Untitled record

The present invention relates to certain (substituted phenyl) -aryl-ketones and their production. The invention also relates to benzo-diazepinones, obtained in particular from the abovementioned phenyl-aryl ketones, and methods of

5 manufacture and transformation of these various compounds into substances having various pharmacological properties and useful from the pharmaceutical point of view.

In one of its aspects, the invention provides a process for the manufacture of a ./o-(2-hydroxyamino- or 2-N10acyloxy-N-acylamino-acylamino) -phenyl7-aryl-ketone, according to which one reacts the hydroxylamine with an ô- (2 ~ substituted-acylamino) -phenyl7-aryl-ketone, reaction in which the substituent fixed in position 2 is subjected to a nucleopbile displacement due to the hydroxylamine, and if necessary, the acyl / (2-hydroxy ~ aminO “acylamino) -phenyl7-aryl · ketone thus formed is acylated under conditions which do not determine cyclization.

The invention also provides a / (2- hydroxyamino or 2-R-acyloxy-R-acylamino-acylamino) -phenyl7-aryllOketone, for example a corresponding acetaminophenyl-aryl ketone or a corresponding benzophenone.

Examples of / ôrtho- (2-hydroxyamino- or 2-N-acyloxy-D-acylamino-acylamino) -phenyl7-sryl-ketones are represented by the ketones corresponding to the formula:

<img file="OA2171A_D0001.tif" />

Where the nucleus À may not carry a substituent or else bear one or more substituents. not annoying and for example carry one or two hydrogen atoms or one or more lower alkyl groups, chlorine or bromine atoms, nitro groups, lower haloalkyl, for example

Trifluoromethyl, or alkyl-sulfonyl groups and for example methyl-sulfonyl; R is a hydrogen atom or an alkyl group and for example lower alkyl or lower aralkyl; R and. R are hydrogen atoms or represent one or two alkyl groups, for example lower alkyl,

Aralkyl, for example lower aralkyl, or aryl; R ^ and

- 3 τΛ are tones both of the hydrogen atoms one well they are tones both of the acyl groups and for example aeétyle; and Ar is nn an aryl group, for example a 1- on 2-naphthyl group, but preferably a monocyclic aryl group, for example

5phenyl or phenyl bearing as substituent (s) one or more atoms or groups which do not interfere, such as halogens' and for example chlorine or bromine atoms, lower alkyl, lower alkoxy, halo-lower alkyl, lower alkoxy, halogeno-lower alkyl, for example trifluoromethyl or alkyl- (for example methyl-) sulfonyl, 2- or 3-furyl, 2- or J- ^ hienyl, or 2-, 3- or 4pyridyl.

It will be understood that according to the present invention, some of the carbon and nitrogen atoms of the / ortho- (2-subs15titué-acylamino) -phenyl7-aryl-ketone can carry as substituents groups which do not interfere with the hydroxy reaction lamination and that, taking into account the limitations and exceptions indicated in the present description, it is possible to use all the compounds of this type.

The term alkyl group used herein includes methyl, ethyl, propyl, isopropyl, n-butyl, iso-amyl groups; alkenyl and alkynyl groups such as allyl, methallyl, ethynyl, propenyl and vinyl; and cycloalkyl groups such as cyclopropyl, cyclobutyl and cyclopen25tyle. The term “lower alkyl group” is understood to mean an alooyl group having up to 6 carbon atoms. The term “lower aralkyl group” is understood to mean an aralkyl group having up to 9 carbon atoms and for example a benzyl or phenethyl group. By lower alkoxy group is meant a

3 ^ group having up to 6 carbon atoms.

