IE41844B1

IE41844B1 - Imidazo diazepine derivatives and pharmaceutical compositions containing them

Info

Publication number: IE41844B1
Application number: IE1973/75A
Authority: IE
Original assignee: Hoffmann La Roche
Priority date: 1974-09-11
Filing date: 1975-09-11
Publication date: 1980-04-09
Also published as: HK63381A; YU40267B; ES440850A1; SE425785B; NO802718L; DE2540522A1; SU814278A3; NO147109C; LU73356A1; CU20892L; IL48069A0; FI63234C; AT360023B; NO146573C; SE7509991L; KE3173A; DE2540522C2; SE7902668L; CH619953A5; NO147914C

Abstract

Imidazo[1,5-a][1,4]diazepine compounds of the formula in which the symbols , A, R1, R2 and R3 have the meaning given in Claim 1, analogues thereof as are defined in Claims 2 to 4, and pharmaceutical utilisable acid addition salts of these compounds have useful muscle-relaxant, sedative and anti-convulsive properties. They are particularly suitable for the preparation of injection solutions on account of the good water solubility of their acid addition salts. The compounds are prepared by dehydrogenation of the corresponding 3a,4-dihydro derivatives and optional N-oxidation, reduction or reaction with ethylene oxide or propylene oxide.

Description

This invention relates to pharmacologically active imidazo[l,5-a3 diazepinee. The chemical structure of these compounds may be depicted by the following formula: wherein A is -C=N; R, ι 1 is hydrogen, lower ΙΟ alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl; R2 is hydrogen or lower alkyl; R^ is hydrogen or lower alkyl; R^ is hydrogen, alkanoyloxy or hydroxy; R^ is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl; and is selected from the group consisting of T wherein R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower alkanoyl; x is hydrogen, chlorine, bromine or iodine; and T is hydrogen or lower alkyl; and the pharmaceutically acceptable salts thereof. 418 4 4 ΙΟ Various analogous compounds derived from the above compounds, together with various novel intermediates leading to the above compounds, exhibit pharmacological activity per se are useful intermediates to pharmacologically active compounds. Certain of these compounds and intermediates are the subjects of Patent Specification Nos. 4/246 .tU'f/S’fr 7 Analogs of the above compounds which form a part of this invention include compounds of the formula (f) H (g) wherein A SC wherein V = hydrogen or lower alkyl, l β 11 is selected from the group consisting of formulae (a), (b) and (c) above, and R^, R2 , R^ and Rg are as in Formuia I above except that in formula IA with A being structure (f) R^ is not nitro and Rg is not nitro-substituted, and the pharmaceutically acceptable salts thereof.

A particular group of compounds whith which the invention is concerned comprises compounds of formula I where AJI is XT A is -c=i/G I R^ is hydrogen or lower alkyl; R2 and Rj are independently hydrogen or lower alkyl; R5 is hydrogen, alkanoyloxy or hydroxy; R4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, amino, hydroxy lower alkyl and lower alkanoyl; and Rg is selected from the group consisting of phenyl, monosubstituted phenyl, di-substItuted phenyl, pyridyl or mono-substituted pyridyl, and analogs thereof corresponding to formula I but wherein A is the group Η I / / C— N or -ON I \ I \ % H A, 0 and R^ is hydrogen.

As used in this disclosure, the term lower alkyl comprehends both straight and branched chain carbon5 hydrogen radicals, preferably Cj-Cj carbon-hydrogen radicals such as methyl, ethyl, propyl, isopropyl and butyl.

By the term lower alkanoyl or acyl as utilized herein, acyl moiety of a Cj-C7, preferably a C^-C^, alkanoic acid is intended, e.g. acetyl, propionyl, butyryl, i.e. moieties of the 10 formula R2® wherein R2® is C^-Cg aliphatic hydrocarbyl or hydrogen. Also as utilized herein, the term lower alkanoyl” comprehends a protected aldehyde or ketone such as an acetal or ketal having 2 to 7 carbon atoms, e.g. a group of the formula P an wherein R2^ is Cj-Cg aliphatic hydrocarbyl or hydrogen. The ketal or acetal is utilized to prevent conversion of the contained ketone or aldehyde (R20 -C-) in oxidation, reduction and condensation reactions.

The term halogen is used to include all four forms thereof, i.e., chlorine, bromine, fluorine and iodine.

The terms aromatic and aliphatic sulfonyl group comprehend compounds of the formula SO2X’ wherein X’ ts a branched or straight chain preferably C^-C4, aliphatic hydrocarbyl group, e.g., methyl, or a substituted or unsubstituted aromatic group such as a phenyl or substituted phenyl group, e.g. tolyl.

The phenyl moiety Rg may be mono- or di-substituted provided that such di-substitution occurs in the 2,3; 2,5; or, most preferably, in the 2,6 position of the phenyl moiety. When the phenyl ring is mono-substituted the substituent is preferably halogen or nitro and preferably the substituent is in the 2-position of the phenyl moiety.

When the phenyl ring is di-substituted the substituents are preferably 2,6 or 2,5 di-halogen or 2,6 or 2,5 halogen-nitro.

In the case of mono-substituted pyridyl, the preferred substituents are halogen and nitro.

In the case of compounds of formula I in which substituents Rj and R^ are not identical, optical isomerism will occur and such optical antipodes and racemates are within the ambit of this invention.

By the term aryl is meant a substituted or unsubstituted monocyclic aromatic moiety such as phenyl, chlorophenyl and tolyl.

By the term alkoxy is meant straight or branched chain saturated hydroearbyloxy groups containing from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, such as methoxy, ethoxy and propoxy.

By the term substituted amino herein is meant an -ΝΗ? group which may be mono or disubstituted by lower alkyl, e.g. methylamino or dimethylamino groups, and an acyl amino group e.g., acetylamino which may also be substituted on the nitrogen atom by lower alkyl or aryl e.g., methyl, phenyl or tolyl groups.

By the term aralkyl is meant a hydrocarbon group having both aromatic and aliphatic structures, that is, a hydrocarbon group in which a lower alkyl H atom ls substituted by a monocyclic aryl group, e.g., phenyl or tolyl.

Preferred compounds are those wherein R^ is hydrogen or lower alkyl, preferably methyl R3 and R^ are hydrogen. wherein R^ is located preferably in the 8-position of the IO imidazobenzodlazepine molecule and is hydrogen, nitro or halogen, preferably chlorine; A is -C=N^ I R6 wherein Rg is phenyl or halo, nitro, or lower alkyl substituted phenyl, preferably halo e.g., fluoro, with the fluoro substituted in the 2-position of the phenyl moiety e.g., Thus an especially preferred genus included within the preview of the present invention comprises compounds of the formula wherein R^' is hydrogen or lower alkyl preferably methyl, R^ is hydrogen, nitro or halogen, most preferably chlorine, and in a most preferred embodiment R4 is positioned in the 8-position of the imidazobenzodlazepinc, Rg0 ie phenyl or halo; nitro, or lower alkylsubstituted phenyl, preferably halo - substituted phenyl, with fluorine being the preferred halogen. Preferably the substituted fluoro is positioned in the 2-position of the phenyl moiety. R2 is hydrogen or lower alkyl.

Another preferred class of compounds falling within the scope of formula I arc those wherein Rj*» R2’ R4* R5' R6 and A are as in Formula IB* above and R3 is lower alkyl, preferably methyl, e.g., compounds of the formula Compounds of formula IC and their pharmaceutically acceptable salts exhibit optical isomerism. Such compounds have been resolved into their optical enantiomers by a procedure similar to the one generally outlined in Advanced Organic Chemistry, L. Fieser and M. Fieser, 1961 pp. 85-88, Reinholt Publishing Co. Both the optical Isomers and the racemic forms of compounds IC exhibit pharmacological activity. For example, in the case of the tartrate salt of compounds of formula IC the (+) isomer is considerably more active than the (-) isomer. The less active (-) isomer may, if desired, be converted to the active racemic form thereof such as by treatment with a non-aqueous base, e.g., sodium tertiary butoxide in the presence of an organic solvent ln which the isomer is soluble.

The expreesionpharmaceutically acceptable salts, Is used to Include salts with both inorganic and organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid and para toluenesulfonic acid. Such salts can be formed quite readily by those skilled in the art, with the prior art and the nature of the compound to be placed in salt form, in view.

The roost preferred pharmaceutically acceptable acid addition salts of the compounds of formula 1C and ID respectively are: 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo [i.5-a3 [l, 4] benzodiazepine maleate ; 8-chloro-l,4-dimethyl-6-(2-fluorophenyl)-4HimidazoQ.,5-a] [l,4j benzodiazepine maleate.

It has been found that certain compounds of formula I in solution open to compounds of formula ID, ID II R, '6 wherein Y~ Is the anion of an organic or inorganic acid, and R^, R^, r3, R^ and Rg are as ln formula I.

Such open compounds exist ln a pH-dependent equilibrium ln solution with compounds of Formula I i.e., their corresponding ring closed compounds. The compounds of Formula ID can be isolated as acid addition salts by treatment of their corresponding closed ring compounds with an aqueous mineral acid followed by evaporation of solvent. When isolated, these salts, which are also pa-t of the invention, exhibit pharmacological activity comparable to their corresponding closed ring parents.

The imidazo £l,5-a3£i,4j diazepine compounds of the fonnula I, their analogs of formula IA and the pharmaceutically acceptable acid addition salts of these compounds can be prepared by the various process embodiments defined in claim 1, hereinbelow. io Compounds of the formula ΙΛ where Λ is / -C=N I S R 0 R6 are formed by the conversion of corresponding formula I compounds into the N-oxldes thereof. This conversion may be effected for example by oxidising a formula I compound with an organic peracid. A conventional organic peracid, such as peracetic acid, perpropionic acid or mchloroperbenzoic acid can be utilized in carrying out this reaction. The oxidation can be effected at room temperature, or above or below room temperature.

Compounds of the Formula IA where A is z -C=N R6 may be then utilized to produce compounds of Formula I wherein R^ is alkanoyloxy or hydroxy by methods known in the art, such as, for example, a Polonvski rearrangement utilizing an acid anhydride to form the alkanoyloxy radical which may be converted to the hydroxy radical by treatment with an alkali metal hydroxide such as sodium hydroxide.

An example of such a Polonovski rearrangement is found in U.S. Patent No. 3,296,249 issued January 3, 1967 to S.C. Bell.

Compounds of the formula IA where A is f / -C -N I \ r6 H are formed by the reduction of corresponding formula I compounds to compounds of the formula 41B41 wherein R^.Rj, Rj and sC are as ln Formula X and I xo oo xn xuxrauxa x wut xa uuu *>g as in Formula I but not nitro substituted phenyl or nitro substituted pyridyl (since nitro substituents may be reduced to amino under the reaction conditions) which may then be converted to other compounds of the formula '3' IA1 wherein R^, R?, R, and Rc are as in formula XA* and R? is hydroxy, acyl or an aromatic or aliphatic sulfonyl group. These compounds of formula IA form the subject of Patent Specification No.

The reduction of formula I compounds to IA* compounds is accomplished by any suitable reducing agent but most preferably accomplished by hydrogen in the presence of a platinum oxide catalyst or zinc in the presence of acetic acid. These compounds (IA*) may be converted to IA compounds having an R^-radical other than hydroxy by reaction with an alkyl or aryl sulfonyl halide, e.g. tosyl chloride, mesyl chloride, or lower alkanoyl group providing agent, e.g. acetyl chloride.

This process is conveniently effected in the presence of an inert organic solvent such as an alkanol, e.g., ethanol and methanol, an ether such as diethyl ether and tetrahydrofuran or dimethylformamide. Suitably, an acid acceptor is provided to accept the hydrogen halide formed when utilizing a halide, e.g., an aryl sulfonyl (e.g. tosyl, halide or an alkyl sulfonyl (e.g. mesyl) halide, with a compound of the formula IA* above. Preferred acid acceptors are tertiary amines, e.g., triethylamine and pyridine.

Temperature and pressure are not critical aspects of the first stage of the process involving the conversion of the compound of the formula 1 above to the corresponding compound of the formula IA. However, the reaction is most preferably effected at about room temperature and atmospheric pressure for the preparation of compounds IA* and at room temperature and above for the conversion of compounds IO IA* to IA· bearing an R? radical other than hydrogen Reduction of IA compounds wherein A is -C-N R6 with hydrogen in the presence of platinum catalyst and acetic acid leads to IA” compounds wherein R? is hydroxy.

Compounds of formula IA“ wherein R? is hydroxy, may be converted to the corresponding formula I unsaturated imine by treatment of the IA compound with an acetic anhydrlde/pyridine mixture. No solvent is necessary for this reaction and temperature is not critical although tbe reaction is best effected at room temperature.

Compounds of formula IA above wherein R? is acetyl, mesyl or tosyl may be converted to the corresponding formula I unsaturated imine by treatment of the IA compound with a non-aqueous base, e.g., potassium tertiary butoxide, 2$ in the presence of an inert solvent e.g., THF or DMF.

Such a reaction and the conditions at which it is run are well known in the art, see, for example U.S. Patent No. 3,625,957 issued December 7, 1971 to Fryer et al.

Compounds of Formula IA* above may be converted to the analogous formula I unsaturated compounds by oxidation of the secondary amine at the 5-position. Such a selective oxidation may be accomplished by known 5 oxidants and reaction schemes see, for example, U.S. Patent No. 3,322,753 issued May 30, 1967 to Fryer et aL Conversion of compounds of formula 1 wherein R^ is amino to compounds wherein R^ is nitro may be suitably effected by, for example, the Sandmeyer Reaction wherein the amino group is replaced by a nitro group. The treatment of a formula I compound wherein amlnophenyl with excess sodium nitrite in the presence of a copper sulfate/ sodium sulfite mixture and utilizing as a solvent dilute sulfuric acid may result in an intermediate of the formula wherein R^, R2, Rg and Rg are as in Formula I, which may then be converted to an anlogous formula I compound. This process may be effected in a two-step sequence without Isolation of the intermediate formed by treatment of the above formula XXIII' compound with phosphorus tribromide in an inert organic solvent e.g., diehloromethane at about -10° to 25°C (although temperature is not critical) and then subsequent treatment ln situ with ammonia, preferably liquid ammonia which is allowed to warm to room temperature.

The Sandmeyer reaction has been found to also be applicable in producing compounds which contain a cyano, chloro or bromo group in place of a nitro group. Corresponding compounds of formula XXIII can be converted to their ring closed analogs in the same manner as described above for nitro compounds.

It is obvious to one skilled in the art that certain other substituents may also be attacked during the above reactions, but such vulnerable groups may be blocked by a suitable protecting group or modified before the above reaction sequence is carried out. Such methods of modifying or protecting groups subject to attack are well known in the art.

Compounds of the formula IA where A is may be formed by the direct reaction of formula I compounds with ethylene oxide or propylene oxide in the presence of a Lewis acid catalyst (yielding a compound wherein V is hydrogen or methyl) or by the reaction of a compound of the formula I *6 XXIII and Rg are as in Formula I wherein R^, Rj, R^ cr (except that R^ is not amino or substantial amino) with phosphorus trlbromide and subsequent treatment of the intermediate (XXIV) with ethanolamine, a 1-alkyl substituted ethanolamine or a 2-alkyl substituted ethanolamine as shown in the following reaction scheme: V is hydrogen or lower alkyl AX rr( · C—O pBrj | > *6 xxm . The compounds of formuia XXIII may be formed by the roaciion of a compound of the formula Id with sodium nitrite in the presence of a compatible solvent such as water or dilute mineral acid. The temperature of the reaction may bo -10°C to room temperature. The reaction of Formula XXIII compounds with phosphorus tribromide is effected as illustrated above, preferably in an inert organic solvent such as dichloromethane at about room temperature although such temperature is hot critical.

The reaction of the compound of formula XXIV with ethanolamine or 1-alkyl or 2-slkyl substituted ethanolamine is effected in situ, in the presence of an inert solvent such as dichloromethane, at a temperature in the range -10°C to reflux, preferably about room temperature.

The diroct reaction of formula Z compounds with ethylene oxide or propylene oxide is preferably catalyzed by a Lewis acid, e.g. titanium tetrachloride or boron trifluoride.

Zn compounds of formula Z and their analogs wherein the ketal group e.g. is present as a 8-position substituent in an imidaxobenzodiazepine, such ketal group may be converted to an 8-position ketene by subjecting the ketal group to a mild aoid hydrolysis. The 8-ketone can then be converted to a 8-position secondary or tertiary aloohol which is racemic in nature. The reaction conditions for the above two steps, are found in U.S. Patent No. 3,846,410 issued November 5, 1974.

As stated above compounds of formula I may be directly reacted with ethylene oxide or propylene oxide to produce formula IA' compounds i.e., oxazolo type compounds. Reaction parameters and. conditions to effect such a reaction are known in the art, see for example U.S. Patent No. 3,868,362 issued February 25, 1975 to Fryer et al.

Tb- compounds of 'formula I above can be prepared according to the following novel process aspects which form a part of the present invention.

In one of the aforementioned novel process aspects of this invention, the compound* of formula X above may be prepared by the nitrosation of a compound of the formula wherein A is -C-N or -C=N I \ and R3 is hydrogen or lower alkyl and Rg are as described in formula I, to produce a compound of the formula III wherein A, R^ and in Formula II. are as described Such a nitrosation may be effected by in situ formed nitrous acid.

Reagents which may be employed include (1) alkali metal nitrites, e.g sodium nitrite , in the presence of organlo or inorganic acids, e.g., glacial acetic acid, and aqueous or non-aqueous solvents; (2) alkyl nitrites,e.g., methyl nitrite, in the presence of an inert advent such as an alcohol or a chlorinated hydrocarbcn or, for example, dimethylfanraraide; and (3) a nitrosyl chloride solution In an inert solvent and in the presence of an add acceptor such as pyridine. Such a nitrosation reaction should be affected at around or below room temperature, i.e., in the range of -20°C. to 25’C.

The 2-poaltlon nitroeoalkylamina, e.g., —H—NO, represents a leaving group. Equivalent leaving groups which may be utilized as 2-position substituents include groups such as alkoxide, e.g., -OCH.; aS alkylthio, e.g., -SCH^; halo, e.g., chloro; cyano, i.e,, -CN, and phosphate,e.g.

-O-PO0: . Reactions which form the alkoxide and alkylthio 2-poaltlon substituents are well known in the art; see. for example, G. A. Archer and L. H. Sternbach, Journal of Organic Chemistry, 29 , 231 0964) and U.S. Patent No. 3,681,941, issued August 1, 1972 to Fryer et al.

Compounds of formula III may then be condensed with a nitroalkanc to form a novel intermediate of the formula wherein Rj ^-8 hydrogen or lower alkyl, and A, Rj and aro as described in Formula II.

The condensation reaction is effected with a nitroalkanc, (R2~CH2-NO2), e.g. nitromethane or nitroethane, in the presence of a base which is strong enough to generate the nitroalkane anion. Suitable bases include the alkali metal or alkaline earth metal alkoxides, e.g., potassium tertiary butoxide, amides, e.g., lithium amide or hydrides, e.g., sodium hydride. The reaction is preferably carried out in an inert solvent, such as dimethylformamide, dimethylsulfoxide, or an ether, e.g. THF, at temperatures below or above room temperature, i.e., in the range of -50°C. to 150°C., preferably at about room temperature.

The novel compounds of formula IV and formula V below, besides being major intermediates in the synthesis of compounds of formula I, also exhibit activity as central nervous system depressants.

Compounds of formula IV may then be catalytically hydrogenated, for example, with Raney nickel in the presence of hydrogen or by other reductants such as lithium aluminium hydride (with limitation that A is not N-oxide) to produce α compound of tho formula in Formula 11, except that is not nitro or cyano, and 5 R is not nitro substituted, and R-, is hydrogen or lower alkyl.

