Claim 17 or by an obvious chemical equivalent there of. 33. 1, 3-Dihydro-7-(1-h droxypropyl)-5-pheny1-2H-1,4-benzodiazepin-2-one, whenever prepared by the process of Claim 18 or by an obvious chemical equivalent thereof. 39. 1, 3-Dihydro-7- (1-h droxypentyl )-5-pheny1-2H-1,4-benzodiazepin-2-one, whenever prepared by the process of Claim 19 or by an obvious chemical equivalent thereof. 40. 5- ( -Fluorophenyl )-2 ,3-dihydro-7- (1-hydrox ethyl)-l-methyl-lH-l^-benzodiazepine, whenever prepared by the process of Claim 20 or by an obvious chemical equivalent thereof. 41. 1,3-Dihydro-7- (1-h droxy-l-methyleth 1)-5-phen 1-2H-l,4-benzodiazepin-2-onef whenever prepared by the process of Claim 21 or by an obvious chemical equivalent thereof. 42. 5- (2-Fluorophenyl)-1, 3-dihydro-7- (1-hydroxy-l-methyl ethyl)-2H-l,4-benzodiazepin-2-one, whenever prepared by the process of Claim 22 or by an obvious chemioal equivalent there of. 43. 7- (1-Bydrox ethyl)-5-pheny1-1, , , 5-tet ahydro-2H÷-' 1, 4-benzodiazepin-2-one, whenever prepared by the process of Claim 23 or by an obvious chemical equivalent thereof. 44. Benzodiazepine derivatives of the general formula R, wherein B represents methylene (-CH^-) or carbonyl (-CO-); ^, R^, ^ and ^ represent hydrogen,or lower alkyl, R-. represents hydrogen or halogen and Rg and ^ represent hydrogen or taken together an additional C—W— bond, and pharmaceutically acceptable acid addition salts thereof, 45. Benzodiazepine derivatives of the formula I in Claim 4^, wherein R_ is hydrogen and R,- is joined fro the 2'-position. 46. Benzodiazepine derivatives of the formula I in Claim wherein R. is hydrogen. 47. Benzodiazepine derivatives of the formula I in Claim wherein B is carbonyl. 48. Benzodiazepine derivatives of the formula I in Claim 2,-position, 49. Benzodiazepine derivatives of the formula I in Claim 50. Benzodiazepine derivatives of the formula I in Claim 4/, v/herein R^ is hydrogen, is methyl, R^ is hydrogen or methyl, R^ is hydrogen, R-. is fluorine joined to the 2*-position and B is carbonyl. 51. 1,3-Dihydro-7-(1-hydroxyethyl)-5-phenyl-2H-l,4-benzo-diazepin-2-one. 52. 5-(2-Fluorophenyl)-l,3-dihydro-7-(1-hydrox ethyl)-2H-l,4-benzodiazepin-2-one. -..,.,·... '., , 53. 5-( -Jluorophenyl)-l,3-dihydro-7-(1-hydrox ethyl)-l-. niethyl-2H-l,4-benzodiazepin-2-one« 5 . 1,3-Dih dro-7-(1-hydroxypropyl)-5-phenyl-2H-l,4-benzodiazepin-2-one. 55. l,3-Dihydro-7-(l-hydroxypentyl)-5-phenyl-2H-l,4-benzodiazepin-2-one. methyl-lH-l,4- enzodiazepine. 57. 1,3-15ihydro-7-(1-hydroxy-l-methylethy1)-5-pheny1-2H- l,4-benzodiazepin-2-one. 58. 5-(2-- .uorophenyl)-1,3-dihydro-7-(1-hydroxy-l-methyl- ethyl)-2H-l,4-benzodiazepin-2-one. 59. 7-(l-H droxyethyl)-5-phenyl-l,3,4,5-tetrahydro-2H- l,4-benzodiazepin-2-one.