- 4 1 2

In particular one of the two radicals R and R, or both, may, by way of illustration, be: alkyl groups and for example methyl, ethyl, propyl ,. isopropyl, n-butyl, t-butyl, isoamyl, and when these two radicals represent such groups, they may be the same or different, or they may be linked together to form a hydrocarbon ring, or they may be lower cycloalkyl radicals such as cyclopropyl, cyclobutyl or cyclopentyl or unsaturated alkyl groups such as vinyl, ethynyl or propenyl, and they may be aryl groups such as phenyl or phenyl bearing as substituents) groups which do not interfere, such as halogen atoms or lower alkyl or hydroxyl groups, or they may be aralkyl groups such as benzyl or

15phenethyl in which the phenyl group may similarly carry or not substituents:

In the above-mentioned process, the substituent attached in position 2 to the ortho-acylamino-phenyl-7-aryl ketone can be a halogen atom and for example a chlorine atom,

2Obromine or iodine; when the substituent is a chlorine or bromine atom, the reaction is preferably carried out in the presence of a small amount of a water-soluble salt iodide.

Z

The substituent attached in position 2 can be an organo-sulfonoxy group, for example a (lower alkoxy) · sulfonoxy or aryl-sulfonoxy group such as methyl-sulfonoxy or phenyl-sulfonoxy and for example phenylsulfqnoxy "para-halophenyl-sulfonoxy or para -toluene-suifonoxy. The reaction with 1¹hydroxylamine-includes a reaction, with a. of its

Soluble JOsels. ·. .

This reaction, contrary to what one would normally expect, results, even in the presence of a large excess of hydroxylaaine, in a substantially selective displacement of the substituent fixed in position 2 to form with a

5good yield a / othro- (2-hydroxyamino-acylamino) -phenyl7aryl-ketone rather than forming an oxime to. which we expected. The reaction is preferably carried out at a pH of between approximately 4 and approximately 9 and preferably in a mixture of solvents comprising water and a water-soluble oral solvent, such as methanol, ethanol, dioxane or dimethylformiamide, in order to obtain an excellent yield. The reaction can also be carried out in non-aqueous media with or without a water-soluble organic solvent. Preferably the reaction is carried out

15 Temperatures between 50 ° C. approximately and the reflux temperature of the solvent mixture for a period of time between approximately a quarter of an hour and approximately two hours. The reaction mixture can then be diluted with water to precipitate the / ortho- (2-hydroxyami20_noto-acylamino) -phenyl7-aryl-ketone in an easy to isolate form. The reaction is conveniently carried out with substantially stoichiometric amounts of substances involved in the reaction.

The starting rtho- (2-substituted-acyla25mino) -phenyl7aryl-ketones can be made by reacting an ortho-aminophenyl-aryl ketone with a 2-substituted-acyl halide, anhydride or carbodiimide (substituted appropriate) and for example with a halide, anhydride or a carbodiimide of 2-halogeno-acyl or a halogenide, anhydride or carbodiimide of 2-organo-sulfonoxyacyl. and for example a halide, an anhydride or an arbodiimide of 2- (lower alkyl) - or 2-aryl-sulf onoxyacyl.

Thus, for example, an ortho (lower 2-alkyl or aryl-sulfonoxy-acetamido) -benzophenone can be produced by treating ortho-aminobenzophenone in chloroform by dropwise addition of a d * halide (lower alkyl) -sulfonyl or arylsulfonyl, also in the

10chloroforme. Once the addition is complete, the reaction mixture is heated on a boiling water bath for about 15 minutes to ensure obtaining optimum performance. Removal of the solvent and recrystallization give the desired product,

Alternatively, a _&lt;/ ôrtho- (2-organosulfonoxy-acylamino) -phenyl7-aryl-ketone starting by a series of reactions including the transformation of an orthoaminophenyl-aryl-ketone into a / ôrtho- (2-acyloxy-acylamino) phenyl7-aryl- ketone by treatment with a halide, a

20ahhydride or an acyl-glycolyl carbodiimide or with an 'acyl-glycolic acid', the removal of the 2-acyl group by hydrolysis to obtain the₍/ ôrtho- (2-hydro: &lt;yacylamino) -phenyl7aryl-ketone and the transformation of the latter ketone by reaction with a halide, an anhydride

250U an organo-sulfonyl carbodiimide, en / ortho- (2-organosulfonoxy-acylamino) -phenyl7-aryl-ketone.