O 4» The exclusion of nitro and cyano from the substituent groups present results from the conversion of nitro into amino and cyano into methylamino under the reaction conditions employed in the step IV—?V.

Solvents suitable for hydrogenation with Raney nickel include alcohols. e-g·, ethanol, ethers, e.g., THF and diethylether, hydrocarbon solvents, e.g. toluene and dimethylformamide. The reaction temperature may be above or below room temperature (i.e., -50°C. to 150°C.) and the reaction may be carried out with or without pressure, i.e. at a pressure of one atmosphere or higher.

Solvents suitable for hydrogenation employing a reductant such as lithium 15 aluminum hydride Include ethers, o.g, THF. dioxane, diethylether and mixtures of ethers and hydrocarbon solvents, e.g., THF and benzene. The reaction may be carried out from below room temperature to reflux temperature, i.e., preferably in the range of - 50°C. to 60°C.

Tho compounds of fonnula V may then bo acyluted with un ucylotlng ouent such as an acid halide or acid anhydride, I.e., a group of the fonnula RjCCCl or (R^CO)20 wherein R^ is as defined in fonnula 1, e.g.acetic anhydride and acetyl chloride, to produce a ccnpound of the foznula VI wherein A . Rj, R3ant| are as described in Formula V, R^ is as in formula I and Y Is hydrogen or -COR1. ln acylating the compounds of formula V to compounds of formula VI. there 10 may be obtained a mixture consisting predaninantly of the mcnoacylated product, i.e., wherein the NHj group of V (position2) is converted to NHCOR^, and the dlacylated product wherein both the NHj of V (position 2) and 1-position nitrogen are acylated. The yield of dlacylated product may be increased by subjecting the compounds of formula V to more rigorous conditions, i.e., excess of acylating agent and increased reaction time.

The acylation Is preferably carried out in the presence of an aqueous or non-aqueous solvent e.g., water, methylene chloride, benzene or chloroform, and preferably with an acid acceptor such as an organic or inorganic base such as triethylamine, pyridine or an alkali metal carbonate. The compounds of formula VI may then be cyclized to novel compounds of the formula wherein A, R^, R2, R3 and The cyclization reaction is effected with a dehydrating agent such as phosphorus pentoxide, polyphosphoric acid or other acid catalysts, i.e., organic or inorganic acids e.g., cone. H2SO^. A solvent is not essential but a solvent such as an aromatic hydrocarbon solvent, e.g, toluene, xylene, may be employed. The reaction is carried out at a temperature in the range of from about 100°C to 2OO°C.

These compounds of formula VII form the subject of Patent Specification No.

The compounds of formula V may also be reacted with an 15 acylating agent such as an orthoester, e.g., triethylorthoacetate, an orthoamide, e.g., the dimethylacetal of N,N-dlmethylformamide, or a compound of the formula i3 N-CH, CH, I I CH- N -CH, I 3 N-CH, optionally in the presence of an acid catalyst, e.g., an organic or inorganic acid, e.g., £-toluene sulfonic acid or phosphoric acid, and at room temperature or above, i.e., 25°c· to 150°C., in which instance the cyclization to compound VII occurs spontaneously. Other useful acylating agents include esters, e.g., methyl acetate; amidines, e.g., acctamidine; nitriles, e.g., acetonitrile and ester lmidates, e.g., a compound of the formula ch3-c=nh The compounds of formula VII may then be dehydrogenated to yield compounds of the formula are as described in formula VI. 41344 Preferred reactants for the dehydrogenation Include manganese dioxide and palladium on carbon although potassium permanganate may also be utilized. Solvents which may be utilized Include chlorinated hydrocarbon solvents, aromatic hydrocarbons and dimethylformamide. The dehydrogenation is carried out at room temperature or above, i.e., in the range of about 25°C. to 200°C.

The novel compounds of formula VIZ also exhibit activity as central nervous depressants.

The above novel process may proceed, if desired, from intermediate compounds IV or V to compounds of formula IF without the requirement of isolating any formed intermediate compounds before proceeding to the next process step.

It should be noted that, in acylating the compounds of formula V to the compounds of Formula VI when R^ is amino, the amino substituted R^ may also be acylated to acylamino. The acylamino may be converted back to amino by subjecting the compounds of Formula VII or Formula I to a mild hydrolysis.

Also it has been found that compounds of the formulas IV, V, VI and VII may exhibit both optical and geometric isomerism.

The reaction of a compound of the formula V with acetic acid and zinc or any other suitable reductants e.g., hydrogen in the presence of a catalyst e.g., platinum in dilute acetic acid solution, produces a compound of the formula wherein A is -Lh ί \ and I®q and are as in formula v Depending on the above method of reduction chosen, formula V when Rj Is hydrogen can be Isolated as a racemic mixture of either of the two possible dlastereomers.

A compound of the formula V* may be converted to the dihydroimidazo derivative of the formula gen or lower alkyl, with retention of stereochemistry, by utilising the direct reaction set forth above i.e. the reaction of formula V compounds with an acylating agent such as an orthoester e.g., triethylorthoacetate and maintaining the reaction parameters set forth abovo for such a reaction. 1θ Compounds of formula VII' can also be prepared by reduction of a compound of formula VII by utilizing reductants as mentioned above e.g., acetic acid and zinc or Hj/platinum catalyst in dilute acetic acid, with the particular stereoisomer produced dependent on the reductant chosen.

Compounds of the formula VII* can, if desired, be oxidized directly to analogous compounds of the formula X using an oxidant such as manganese dioxide in toluene or benzene solution. Reaction conditions utilized and various alternate useful oxidants are found in O.S. Patent No. 3,322,753 issued May 30, 1967 to Fryer et al.

Another process to produce tho novel intermediates of formula V where and Ηθ are other than nitro or cyano and is hydreqen consists of the reduction of oanpounds of the formula wherein A is and Rj, and R. o are as described in formula II except that ls not nitro or- cyano and Rg is not nitro-substituted.

The reduction comprises the reaction of the compounds of formula X with a known reductant such as Raney nickel tn the presence of hydrogen or by other reductants such as lithium aluminum hydride. Solvents suitable for hydrogenation with Raney nickel include alcohols e.g., ethanol, others e.g., THF, hydrocarbon solvents e.g., toluene, and dimethylformamide. The reaction temperature may ba above or below room temperature (i.e., - 50°C. to 150°C.) and the reaction may be carried out with or without pressure, i.e., at a pressure of one atmosphere or higher.

Solvents suitable for hydrogenation employing a reductant^auch es lithium aluminum hydride include ethers, such as dioxane, diethyl other and THF.

The reaction may be carried out from below room temperature to reflux temperature, - preferably in the range of -50°C to 80°C.

A variation of the above process comprises a mild add hydrolysis of the compounds of formula X to produce compounds of the formula The mild add hydrolysis is suitably effected by a dilute mineral add. e.g., aqueous HjSO^ in aqueous alcohol. The reaction temperature may range from room temperature, i.e.. about 25°C., to above room tenperature, i.e., about 60*C.

The compounds of formula XI may then be reduced to the novel intermediates of IbrmLa v.

Another process, although it does not form a part of the present Invention, is usefol in produdng novel intermediates of formulas IV and v. The following process is included in this spedflcatlon for the sake of unity.

Compounds of formula IV above may be produced by ttye successive reaction of the compounds of the formula is not amino or substituted amino, with dimorpholinophosphinic chloride to produce compouids of tie formula XIII wherein A which imino phosphates are then displaced by the anion of a nitroalkane to produce the novel intermediates IV.

The displacement reaction is effected with a nitroalkane, e.g.nltromethane or nitroethane, iri the presence of a base which is strong enough to generate the nitroalkane anion. Suitable bases include the alkali metal or alkaline earth metal alkoxides, hydrides, amides or hydroxides. The reaction is preferably carried out in an inert solvent, such as dimethylformamide, dimethylsulfoxide, or an ether, at temperatures below or above room temperature, i.e., in the range of -50eC. to 150eC.

Another process to produce intermediates of formula IV wherein R2 Is hydrogen and a is an N-oxide comprises the ring expansion of compounds of the formulae described in formula II except that R* is not amino.

The ring exponcicn comprises the reaction of the compounds of formulae VIII or IX with nitromethane in the presence of a base strong enough to generate the nitromethane anion. Suitable bases Include the alkali metal and alkaline earth metal alkoxides e.g., potassium tertiary butoxide. amidps e.g., lithium amide or hydrides e.g., sodium hydride. The reaction may preferably be carried out in an inert solvent such as anhydrous ether e.g. , TH F, dimethylformamide or dimethylsulfoxide, and at a temperature in the range of about -2O°C. to 25°C.

\ Compounds of the formulae I, IA and ID and their pharmaceutically acceptable acid addition salts are useful as muscle relaxants, sedativee and anticonvulsants and many are particularly useful when utilized in intravenous and intramuscular preparations because of the acid addition salts* solubility ln aqueous solution. As contemplated by this invention, the novel compounds of the formula I and their acid addition salts can be embodied ln pharmaceutical dosage formulations containing from about 0.1 to about 40 mgs. most preferably 1-40 mg with dosage adjusted to species and individual requirements. The novel compounds of Formulae I, IA and ID and their pharmaceutically acceptable salts can be administered Internally, for example, parenterally or enterally in conventional pharmaceutical dosage forms. For example, they can be incorporated ln conventional liquid or solid vehicles such as water, gelatin, starch, magnesium stearate, talc and vegetable oils to provide tablets,^lixira, capsules, solutions and emulsions according to acceptable pharmaceutical practices; and according to another aspect of the invention a process for the manufacture of preparations having muscle relaxant, sedative and anti-convulsant properties comprises mixing a compound of formula I or an analog thereof or a pharmaceutically acceptable acid addition salt, as active substance, with a non-toxic, inert, therapeutically compatible solid or liquid carrier commonly used in such preparations, and/or an excipient.

The following examples are illustrative but not limitative of the present invention. All temperatures are stated in degrees Centigrade. — Example 1 A solution of 200 g (0.695 m) of 7-chloro-l,3-dihydro5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-one in 2 1 of tetrahydrofuran and 250 ml of benzene was saturated with methy lamine with cooling in an ice bath. A solution of 190 g (1 m) of titanium tetrachloride ln 250 ml of benzene was added through dropping funnel within 15 minutes. After addition the mixture was ntirred and refluxed for 3 hours. Water (600 ml) was added slowly to the cooled reaction mixture. The inorganic material was separated by filtration and was washed well with tetrahydrofuran. The water layer was separated and the organic phaee was dried over sodium sulfate and evaporated. The crystalline residue of 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-l,4-benzodiazepine was collected, m.p. 204-206°. The analytical sample was recrystallized from methylene chloride/ ethanol, m.p. 204-206°.

Sodium nitrite, 8.63 & (0.125 m), was added in three portions over a 15 minute period to a solution of 30.15 g (0.1 m) of 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-l,420 benzodiazepine in 150 ml of glacial acetic acid. After stirring for 1 hour at room temperature the reaction mixture was diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, were dried over sodium sulfate and evaporated, at the end azootropicully with toluene to yield 29 g of crude 7-ohloro-5-(2-fluorophenyl)-2-(N-nitroBomo thy lamino )-3Η-1,4benzodiazepine as a yellow oil.

Thia material was dissolved in 100 ml of dimethylformamide and added to a mixture of 200 ml of dimethylformamide, 50 ml of nitromethane and 11,1 g (0.1 m) of potassium t-butoxlde which had been stirred under nitrogen for 15 minutes.

After stirring for 1 hour at room temperature, the reaction mixture was aoidlfied by addition of glaolal acetic add, was diluted with water and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate and evaporated.

Czystallizatlon of the residue from ether yielded 7-chloro-l, 3-dihydro-5- (2-fluorophenyl )-2-nitromethylene-2H1,4-benzodiazepine, m.p. 170-172°. The analytical sample was reorystallized from methylene chloride/ethanol, m.p. 174-176°.

A solution of 16.5 g (0.05 m) of 7-chloro-l,3-dihydro5 - (2-fluorophenyl) -2-nitromethylene-2H-l, 4-benzodiazepine in 500 ml of tetrahydrofuran and 250 ml of methanol was hydrogenated with 5 teaspoons of Raney nickel for 2 1/2 hours at atmospherio pressure. Separation of the catalyst and evaporation of the solvent left crude 2-aminomethyl-7-chloro-2,3-dihydro -(2-fluorophenyl)-1H-1,4-benzodiazepine.

Propionic anhydride (20 al) waa added to a solution of 12 g of the above material in 500 ml of methylene chloride.

The solution was added to 300 ml of 10% aqueous sodium carbonato and the two phase mixture was stirred at room tomporaturo for 50 minutes. The organic layer wan noparatud, washed with sodium carbonate solution and dried over sodium sulfate. Evaporation yielded crude 7-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-propionylaminoaethyl-lH-l,4-benzodiazepine.

This material was heated in 50 g of polyphosphoric acid at 150-170° for 10 minutes. The reaction mixture was cooled, dissolved in water and made alkaline with concentrated ammonia and ice. The base was extracted with methylene chloride and the extracts were dried over sodium sulfate and evaporated. The residue was chromatographed over 300 g of silica gel using 20% methanol in methylene chloride. The clear fractions were combined, evaporated and the residue was crystallized from ether to yield 8-chloro-3a,4-dihydro-lo thy1-6-(2-fluorophenyl)-3H-imldazo(1,5-a J[1,4]benzodiazepine m.p. 131-133°.

A mixture of 3.4 g of 8-chloro-3a,4-dihydro-l-ethyl6-(2-fluorophenyl)-4H-imidazo[l,5-a][l,4]benzodiazepine, 400 ml toluene and 30 g activated manganese dioxide was refluxed with separation of water in a Dean-Stark trap for 2 hours. The manganese dioxide was separated by filtration over Celite(trade mark) and the filtrate was evaporated. Crystallization of the residue from ether yielded 8-chloro-l-ethyl-6-(2-fluoropheny1)-4H37 imidazo[l,5-a][l,4]benzodinzepin6, m.p. 140-143°. For analysis it was reoryetallized from ether, m.p. 143-145°.

Example 2 Aoetio anhydride (7 ml) was added to a solution of I 6.16 g of orude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl )-IH-l,4-benzodiazepine ln 200 ml of methylene chloride. The solution was added to 200 ml of saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organlo layer was separated, washed with sodium bicarbonate dried over bodium eulfate and evaporated to leave resinous 2-acetylamlnomethyl-7-chloro-2,3-dlhydro-5-(2-1luorophenyl)-IH 1,4-benzodlazeplne. Shis material was heated with 40 g ot polyphoephoric acid at 150° for 10 minutes. The cooled reaction mixture was dissolved ln water, made alkaline with ammonia and ice and extraoted with methylene chloride. The extraots were dried and evaporated and the residue was chromatographed over 120 g of silica gel using 20 % methanol in methylene chloride. The olean fractions were combined, and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-120 methyl-4H-imldazo[l,5-a][l,4]benzodiazepine. A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 1 1/2 hours. The manganese dioxide was separated by filtration over Celite. The filtrate was evaporated and the residue was crystallized from ether to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][l,4]benzodiazepine, m.p. 152-154°. The analytical sample was ‘ recrystallized from methylene chloride/hexane.

Example 5 Reaction as ln the first paragraph of Example 1 of 152.5 g (0.5 m) of 7-chloro-5-(2-chlorophenyl)-l,3-dihydro2H-l,4-benzodiazepin-2-one saturated with methylamine with 133 g (0.7 m) of titanium tetrachloride In 2 1 of tetrahydrofuran and 400 ml of benzene yielded 7-chloro-5-(2-chlorophenyl)-2-methylamino-3H-l,4-henzodiazeplne> m.p. 216-219°.

The analytical sample was recrystallized from methylene chloride/ethanol and tad m.p. 217-219°.

Sodium nitrite (10 g, 0.145 m) was added in portions over 45 minutes to a solution of 22.4 g (0.07 m) of 7-chloro5-(2-chlorophenyl)-2-methylamlno-3H-l,4-benzodiazepine in 150 ml of glacial acetic acid. After addition stirring was continued for 20 minutes under nitrogen. The product was precipitated by addition of ice-water, collected and dissolved in toluene.

The solution was washed with saturated aqueous sodium bicarbonate, dried and evaporated under reduced pressure. The yellow viscous oil consisted according to thin layer chromatogram mainly of the desired nitrosoamine. This material was dissolved in 100 ml of dimethylformamide and was added to a mixture of 50 ml of nitromethane, 100 ml of dimethylformamide and 10 g of potassium t-butoxide. The reaction mixture was slowly heated up to 85° with stirring under a nitrogen stream. After 5 minutes, the reaction mixture was cooled, and then acidified by addition of 10 ml of glacial acetic acid. The product was crystallized by gradual addition of water with seeding (seeds were obtained by chromatography over silica gel using 10% ethyl noetate in methylene ohloride). The separated crystals were colleoted, washed with water and reorystallized from methylene chlorlde/ethanol to yield 7-chloro-5-(2-chlorophenyl )-1, 3-dlhydro-2-nltromethylene-ZH-l, 4-benzodiazepine, m.p. 182-185«.

Hydrogenation of 7 g of 7-ehloro-5-(2-chlorophenyl)10 l,3-dihydro-2-nitromethylene-2H-l,4-benzodiazepine in 300 ml of tetrahydrofuran and l?0 ml of methanol in the presence of Raney nickel (5 teaspoonsful) for 1 hour yielded crude 2-aminomethyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-lH-l,4benzodlazepine. This material was acetylated in the usual fashion to produce oily 2-acetylaminomethyl-7-chloro-5-(2-chloro pheny1)-2,3-dihydro-lH-l,4-benzodiazepine which was heated in 15 g of polyphosphoric acid for 10 minutes at 140-150°.

The usual workup afforded a yellow resin which was chromatographed over 250 g of silica gel using 20% methanol in methylene chloride.

The clean fractions left resinous 8-chloro-6-(2-chlorophenyl) -3a,4-dihydro-l-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine. This material was oxidized with 10 g of manganese dioxide in 200 ml of toluene. After heating to reflux for 1 1/2 hour, the manganese dioxide was separated and the filtrate was evaporated. Crystallization of the residue from , 4041844 ether yiolded 8-chloro-6-(2-chlorophcnyl)-l-methyl-4H-ioldnzo[1,5-a][1,4]benzodiazepine, m.p. 140-144°. For analysis it was reerystallized from methylene chloride/hexane, m.p. 142-144° Example 4 A solution of 94.6 g (0.3 m) of 5-(2-chlorophenyl)l, 3-dihydro-7-nitro-2H-l,4-benzodiazepin-2-one in 2 1 of tetrahydrofuran and 300 ml of benzene was cooled in ice-water and saturated with methylamine. A solution of 40.2 ml (0.36 m) of titanium tetrachloride in 300 ml of benzene wn« added through a dropping funnel. After addition the mixture was stirred and refluxed for 3 hours. Water (300 ml) was added slowly to the cooled reaction mixture. The inorganic 3olida were separated by filtration and washed well with tetrahydrofuran. The water was separated from the filtrate and the organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed over 500 g of silica gel using 10% (v/v) ethanol in methylene chloride. Crystallization of the clean fractions from methylene chloride/ethanol yielded 5-(2-chlorophenyl)-7-nitro-2-methyl20 amino-3H-l,4-benzodiazepine as a yellow product with m. p. 219-221°.

Sodium nitrite (8.63 g, 0.125 m) was added in three portions over a 15 minute period to a solution of 33-9 g (0.1 m) of 5-(2-chlorophenyl)-7-nitro-2-methylamino-3H25 1,4-benzodiazepine in 200 ml of glacial acetic acid. After addition stirring van continued for 1 1/2 hours at room temperature and the product was precipitated by addition of water. The yellow solids were collected, washed with water, sucked dry and recrystallized from ethanol to yield 5-(2-chlorophenyl)-7-nitro-2-(N-nitrOBomethylamino)3H-1,4-benzodiazepine ae yellow crystals with m.p. 164-166°.

The analytical sample wae recrystallized from methylene chloride/ethanol, m.p. 167-169°.

A mixture of 3·58 g (0.01 m) of 5-(2-chlorophenyl)10 7-nitro-2-(N-nitrosomethylamino)-3H-l,4-benzodiazepine, 20 ml of dimethylformamide, 5 al of nitromethane and 1.3 g (0.0115 m) of potassium t-butoxide was stirred at room temperature for 15 minutes under nitrogen. After addition of 2 ml of glacial acetic acid the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water, dried over eodium sulfate and evaporated. The residue was chromatographed over 80 g of silica gel using 10# (v/v) ethyl acetate in methylene chloride. Crystallization of the clean fractions from methylene chloride/ethanol yielded straw colored crystals of 5-(2-chlorophenyl)-l,3-dihydro-7-nitro-2-nitromethylene-2H-l,4-benzodiazepine with m.p. 240-243° (dec.).

Example 5 A solution of 33 g (0.1 m) of 7-chloro-2-(N-nitroso25 methylamino)-5-phenyl-3H-l,4-benzodiazepine 4-oxide in 100 ml of dimethylformamide wae added to a mixture of 50 ml of nitromethane, 12.5 g (0.11 m) of potassium t-butoxide and 100 ml of dimethylformamide. The reaction mixture was stirred under a stream of nitrogen for 1 hour. After addition of 10 ml of glaoial acetic acid, the product was crystallized by gradual addition of 250 ml of water. The precipitated yellow material was collected, washed with water, methanol and ether to leave 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-l,4-benzodiazepine 4- oxide, m.p. 253-255° (deo.).The analytical sample was recrystal 10 lized from methylene chloride and showed the same melting point.

Raney nickel (5 teaspoons) was added to a solution of 16.5 g (0.05 m) of 7-chloro-l,3-dihydro-2-nitromethylene5- phenyl-2H-l,4-benzodiazepine 4-oxide in 500 ml of tetrahydrofuran and 250 ml of methanol. The mixture was hydrogena15 ted for 5 hours at atmospheric pressure. The catalyst wae removed by filtration and the filtrate was evaporated. The residue was dissolved in 2-propanol and the solution was made strongly acidic with ethanolie hydrogen chloride. The dihydrochloride of the product crystallized upon evaporation of part of the solvent. The orange crystals were collected to leave 2-aminomethyl-7-ehloro-2,3-dihydro-5-phenyl-lH-l,4benzodiazepine dihydrochloride, m.p. 230-240°.

Acetic anhydride (10 ml) was added to a solution of 10 g of the above dihydrochloride in 50 ml of water and 50 ml of methanol. A 10% aqueous solution of sodium carbonate (100 ml) was added with stirring over a period of 5 minutes. After addition tho mixture was atirred for an additional ten minutes and was then extracted with methylene chloride.

The extracts were washed with sodium carbonate solution, dried over sodium sulfate and evaporated, at the end azeotroplcally with toluene. 2^Acetami4omethyl-7*-chloro2,3-dihydro-5-pheoyl-lH-l,4-benzodiazepine was obtained as a yellow reein.

The above material was heated in 50 g oi polyphosphoric acid to 135-140° for 10 minutes. The Initially orange color of the reaction mixture faded to a light yellow. The cooled reaction mixture was dissolved ln wator, made alkaline with concentrated ammonia and ice and extracted with methylene chloride The extracts were dried and evaporated. The yellow reein wae dissolved in 2-propanol and treated with ethanolic hydra gen chloride whereupon the colorless dihydrochloride of the product crystallized. Melting point was 240-245°.

This hydrochloride was partitioned between methylene chloride and aqueous ammonia. The organic phase was dried and evaporated. Crystallization of the residue from ether yielded 8-chloro-3a,4-dihydro-l-methyl-6-phenyl-3H-imidazo [1,5-a][1,4]benzodiazepine as a colorless product with m.p. 116-118°.

A mixture of 3.1 g (0.01 m) of 8-chloro-3a,4-dihydrol-oethyl-6-phenyl-3H-imidazo[l,5-a][l,4]benzodiazepine, 20 g of activated manganese dioxide and 150 ml of toluene was 41644 refluxed for 1 hour. The manganese dioxide was removed by filtration over Celite and was washed well with methylene chloride. The filtrate was evaporated and the residue was crystallized from other to yield 8—chloro-l-mcthyl-6-phenyl5 4H-imidazo[l,5-a][l,4]benzodiazepine as colorless crystals with m.p. 187-188°.

Example 6 A mixture of 11.2 g (0.1 m) of potassium tert.butoxide, 50 ml of nitroethane and 200 ml of dimethylformamide was stirred at room tomperaturc for 15 min. Λ solution of 29 g (0.088 m) of crude 7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-l,4-benzodiazepine in 100 ml of dimethylformamide was then added and stirring under nitrogen was continued for 6 hrs. The reaction mixture was neutralized by addition of glacial acetic acid and diluted with water. The product was extracted with ether. The extracts were washed with saturated aqueous sodiumbicarbonate solution, dried over sodium sulfate and evaporated. Crystallization from ether yielded 7-chloro-l,3-dihydro-5-(2-fluoropheny3)-2-(1-ni tro20 ethylene)-2H-l,4-benzodiazepine as yellow crystals with m.p. 156-142°.

Raney nickel (5 teaspoonsful) was added to a solution of 17.3 g (O.O5 m) of 7-chloro-l,3-dihydro-5-(2-fluorophenyl)2-(l-nitroethylene)-2H-l,4-benzodiazepine in 750 ml of tetra25 hydrofuran. The mixture was hydrogenated at atmospheric pressure for 4 hre. The catalyst was removed by filtration over Celite and was washed well with methanol. The filtrate was evaporated to leave crude 2-(l-aminoethyl)-7-ohloro2,3-dihydro—5-(2-fluoropheny1)-1H-1,4-benzodiazepine as a reddish oil.

Thia material was dissolved in 300 ml of methylene chloride. Polloving the addition of 14 ml of acetic anhydride, 300 ml of saturated aqueous sodium bicarbonate solution was added and the two-phase mixture was stirred at room temperature for 1 hr. The methylene chloride layer wae separated, washed with bicarbonate, dried over sodium sulfate and evaporated. The residue was heated with 40 g of polyphosphoric acid for 10 minutes at 160-170°. The cool reaction mixture was diluted with water, made alkaline with ammonia and extracted with methylene chloride. The extracts were washed with water, dried and evaporated to leave a brown residue which was chromatographed on 250 g of silica gel using 20% (v/v) methanol in methylene chloride. The thin layer chromatographically homogeneous fractions were combined to yield a resin which was subjected to the following oxidation.

A mixture of the above material, 20 g of activated manganese dioxide and 300 ml of toluene was heated to reflux for 3 hre using a Dean-Stark trap to remove the water. The manganese dioxide was separated by filtration over Celite and was washed well with methylene chloride. The filtrate was evaporated and ths residue was chromatographed with pressure over 150 g of silica gel H using 3% ethanol in methylene chlori de. The first eluted major component was 8-chloro-l,4-dimethyΙό- (2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine.

It was converted to a crystalline dihydrochloride by treatment with ethanolic hydrogen chloride in ether, Mp. 247-250« (dec.).

The more polar component could be crystallized from methylene chloride/ether/hexane to yield 8-chloro-l,3-dimethyl6-(2-fluorophenyl)-4H-imidazo[l,5-a][l,4]benzodiazepine with mp. 178-1806.

Example 7 Λ mixture of 3.1 g (0.01 m) of 8-chloro-l-methyl-6phenyl-4H-imidazo[l,5-a][l,4]benzodiazepine, 2.15 g (0.0125 m) of m-chloroperbenzoic acid and 100 ml of methylene chloride was stirred for 48 hrs. at room temperature. It was then washed with 10% aqueous sodium carbonate solution and water.

The residue was ohromatographed over 80 g of silica gel using 10% (v/v) of ethanol in methylene chloride. Tho Tlc-homogencou:j fractions were combined and evaporated. Crystallization of the residue from methylene chloride/ether yielded 8-chloro-lmethy 1-6-pheny l-4H-imidazo[1,5-a][1,4]benzodiazepine 5-oxide, mp. 260-261°.

Example 8 A solution of 1 g of 8-chloro-l-methyl-6-phenyl-4Himidazo[1-5-a][1,4]benzodiazepine 5-oxide in 20 ml of acetic anhydride was heated on the steam bath for 24 hrs. The reagent was evaporated undor reduced pressure and the residue was crystallized from ether to yield 4-acetoxy-8-chloro-l-methyl6-phenyl-4H-imldazo[l,5-a][l,4]benzodiazepine, mp. 200-201°.

Example 9 Sodium methoxide (0.54 g) was added to a solution of 10 0.73 g (2 mmol) of 4-acetoxy-8-chloro-l-methyl-6-phenyl-4Himidazo[l,5-a][l,4]benzodiazepine in 20 ml of methanol. After sitting at room temperature for 30 min, the solvent was evaporated under reduced pressure after neutralization with acetic acid. The residue was partitioned between methylene chloride and eodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. Crystallization of the residue from ether yielded 8-chloro-4-hydroxy-l-methyl6-phenyl-4H-lmidazo[l,5-a][l,4]ben2odiazepine, mp. 173-174°.

Example 10 A warm solution of 6.5 g (0.02 m) of 8-chloro-6-(2-fluorophenyl) -1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 30 ml of ethanol was combined with a warm solution of 2.6 g (0.022 m) of maleic acid in 20 ml of ethanol. The mixture wao diluted with 150 ml of ether and heated on the steam bath for 3 min. After cooling, the crystals were collected, washed with ether and dried in vacuo to yield 8-chloro-6-(2-fluorophenyl)l-methyl-4H-lmidazo[l,5-a][l,4]benzodiazepine maleate, mp. 148-151°.

Example 11 A mixture of 17.4 g (0.05 m) of 7-chloro-l,3-dihydro5- (2-fluorophenyl )-2- (1-nitromethylene) -2H-1,4-benzodiazepine 4-oxide, 500 ml of tetrahydrofuran, 200 ml of methanol and 5 teaapoonsful of Raney nickel wae hydrogenated at atmospheric prosourc for 5 hrs. The catalyst was removed by filtration and tho filtrate was evaporated,at the end azcotropicaliy with xylene to leave crude 2-aminomethyl-7-chloro-5-(2-fluorophenyl)2,3-dihydro-lH-l,4-benzodiazepine.

This material wae dissolved in 200 ml of ethanol and the solution was heated to reflux for 2 hrs. after addition of 14 ml of triethylorthoacetate and 2.8 g of p-toluenesulfonic acid. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and 10# aqueous sodium carbonate solution. The organic layer was dried and evaporated to yield oily 8-chloro-3a,4-dihydro6- (2-fluorophenyl)-1-methyl-3H-imidazo(1,5-a][1,4]benzodiazepine. Thia crude product was dissolved in 500 ml of xylene.

After addition of 50 g of activated manganese dioxide, the mixture wae otirred and heated to reflux for 1 1/2 hrs with separation of water in a Dean-3tark trap. Tho inorganic material wae removed by filtration and the filtrate was evaporated to leave 10 g of brown oil.

A warm solution of 4.65 g (0.04 m) of maleic acid in 5 50 ml of ethanol was added to this residue. After the solution was complete, the product was crystallized by addition of ether. It was collected and washed with ether to leave 8-ohloro-6- (2-f luoro pheny 1) -1-methy l-4H-imidaz o[1,5-a][1,4]benzodiazepine maleate, mp. 112-115°. Heating under vacuum at 90’ to 100° converts this product to the higher melting form with mp. 148°-151*.

Example 12 A solution of 0.32 g (1 mmol) of 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidaao[l,5-a)[l,4]benzodiazepine in 5 ml of ethanol was treated with excess ethanolie hydrogen chloride. Tho salt was crystallized by addition of 2-propanol and ether. The colorless crystals were collected, washed with ether and dried to leave 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine dihydrochloride, mp. 290-295°.

Example 13 A solution of 0.325 g (1 mmol) of 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine in 3 ml of ethanol was combined with a suspension of 0.4 g (1 mmol) of the dihydrochloride of tho sane compound in 5 ml of ethanol After filtration, the solution was treated with ether and heated on the steam bath for 5 min to crystallize. The crystals were collected, washed with ether and dried to leave 8-chloro5 6-( 2-fluorophenyl) -l-oethyl-4H-imidazo [ 1,5-a] [ 1,4 ] benzodiazepine hydroohloride, mp. 295-297°.

Example 14 A solution of 23.6 g (0.10 mole) of l,3-dihydro-5-phenyl2H-1,4-benzodiazepin-2-one in 1 liter of tetrahydrofuran containing about 20 moles of monomethylamine was chilled in an ice bath. To this mixture was added 14 ml. (d-1.73, 0.125 mole) of titanium tetrachloride in 200 ml of benzene.

This mixture was stirred at room temperature for two days. The titanium complex was destroyed with 20 ml of water.

The inorganic salts that precipitated were removed by filtration, the solvent was evaporated in vacuo, and the residue partitioned between methylene chloride and water. A colorless amorphous solid mp. 227-229° was removed by filtration. An additional sample, mp. 226-229° of the.colorless solid was obtai ned from the methylene chloride mother liquors after drying over anhydrous sodium sulfate, evaporation to dryness, and crystallization from ethyl acetate.

An analytical sample was prepared by recrystallization from dimethylfonnamide to yield colorless priums, mp. 227-229°C.

To a cooled (10°), stirred solution of 10.0 g (0.04 m) of the product, 2-mothylamino-5-phenyl-3H-l,4-benzodiazepine,in 100 ml of pyridine was added 100 oil of a saturated solution of nltrosyl chloride in acetio anhydride. The solution was stirred for 3.5 hr. during which time it was allowed to warm to ambient temperature. The solution was poured into 300 ml of ice-water, and the aqueous solution wae extracted with five 150 oil portions of methylene chloride. The combined organic extracts were washed with water and brine, dried (CaSO^), and the solvent removed under reduced pressure affording a dark semi-solid. Chromatography on 500 g of silica gel (chloroform elution) afforded the ?-(N-nitrosomethylamino)-5-phenyl-3H1,4-benzodiazepine, mp 192-199° (dec.). This material was used in the following step: The conjugate base of nitromethane was prepared by treatment of 50 ml of nitromethane in 200 ml of dimethylformamide with 5.7 g (0.05 m) of potassium tert-butoxide. The reeultant stirred yellow suspension was treated with 10.9 g of orude 2-(N-nitrosomethylamino)-5-pheny1-3H-1,4-benzodia20 zepine in 100 ml of dimethylformamide. The dark mixture thus obtained was Btirred for 2 hrs. at 25° and for 1 hr at 85° and then cooled to 25® and poured onto 1 1 of water. After acidification with acetic acid, the aqueous solution was extracted with four 250 ml portions of methylene chloride, and the combined organic extracts were then washed with water and brine, dried (CaSO^), and concentrated in vacuo to give a dark oil which wan purified by chromatography over 1 kg of 1844 nLlica gel (CHCl^ elution) to afford crude 1,3-dihydro2-nitromothylene-5-phenyl-2H-l,4-benzodiazepine, mp. 131-142°.

An analytical eamplo, mp 141-142°, was prepared by recrystallization from ethanol.

A mixture of 8.4 g (0.03 m) of l,3-dihydro-2-nitromethylene-5-pheny1-2H-1,4-benzodiazepine, 75 ml of tetrahydrofuran, 75 ml of methanol and 2 teaspoonsful of Raney nickel was hydrogenated at atmospheric pressure for 6 hrs, Tho catalyst was removed by filtration and the filtrate vuu evaporated to leave crude 2-aminomethyl-2,3-dihydro-5-phenyl1H-1,4-benzodiazepine.

This material was dissolved in 50 ml of methylene chloride and was treated with 6 ml of acetic anhydride and 200 ml of saturated aqueoue sodium bicarbonate solution for min. with stirring. The methylene chloride layer was separated, washed with bicarbonate solution, dried and evapora ted. The residue was treated with 25 g of polyphosphoric acid to 130-150° for 15 min. The cooled teaction mixture was partitioned between water and ether. The aqueous phase was made alkaline with ammonia and was extracted with methylene chloride. The extracts were dried and evaporated. Chromatography of the residue over 70 g of silica gel with 20% (v/v) ethanol in methylene chloride yielded 3a,4-dihydro-l-methyl6-phenyl-3H-imidazo[l,5-a][l,4]benzodiazepine as a light yellow resin.

Thia material was heated in 50 ml of toluene with 7 g of activated manganese dioxide to reflux for 1 1/2 hrs. The inorganic material was filtered off and the filtrate waa evaporated. The residue was purified by chromatography over 30 g of silica gel using 10% ethanol ln methylene chloride. The clean fractions were combined and evaporated. Crystallization of the residue from ether yielded l-methyl-6-phenyl-4H-lmidazo[l,5-a][l,4]benzodlazepine.

To a stirred solution of 6 g (0.02 m) of 7-chloro1,3-d ihydro-5- (2-f luorophenyl) -3-methyl- 2H-1,4-benzodiazepin2- one in 100 ml of dry tetrahydrofuran was added 1.05 g (0.25 m) of 57% sodium hydride dispersion in mineral oil.

The mixture was placed under argon and refluxed for 1 hr.

After cooling to room temperature, the mixture was treated with 7.4 g (0.03 m) of dimorpholinophosphinic chloride and stirring under argon was continued at room temperature for 2 hrs. The mixture was filtered and evaporated at reduced pressure to give a gummy residue. Stirring the gum with 100 ml of anhydrous ether gave white crystals which were collected by filtration, washed with a little ether and air dried. 7-Chloro-2-di- (morpholino) -phosphinyloxy-5 - (2-f luorophenyl) 3- methyl-3H-l,4-benzodiazepine thus obtained had a mp. of 90-95° A stirred solution of 2.4 g (0.04 m) of nitromethane in 50 ml of dry dimethylformamide was treated with 1 g (0.024 m) of 57% 3odiuo hydride dispersion in mineral oil at room temperature under argon. After stirring for 1 hr. at room temperature, the mixture was treated with 5.2 g (0.01 m) of 7-chloro2-di(-morpholino)-phosphinyloxy-5-(2-fluorophenyl)-3-methy13H-1,4-benzodiazepine in one portion and stirring under argon was continued at room temperature for 24 hrs. The dark mixture was poured over a mixture of ice and glacial acetic acid with stirring to give a yellow solid. Stirring wae continued until the ice had melted. The solid was filtered, washed with water and air dried on the funnel to yield 7-chloro-l,3-dihydro-5(2-fluorophenyl)-3-nethyl-2-nitromethylene-2H-l,4-benzodiazepine having mp of 215° (dec.). Recrystallization of u sample from 1:1 methanol/methylene chloride gave yellow needles, mp. 219-221° (dec.).

A solution of 5.2 g (0.015 m) of 7-chloro-l,3-dihydro5-(2-fluorophenyl)-3-methy1-2-nitromethylene-2H-l,4-benzodiazepine in 450 ml of 2:1 tetrahydrofuran-methanol was hydrogenated for 3 hrs. using a Parr apparatus, Raney nickel catalyst (3 teaepoonsful) and an initial pressure of 18 psi. The mixture was filtered and evaporated at reduced pressure to give crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-3-methy1lH-l,4-benzodiazcpine as a yellow oil.

The crude aminomethyl compound was mixed with 5 ml of triethyl orthoacetate and 0.5 g of p-toluenesulfonic acid monohydrate in 100 ml of ethanol. After heating under reflux for 2 hrs, the solution was evaporated at reduced pressure.

The residue was cooled to room temperature, treated with a mixture of loe and concentrated ammonium hydroxide and extracted with methyleneohloride. Evaporation of the dried extracts in vacuo gave crude 8-chloro-3a,4-dihydro-l,4-dimethy1-6-(25 fluorophenyl)-3H-imidazo[1,5-a][l,4]benzodiazepine as a gum.