For example, when an ortho-amino-benzophenone is treated with an acyl-glycolyl halide, an ortho- (2-acyloxy-acetamido) -benzophenone is obtained. To obtain the best yields, the benzophenone is dissolved in a solvent such as chloroform and the acyl glycolyl halide is added dropwise. The solution heats up during the addition, and preferably the reaction mixture is heated for about 15 minutes on a boiling water bath.

5on completion of the addition. Any acyl glycolyl halide can be used because the aoyl group is removed by subsequent hydrolysis. Similarly, anhydrides of an acylated glycolic acid can be used. Other means can also be used to aoy the amines and, for example, glycolic acid and carbodiimide can be used.

It is also possible to manufacture /Ôrtho-(2-acyloxy-acétamido)-ph.ényl7-aryl- kétone, for example benzophenones, by reacting, for example under reflux, a mixture of a / ortho (2-iodo- acetamido) -phenyl7-aryl-ketone, for example a benzo15phenone, with an alkali metal salt of a carboxylic acid, for example sodium acetate, operating for example in glacial acetic acid.

The aryl group can be removed by hydrolysis. This can be done by dissolving 1¹ortho- (2-acyloxy-acetamido) 2Qbenzophenone in a non-polar, water-soluble solvent, for example an alcohol, and adding with stirring an alkali metal hydroxide or an amine, for example an aqueous hydroxide solution sodium. Surprisingly, while the reaction can occur on the ester bond

25or on the amide bond or on both, a selective hydrolysis of the ester bond occurs. When the reaction is complete, as indicated by the clarification of the solution, dilution with water precipitates the ortho (2-hydroxy-acetamido) -benzophenone thus produced.

30A ortho (2-hydroxyacetamido) ~ benzophenone on

Μ g ~ can add, for example, a halide, an anhydride or a carbodiimide of (lower aïcoyl) -sulfo: üyle or aryl sulfonyl and the reaction mixture can be heated on a boiling water bath for 30 to 60 minutes about. Through

When the solution is cooled by means of ice water, the corresponding ortho- (2-lower alkyl- or -aryl-sulfonoxy-acetamido) -benzophenone is obtained. One can, for example, use the latter compound for the reaction with hydroxylamine by dissolving this compound in A-solvent, for example

10methyl-cellosolve, heating up to 85 ° C. approximately and adding a solution of hydroxylamine hydrochloride and water containing sodium hydroxide. The temperature is maintained at 85 ° -9O ° C. approximately for approximately 15 minutes and the water is obtained by cooling and diluting

15 precipitation of ortho- (2-hydroxyamino-acetamido) ~ benzophenone.

The starting ortho-aminophenyl-aryl-ketones can carry as substituents any group which does not interfere with the subsequent reactions involving the amino group

And these may be, for example, the groups of substituents mentioned for the substitution on the phenyl ring A of the formula (I). The aryl group can be for example a phenyl, 2- or 3-thienyl group; 2- or 3-furyl; 2-, 3or 4-pyridyle or 1- or 2-naphthyle which can in turn carry

25 substituents as indicated above (Ar 'in' formula I).

While these starting materials are preferably transformed into 2-substituted-acetamido compounds (corresponding to 12 i with R, R and R = H in formula I) and while R and R are hydrogen atoms if the desired end product

30is a 3-acyloxy- or 3 “hydroxy-1,3-dihydro-5-ary 1-211-1,4—9-benzo-diazepine-2-one; the carbon atom in position 2 of the acetamido group, that is to say that to which the carbonyl group is attached, can carry substituents as indicated above with regard to formula I, if it is desired

5a transformation into a 4-oxide of 1,3-d.ihydro-5-ai^,2HL-yl, 4-benzodiazepine-2-one. The nitrogen atom of the acetamido group can also carry substituents as already mentioned in connection with the formula !.

The /rtho- (2-H-acyloxy - NlOacyl-amino-acylamino) -phenyl7-aryl-ketones are conveniently manufactured in the absence of a cyclizing agent by treatment of the ortho- (2hydroxyamino) compound by means of '' an excess of a cyclic agent such as acetic anhydride, acetyl chloride, ketene, isopropenyl acetate or another generator

15 of ketene, ithyl chloroformate, tert-butoxy-para-nitrophenyl carbonate and a carbo-tert-butyloxyezide. The acylation can be carried out in the presence or in the absence of a solvent and the operation is carried out by gentle heating, the solvent, if one is used, being inert with respect to the acylating agent.