The crude dihydroimidazobenzodiazepinc was mixed with 20 g of aotivated manganese dioxide and 200 ml of toluene and heated under reflux for 2 hrs. The mixture was filtered and the manganese dioxide was washed with methylene chloride. Evapora10 tion of the combined filtrate and washings at reduced pressure gave a brown gum. The dj hydrochloride of 8-chloro-l,4-dimethy 16-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]-benzodiazepine was obtained as a white powder by stirring the gum with ethanol-in hydrogen chloride for a few minutes. The salt melted at 247-250° Example 16 Zinc duot, 3 g, wa3 added to a solution of 2.8 g of y-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[1,5-a] [ 1,4]benzodiazepine in 75 mi of methylene chloride and 75 ml of glacial acetic aoid. After stirring at room temperature for 2 hrs, the inorganic material was filtered off and washed with methylene chloride and water.

The filtrate was diluted with 100 ml of methylene chloride and 200 ml of water and was made alkaline with ammonia. The methylene chloride layer was separated, dried and evaporated. Crystallization of the residue from ether/ hexane yielded 8-chloro-5»6-dihydro-6-(2-fluorophenyl)-lmethyl-4H-imidazo(l,5-a)[l,4]benzodiazepine, mp. 200-203°.

Example 17 A mixture of 100 g (0.8 m) of chloroacetaldehyde dime thylaoetal and 100 ml of 1.5 N hydrochloric acid was heated under reflux for 15 min. and then cooled and added to a solution of 130 g (0.5 m) of 2-amino-2’-fluoro-5-nitrobenzophenone and 46 g (0.28 m) of hydroxylami ne 9ulfate and 1 1 of ethanol. The mixture was stirred at room temperature for 2 hr. and then heated to reflux for 1.5 hr. The mixture was cooled and the product obtained by filtration. Recrystallization from a mixture of chloroform and methanol gave pure 2-chloromethyl-4-(2-f luore pheny 1) -6-ni tro-1,2-dihyuroquina15 zollne 3-oxide as yellow prisms, mp. 220-224°.

A solution of 142 g (0.423 m) of 2-chloromethyl-4(2-fluorophenyl)-6-nitro-l,2-dihydroqulnazoline 3-oxide in 2.3 1 of dichloromethane was treated with 400 g of manganese dioxide, and after stirring for 18 hr. the solution was filte red. The manganese dioxide was washed with 600 ml of tetrahydrofuran and 800 ml of dichloromethane. The combined filtra tes were concentrated to 400 ml and 1 1 of ether was added. This was cooled and filtered to give 2-chloromethyl-4-(2fluorophenyl)-6-nitroquinazoline 3-oxide. Λ sample was recrystallized from a mixture of dichloromethane and methanol to give the pure product ae pale yellow prisms, mp. 127-130°.

To 500 ml of dimethylsulfoxide and 75 ml (1.4 m) of nitromethane was added with stirring under nitrogen 15.6 g (0.678 a) of lithium amide. After 30 minutes the solution was oooled to 5° and 104 g (0.31 m) of 3-chloromethyl4-(2-fluorophenyl)-6-nltroquinazoline 3-oxide was added slowly, keeping the temperature below 8°. After 68 hr. at room temperature the reaction mixture was poured into a mixture of 2.5 1 of ice and water and 25 ml of aoetio acid, and the solution was filtered.

The gummy precipitate was dissolved in 1 1 of dichloromethane which was washed with aixute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from ethyl acetate to give l,3-dihydro-5-(2fluorophenyl)-7-nitro-2-nitromethylene-2H-l,4-benzodiazepine 4-oxido, and the filtrates were evaporated, dissolved ln dlchloromethane and filtered through a Bintorod glass funnel containing 200 g of Florisil (trade mark).The Florisil was eluted with dichloromethane (600 ml), ether (600 ml) and ethyl acetate (1.2 1). The ether and ethyl acetate fractions were combined and concentrated to give additional final product. A sample was recrystallized from a mixture of tetrahydrofuran and hexane to give the pure product as yellow prisms, mp. 216-220°.

A suspension of 25 g (0.0698 m) of l,3-dihydro-5-(2f luorophenyl)-7-nitro-2-nltromethylene-2H-l, 4-benzodiazepine 4-oxlde in 1.3 1 of absolute ethanol was treated with 10 teaspoons of Raney nickel and hydrogenated at atmospheric pressure and room temperature for 9 hr. The mixture wao filtered through Celite and the filtrate was evaporated, to dryneou.

A sample of the oil was crystallized from tetrahydrofuran to give the intermediate 7-amino-2-aminomethyl-l,3-dihydro-5(2-fluorophenyl)-2H-l,4-benzodiazepine as yellow prisms which melted with decomposition at 185-192°.

Without further purification, the oil obtained from the reduotion was heated under reflux for 2 hr. in a solution of 300 ml of absolute ethanol, containing 4.5 ml (0.0257 m) of ethanolic hydrogen chloride and 50 g (0.309 m) of triethy 1orthoaoetate. The mixture was then evaporated to dryness and the residue wae dissolves in 150 ml of dichloromethane which was washed with 100 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness.

The residual oil, which was crude 8-acetylamino-3a,4dihydro-6-(2-fluorophenyl)-1-methy1-3H-imidazo[1,5-a][1,4]benzodiazepine, was dissolved in 500 ml of benzene and treated with 100 g of activated manganese dioxide. The mixture was refluxed and stirred for 9 hr. using a Dean Stark trap. An additional 25 g of activated manganese dioxide was added and after 4 hr. of refluxing the manganese dioxide was removed by filtration and was washed with 500 ml of tetrahydrofuran.

The filtrates were combined and evaporated to drynese. The reeidual oil, whioh was 8-acetylamino-6-(2-fluorophenyl)-1mothyl-4H-imidazo-[l,5-a][l,4]benzodiazepine, was disoolvcd ln 75 ml of methanol and an excess of ethanolic hydrogen chloride was added. After 10 min, 100 ml of water was added, and after an additional 20 min, during which time the 8-ocetyl group was hydrolyzed, a mixture of ice and dilute ammonium hydroxide was added until the solution waa basic.

The reaction was filtered and the precipitate and filtrates were extracted separately with diehloromethane. The extraots were dried, and evaporated. The extract from the filtrates were crystallized from isopropanol to give 8-amino-6-(2-fluorophenyl )-l-methyl-4H-imidazo-(1,5-a][1,4]benzod iazepine isopropanol and the extraot from the precipitate was chromatographed through Florisil, first with diehloromethane and then with ether and ethyl acetate containing 10% (v/v) of methanol gave, after evaporation and crystallization from isopropanol, additional product. Recrystallization of the combined products from isopropanol gave the product as white rods, m.p. 135-145° Example 19 A mixture of 17 g (0.05 m) of racemic 8-chloro-l,4d imethy1-6-(2-fluorophenyl)-4H-imidaeo[1,5-a](1,4]benzodiazepine which had been obtained from its dihydrochloride by partitioning between methylene chloride and aqueous ammonia, 18,8 g (0.05 m) of Ο,Ο’-dibenzoyl-d-tartaric acid hydrate and 170 ml of ethanol waa boiled until solution was complete. For crystallization the solution was allowed to sit overnight. The separated crystals were collected, washed with ethanol and ether to yield the Ο,Ο'-dibenzoyl-d-tartrate with m.p. 140-142 Recrystallization from ethanol/ether yielded a product with m.p. 141-142° and [α]^ - 43-39 (c = 1% in methanol). - 60 41844 A solution of 1.6 g (0.0106 a) of 1-tartaric aoid in 11 ml of ethanol was added to a solution of 3*5 g of the levorotatory base liberated from the above Ο,Ο'-dibenzoyl-d-tartrate in 11 ml of ethanol. The crystals obtained were collected and washed with ethanol and ether to yield (+)-8-chloro-l,4dimo thyl-6- (2-f luorophenyl) -4H-imidazo [1,5-a] [ 1,4 ]benzodiazepine 1-tartrate, m.p. 178-180°. Recrystalllzation from ethanol gave produot with m.p. 183-185° and [a]^ +25.69° (c = 1.012% in methanol). The amorphous base liberated from this salt showed a rotation of [o]^ -36.74° (c = 0.939% in methylene chloride).

Example 19 The mother liquor left after separation of the crystalline salt with Ο,Ο'-dibenzoyl-d-tartaric acid described in the preceding ·. example was evaporated and reconverted to the base by partitioning between aqueous ammonTa and methylene chloride.

The methylene ohloride solution was dried over sodium sulfate and evaporated to yield partly resolved base.

A solution of 9.7 g (0.029 m) of this material in 15 ml of ethanol was treated with a solution of 4·4 g of d-tartaric acid in 14 ml of ethanol. The crystals which separated after several hours were collected to yield (-)-8-chloro-l,4-dimethy16-(2 -fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine d-tartrate, m.p. 176-178°. Recrystallization from ethanol gave a product with m.p. 182-184° and [α]ρ5ο -24.96° (0.9616% in methanol). The amorphous base liberated from this salt showed a rotation of (a]25° +37.6° (c = 1.0% in methylene chloride). - 61 41844 Example 20 A solution of 19-3 g (0.06 m) of l,3-dihydro-7-(2-methy 11.3- dloxolan-2-yl)-5-phenyl-2H-l,4-benzodiazepin-2-one In 300ml of dry tetrahydrofuran was treated under an atmosphere of argon with 3.1 g (0.075 m) of a 57% suspension of sodium hydride in mineral oil. The mixture was heated under reflux for I hr., cooled to room temperature when 22.2 g (0.087 m) of dimorpholinophoephinic chloride was added. The mixture was allowed to stir at room temperature for 2 hr. and then stand overnight. Sodium chloride was removed by filtration and the crude 7-(2mothy1-1,3-dioxolan-2-yl)-2-[bis(morpholino)phosphinyloxy]-5phenyl-3H-l,4-benzodiazepine was obtained by removal of the solvent and crystallization of the residue from ether.

A mixture of 100 ml of dry N,N-dimethylformaaide and 6.8 g of nitromethane was treated under an atmosphere of argon with 2.8 g (0.066 m) of a 57% suspension of sodium hydride in mineral oil. The mixture was 3tirred for 1 hr. at room temperature when a solution of 18 g (0.033 m) of crude 7-(2-methyl1.3- dioxolan-2-yl)-2[bis(morpholino)phosphinyloxy] 5-phenyl3H-1,4-benzodiazepine in 50 ml of dry N,N-dimethylformamide was added. The reaction mixture was allowed to stand at room temperature for 15 hrs. when the dark viscous liquid was poured over a mixture of ice and dilute acetic acid. The bright yellow precipitate was removed by filtration, dissolved in dichloromethane which was washed with dilute ammonium hydroxide and* water, dried over anhydrous sodium sulfate and evaporated. The original filtrate was extraoted with dichloromethane which wae washed, dried and evaporated as above. The two crude residuee were combined and chromatographed over Florisil.

Using dichloromethane, 10% (v/v) other as the eluent and monitoring the fractions by tic, several fractions containing the product were collected and evaporated. Crystallization and reoryatallization from a mixture of a i eht oromethane and hexane gave the pure 2,3-dihydro-7-(2-methyl-l,3-dioxolan2-yl)-2-nltromethylene-5->phenyl-lH-l,4-bensodiazepine as pale yellow prisms, m.p. 158-161°.

Hydrogenation cf 5 g (0.0137 m) of 2,3-dihydro-7(l-methyl-l,3-dioxolan-2-yl)-2-nitromethylene-5-pheny1-1Ή1,4-benzodiazepine ln 250 ml of absolute ethanol in the presence of 1 teaspoon of Raney nickel for 3-5 hours yielded crude 2-aminomethyl-2,3-dihydro-7-(l-methyl-l,3-dioxolan2-yl)-5-phenyl-lH-l,4-benzodiazepine. To a solution of 4 g (0.0119 m) of this compound in 75 ml of absolute ethanol was added 0.7 g (0.0037 m) of p-toluene sulfonic acid and 6 g (0.037 m) of triethyl orthoacetate. The mixture was refluxed for 2 hours, evaporated to dryness and the residue was dissolved in 50 ml of dichloromethane. This was washed with 25 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to give crude 3a,4-dihydro-lmethyl-8- (1-methy 1-1,3-di oxolan-2-yl) -6-phenyl-3H-imidazo [ 1,5-a] [1,4]benzodiazepine as an oil.

A solution containing 3-8 g (0.0105 m) of this crude oil, and 18 g of activated manganese dioxide in 100 ml of toluene was refluxed and stirred for 2 hours using a Dean Stark trap.

The mixture was filtered and washed with a mixture of 250 ml of diehloromethane and 250 ml of tetrahydrofuran. The filtrates were evaporated and dlaoolvod ln a small amount of isopropanol and treated with 1.4 g (0.0121 m) of maleic acid in ethanol. Ether was added and the precipitate waa filtered and reorystollized from a mixture of methanol and ether to give l-methyl-8(2-mothy1-1,3-dioxolan-2-y1)-6-phenyl-4H-imidazo[l,5-a][l,4]10 benzodiazepine maleate methanol (2/1) as off white prisms, m.p. 179-182°.

Example 21 A solution of 0.3 g (0.1000607 m) of l-methyl-8(2-methy 1-1,3-dioxolan-2-yl) -6-phenyl-4H-imidazo[ 1,5-a J [ 1,4 ] benzodiazepine maleate methanol (2/1) in 10 ml (0.01 m) of IN hydrochloric acid was allowed to stand for 18 hours. A small amount of charcoal was added and the reaction mixture was filtered. The solution was made basic with nmmnninm hydroxide, extracted with 25 ml of diehloromethane, dried over anhydrous sodium sulfate and evaporated to dryness.

The residue was dissolved in isopropanol and 0.35 g (0.10015 m) of picric acid in 5 ml of ethanol was added. The solution was evaporated and the residue was crystallized from methanol. Reorystallization from a mixture of tetrahydro25 furan and isopropanol gave 8-acetyl-l-methyl-6-phenyl-4Himidazo[l,5-a][l,4]benzodiazepine dipicrate as yellow prisms 41644 m.p. 225-230°.

Example 22 A solution of 1 g (0.00317 m) of 8-acetyl-l-methyl6-phenyl-4H-imidazo[l,5-a][l,4]benzodiazepine dipicrate in 75 ml of absolute ethanol was treated with 0.78 g (0.0205 m) of sodium borohydride and after 18 hours the solution was evaporated to drynese. The residue was acidified with dilute acetic acid, made basic with ammonium hydroxide and the mixture was extracted with 75 ml of dichloromethane. The organic layere were combined, dried over anhydrous sodium sulfate and evaporated to dryness. The oil thus obtained was dissolved in isopropanol and 1.6 g (0.007 m) of picric acid in 20 ml of ethanol was added. The precipitated salt was filtered and recrystallized twice from methanol to give 8-(l-hydroxyethyl)-l-oethyl-6-phenyl-4H-imidazo( 1,5-a] [1,4]benzodiazepine dipicrate as yellow rods, m.p. 223-225°.

Example 23 The filtrates from the reaction of Example 22 were concentrated and the crude product was filtered off. Re20 crystallization twice from a mixture of tetrahydrofuran and methanol gave pure 8-(l-hydroxyethyl)-l-methyl-6-phenyl5,6-dihydro-4H-imidazo[1,5-a][l,4]benzodiazepine dipicrate ae yellow rods, m.p. 143-145°. 41344 Example 24 A solution of 56·4 g (0.20 mole) of l,3-dihydro-7ethyl-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-one in 2.0 1 of tetrahydrofuran containing 4 moles of monomethyl5 amine was chilled in an ice bath. To this was added 33.0 ml (0.30 mole) of titanium tetrachloride in 350 ml of benzene. The mixture was stirred at room temperature for three days.

The titanium tetrachloride was decomposed with 100 ml of water. The inorganic salts were removed by flltra10 tion. The filtrate was evaporated to drynees in vacuo. The residue was partitioned between methylene chloride and water. The methylene chloride layer was dried over anhydrous sodium sulfate, evaporated to drynees in vacuo. The residue en crystallization from acetonitrile yielded 7-ethyl-5-(2-fluoro15 phenyl)-2-methylamino-3H-l,4-benzodiazepine as light yellow prisms, m.p. 172-174°.

An analytical sample was prepared by recrystallization from acetonitrile to give light yellow prisms, m.p. 172-174°.

Sodium nitrite (8.6 g, 0.125 m) was added in three portions over a 1/2 hour period to a solution of 29.5 g (0.1 m) of 7-athy 1-5-(2-fluorophenyl)-2-methylamino-3H-l,4benzodiazepine in 100 ml of glacial acetic acid. After stirring for another 1/2 hour at room temperature, the mixture was diluted with ice-water and extracted with methylene ohloride. The extraots were washed with water and aqueous bicarbonate, dried over 'sodium sulfate and evaporated to leave orude 7-ethyl-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-l,4-benzodiazepine as a yellow oil.

The material prepared above was dissolved in 100 ml of dimethylformamide and the solution was added to a mixture of 100 ml of dimethylformamide, 35 ml of nitromethane and 9.9 g of potassium t-butoxids which had been stirred for 1/2 hour at room temperature. After completion of the addition,the reaction mixture was atirred for 1 hour at room temperature and for 30 minutes on the steam bath. The oooled solution was .. acidified with glacial acetic aoid, diluted with water and extracted with methylene chloride. The extracts were washed with water, dried and evaporated. The residue wa3 dissolved in 50 ml of ethanol and vao allowed to crystallize in the refrigerator overnight after seeding. The yellow crystals were collected and recrystallized from ethanol yielding 1.3- d ihydro-7-ethy l-5-(2-fluorophenyl)-2-nitromethy lene-2H1.4- benzodiazepine, m.p. 138-140°. Seed crystals were obtained by chromatography of the crude product over 40-fold amount of silica gel using 5% (v/v) of ethylacetate in methylene chloride. The analytical sample was recrystallized from ether/hexane, m.p. 138-141°. 1,3-Dihydro-7-ethy1-5-(2-fluorophenyl)-2-nitromethylenc25 2H-1,4-benzodiazepine (2.6 g) wae hydrogenated for 4 hours with Raney nickel (1 teaspoonful) in 30 ml of ethanol. The catalyst _ who .'Kipnml.i’d by filtration mul the filtrate wan eva|«»rate«l.

Tho residue wan diaaolved in ether and the amine waa extracted with 10# aqueous acetic acid. The extracts were washed with ether and made alkaline with ammonia. The precipitated amine was extraoted with methylene chloride. The extraots were dried and evaporated to leave 1.5 g of orude 2-aminomothy1-2,3dihydro-7-ethyl-5-(2-fluorophsnyl)-lH-l,4-benzodiazepine. This material was dissolved in 50 ml of xylene. The solution was then heated to reflux for 2 hours after addition of 3 ml of triethyl10 orthoacetate. The residue obtained after evaporation under reduced pressure was chromatographed over 50 g of silica gel using 20# methanol in methylene chloride. The homogenous fractions were combined and evaporated to yield 3a,4-dihydro8-ethy 1-6-( 2-f luorophenyl) -1-methy l-3H-imidazo[1,5-a][1,4]15 benzodiazepine. This material was dissolved in 50 ml of toluene and the solution was heated to reflux for 1 hour after addition of 5 g of activated manganese dioxide. The inorganic material was separated by filtration and the filtrate was evaporated.

The reeidue was dissolved in ether and treated with ethanolic hydrogen chloride and acetone. The crystalline dihydrochloride (m.p. 248-255°) was collected and reconverted to the base by partitioning between methylene chloride and aqueous ammonia.

The methylene chloride layer was dried and evaporated. Crystallization of the residue from ether/hexane yielded 8-ethyl25 6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine, m.p. 152-154°.

Example 25 Sodium nitrite (27.6 g, 0.4 m) was added in portions over a period of 30 minutes to a solution of 90.45 g (0.3 m) of 7-chloro-5-(2-fluorophenyl)-2-methylaraino-3H-l,4-benzodiazepine in 400 ml of glacial acetic acid. Following cv.apletion of the addition, the mixture was stirred at room temperature for 1 hour and was then diluted with 1 1 of water and extracted with methylene chloride. The extracts were washed twice with water and then with 10% aqueous sodium carbonate solution.

The solution was dried and evaporated to yield crude 7-chloro5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine as a yellow oil.

Example 26 To 5 ml of aeetic anhydride was added 0.3 g (0.00082 m) of 8-amino-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiaseplne lsopropanol and the reaotion mixture was heated on the steam bath for 1 hour, and then evaporated to dryness. The residue was dissolved in 25 ml of dichloromethane vhich was washed with 15 ml of 5% potassium oarbonats solution, dried over anhydrous sodium sulfate and evaporated to dryness. The product was reorystallized twice from a mixture of methanol and ethyl acetate to give 8-acetamido-6-(2-fluoropheny 1)-1mothyl-4H-imidazo[l,5-e]rl,4]benzodiazepine as white rods, m.p. 326-331°.

Example 27 A solution of 0.8 g (0.0024 m) of 8-acetamido-6-(2-fluo25 rophenyl)-l-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine in 10 ml of dry Ν,Ν-dimethylformamide under nitrogen was treated with 0.13 R (0.003 a) of 55% sodium hydride in mineral oil and after 30 minutes the reaotion mixture was oooled in an ice bath. To the stirred reaction mixture 0.43 g (0.003 m) of methyl iodide was added and after 18 hours at room temperature the reaction mixture was poured into water. Filtration afforded the crude product which was reorystallized from a mixture of ethyl acetate and ether to give 6-(2-fluorophenyl)-1-methy 1-8(N-mothylacetamido)-4H-imidazo[1,5-a][1,4]benzodiazepine as off white prisms, m.p. 217-223°.

Example 20 Λ solution of 0.3 g (0.000828 m) of 6-(2-fluorophenyl)1-methy1-8-(N-methylaoetamido) -4H-imidazo[ 1,5-a] [ 1, ^benzodiazepine in 10 ml of methanol was treated with 3 ml of concentra5 ted hydrochloric aoid and refluxed for 1 hour. The solution was made basic with ammonium hydroxide and then partitioned between 50 ml of diehloromethane and 50 ml of water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in 10 ml of dichloro10 methane and filtered though Florisil. It was eluted with ether/ ethyl acetate and finally ethyl acetate containing 5% methanol. This last mixture was evaporated and the residue crystallized from a mix ture of ethyl acetate and ether to give 6-(2-fluorophenyl)-1-methyl 8-methylamino-4H-imidazo[l,5-a][l,4]benzodiazepine as off white prisms, m.p. 255-259°.

Example 29 A solution of 0.3 g (0.00082 m) of 8-amino-6-(2-fluorophenyl )-1-methyl-4H-imidazo[l,5-a][1,4]benzodiazepine isopropanol in 0.5 ml of sulfuric acid was treated with 4 g of ice followed by 0.2 g (0.0029 m) of sodium nitrite. After 5 minutes this was added to a fresh solution prepared by adding 1 g (0.00625 m) of copper sulfate in 10 ml of water to 1 g (0.00794 m) of sodium sulfite in 5 ml of water and then adding this to 8 g (0.116 m) of sodium nitrite in 40 ml of water.

After 15 minutes the reaction mixture was wanned to 35° for 5 minutes made basic with 10% potassium carbonate solution and extracted with 100 ml of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and applied to a silica gel thick layer plate. This was developed in a mixture of ethyl acetate and ethanol (10/1), and the spot having an Rf of 0.5 was scraped off. Crystallization from methanol and reorystallisation from a mixture of dlchloromethano and ether gave (2-f luoropheny l)-[ 2-( 5-hydroxyme thy 1-2methy1-1-lmidazoly 1)-5-nitrophenyl]methanone as off white prisms, m.p. 188-192°.

Bxamrle 30 A solution of 0.5 g (0.00137 m) of 8-amino-6-(2-fluoropheny 1 )-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine isopropanol in 20 ml of formic acid and 5 ml (0.062 m) of 37# formal15 dehyde waB heated on the steam bath for 3 hours, and then evaporated to dryness. The residue was dissolved in 50 ml of dichloromethane, which was washed with 15 ml of 10% potassium carbonate solution, dried over anhydrous sodium sulfate and concentrated. The residual oil was applied to and developed on 2 silica gel thick layer plates in a mixture of ethyl acetate and ethanol (7/1). The material having an Rf of 0.4 was scraped off, washed with methanol, filtered and evaporated.

The oil was dissolved in ether and 5 ml of‘a 10% ethanolic solution of picric acid was added. The precipitate was filtered and reorystallized from a mixture of tetrahydrofuran and isopro panol to give (2-fluorophenyl)[2-(2-methyl-5-dimethylamino72 methyl-l-imidazolyl)-5-dimethylaminophenyllmuthanone dipicrate as yellow prisms, m.p. 228-230°.

I Example 31 A) A solution of 3 g (O.OO92O m) of 8-chloro-6-(2-fluoro5 phenyl)-l-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine in 50 ml of water and 0.5 ml (0.4092 m) of concentrated sulfuric acid was treated with 1.5 g (0.0217 m) of sodium nitrite. After 18 hours an additional 0.5 ml ot sulfuric acid and 1.5 g of sodium nitrite Was added, and after 10 minutes the reaction was made basic with ION sodium bydroxlde. The reaction mixture was extracted with 75 ml of dichloromethane, which was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of tho residue from a mixture of ethyl acetate and ether gave (2-fluorophenyl)-[2 - (5-hydroxymethyl-2-methyl-1-imidazolyl )15 5-chlorophenyl]methanone as white prisms, m.p. 165-168°.

B) A solution of 1 g (0.00240 m) of 5-aminomethyl-l-[4chloro-2-(2-fluorobenzoyl)-phenyl]-2-methylimidazole dihydrochloride waa dissolved in 20 ml of water and 1 g (0.0145 m) of sodium nitrite wae added slowly with stirring in an ice bath.

After 3 hours the reaction was made basic with ION sodium hydroxide and extracted with 50 ml of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethyl acetate gave (2-f luorophenyl) μ 2- (5-hydroxymethyl-2-methy1-1-imidazoly 1) -525 chlorophenyljmethanone as white prisms, m.p. and amp with a sample prepared as above 163-166®.

To a mixture of 0.1 g (O.OOO275 m) of 8-amino-6-(2-fluo• I rophenyl) -l-aethyl-4H-imldazo [ 1,5-a] [1,4] benzodiazepine lsopropanol and 5 ml of water was added 1 ml of concentrated hydro5 ohlorio aoid. The reaotion was cooled ln on ice bath and 0.15 g (0.00217 m) of sodium nitrite was added slowly with stirring. After 1 hour the reaotion mixture was poured into a solution of 0.2 g (0.00202 m) of cuprous chloride ln 50 ml of water whioh had been heated to 70°. After 18 hours the reaotion was mads baslo with sodium hydroxide, extraoted with dichloromethane (2 x 50 ml) drie* over anhydrous sodium sulfate and evaporated to dryneeB. The residue was developed on a silica gel thick layer plate in a mixture of ethyl acetate and methanol (10/1). The produot which had an Rf or 0.7 was scraped off the plate, stirred with methanol and filtered. Evaporation and crystallization of the crude product from a mixture of ethyl acetate and ether gave (2-fluorophenyl)-[2-(5-hydroxymethyl-2methy1-1-imidazolyl)-5-chlorophenyl]methanone as white prisms, m.p. and mmp with an authentic sample 159-166°.

Example 32 A solution of 0.5 g (0.00145 m) of (2-fluorophenyl)[2-( 5-hydroxymethyl-2-methy 1-1-imidazoly 1) -5-chloropheny 1 ] methanone in 25 ml of dichloromethane. was treated with 0.15 ml (0.00155 m) of phosphorous tribromide in an ice bath and after 1 hour at room tempera74 ture was poured into 50 ml of liquid ammonia. After the ammonia had evaporated the reaction was partitioned between 50 ml of dichloromethane and water. The organic phase was separated and dried over anhydrous sodium sulfate. The solution was concentrated and the residue was applied to 2 silica gel thick layer plates which were developed in a mixture of ethyl acetate/10% methanol.

The compound which had an Rf of 0.6 was scraped off, stirred with methanol and filtered. The solution was treated with 0.1 g (0.000962 m) of maleic acid and evaporated. The residual salt was crystallized from a mixture of lsopropanol and ether to give the maleate of 8-chloro-6-(2-fluorophenyl)1-methyl-4H-imidazo (l,5-aj Jl,4] benzodiazepine as white prisms, m.p. and mmp with an authentic sample 112-115° (melting point of solvated product). The base was obtained by partitioning the salt between dichloromethane and water, adjusting the pH, separating the layers and evaporating the organic phase. Crystallization of the product from ether gave white prisms, m.p. and mmp with an authentic sample 154-157°.

Example 33 A mixture of 9.75 g (0.03 m) of 8-chloro-6-(2-fluorophenyl) -1-methy1-4H-Imidazo[1,5-aJ [l,4}benzodiazepine, 200 ml of methylene chloride and 12 g (0.07 m) of m-chloroperbenzoic acid wae stirred for 1 1/2 hours. The solution was then extracted with 3 x 150 ml of IN hydrochloric acid. The extracts were washed with ether, made alkaline with ammonia and extracted with methylene chloride. The methylene chloride extracts were dried and evaporated and the residue was crystallized from ethyl acotato to loavo a product which was further purified by chromatography over 100 g of silloa gel using 5% (v/v) of ethanol In methylene chloride· The clean, fractions were combined and evaporated. Crystallization of the residue from ethyl aoetate/ether yielded 8-chloro-6-(2-fluorophenyl)1-ms thy l-4H-imidazo[ 1,5-a] [1,4] benzodiazepine 5-oxide as colorless crystals, m.p. 245-246° (deo.).

Example 34 A solution of 4 g of 8-chloro-6-( 2-f luoro phenyl)-ΙΙΟ msthyl-4H-imidazo[ L,5-4-][i,4]bonzodiazepins 5-oxide in 100 ml of acetic anhydride was heated on the steam bath for 24 hours. The rsagont was evaporated under reduced pressure, at the end azeotroplcally with xylene. The residue was chromatographed over 80 g of silica gel using 20% (v/v) methylene ohloride in ethyl acetate. Crystallization of the clean fractions from methylene chloride/ether yielded 4-acetoxy-8-chloro-6-(2-fluorophenyl) -1-methyl-4H-imidazo[ 1,5-a][1,4]benzodiazepine as colorless crystals, m.p. 201-202°.

Example 35 4-Aoetoxy-8-chloro-6- (2-f luorophenyl) -l-methyl-4Hlmidazo[l,5-a][ 1,4]benzodiazepine (0.5 g, 1.3 mmol) was added to 40 ml of methanol containing 4 mmol of sodium methoxide. After stirring under nitrogen for 1/2 hour at room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved ln water and the solution was acidified with acetic acid. The precipitated crystals were collected and dissolved in methylene chloride. The solution was dried and evaporated and the residue was crystallized from methylene chloride/ether to yield 8-chloro-6-(2-fluorophenyl)-4-hydroxy1-raethyl-4H-imidazo £l,5-a)(1,4] benzodiazepine as colorless crystals, m.p. 185-186°.

Example 36 A solution of 10 g (0.0358 m) of 7-cyano-2,3-dihydro-5(2-fluorophenyl)-lH-l,4-benzodlazepin-2-one in 150 ml of dry tetrahydrofuran under argon was treated with 2.4 g (0.0537 m) of 54% sodium hydride and the reaction was stirred and refluxed for 1 hour. This was cooled to 0° and 13.7 g (0.0537 m) of phosphorodimorpholidic chloride was added. After 18 hours the reaction mixture was filtered, concentrated to a small volume and ether was added. The precipitate was filtered and recrystallized from a mixture of diehloromethane and ether to give 7-cyano-5-(2-fluorophenyl)-2-bis-(morpholino) phosphinyloxy-3H-l,4-ben2odiazepine as white rods, m.p. 194-197°.

Example 37.

To a solution of 1.6 g (5 mmoles) of 8-chloro-5,6-dihydro-6-(2-fluorophenyl)-l-methyl-4H-imidazo (l,5-a][l,4] benzodiazepine in 10 ml of pyridine was added 1.2 g (6 mmoles) of E“toIuenesulfonyl chloride. After standing at room temperature for 19 hours, the reaction mixture was diluted with water and extracted with methylene chloride. The organic extract was dried and concentrated in vacuo to dryness. The residue was crystallized from a mixture of methylene chloride, ether and gave 8-chloro-6-(2-fluorophenyl)-5,6-dihydro-l-methyl-5-(4-methyl5 phenylsulfonyl)-4H-imidazoQl,5-a](l,43 benzodiazepine melting at 252-253°. After recrystallization from tetrahydrofuran the pure product formed yellow prisms with the same melting point.

To a stirred solution of 2.4 g (5 mmoles) of 8chloro-6-(2-fluorophenyl)-5,6-dihydro-l-me thy1-5-(4-methylphenylsul fonyl)-4H-imidazoQ.,5-a)[i,4lbenzodiazepine in 120 ml of dry tetrahydrofuran was added 1.1 g of potassium tert-butoxide.

After stirring at room temperature for 2 hours the reaction mixture was poured into ice water and extracted with a 50% mixture of ether and petroleum ether. The organic extract was dried and concentrated In vacuo to dryness. The residue was crystallized from a mixture of ether, petroleum ether and gave 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imldazo Q,5-a]Q.,4] benzodiazepine melting at 152-153°. The mixed melting point with an authentic sample gave no depression. 2o Example 38 To a stirred solution of 1.2 g (3.5 mmoles) of 8-chloro6- (2-fluorophenyl) -1-methyl-4H-imidazo [Ϊ,5-ajQ.,4] benzodiazepine -oxide in 120 ml of ethanol was added slowly 1.2 g (31 mmoles) of eodium borohydride. After stirring for 4.5 hours at room temperature the reaction mixture was diluted with about 175 ml of water and produot melting at 246-248° was separated by filtration, After recrystallization from a mixture of methylene chloride/ether, the pure 8-chloro-6-(2-fluoropheny 1)-5,6-dihydro-5-hydroxy-l-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine formed colorless needles melting at 251-252°.

A solution of 0.3 g of 8-chloro-6-(2-fluorophenyl)5,6-d lhydro-5-hydroxy-l-methy l-4H-imidazo[l, 5-a] [1,4]benwr>10 diazepine in a mixture of 10 ml of pyridine and 2 ml of acetic anhydride was left at room temperature for 19 hours. The reaction mixture was concentrated in vacuo to dryneas. The residue was dissolved in 20 ml of methanol and 0.2 g of sodium methoxide added. After standing at room temperature for 45 minutes, the reaction mixture was concentrated in vacuo to dryness. The residue was partitioned between methylene chloride and water. The organic layer was separated, dried and concentrated in vacuo to dryness. Tho residue was crystallized from a methylene chloride/ether mixture and gave starting material melting at 255-256°. Concentration of the filtrate and crystallization of the residue from ether gave 8-chloro-6-(2-fluorophenyl)-1methyl-4H-imidazo[l,5-a][l,4]benzodiazepine melting at 158-160°. The mixed melting point with an authentic sample gave no depression.

Example 39 A solution of 1.5 g of 8-chloro-5,6-dihydro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in a mixture of 10 ml pyridine and 5 ml of acetic anhydride was left at room temperature for 18 hours. The reaotion mixture was concentrated in vacuo to dryness. The residue was dissolved in methylene ohloride and washed with dilute potassium hydroxide. The organic layer was separated, dried and concentrated in vacuo to dryness. The residue was crystallized from a 10 mixture of methylene chloride, ether, petroleum ether and gave 5-acetyl-8-chloro-6-(2-fluorophenyl)-5»6-dihydro-l-methyl4H-imidazo[1,5-a][1,4]benzodiazepine melting at 185-186°. After recrystallization from methylene chloride the pure product formed eolorless prisms melting at 186-187°.

Example 40 To a stirred solution of 27.8 g (92 mmoles) of DL-2-amino methy1-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in a mixture of 450 ml of methylene chloride and 300 ml of acetic acid was added slowly 27.8 g of zinc dust. After stirring at room temperature for 4 hours the reaction mixture wae filtered over Celite. The filtrate was diluted with ice water, made alkaline with 50# potassium hydroxide solution and extraoted with methylene chloride. The organlo extract wae separated, dried and concentrated in vacuo to dryness.

The residue was orystallized from ether and gave 2-aminomethyl7-chloro-2,3,4,5-t etrahydro-5- (2-f luoropheny 1) -lll-l, 4-benzodiazepine melting at 119-120°. After reoryatallization from ether the pure produot formed, slightly yellow prisms melting at 127-128«.

The hydrochloride was prepared by treating a solution of the base in lsopropanol with an excess of concentrated hydrochloric acid. After recrystallization of the salt from a mixture of water and lsopropanol the pure product formed elightly yellow needles melting at 268-271°.

A) A solution of 3 g (10 mmoles) of rac.2-aminomethyl-7ohloro-2,3,4,5-tetrahydro -5- (2-f luorophenyl) -1H-1,4-benzozodiazepine in a mixture of 30 ml of xylene and 10 ml of triethy lorthoacetate (97#) was refluxed for 4 hours. The reaction mixture was diluted with ether and extracted with dilute ice cold hydrochloric acid. The acid extract was made alkaline with dilute potassium hydroxide and extracted with methylene chloride. The organic layer was separated, dried and concentrated in vacuo to dryness. The residue was crystallized from ether and gave 8-chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydrol-methyl-3H-imldazo(l,5-a][l,4]benzodiazepine (Isomer A) melting at 187-189°. After recrystallization from a mixture of methylene chloride and ether the pure product formed slightly yellow prisms melting at 189-190°.

B) To a stirred solution of 2.5 g of 8-chloro-3a,4-dihydro6-(2-fluorophenyl)-1-methy l-3H-imidazo[ 1,5-a] [l,4]benzodiazcpine in a mixture of 100 ml methylene ohloride and 25 ml of acetic aoid was added slowly 2.5 g of zino dust. After stirring at room temperature for 4 hours, the reaction mixture was filtered over Celite. The filtrate was diluted with ice water, made alkaline with 50% potassium hydroxide and extracted with methylene chloride. The organio extraot was separated, dried and concentrated in vaouo to dryness. The residue wae crystallized from ether and gave 8-chloro-6-(2-fluor&pkenyl)-3a,4,5,6-tetrahydro-l-methyl3H-imldazo[l,5-a][l,4]benzodiazepine (Isomer A) which was identical with the product prepared above, m.p. and mmp 189-190°.

C) A solution of 3.2 g (10 mmoles) of 8-chloro-3a,4-dlhydro15 6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzod iaz epine in 50 ml acetic acid and 10 ml of water was hydrogenated at room temperature and atmospheric pressure in the presence of 0.4 g of prehydrogenated platinum oxide. After 15 minutes, 10 mmoles of hydrogen were absorbed. The catalyst was separated by fil20 tration and the filtrate concentrated in vacuo to dryness. The residue was dissolved ln methylene chloride and washed with an excess of ice cold dilute sodium carbonate. The organio layer was separated, dried and concentrated in vacuo to dryness. The residue was orystalllzed from a mixture of ether/petroleum ether and gave 8-chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydrol-methyl-3H-imidazo[l,5-a][l,4]benzodiazepine (Isomer B) melting at 108-110°. After recrystallization from ether the pure product formed colorless prisms melting at 110-112°.