20When no solvent is used, the course of the reaction can be followed by observing the disappearance of the ortho (2-hydroxyamino-acetamido) compound. Generally the reaction takes place quickly but to ensure a good yield the reaction mixture is left to stand for several hours in

251e heating gently - although the temperature at which the reaction takes place should not be so high that decomposition of the desired end product occurs.

The / ortho- (2-hydroxyamino- or 2-lT-acyloxy-N-acylamino-acylamino) -phenyl7 “aryl ketones of the invention can,

30 under appropriate cyclization conditions, undergo a

- 10 ring closure to form 4-oxides of l, 3-àihydro-5aryl-2H-l, 4-benzodiazepine-2-one or 3-acyloxy-l, 3-dihydro-5-aryl-2H ~ l , 4-benzodiazepine-2-ones (which can be hydrolyzed if desired to the corresponding 5-bydroxy-1,3-â.ibydro-5-aryl5 2H-1,4,4-benzodiazepine-2-ones). These cyclized compounds have psycholeptic effects in mammals, as shown by conventional test procedures. They are interesting for medicinal purposes, because they are active as anti-convulsants, as sedatives and / or Otranquillisers or muscle relaxants. Some of them exercise central nervous system depression activity or are disinhibitors.

In another of its aspects, the invention relates to the manufacture of these cyclized compounds which can respond

15 to the following formulas:

<img file="OA2171A_D0002.tif" />

II III

<img file="OA2171A_D0003.tif" />

In acidic media, the ortho (2-hydroxyamino or 2-N ~ acyloxy-N ~ acylamino-acylamino) -phenyl7-aryl-ketones of the present invention cyclize to 4-oxides of 1,3dihydro-5-aryl -2H-l, 4-henzodiazepine-2-ones corresponding,

- 11 and these compounds or their salts and for example the alkali metal salts, are also formed by treatment of ortho- (2-hydroxyamino) compounds by means of bases. When a salt is obtained, treatment with an acid gives the free 1,55dihydro-5-aryl-2H-1,4-benzodiazepine-2-one 4-oxide. Thus, the cyclization medium can be a medium containing an ionizable acid such as acetic, sulfuric, benzenic acid, para-toluene-sulfonic or hydrochloric acid, or a medium containing an alkali metal hydroxide or alkaline earth metal such than sodium hydroxide, potassium or calcium. In the case of ortho- (2-N-acyloxy-Nacylamino) compounds, the cyclization is preferably carried out in the presence of a non-oxidizing mineral acid such as hydrochloric acid; we preferably put the bodies participating in the

The reaction is suspended or dissolved in a non-reactive solvent, for example ethanol, and the mixture is brought to the boil for several minutes, to cooling, the cyclized product separates.

We can transform the 4-oxides of 1,3-dihydro-5 ~

2

20aryl-2H-1,4-benzodiazepine-2-ones (in which S and S are hydrogen atoms) in 3 “&amp; cyloxy-1,3-dihydro-5 - aryl-2Hl, 4-benzo-diazepine- Corresponding 2-ones by treatment with an acylating agent.

It is not necessary to isolate the / ortho- (2-hydroxy25amino- or 2-N-acyloxy-N-acylamino-acylamino) -phenyl7-arylketone intermediate from the reaction mixture in which it is formed and can be for example acidify this mixture with a strong acid or alternatively, in the case of / ortho- (2-hydroxyamino-acylamino) -phenyl7-aryl-ketones, basify with

50d "an alkali metal hydroxide, when forming the compound

- 12 corresponding cyclized, and this is advantageous for reducing the number of operating stages requiring the isolation of an intermediary. If the reaction mixture is simply diluted with water, the intermediate is obtained and can be redissolved in an aqueous or non-aqueous wettable organic solvent, and then the intermediate is treated with the cyclizing agent.