A mixture of 2.9 g of 8-chloro-6-(2-fluorophenyl)3a, 4,5,6-tetrahydro-l-methyl-3H-imidazo Q, 5-^0·»41 benzodiazepine, 90 ml of toluene and 15 g of activated manganese* dioxide was stirred and refluxed for 2 hours. The reaction was filtered over Hyflo and the filtrate concentrated in vacuo to dryness. The reeidue was crystallized from ether and gave 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo £l ,5-a](l ,4jbenzodiazepine which gave no melting point depression with an authentic sample.

Example 41 A suspension of 17 g (0.05 m, of 7-chloro-l,3-dihydro5-(2-fluorophenyl)-2-nitromethylene-2H-l,4-benzodiazepine-4oxide in 200 ml of tetrahydrofuran and 100 ml of methanol was hydrogenated in the presence of 17 g of Raney nickel at an initial pressure of 155 psi for 24 hrs. The catalyst was removed by filtration and the filtrate was evaporated. The residue was dissolved in 50 ml of 2-propanol and warmed on the eceambath. A warm solution of 17 g of maleic acid in 60 mi of ethanol was added and the salt was allowed to crystallize by cooling in the ice bath. The 2-aminomethyl-7-chloro-2,3dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine dlmaleate consisted of yellow crystals with mp. 196-198®. 2-Aminomethy 1-7-chloro-2,3-dihydro-5-(2-fluoro phenyl) lH-l,4-benzodiazeplne dimaleate (8.0 g, 0.015 m) was partitioned between methylene chloride and aqueous ammonia. The methylene chloride solution was washed with water, dried over sodium sulfate and evaporated. The residue wae dissolved in 50 ml of pyridine. After addition of 10 ml of acetic anhydride the mixture was heated on the steam bath for 4 hours. The reagents were evaporated under reduced pressure and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organlo layer was dried and evaporated. Crystallization of the residue from methylene chloride/ ether with seoding yielded l-acetyl-2-acetylaminomethyl-7chloro-2,3-dihydro-5- (2-fluorophenyl)-1H-1,4-benzodiazepine, mp. 213-215°. Seeds were obtained by chromatography over silica gel (40 fold amount) using 10% (v/v) ethanol in methylene chloride for elution. The analytical sample was recrystallized from ethylacetate/hexane and had a melting point of 215-217°.

A mixture of 0.5 g of 1-acety 1-2-acetylaminomethyl-720 chloro-2,3-dihydro-5-(2-fluorophenyl)-lH-l,4-benzodiazepine and 10 g of polyphosphorio acid was heated to 150-170° for 10 min. The cool reaction mixture was dissolved in ice-water and the solution was made alkaline with ammonia. The precipitated base was extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over 10 g of silica gel using 20% methanol in methylene ohloride. The clean fractions were combined and evaporated. The residue was crystallized from ether to yield 8-ohloro-3a,4-dihydro-6-(2-fluorophenyl)l-mothyl-3H-imidazo[l,5-a][l,4]benzodiazepine, mp. 142-144°.

Example 42 A solution of 2.9 g (0.00927 m) of 2,3-dihydro-5-(2f luorophenyl) -2-nitrome thylene-lH-1,4-benzodiazepine-4-oxide in a mixture of 1 teaspoon of Raney nickel, 90 ml of tetrahydrofuran and 45 ml of methanol was hydrogenated at atmospherio pressure and at room temperature for 2.3 hr. The mixture was filtcrod, and the nickel was washed with dichloromethane. The combined filtrates were evaporated and the resulting oil was dissolved in 50 ml of dichloromsthane which was waehed with 50 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to drynees. A solution of 2.2 g (0.019 m) of maleio add in 15 ml of ethanol was added to the oil and after ether was added 2-aminomethy 1-2,3-dihydro-5(2-fluorophenyl)-lH-l,4-benzodiazepine dimaleate hemihydrate crystallized. Recrystallization from a mixture of methanol and ether gave a product as yellow rods, m.p. 147-150°.

A solution of 4.0 g (0.0149 m) of the base of 2-aminomethyl-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine dimaleate hemihydrate in 125 ml of absolute ethanol was treated with 4 g (0.0247 m) of triethylorthoacetate and 0.5 g (0.00263 m) of p-tolucne sulfonic acid. After refluxing the mixture for hr. the reaction mixture was evaporated to dryness. The resulting oil was dissolved in 50 ml of dichloromethane, which was washed with 50 ml of dilute ammonium hydroxide, dried over anhydrous □odium eulfate and evaporated to dryness to yield ths crude 3a, 4-dihydro-6- (2-fluoro phenyl) -1-methyl-3H-imidaso [1,5-a][l,4]benzodiazepine ae an oil.

A) The crude product from the previous paragraph was dissolved in 100 ml of toulene, treated with 18 g of activated manganese dioxide and the mixture was stirred and reflu10 xed for 3.5 hr. using a Dean Stark trap. The reaotion mixture was filtered through Celite and the precipitate was washed with 100 ml of tetrahydrofuran and then 100 ml of dichloromethane.

The combined filtrates were evaporated and the residue was dissolved in 25 ml of dichloromethane. This solution was chromatographed through a Florisil column with dichloromethane, and then eluted with ether. Elution with ethyl acetate and then a 10# (v/v) solution of methanol in ethyl acetate gave the crude product, which was crystallized from ether and then recrystallized from ethyl acetate to give 6-(2-fluorophenyl)20 l-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine as white prisms, m.p. 164-168°.

B) A solution of 1.2 g (0.0041 m) of 3a,4-dihydro-6-(2-fluorophenyl )-l-methyl-3H-imidazo[ 1,5-a][1,4]benzodiazepine in ml of mesitylene and 0.5 g of 10# palladium on charcoal was stirred and refluxed for 28 hr., and then lt was filtered and evaporated to dryness. Crystallization from ethyl acetnte gave 6-(2-fluorophenyl)-l-methyl-4H-imidazo[ l,5-e][ 1,4] benzodiazepine as white prisms, m.p. 162-167°, and a mixture with authentic product melted at 162-168°.

Example 43 A solution of 0.3 g (0.00103 m) of 6-(2-fluorophenyl)l-aethyl-4H-imidazo[l,5-a][l,4]benzodiazepine in 2 ml of concentrated sulfuric aoid was cooled to 0°, and a solution of 0.11 g (0.0011 m) of potassium nitrate in 1.5 ml of concentrated sulfuric acid wae added dropwise. After 18 hr. at room temperature an additional 20 mg (0.0002 m) of potassium nitrate was added and the reaction was stirred for 5 hr. and then poured into a beaker containing ice. The mixture was made baeic with ammonium hydroxide, and extracted with 50 ml of dichloromethane which was separated, dried over anhydrous sodium sulfate, and evaporated to dryness. The oil was dissolved in 3 ml of dichloromethane and applied to a silica gel thick layer plate which wae developed in a mixture of ethyl acetate and ethanol (3:1). The nitrated product was scraped off the plate and stirred with a 1:1 (v/v) mixture of methanol and dichloromethane and filtered. The filtrate# were evaporated and the residue was crystallized from methanol. Recrystallization from a mixture of dichloromethane and petroleum ether gave 6-(2-fluoro-5-nitrophenyl)-l-methyl-4H-imidazo[l,5-a] [1,4Jbenzodiazepine as white prisms, m.p. 199-203°. - 87 41844 Example 44 41.3 g of 8-ohloro-l,4-diaethyl-6-(2-fluorophenyl)4H-imidazo[l,5-a][l,4]bsnzodiazepine dihydrochloride was partitioned between methylene ohloride and aqueoue ammonia. The methylene chloride solution was washed with water, dried over sodium sulfate and evaporated to leave the free base. This material was dissolved in 50 ml of 2-propanol and the solution was treated with a solution of 12 g of maleic aoid in 40 ml of 2-propanol. The solution was gradually diluted with 300 ml of ether. The precipitated crystals were collected and dried to leave 8-chloro-l,4-diu3thyl-6-(2-fluorophenyl)-4H-imldazo[l,5-a][l,4]benzodiazepine maleate,m.p. 130-132° after recryatallizatlon from ethanol/ether.

Example 45 A solution of 5 g (0.00153 0) of 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine in 75 al of dry ethylene dichloride was cooled in an ice bath and 5 g (0.0352 m) of boron trifluoride etherate was added. After 10 minutes a solution of 4 g (0.091 m) of ethylene oxide in 5 ml of ethylene dichloride was added with stirring. After 1 hour at room temperature the mixture was made basic with a solution of potassium carbonate in water. The organic layer was separated, dried over anhydrous sodium sulfate, and evaporated. The roaiduc was dissolved in 50 ml of dichloromethane and fLl— tored through 150 g of Florisil. The Florisil was eluted with 750 ml of diehloromethane and then with 750 ml of ether.

The diehloromethane solution was evaporated and partitioned between 100 ml of ether and 100 ml of 0.5N hydrochloric acid. The aoid layer was separated, made basic with ammonium hy5 droxlde and extracted with 100 ml of dlohloromethane which was dried and evaporated. The oil was dissolved in 15 ml of isopropanol and 0.8 g (0.0069 m) of maleic aoid was added. The solution wae wanned on the steam bath for 5 minutes, cooled and ether was added. The precipitate was filtered, and recrystalli10 zed from a mixture of methanol and ether to give 2-chloro-13a(2-fluorophenyl)-12,l?a-dihydro-6-methyl-9H-llH-imidazo[l,5-a]oxazolo[3,2-d][l,4]benzodiazepine maleate as white prisms, m.p. 195-200°.

The ether solution from the Florisil was concentrated, filtered and recrystallized from ether to give the base as whito prisms, m.p. 178-180°.

Example 46 A stirred solution of 29.9 g (0.1 m) of l,3-dihydro-5(2-fluorophenyl)-7-nitro-2H-l,4-benzodiazepin-2-one in 500 ml of dry tetrahydrofuran was treated portionwise under argon with .5 g (0.125 m) of a 54% mineral oil dispersion of sodium hydride and stirring was continued for 1 hour longer. Dimorpholinophosphine chloride (38 g, 0.15 m) was added to the dark solution in one portion and stirring under argon was continued for hours. The resultant dark mixture was filtered over filter aid and concentrated ln vacuo at 50° to give a dark gum. When the dark gum was stirred at room temperature in 75 ml of ethyl acetate, crystallization occurred to give a paste. After cooling ln an ice bath for 30 minutes the mixture was filtered and the light tan solid was washed 3 times with 35 ml portions of 2tl ether/ethyl acetate and finally with ether. Air drying on the funnel yielded nearly pure 5-(2-fluorophenyl)-2-[bis(morpholino) phosphinyloxy3-7-nltro-3H-l,4-benzodiazepine. Recrystallization from 15 fold amount of ethyl acetate gave off-white needles, m.p. 169-172°.

Example 47 Plfty-four percent eodium hydride ln mineral oil dispersion (11 g, 0.25 m) was added in portions to a stirred solution of 63.2 g (0.2 m) of 7-bromo-l,3-dihydro-5-(2-pyridyl)2H-l,4-benzodiazepin-2-one In 1 1 of tetrahydrofuran under argon. After refluxing on a steam bath for 1 hour, the solution was cooled to room temperature and treated with 76.2 g (0.3 m) of dimorpholinophosphinic chloride portionwise. 2o Stirring at room temperature was continued for 5 hours. The dark mixture was filtered through Celite. Concentration of the filtrate in vacuo and boiling the dark residue with ether gave tan crystals of 7-bromo-2-Qjis(morpholino)phosphinyloxyj5-(2-pyridyl)-3H-l,4-benzodiazspine. A sample was recrystalli25 zed by dissolving it in 2 ml of methylene chloride, filtering, diluting with 10 ml of ethyl acetate and cooling ln an ice bath to give light tan plates, m.p. 180-182° (dec.).

Example 48 g (0.125 m) of sodium hydride dispersion (50% in 3q mineral oil), was added to a solution of 28.1 g (0.1 m) of 1,3-dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one in 300 ml of dry tetrahydrofuran. After stirring for 1 hour at room temperature 30.2 g (0.12 m) of dimorpholinophosphlnic chloride was added and stirring was continued for 4 hours.

The product was crystallized by addition of water and ether.

The proclpitato was collected and dissolved In methylene chloride. The solution was dried and evaporated and the residue was crystallized from ethyl acetate to yield crude 7-nitro-2-[bi8(morpholino)phosphinyloxy]-5-phenyl-3H-l,4benzodiazepine, m.p. 208-209°.

Example 49 A solution of 25 g of 8-chloro-6-(2-fluorophenyl)-lmethyl-4H-imidazo[l,5-a)(i,4}benzodiazepine in 50 ml of water and 50 ml of concentrated hydrochloric acid was allowed to stand at room temperature for 3 hours. Following addition of 250 ml of 2-propanol the mixture was evaporated pax daily under reduced pressure without heating. Additional 200 ml of 2-propanol were added and partial evaporation was resumed.

The precipitated crystals were collected and washed well with 2-propanol and ether to yield 5-aminomethyl-l-(4-chloro-2(2-fluorobenzoyl)phenyl]-2-methylimidazole dihydrochluride, 2o m.p. 302-307° (dec.). The analytical sample was recrystallized from methanol/2-propanol without heating.

Example 50 A mixture of 49.9 (0.2 moles) of 2-amino-5-chloro-2’fluorobenzophenone, 38.0 g (0.3 moles) of 2,2-dichloro propa25 nal; 18.0 g (0.11 moles) of hydroxylamine sulfate and 500 ml of ethanol was stirred at room temperature for 2 days.

The mixture was diluted with 200 ml of 10% aqueous sodium carbonate solution with vigorous agitation. A gummy material precipitated from solution and the solution was diluted with 1.0 1 of ice-water. The solution was extracted with 3 x 300 ml of dichloromethane. The extracts were combined, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The residue was crystallized from dichloromethane and petroleum ether giving 6-chlou-2-(l,l-dichloroethyl)l, 2-dihydro-4-(2-fluorophenyl)-quinazoline 3-oxide as yellow prisms, m.p. 195-8° (dec.), 3.8 ml of nitromethane was added to 50.0 ml of dimethylformamide with stirring and under an atmosphere of nitrogen. The solution was chilled to 0° and 1.3 g (0.012 moles) of potassium tertiary butoxide was added ln portions. The temperature was maintained at 0 to 10° by means of an ice water bath. The mixture was stirred at room temperature for 1 hour.

The mixture was chilled to 5° with stirring and 2.2 g (0.006 moles) of the quinazoline prepared above was added at 5° to 9° in portions. After the addition had been completed, the mixture was stirred at room temperature for 17 hours.

The reaction mixture was poured into ice water and dichloromethane neutralizing with glacial acetic acid. The dichloromethane was washed with water; brine and dried over sodium sulfate. After filtration and concentration an amber residue was obtained which was crystallized with ethyl acetate. The crystals were collected and dried giving orange 7-chloro-l,3-dihydro-5-(2-fluorophenyl)-3-methyl-2-nitromethylene2H-1,4-benzodiazepine-4-oxide as prisms, m.p. 198-200°. Recrystal lization from dichloromethane/ethyl acetate gave pure material m. p. 216-218° (dec.).

Example 51.

A solution of 0.7 g (Ο.ΟΟ2Ο3 m) of (2-fluorophenyl)p-(5-hydroxymethyl-2-methyl-l-imidazolyl)-5-chlorophenyl]methanone in 40 ml of dry dichloromethane was cooled ln an ice bath and 0.22 ml (0.00227 m) of phosphorus trlbromide was added with stirring. After 1 hr. at room temperature the mixture was cooled ln an ice bath and 2 ml (0.0328 m) of ethanolamine was added. The solution was stirred for 2 hrs. at room temperature, refluxed for 1 hr. and then poured into 50 ml of water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to a small volume. The residue was developed on 4 silica g°l thick layer plates in a solution of % methanol in ethyl acetate (v/v). The material corresponding to an Rf of 0.5 was removed from the plate and treated with methanol. The solution was filtered and the filtrates were evaporated. The residue was crystallized from ether yielding 2-chloro-13a-(2-fluorophenyl)-12,13a-dihydro-6-methyl-9H,llHimidazo [l,5-a] oxazolo- [3,2-d](Ϊ,4jbenzodiazepine. Recrystallization from a mixture of methanol and ether gave pure product as white prisms, mp and mmp with an authentic sample 176-181? Example 52 9·5 ml of nitromethane was dissolved in 100 ml of dimethylformamide under nitrogen and with stirring 5.0 g (0.045 moles) of potassium tertiary butoxide was added at 0—10° and the mixture was stirred at room temporaturo for hour. Ths mixture was then chilled on ice and 5.1 g (0.015 moles) of 6—chloro—2-dichlonomethy1-1,2-dihydro—4-phenyl— qulnazoline 3—oxide was added slowly at a temperature below 9°. Ths reaction mixture wae stirred at room temperature fbr 17 hours.

The mixture was poured onto ice-water end dlchloromethane and made slightly aoid with glacial acetic acid. The aqueous phase was re—extracted three t^es with dlchloromethane. The organios were combined; washed consecutively with water and brine, dried over sodium sulfate; filtered and concentrated to dryness in vaouo giving an amber residue. Crystallization from boiling ethanol afforded 7-chloro-l,3-dihydro-2-nitromethylene5-phenyl-2H-l,4-benzodiazepine-4-oxide as yellow prisms, mp. 245-248° (dee.). Admixture with authentic material gave no depression in melting point.

Example 53 Potassium tert, butoxide (3.37 g, 0.03 m), was added to a stirred suspension of 3.5 g (0.01 m) of 7-chloro-l,3dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-l,4-benzodia94 zepine 4—oxide in 100 ml of dimethylformamide cooled to -20°. After stirring under nitrogen for 10 min at this temperature 2.13 g (0.015 m) of methyl iodide was added and stirring was continued for 10 min. The reaotion mixture was neutralized by addition of glacial aoetio acid and was partitioned between water and methylene ohloride. The organic phase was separated, dried over sodium sulfate and evaporated. The residue was crystallized from methylene ohloride/ethyl acetate to yield 7-chloro—1,3-dlhydro-5-(2-fluorophenyl)-3-methy 1-2-ni tromethy110 ene-2H-l,4-benzodiazepine 4-oxide as yellow crystals, mp. 215-216°. The analytical sample was reorystallized from the same solvents, mp. 216-218°.

Example S 4 A mixture of 7-chloro-l,3-dihydro-5-(2-fluorophenyl)15 2H-l,4-benzodiazepine-2-carboxamide (64 mg, 0.2 mmole) and lithium aluminum hydride (15 mg, 0.4 mmole) in dry THF (3 ml) was boiled for 15 min. The cooled reaotion mixture was quenched by addition of saturated aqueous sodium sulfate solution. Tic analysis of the resulting solution showed the presence of starting material as the major, more mobile component and the free base 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl) 1H-1,4-benzodiazepine as the minor component. The solution p was transferred directly to a 20 x 20 cm preparative tic plate (silica gel) and the plate was developed with ethanol.

The lower yellow band was removed and extracted twice with methanol/methylene chloride (2:1). Evaporation of the filtered extract left a clear, colorless oil. This was taken up in ethanol (1 ml), treated with excess maleic acid (50 mg), scratched and stored overnight in the freezer. The yellow crystals were collected, washed with ether and air-dried. ' The product was identified as 2-aminomethyl-7-chloro-2,3dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine dimaleate by comparison of its infrared spectrum in NujoKtrade mark) and of its melting point 185-186.5° with those of an authentic sample (mp. 188°). The mixture melting point was 184-7°.

Bxample 55 A mixture of 10 g (0.036 m) of 1,3-dihydro-5-pheny12H-thieno-[3,2-e][l,4]diazepine-2-one in 50 ml of benzene and 300 ml of tetrahydrofuran was stirred on an ice bath and saturated with methylamine gas. To this mixture was added dropwise a solution of titanium tetrachloride (9-48 g, 0.05 m) in 50 ml of benzene. After the addition was complete, the mixture was stirred on the ice bath for 15 minutes. The ice bath was then replaced with a heating mantle and the mixture refluxed for l/2 hour. The mixture was cooled and 100 g of ice carefully added. The mixture was filtered and the residue washed with tetrahydrofuran. The filtrates were combined, dried and evaporated. The product was crystallised from methylene chloride to yield 2-methylamino-5-phenyl-3H-thieno-[3,2-e) [l,4]diazepine, m.p. 223-227°. From the concentrated mother liquors was obtained additional product, m.p. 222-225°. The .•uuiJytlcal sample wa3 recryntulllzed from metliylene chloride, m.p. 222-229°.

Nitrosyl chloride was Introduced Into a solution of 7.8 g (0.03 m) of 2-methylamino-5-phsnyl-3H-thieno[3,2-e][l,4]diazepine in 100 ml of methylene ohloride and 40 ml of pyridine cooled in ice water. The reaction was monitored by thin layer ohromatography and when the starting material had disappeared the nitroayl chloride addition was terminated and the reaction mixture was partitioned between methylene chloride and water. The methylene chloride solution was dried and evaporated. Crystallization of the residue from methylene chloride/hexane yielded 2-(N-nitrosomethylamino)-5-phenyl-3Hthieno[3,2-e][l,4]diazepine as yellow crystals, m.p. 156-159°. The analytical sample wae recrystallized from ether/hexane, m.p. 158-160°. 2-(N-nitrosomethylamino)-5-phenyl-3H-thieno[3,2-e][1,4 ) diazepine (5-7 g, 0.02 m) was added to a mixture of 15 ml of nitromethane, 4.5 g of potassium t-butoxide and 60 ml of dimethylformamide which had been stirred for 10 minutes at room temperature. Following addition, the reaction mixture wae stirred under nitrogen and heated on tho steam bath for 10 minutes. After acidification with 4 ml of glacial acetic acid the mixture was partitioned between methylene chloride/ toluene and saturated sodium bicarbonate solution. The organic layer was washed with water, dried and evaporated. Crystallization of the residue from methanol with seeding yielded 1,2-dihydro-2-nitromethylene-5-pheny1-3H-thieno[3,2-e][1,4]97 dIazepine as yellow cryetale, m.p. 160-163°. Seeds were obtained by chromatographic purification over 30 fold amount of silica gel using 10% (v/v) of ethyl acetate in methylene chloride. The analytical sample was reorystallized from methanol, m.p. 163-164°.

A solution of 1.42 g (5 mmol) of l,2-dihydro-2-nitromethylene-5-phenyl-3H-thieno[3,2-e][l,4]diazepine ln 200 ml of ethanol was hydrogenated over Raney nickel (2 teaspoonBful) for 1 hour at atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated. The residue was treated with 1.2 g of maleic acid ln 10 ml of 2-propanol. The salt was crystallized by addition of ether to yield 2-amino methyl-2,3-dihydro-5-phenyl-lH-thieno[3,2-e] [ 1,4 jdiazepinc dimaleate as yellow cryataxs, m.p. 170-173°. The analytical sample was recrystallized from methanol/2-propanol, m.p. 187-189°. 2-Aminomethyl-2,3-dihydro-5-phenyl-lH-thieno[3,2-e|[l,4]diazepine dlmaleate (1 g, 2 mmol), was partitioned between methylene chloride and aqueous ammonia. The methylene chloride layer was dried and evaporated. The residue was heated to reflux for 1 hour with 1 ml of triethyl orthoacetate in 20 ml of xylene. The solvent was evaporated under reduced pressure and the residue was crystallized from 2-propanol/ethcr to yield l-methyl-3a,4-dihydro-6-phenyl-3H-imidazo[l,5-a]thieno· [2,3-fjdiazepine, m.p. 150-152°. This material was heated to reflux in 30 ml of toluene with 2 g of activated manganese98 dioxide for 2 hours. The manganese dioxide was filtered off and washed well with methylene chloride. The filtrate was evaporated and the residue was chromatographed over 7 g of silica gel using 3% (v/v) of ethanol in methylene chloride. The fractions containing pure produot were combined and evaporated. Crystallization from methylene chloride/ether and recrystallization from ethyl acetate/hexane yielded l-methyl-6-phenyl-4H-imidazo[l,5-e]thieno[2,3-f]diazepine, m.p. 223-225°.

Example 56 A mixture of 7.7 g (0.278 m) of 7-chloro-l,3-dihydro-5phenyl-2H-thleno[2,3-e][l,4]diazepin-2-one, 50 ml of benzene and 250 ml of tetrahydrofuran was stirred on an ice bath and saturated with methylamine gas. To this mixture was added a solution of titanium tetrachloride (7.38 g, 0.0389 m) in 50 ml of benzene from a dropping funnel. After the addition was complete, the mixture was stirred on the ice bath for 15 minutes. The ice bath was then replaced by a heating mantle and the reaction mixture was refluxed for 20 minutes. The mixture wa3 cooled and 100 g of ice were carefully added. The mixture was then filtered, and the residue washed with tetrahydrofuran. The filtrate were combined, dried and evaporated. The residue was crystallised from methylene chloride/ether yielding 7-chloro-5-phenyl-2-methylamino-3H-thieno-[2,3-e][1,4 Jdiazcpi nv m.p. 246-249°. The analytical sample was recrystallized from methylene chloride, m.p. 247-250°.

Nitrosyl chloride wae Introduced into a solution of .8 g (0.02 m) of 7-chloro-5-phenyl-2-methylamino-3H-thlcno[2,3-e]ll,4]diazepine in 100 ol of methylene chloride and 50 ml of pyridine until the reaction was complete according to thin layer chromatogram. The mixture was partitioned between water and toluene. The organic phase was dried and evaporated. Crystallization of the reeidue from ether/hexane yielded 7-chloro2-(N-nitrosooethylaolno)-5-phenyl-3H-thieno(2,3-e][l,4]diazepine aa yellow crystals, m.p. 108-110°. For analysis it was reoryetallized from ether/hexane, m.p. 111-113°. 7-Chloro-2-(N-nltrosooethylamino)-5-phenyl-3H-thieno[2,3-e](l,4]diazepine (3-2 g, 0.01 o) was added to a mixture of 10 ml of nitromethane, 35 ml of dimethylformamide and 2.26 g (0.02 m) of potassium t-butoxide which had been stirred under nitrogen for 10 minutes at room temperature. After heating for 10 minutes on the steam bath the reaction mixture was acidified by addition of 2 ml of glacial acetic acid and was partitioned between water and toluene. The toluene layer was washed with water, dried and evaporated. The residue was crystalli20 zed from ethyl acetate/hexane to yield crude 7-chloro-2,3dihydro-2-nitromethylene-5-phenyl-lH-thieno[2,3-e][1,4Jdiazopine. It was purified by chromatography over 40 g of silica gel using 10# (v/v) of ethyl acetate in methylene chloride.

The pure product was obtained as yellow crystals with m.p. 154-156». 100 41844 Λ) A solution of 320 mg (1 mmol) of 7-chloro-2,3-dihydro2-nitromethylene-5-phenyl-lH-thieno[ 2,3-e 1 [ 1,4 [diazepine in 20 ml of ethanol was hydrogenated over Raney nickel for 5 hours at atmospherio pressure. The catalyst was removed by filtration and the filtrate was evaporated. The residue was ohromatographed over 7 g of silica gel using methylene chloride, methanol and triethylamine in a ratio of 13:6:1. The fractions containing pure produot were combined, evaporated and the residue was treated with maleic acid in 2-propanol. Crystalli10 zation of the dimaleate salt from 2-propanol/ether and reorystallization from ethyl aeetate/ethanol yielded 2-aminomethyl-7-chloro-2,3-diA, dro-5-pheny1-lH-thieno(2,3-e][l,4jdiazepine dimaleate ae yellow crystala, a.p. 176-177°.

B) A solution of 320 mg (1 mmol) of 7-chloro-2,'5-dihydro15 2-nitromethylene-5-phenyl-lH-thieno[2,3-o]ll,4]diazepine in 3 ml of tetrahydrofuran wae added to a suspension of 0.8 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. After heating to reflux for 5 minutes, the reaction mixture was cooled and hydrolyzed by addition of 5 ml of water. The inorga20 nic material was separated by filtration and the filtrate was evaporated. The residue was chromatographed as described above and the pure product was converted to the maleatv to give 2-aminomethy l-7-chloro-2,3-dihydro-5-pheny 1-lH-thi eno[ 2,3-e]~ [1,4]diazepine dlmaleate as, m.p. 176-178°. 2-Aminomethyl-7-chloro-2,3-dihydro-5-phenyl-lK-thieno[2,3-e][l,4]diazepine dimaleate (0.52 g, 1 mmol) wae partitioned 101 between methylene ohlorlde and aqueous ammonia. The mothylene chloride solution was dried and evaporated. The residue was heated to reflux for 1 hour with 0.5 ml of triothyl orthoaoetate in 10 ml of xylene. The orude product obtained after evaporation under reduced pressuru was dissolved in 25 ml of toluene and the solution was heated to reflux for 1 1/2 hours after addition of 2.5 g of activated manganese dioxide. The manganese dioxide was then filtered off and the filtrate was evaporated. The residue wae ohromatographed over 6 g of silica gel using 4% (v/v) of ethanol in methylene chloride. Fracrions containing the pure compound were combined and evaporated. Crystallization of the residue from ether/hexane yielded 8-chloro-l-methy 1-6-pheny1-4H-imidazo[1,5-a J thieno[3,2-f][1,4]diazepine, m.p. 168-170°.

Bxample 57 A solution of 50 g (0.161 m) of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one in 900 ml of dry tetrahydrofuran and 300 ml of dry benzene was cooled in an ice bath, methylamine was bubbled in until the solution was saturated and a solution of 40 g (0.209 m) of titanium tetrachloride in 100 ml of benzene wa3 added dropwise with stirring. After 4 hours at room temperature a few gram- of ico were added and the reaction was filtered. The precipitate was washed several times with hot tetrahydrofuran, and the combined filtrates were evaporated. The residue was partitioned between 260 ml of diehloromethane and 200 uil of water and l'il102 tered. The dlchloromethane solution was separated, dried and evaporated. This residue and the preolpitate were recrystallized from a mixture of tetrahydrofuran and ethanol to give 7-chloro-5-(2-ohlorophenyl) -2-methylamino-3H-thieno [ 2,3-e ] 5 [l,4]diazepine. A sample was recrystallized for analysis from a mixture of tetrahydrofuran and hexane to give pale yellow prisms, m.p. 259-262°.

A mixture of 40 g (0.123 m) of 7-chloro-5-(2-chlorophenyl)-2-methylaalno-3H-thieno[2,3-e][1,4ldiazepine, 700 ml of dlchloromethane and 350 ml of pyridine was cooled in an loe bath and nltrosyl chloride was bubbled in for 20 minutes with stirring. After 1 hour it was bubbled in for 5 minutes more axxd then 600 ml of water was added slowly. The dichloromethane layer was separated, washed with 200 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness. The oil was dissolved in dlchloromethane and filtered through 400 g of Florisil. This was eluted with dlchloromethane, and then ether. Crystallization of the dlchloromethane fraction from a mixturo of ether and petroleum ether gave 7-chloro-5-(2-chloro20 phenyl) -2- (N-nitrosome thy lamino) -3H-thieno [2,3-e][l,4]d iar-e pi ne and more product was obtained from the ether fraction. A rumple was recrystallized for analysis from a mixture of ether and petroleum ether to give yellow prisms, m.p. 104-107°. 103 «1844 Ssangi?-,.5.! A solution of 6.8 g (0.0255 m) of 6,8-dihydro-3-ethyl-lmethyl-4-phenylpyTaeolo[3,4-e][l,4]diazepin-7(lH)-one in 125 ml of dry tetrahydrofuran and 50 ml of dry benzene was cooled in 5 an ioe bath and methylamine wae bubbled in until the solution was saturated. A solution of 6.3 g (0.0331 m) of titanium tetra chloride in 20 ml of benzene was then added dropwise with stirring and after 18 hr at room temperature the mixture was refluxed for 30 minutes. The solution was cooled, and treated IO with 4 g of ice. The reaction mixture was filtered and the precipitate wae washed with tetrahydrofuran and then with dichloromethane. The combined filtrates were evaporated to dryness and the residue was crystallized from a mixture of methanol and ether, and recrystallized from a mixture of dichlo· romethane and ether to give 3-ethyl-l,6-dihydro-l-methyl-7methylamino-4-phenylpyrazolo[3»4-e][l,4]diazepine as off-white prisms, mp.‘ 218-221°.

A solution of 5.6 g (0.0199 m) of 3-ethyl-l,6-dihydrol-methyl-7-methylamino-4-phenylpyrazolo[3,4-e][1,4]diazepine 20 in 100 ml of dichloromethane and 50 ml of pyridine was stirred in an ice bath and nitrosyl chloride was bubbled in for 10 min. 104 After 2 hr at room temperature, nitrosyl chloride was bubbled In for an additional 5 min. The mixture was allowed to stand for 30 min when it was poured into 200 ml of ice water. The organic layer was separated, washed with 100 ml of water, dried over anhydrous sodium sulfate, and filtered through 100 g of Florisil. The Florisil was thoroughly washed with ether, and the combined filtrates were evaporated to dryness. The intermediate N-nitroso derivative was not further purified but was used In the next step. 105 Example 59 I A mixture of 3.3 g (0.01 a) of 7-chloro-l,3-dihydro2-nitromethyleno-5-pheqyl-2H-l,4-benzodiazepine 4-oxido, 3.3 ml of phosphorus trichloride and 300 ml of methylene chloride wae stirred at room temperature for 4 hours. The solution was washed with 10% aqueoue sodium carbonate solution, was dried over sodium sulfate and evaporated. The crude product was purified by ohromatography over 100 g of silica gel using 10% (v/v) ethyl aoetate in methylene ohloride. The combined clean fractions were crystallized from methylene chloride/ hexane to yield 7-chloro-l,3-dihydro-2-nitromethylene-5-phenyl2H-1,4-benzodiazepine as light yellow crystals, m.p. 184-186°.

Example 6Q Λ mixture of 3.6 g (0.01 m) of 7-bromo-2-(N-nitrosomethyl amino)-5-(2-pyridyl)-3H-l,4-benzodiazepine, 30 ml of dimethylformamide, 5 ml of nitromethane and 2 g (0.018 m) of potassium t-butoxide was stirred at room temperature for 15 minutes and then heated up slowly. When the temperature reached 100° the mixture was oooled and neutralized by addition of glacial acetic aoid. The product was precipitated by addition of saturated aqueous sodium bicarbonate and was collected, washed with water and dissolved in methylene chloride. The solution was dried over sodium sulfate and evaporated. Crystallization of the residue from methylene chloride/ethanol yielded 7-bromo25 1,3-dihydro-2-nitromethy lene-5-(2-pyridy 1)-2H-1,4-benzodiazcpi ne 106 as a light yellow product, m.p. 232-235° (dec.). For analysis it was recrystallized from tetrahydrofuran/ethanol, m.p. 240-245° (dec.).

Example 61 A solution of 2.8 g (0.00932 m) of DL-2-aminomethyl7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 40 ml of dichloromethane was treated with 2.5 g (0.0119 m) of trifluoroacetic acid anhydride and after 5 minutes the reaction mixture was washed with 15 ml of a 10% potassium carbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from dichloromethane and was recrystallized from a mixture of dichloromethane and hexane to give 7-chloro-2,3-dihydro-5(2-fluorophenyl)-2-trifluoroacetamidomethyl-lH-1,4-benzodiazepine as pale yellow prisms, m.p. 140-143°. 107 Example 62.

To a solution of 10 g (0.0264 m) of 5-(2-fluorophenyl)l,3-dlhydro-7-*lodo-2H-l,4-bsnzodlazepln-2-one in 140 ml of dry tetrahydrofuran was added 1.8 g (0.039 m) of 54# of sodium hydride under argon with stirring. The reaction was refluxed for 1 hour, cooled to 0®, and 10.8 g (0.0422 m) of phosphorodimorpholidio chloride was added. After 18 hours the solution wae filtered, concentrated to a small volume and ether wae added. The solid was filtered and reoryetallized from a mixture of dichloromethane and ether to give 5-(2-fluorophenyl)-7-iodo2-bis(morpholino)-phosphinyloxy-3H-l,4-benzodiazeplne as white plates, m.p. 104-112°.

A solution of 27 g (0.443 m) of nitromethane in 450 ml of dry dimethyl sulfoxide was cooled to 0° under argon and then 5.4 g (0.119 m) of 54# sodium hydride was added with stirring. After 2 hours at room temperature the mixture was cooled to 0° and 39.5 g (0.066 m) of 5-(2-fluorophenyl)-7iodo-2-bis- (morpholino) -phosphinyloxy-3H-l, 4-benzodiazepinc wa3 added all at onoe. The reaction was stirred for 18 hours and then poured into 3 1 of ice and water, which contained 15 ml of acetid' acid. The mixture was filtered, the precipitate was dissolved in 700 ml of dichloromethane which was then washed with 300 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized and recrystallized from a mixture of dichloromethane and ether to give 2,3-dihydro-5-( 2-f luoropheny l)-7-iodo-2-ni trome thy lenelH-1,4-benzodiazenine as yellow prisms; m.p. 214-216°C. 108 Example A A parenteral formulation containing the following ingredients: per ml 8-Chloro-l-methy1-6-(2-fluorophenyl)-4H-imidazoCl«5-aj(l,4jbenzodiazepine maleate 1.0 mg Benzyl Alcohol 0.15 mg Tartaric Acid Buffer containing Sodium hydroxide Water for Injection q.s.ad 1 ml Ιθ was prepared as follows (for 10 liters).

In a clean glass or glass-lined vessel, 8 1 of water for injection were heated to 90°. It was then cooled to 50-60°, and 1.5 1 of benzyl alcohol was added and dissolved with stirring. The solution was then allowed to cool to room temperature. The 10.0 g of 8-chloro-l-methyl-6-(2-fluorophenyl) 4H-imidazo[l,5-a]{l,4j benzodiazepine maleate were added under an atmosphere of nitrogen and stirred until completely dissolved. The pH was now adjusted to 3.0 i 1.0, preferably 3.0 - 0.5 109 with a combination of tartaric add buffer and sodium hydroxide solution. Sufficient water for injection was then added to make a total volume of 10 liters. This solution vas then filtered through candle,, filled into suitable size ampoules, gassed with nitrogen and sealed.