In acidic media in the presence of an acylating agent, an / ”ortho- (2-hydroxyamino-acylamino) -phenyl7aryl-ketone (in which R¹ and R ^ are hydrogen atoms) lOdirectly into 3-aoyloxy-1,3-dihydro-2H-1,4-benzodiazepine-2one corresponding with the advantages of having avoided the isolation of intermediates and of having reduced the number of process steps.

The acylating agent may have the formula R ^ -GO-X, where R ^ l ^ is a lower alkyl, aryl, haloalkyl or aralkyl group and X is a halogen, isopropenyloxy group or R ^ -GOO-, or well this agent can be a ketene (and in this case, in the formula 5 -CO-X, R^X and X taken together are a methylene group) Thus, the treatment of a hot solution of / ~ or20tho- (2-hydroxyamino-acylamino) -phenyl7-aryl-ketone in an acid cyclization medium, for example a medium containing an acid such as acetic, sulfuric, benzene-sulfonic or para-toluene-sulfonic or hydrochloric acid, by means of an acylating agent used conveniently in a

25 substantially stoichiometric amount, such as an anhydride or halide of a carboxylic acid, for example acetic, propionic, caproic, benzoic, toluic, phenylacetic, beta-phenylpropionic, cinnamic, aminobenzoic, chloroacetic, chlorobenzoic acid

30or bromobenzoic acid, or by means of a compound capable of

-Informing ketene in situ, such as isopropenyl acetate, under substantially anhydrous conditions and with heating, forms 5-acyloxy-1,3-dihydro-5-phenyl-2H-1,4-benzodiaaepine

2-one matching. The solvent used should

5 does not react with the acylating agent, and therefore cannot be a solvent which, such as water or an alcohol, has hydroxyl groups. By cooling and diluting with water, the compound produced is precipitated.

It is also possible to close the cycle with 101 'using ammonia. This is how the treatment of a 2Z * 2 - (N-acyloxyacyl-amido) acylamido7phenyl-aryl-ketone with ammonia at low temperature for example at 0 ° C. determines the elimination of an acyloxy residue, and the fixation of ammonia without closing the nucleus, leading to 2- / 2- (N-acylamido) 152-amino-acylamido7-phenyl aryl ketone and, at higher temperatures these compounds undergo closure of the nucleus with the splitting of the elements forming water.

The reaction is preferably carried out at room temperature by treating a solution of the starting material.

20 by an alcoholic solvent saturated with gaseous ammonia. Similarly, a concentrated solution of ammonium hydroxide in ethanol, and ammonia also give good yields. The reaction can be carried out with any dispersion in an inert liquid phase, and

25is not limited to liquids in which the starting materials are soluble and ammonia can be used without other liquids. Although the reaction seems rapid, the reaction mixture is left to stand for several hours in order to ensure good yields. The temperature at which the reaction is carried out is not critical, but it

- 14 should not be too high, in order to avoid decomposition of the desired final product. A 3-a-cylamido-5-aryl-1,3-dihydro-2H-1,4-benzodiazepine-2-one can be converted by hydrolysis to 5-amino-5-aryl-1,3-dih.ydro- 2H-1,4-benzodia5zepine-2-one, in particular by hydrolysis using an acid such as hydrochloric acid contained in a lower alkanol, for example methanol. These latter compounds, 3amino, have anticonvulsant, sedative or muscle relaxant properties and they can also be converted into 3-hydroxy-5-aryl-1,3, dihydro-2H-1,4, benzodiazepine-2ones having the same properties and some of which have recognized clinical utility.

Hydrolysis of a 3-acylamido-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is carried out, preferably in

151st methanol containing a large excess of hydrochloric acid and at room temperature. It is also possible to operate under moderate hydrolysis conditions, but it is necessary to avoid concentrations of strongly hydrolysing agents which would be capable of splitting the heterocyclic nucleus of the desired product. In this reaction, the temperature is also not critical, but as for the closing phase of the core, it must not be too high, so as not to cause decomposition of the desired final product. To ensure good yields, the mixture is allowed to stand

25 reaction used for hydrolysis for a few hours.