Example B A tablet formulation containing the following ingredients: per tablet 8-Chloro-6-(2-fluorophenyl)-l-methyl4II-iaidazo[ 1,5-a][1,4]benzodIazepine maleate 10.0 mg lactose 113.5 mg Corn Starch 70.5 mg Pregelatinized Corn Starch 8.0 mg Calcium Stearate 3.0 mg 15 Total Weight 205.0 mg 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-aJ [1,4[benzodiazepine maleate was mixed with the lactose, corn starch and pregelatinized corn starch in a suitable size mixer and pass?d through a comminuting machine. The mixture was retur20 ned to the mixer and moistened with water to a thick paste . The moist mass was pussed through a comminuting machine and the moist granules were dried on paper lined tray3 at 45°C. The dried granules were returned to the mixer, the calcium stearate was added and mixed well. The granules were compressed at a tablet weight of 200 mg. 110 Example Ο A tablet formulation containing the following ingredients: per tablot 8-Chloro-6-( 2-fluoro phenyl )-l-mothyl-4Himidaso[1,5-a][1,4]benzodiazepine maleate Laotose .00 ng 64.50 mg Corn Starch .00 mg Magnesium Stearate 0.50 mg Total weight 100.00 mg was prepared as follows: 8-Chloro-6- (2-f luorophenyl) -4H-imidazo [ l,5-a][l,4]benzodiazepine maleate was mixed with the lactose, corn starch and magnesium stearate in a suitable mixer. The mixture was further blended by passing through a comminuting machine. The mixed powders were slugged on a tablet compressing machine and the slugs were comminuted to a suitable mesh size and mixed well. The tablets were compressed at a tablet weight of 100 mg 111 Example D A capsule formulation nontAlnlng the following ingre- dients: per capsule 8-Chloro-6-(2-fluorophenyl)-1-methy 1-4Himidazo[1,5-a][1,4]benzodiazepine maleate 25 mg Laotoee 158 mg Corn Starch 37 mg Talo 5 mg Total Weight 225 mg waa prepared S3 follows: 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine maleate was mixed with the lactose and corn starch in a suitable mixer· The mixture was further blen— ded by passing through a comminuting machine. The blended powder was returned to the mixer, the talc added and blended thoroughly. The mixture waa then filled into hard-shell gelatin capsules on a capsulating machine. 112 Sxample Β A capsule formulation containing the following ingredients: per capsule 5 8-Chloro-6-(2-fluorophenyl)-l-methyl-4H- imidazo[l,5-a][l,4]benzodiazepine maleate 50 mg laotose 125 mg Com Starch 30 mg Talc 5 mg 10 Total Weight 210 mg was prepared as follows: 8-Chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[1,5-aΙΕ 1,4] benzodiazepine maleate was mixed with lactose and com starch in a suitable mixer. The mixture was further blended by passing through a oommlnuting machine. The blended powder va;: returned to the mixer, the talc added and blended thoroughly. The mixture was filled into hard-shell gelatin capsules on a capsulating machine. 113 Wangle..? Λ capsule formulation containing the following ingredients t per capoulo 8—Chloro—1,4-dimethy—6— (2-f luorophenyl) -a Hlmidazo[l,5-a][l,4]benzodiazepine maleate 50 mg Xaotose 125 mg Corn Starch 30 mg Talc 5 mg 1G Total Weight 210 mg was prepared as follows: 8-Chloro-;l,4-dimethy1-6-(2-fluoropheny1)-4H-lmidazo[l,5-a)[l,4]benzodiazepine maleate was mixed with lactose and corn starch in a suitable mixer. The mixture was further blended by passing through a r?nn»Mwp-Mng machine. The blended powder wa3 returned to the mixer, the talc added and blended thoroughly. The mixture was filled into liard-shell gelatin capsules on a capsulating machine. 114 Bxample Ο A capsule formulation containing the following ingredients: por capsule 5 8-Chloro-l,4-dimethy 1-6-(2-fluorophenyl)-4H- imidazo[1,5-a][1,4]benzodiazepine maleate 25 mg lactose 158 mg Corn Starch 37 mg Talo 5 mg 10 Total Weight 225 mg was prepared as follows: 8-Chloro-l,4-dimethy 1-6-(2-fluorophenyl)-4H-imidazo[l»5-a][1,4]benzodiazepine maleate was mixed with the lactose and corn starch in a suitable mixer. The mixture was further blended by passing through a comminuting machine. The blended powder was returned to the mixer, the talc added and blended thoroughly. The mixture was then filled into hard-shell gelatin capsules on a capsulating machine. 115 Example Η A tablet formulation containing the following ingredients per tablet 8-Chloro-l, 4-dimethyl-6- (2-fluorophenyl) -4Hlmidazo[l,5-«][l,4]benzodiazepinb maleate 25*00 mg Lactose 64.50 mg Corn Starch 10.00 mg Magnesium Stearate O.'jO mg Total Weight 100.00 mg was prepared as follows: 8-Ch.loro-l, 4-d imethy 1-6- (2-f luoro phenyl) -4H-imidazo [l,5-a][1,4]benzodiazepine maleate was mixed with the lactose, corn starch and magnesium stearate in a suitable mixer. Th : mixture was further blended by passing through a comminuting machine. The mixed powders were slugged on a tablet compre :sing machine and the 3lugs were comminuted to a suitable mesh size mixed well. The tablets were compressed at a tablet weight of 100 mg. 116 Example I A tablet formulation containing the following ingredients: per tablet 8-Chloro-l,4-dimethy 1-6-(2-fluoromethy1)-4Himidazo[1,5-a][1,4]benzodiazepine maleate 10.0 mg lactose 113.5 mg Corn Starch 70.5 mg Pregelatinized Corn Starch 8.0 mg 10 Calcium Stearate 3.0 mg Total Weight 205.0 mg was prepared as follows: 8-Chloro-l,4-dimethy1-6-(2-fluorophenyl)-4H-imidazo[ 1 ,5-a] [1,4]benzodiazepine maleate was mixed with the lactose, corn starch and pregelatinized corn starch in a suitable size mixer and passed through a comminuting machine. The mixture was returned to the mixer and moistened with water to a thick paste. The moist mass was passed throu{£i a comminuting machine and moist granules were dried on paper lined trays at 45°C. The dried granules were returned to the mixer, the calcium stearate was added and mixed well. The granules were compressed at a tablet weight of 200 mg. 117 Example J A parenteral formulation containing the following ingredients: per ml 8-Chloro-l,4-dimethy 1-6-(2-fluorophenyl)-4Himidazo[1,5-a][1,4]benzodlazepine maleate Benzyl Alcohol 1.0 mg 0.15 ml Tartario Acid Buffer containing Sodium Hydroxide Water for Injection q.s.ad. ml was prepared as follows (for 10 liters): In a clean glass or glass-lined vessel, 8 1 of water for injection were heated to 90°. It was then cooled to 50-60°, -ind 1.5 1 of benzyl alcohol was added and dissolved with 3tirring.

The solution was then allowed to cool to room temperature. The 10.0 g of 8-ohloro-l,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[l,5-a][l,4]benzodiazepine maleate were added under an atmor.phe re of nitrogen and stirred until completely dissolved. The pH was now adjusted to 3.0 i 1.0, preferably 3.0 ί 0.5 with a combination of tartaric acid buffer and sodium hydroxide solution. Sufficient water for injection was then added to make a total volume of 10 liters. This solution was then filtered through a candle, filled into suitable size ampoules, gassed with nitrogen and sealed.

Claims

CLAIMS:

1. A process for the preparation of imidazo [ϊ, 5-aj [l, 4j dLazepine compounds of the general formula wherein A is s' -C°N; I *6 is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl; R 2 is hydrogen or lower alkyl; is hydrogen or lower alkyl; R^ le hydrogen, alkanoyloxy or hydroxy; is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl, and is selected from the group consisting of (a) (b) ( C ) X UV (c) (d) ι 15 wherein R 4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower alkanoyl; X is hydrogen, chlorine, bromine or iodine; and T is hydrogen or lower alkyl; analogs thereof corresponding to formula I but wherein A is selected from the 20 group consisting of 119 (ο, (f) ιι /\ ΟΙ R< Ν >« (g) and I *6 wherein V^hydrogen or lower alkyl, is selected from the group consisting of formulae (a), (b) and (c) above, R^, Rj, Rj and Rg are as in Formula I above, and Rg is hydrogen except that in Formula I with A having structure (f), R^ is not nitro and Rg is not nitro substituted; and pharmaceutically acceptable acid addition salts of these compounds and analogs, which process comprises (a) for the preparation of a compound of formula wherein A -C=N (IA) Rp Rj, Rj and Rg are as in Formula I above and 120 41844 is selected from the group consisting of formulae (a), (b) and (c) above converting a corresponding compound of formula I into the N—oxide thereof, or (b) converting a compound of formula IA into a corresponding compound of formula I wherein Rg is alkanoyloxy by methods known in the art, or (c) converting a compound of formula I wherein Rg is alkanoyloxy into a corresponding compound of formula I wherein R^ represents hydroxy by methods known in the art, or (d) for preparing a compound of formuia wherein Rp Rp Rp R 4 ,R g and are as in Formula IA but R 4 is not nitro and Rg is not nitro 15 substituted, reducing a corresponding compound of Formula I, or (e) dehydrating a compound of formula IA wherein A is H OH to the corresponding compound of formula I, or 121 (f) converting a compound of formula IA wherein A is -C-N wherein R’ 7 is acetyl, mesyl or tosyl, to the corresponding compound of formula I by treatment with a non-aqueous base in the presence of an inert solvent, or (g) converting a compound of formula IA wherein A is H I -C-NH I to the corresponding compound of formula I by oxidation of the secondary amine of the 5-position,or (h) cyclizing a compound of formula wherein R^, R^, R g , R^ and Rg are as in formula I, to a corresponding compound of formula I, or (1) for preparing a compound of formula IA wherein A is wherein V is hydrogen or lower alkyl, reacting a corresponding compound of formula I with ethylene oxide or propylene oxide in the presence of a Lewis acid catalyst or reacting a corresponding compound of formula 122 (XXIV) are aa ln formula I, except that R^ Is not amino or substituted amino, with a compound selected from the group consisting of ethanol-amine, a 1-alkyl substituted ethanolamine and a 2. -alkyl substituted ethanol-amine, or (j) converting a ketal group present as r 4 substituted in an imidazobenzodiazepine to the corresponding ketone substituent, or (k) converting a ketone group present as R 4 substituent in an imidazobenzodiazepine to a secondary or tertiary alcohol substituent, or (1) dehydrogenating a compound of formula Rj, R 2 * Rj * R 4 * Rg and 123 α are as in formula I but R, is not nitro and R, is not 4 o nitro substituted, to a corresponding compound of formula I, or 5 (m) converting a compound of formula I, wherein Gt represents an aminophenyl group, into the corresponding nitro-, cyano-, chloro or bromo-substituted compound, or (n) subjecting a compound of formula I wherein R^ is acylamino to a mild hydrolysis so as to obtain a corresponding compound of formula I wherein R^ is amino, or (o) oxidizing a compound of formula are as in formula VII, to a corresponding compound of formula I, VII' or 124 (p) resolving a racemic compound into its optical enantiomers, or (q) converting a compound of formula I or an analog thereof corresponding to formula I but wherein λ is selected 5 from the group consisting of (f) H I 'C— (9) and wherein V-hydrogen or lower alkyl, is selected from the group consisting of formula (a), (b) and (c) above, Rp Rp R^ and R g are ae in Formula I above, and Rg is hydrogen or lower alkyl, except that in formula I with A being structure (f) R 4 is not nitro and R g Is not nltro-substltuted, into a pharmaceutically acceptable acid addition salt.

2. A process as claimed in Claim 1, wherein there are prepared compounds of fonnula I wherein is R 4 A is -C=N; 125 ls hydrogen or lower alkyl; R^ and Rg are Independently hydrogen or lower alkyl; Rg is hydrogen, alkanoyloxy or hydroxy; R^ ls hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, amino, substituted amino, hydroxy lower alkyl or lower alkanoyl;- and Rg is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl, analogs thereof corresponding to formula 1 but wherein A is the group -C or -C=N * \ *6 and Rg ls hydrogen, or pharmaceutically acceptable acid addition salts thereof and wherein at least one of the process embodiments (a), (b), (c), (d), (1), (o) and (p) of Claim I is performed.

3. A process as claimed in Claim 1, wherein there is prepared a compound of formula I wherein Rg is hydrogen or lower alkyl, is R 4 is hydrogen, nitro or halogen, is phenyl or halo, nitro or lower alkyl substituted phenyl, R 2 is hydrogen 20 or l° w ®r alkyl, and Rg and Rg are hydrogen.

4. A process as claimed in Claim 3, wherein Rg is lower alkyl and Rj is hydrogen.

5. A process as claimed in any one of clairas 2 to 4, wherein R 4 is 8-halo and R g is 2-halophenyl. 25 6 · A process corresponding to that claimed in any one of claims 3 to 5 but wherein Rg is lower alkyl.

6. 7. A process as claimed in Claim 6, wherein Rg is methyl. 126

7. 8. A process as claimed in claim 5, wherein 8-chloro-6-(2f luorophenyl) -l-methyl-4H-imidazo [l,5-a3|l,4j benzodiazepine or tho maleate thereof is prepared.

8. 9. A process as claimed in claim 7, wherein 8-chloro6- (2-f luoropheny 1) -1,4-dimethyl-4H-imidazo Q., 5-a] [l, 4] benzodiazepine or the maleate thereof is prepared.

9. 10. A process as claimed in claim 1, wherein 2-chloro13a- (2-fluorophenyl)-12,13a-dihydro-6-methyl-9H

10. 11. A process for the preparation of an imidazo ύ>5-&7£1>47 diazepine coapound of tha formula I given and described in Claim 1 substantially as hereinbefore particularly described, especially with reference to any one of the foregoing Examples 1-62.

11. 12. A process for the manufacture of preparations having muscle relaxant, sedative and anti-convulsant properties, wherein a compound of formula I as defined in claim 1 or an analog thereof as defined in claim 1 or a pharmaceutically acceptable acid addition salt of such compound is mixed, as active substance, with nontoxic, inert, therapeutically compatible solid or liquid carriers, commonly used ln such preparations, and/or excipients.

12. 13. Compositions having muscle relaxant, sedative and anti-convulsant properties, containing a compound of formula I as defined ln claim 1 or an analog thereof as defined in claim 1 or a pharmaceutically acceptable acid addition salt of such compound and a carrier.

13. 14. ImidazoQ,5-a]diazepine compounds of the general formula JO wherein A is I 127 - 41844 R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, subs ltuted phenyl, pyridyl or aralkyl, R 2 is hydrogen or lower alkyl; R 3 is hydrogen or lower alkyl; Rg is hydrogen, alkanoyloxy or hydroxy; Rg is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl; and ls selected from the group consisting of 10 wherein R^ is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl or lower alkanoyl; X is hydrogen, chlorine, bromine or iodine; and T is hydrogen or lower alkyl; analogs thereof corresponding to formula I but wherein A is selected from the group consisting

14. 15 of H is selected from the group consisting of formulae (a), (b) and 20 (c) above, Rj_, R 2 , R 3 and R g are as in Formula I above, R 5 is hydrogen except that in formula I with A being structure 128 (f) R 4 ie not nitro and R g is not nitro-substituted, and pharmaceutically acceptable acid addition salts of these compounds and analogs, whenever prepared according to tho process claimed ln Claim 1 or 11 or by an obvious chemical equivalent thereof. 5 15. Compounds as claimed ln Claim 14 which are compounds of formula I wherein Is X A is -C«=N; R 6 Rj is hydrogen or lower alkyl; R 2 is hydrogen or lower alkyl; R 3 is hydrogen or lower alkyl; R 5 is hydrogen, alkanoyloxy or hydroxy; R 4 le hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, amino, substituted amino, hydroxy lower alkyl or lower alkanoyl; and R g is phenyl, monosubstituted phenyl, di-substltuted phenyl, pyridyl or monosubstituted pyridyl, analogs thereof corresponding to formula I but wherein A is the group H i / C-N or -C=N and R 5 is hydrogen, or pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in Claim 2 or by an obvious chemical equivalent thereof.

15. 16. Compounds as claimed in Claim 14 which are compounds of formula I wherein R^ is hydrogen or lower alkyl, is R 4 is hydrogen, nitro or halogen, Rg is phenyl or halo, 129 nitro or lower alkyl substituted phenyl, R 2 is hydrogen or lower alkyl, and Rj are hydrogen, whenever prepared according to the process claimed in Claim 3 or by an obvious chemical equivalent thereof.

16. 17. Compounds as claimed in Claim 16, wherein Rj is lower alkyl and Rj ^ 8 hydrogen, whenever prepared according to the process claimed in Claim 4 or by an obvious chemical equivalent thereof.

17. 18. Compounds as claimed in any one of claims 15 to 17, wherein R^ is 8-halo and R^ is 2-halophenyl, whenever prepared according to the process claimed in claim 5 or by an obvious chemical equivalent thereof.

18. 19. Compounds corresponding to those claimed in any of claims 16 to 18 but wherein Rj Is lower alkyl, whenever prepared according to the process claimed in claim 6 or by an obvious chemical equivalent thereof.

19. 20. Compounds as claimed in claim 19 wherein Rj is methyl, whenever prepared according to the process claimed in claim 7 or by an obvious chemical equivalent thereof.

20. 21. 8-Chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5-a](l, 4] benzodiazepine or the maleate thereof, whenever prepared according to the process claimed in claim 8 or by an obvious chemical equivalent thereof.

21. 22. 8-Chloro-6-(2-fluorophenyl)-1,4-dimethyl-4H-imidazo |l,5-a] £l,4). benzodiazepine or the maleate thereof, whenever prepared according to the process claimed in claim 9 or by an obvious chemical equivalent thereof.

22. 23. 2-Chloro-13a-(2-fluorophenyl)-12,13a-dihydro-6-methyl9H,llH-imldazo £l,5-ajoxazolo £3,2-dJp.,4] benzodiazepine, whenever prepared according to the process claimed in claim 10 or by an obvious chemical equivalent thereof.

23. 24. Imidazo [l,5-a] £l ,4] diazepine compounds of the general formula 130 41844 I wherein A is R^ is hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl or aralkyl; Rj is hydrogen or lower alkyl; R 3 is hydrogen or lower alkyl; ; Rg is hydrogen, alkanoyloxy or hydroxys R g is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl; and IO is selected from the grc-p consisting of T wherein R 4 is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, hydroxy lower alkyl or lower 15 alkanoyl; X is hydrogen, chlorine, bromine or iodine; and T is hydrogen or lower alkyl; analogs thereof corresponding to formula I but wherein A is selected from the group consisting of 131 wherein V®hydrogen or lower alkyl. le selected from the group consisting of formulae(a) , (b) and and Rg are as ln Formula I above, and Rg ls hydrogen except that in formula I with A being structure (f) R^ is not nitro and Rg is not nitro-substituted, and pharmaceutically acceptable acid addition salts of these compounds and analogs.

24. 25. Compounds as claimed in Claim 24 which are compounds of formula I wherein (c, above, 1^, R_ is A is Z -C=N; I R. R^ is hydrogen or lower alkyl, R? ia hydrogen or lower alkyl, is hydrogen or lower alkyl; Rg ls hydrogen, alkanoyloxy or hydroxy; R^ is hydrogen, nitro, cyano, trifluoromethyl, lower alkyl, amino, substituted amino, hydroxy lower alkyl or lower alkanoyl; and Rg is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl, analogs thereof corresponding to formula I but wherein A is the group H I / X —C — N or -C=N , and Rg is hydrogen,and pharmaceutically acceptable acid addition salts thereof. 132

25. 26. Compound· as claimed in Claim 24 which are compounds of formula I wherein R. Is hydrogen or lower alkyl, R^ is hydrogen, nitro or halogen, R g is phenyl or halo, 5 nitro, or lower alkyl substituted phenyl, Rj is hydrogen or lower alkyl, and Rj and Rg are hydrogen.

26. 27. Compounds as claimed in Claim 26, wherein R^ is lower alkyl and Rj is hydrogen.

27. 28. Compounds as claimed in Claim 26 or 27, wherein R^ 10 is 8-halo and R g is 2-halopheny1.

28. 29. Compounds corresponding to those claimed in Claim 27 or 28 but wherein is lower alkyl.

29. 30. Compounds as ciaimed in Claim 29, wherein R^ is methyl.

30. 31. 8-Chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo [1,5-a] 15 [1,4] benzodiazepine.

31. 32. 8-Chloro—6-(2-fluoropheny1)-1,4-dimethyl-4H-imidazo [1,5-a] [1.4] benzodiazepine or the maleate thereof.

32.

33. 8-Chloro-6-(2-fluorophenyl,-l-methyl-4H-imidazo [l,5-aj [1.4] benzodiazepine maleate. 20

34. 2-Chloxo-13a-(2-fluorophenyl)-12,13a-dihydro-6-methyl-9H, llH-imidazo [1,5-a] oxazolo [3,2-d) |I,4] benzodiazepine. F. R. KELLY λ CO. ,