The term alkyl group used herein includes methyl, ethyl, propyl, isopropyl, n-butyl, iso-amyl, alkenyl and alkynyl groups such as allyl, methallyl, propargyl, propenyl, and vinyl, and groups

3Ocycloalkyl such as cyclopropyl, cyclobutyl and

I, „q 5 cyclopentyle. By lower alkyl or lower alkoxy * is meant an alkyl group having from 1 to 6 carbon atoms. By lower aralkyl is meant an aralkyl group having from 1 to 9 carbon atoms, such as a benzyl or phenethyl group.

In general, in the abovementioned starting compounds, the acyl and acyloxy groups carried by the nitrogen atom of the acyloxyacyl-amido group can be identical or different; they may, for example, be a lower Onoyl or lower alkanoyloxy group, such as a formyl, acetyl or propionyl, formyloxy, acetoxy or propionoxy group; a lower aroyl or an aryloxy such as a benzoyl or halogenated benzoyl group benzoyloxy or halogenated benzoyloxy; or a lower aralcanoyl or aralkanoyloxy

15 lower, such as a phenylacetyl or phenylacetoxy group.

The aforementioned starting compounds can generally carry substituents formed by non-reactive groups in the reaction, this at different positions on the phenyl and aryl groups of the phenyl-aryl ketone and also on the nitrogen atom forming the bridge and by a substituent only linked to the carbon atom -2 of the phenylaryl ketone, There must be at least one hydrogen atom in the 2- position of the acetamido group for the formation of a 2-amino intermediate and cyclization to be possible,

25 Consequently, when the term aoylamido or acetamido is used in the description in connection with this group, it is defined as carrying at least 1 hydrogen atom at said position -2. Thus the 2-acetamido carbon atom can carry, as the sole substituent, for example a lower alkyl group such as a methyl or ethyl group. Likewise, the nitrogen atom ~ 16 * of the acetamido group may carry as substituent hydrogen, an alkyl group, for example methyl, ethyl, isopropyl, allyl or methallyl, or a lower aralkyl group such as a benzyl group. or phenetyl; however,

5 when the nitrogen of the acetamido group carries hydrogen as a substituent on the acyl radical of the T-acylamido group cannot be an acyloxycarbonyl residue.

The phenyl ring carrying the 2- (N ~ acyl ~ oxyacylamido) acyl-amido group can also carry substituents such as a lower alkyl group, for example a residue

5-methyl, a halogen, for example a 5-chlorOj · 5bromo, 4,5-dichloro and 5 »6-dichloro, a nitro group, for example 5-mitro, a halogenated lower alkyl group, such as a residue 5-trifluoro-methyl, or alkylsulfonyl, for example a 5-methyl-sulfonyl residue linked in position 3-, 4-, 5 and 6-, Such substituents have no influence on the course of the reaction in accordance with l 'invention. Said phenyl ring may also not carry a substituent at all.

On the other hand, the aryl group can carry substituents which are inactive with respect to the reactions envisaged. It is thus that in this group can be a phenyl group bearing as a substituent a halogen such as chlorine and bromine, in particular an o-chloro group; a lower alkyl group, for example p-methyl; a lower alkoxy group, e.g., p-methoxy; a halogenated lower alkyl group, for example m-trifluoromethyl, or an alkyl-sulfonyl group, for example p-methyl-sulfonyl. As other aryl-monocyclic groups which may be present without influencing the ring closure and hydrolysis reactions, mention may be made of 2- or 3-thienyl groups; 2- or 3-furyl; or groups

2-, 3- or 4-pyridyle.

When the starting materials carry substituents as indicated above, all the intermediates, the 3-acylamino compounds and the 3 ~ amino compounds finally obtained, of course carry the corresponding substituents and linked to the same positions.

Thus, a 3-acylamino-3-aryl-l, 3-dihydro-2H-l, 4bensodiazepine-2-one can have the general formula î

<img file="OA2171A_D0004.tif" />

wherein X and Y denote hydrogen, a lower alkyl group, chlorine, bromine, a nitro group, a halogenated lower alkyl group, for example trifluoromethyl, or an alkyl-sulfonyl group, for example methyl20sulfonyl; h and R ^ denote hydrogen, an alkyl group such as a lower alkyl, or an aralkyl group such as a lower aralkyl; and Ar denotes an aryl group, for example 1- or 2-naphthyl, but preferably a monocyclic aryl group such as a phenyl or substituted phenyl group, for example by a halogen such as chlorine or bromine, a lower alkyl , lower alkoxy, halogenated lower alkyl, for example trifluoromethyl or alkyl-sulfonyl, for example methyl-sulfonyl, 2 or 3 furyl, 2-or 3-thienyl or alternatively 2-, 3 ~ or -4-pyridyl.

3-amino-1,3-dihydro18 21-1,4-benzodiazepine * 2 * oneg can also be produced by aminating a 5-soyl-3 “halol, 5-dihydro-2H-1,4, benzodiazepine-2 -one with ammonia dissolved in a suitable solvent such as ethylene glycol dimethyl ether. This reaction is preferably carried out at room temperature, using an excess of ammonia. The reaction mixture is filtered and the filtrate is concentrated in vacuo to precipitate a residue which is dissolved in cold acetonitrile and treated with alcoholic hydrochloric acid to precipitate the starting product in the form of hydrochloride. for this invention. Before using the salt obtained above in the present process, it is dissolved in water and treated with a dilute solution of sodium carbonate to precipitate the free base.

The chlorine atom at position 5 of these compounds is very reactive and therefore these compounds react with ammonia at room temperature (or even below room temperature). The reaction is preferably carried out in a suitable neutral and inert solvent such as diethyl ether, ethylene glycol dimethyl ether, methanol, ethanol or mixtures of these solvents, with or without water.

The amine obtained

in which R represents

3 Lower alkyl, alkenyl for formula; R

-0=0

<img file="OA2171A_D0005.tif" />

,0

-HH, (VI)

With hydrogen or a lower radical or lower aralkyl:

I

- 19 Ar is a phenyl, thienyl or phenyl radical bearing as a substituent a halogen or a lower alkoxy, lower alkyl or haloalkyl radical; Σ and Y represent hydrogen or a halogen, nitro, haloalkyl or alkylsulfonyl substituent, '1, 3-dihydro-3-hydroxy-2H-l, 4benzodiazepine-2-ones of the formula:

<img file="OA2171A_D0006.tif" />

(VII) (where X, Y, R and Ar are as defined above) by causing nitrous acid to act on the amine represented by formula (VI). Nitrous acid is produced by gradually adding any of several reagents to an acid reaction medium. Sodium nitrite, potassium nitrite or organic nitrites can be added to a solution comprising an organic solvent or a mixture of organic solvents and water containing the amine used as starting material, as well as an excess of 'acid. The nitrite can be added in the form of a solid product or an aqueous solution, preferably at a concentration of approximately 5%. Acids which can be used to acidify the reaction medium include mineral acids such as sulfuric or phosphoric acids, or organic acids such as trichloroacetic acid. To dissolve the starting compound, the acid solution is heated to a temperature between 10 and 80 ° C. During the addition of the nitrite to the acid solution, the reaction mixture is preferably kept at a temperature around 50 ° G.

The benzodiazepinones of formula (VIL) can be esterified in the usual way in position 5 psœ monocarboxylic acid. We can also make them react with

5a esterifying agent consisting of a polycarboxylic acid, to form the 1,3-dihydro-5-aryl-3-carboxyacyloxy2H-1,4-benzodiazepine - 2-on.es, which are advantageous from the pharmaceutical point of view.

The pharmacologically active compounds of this

10invention can be represented by the formula (VIII) below s

<img file="OA2171A_D0007.tif" />

in which R is hydrogen or a hydrocarbon radical invites a lower alkyl radical (for example methyl, ethyl

20 or propyl), lower alkenyl (for example allyl or methallyl), or lower aralkyl (for example benzyl or phenylethyl), Ar is an aryl radical such as phenyl or thienyl or phenyl bearing as substituents chlorine, fluorine, or methoxy radicals , methyl or trifluoro-methyl, X and

25Y each represents hydrogen or a substituent from the group consisting of chlorine, bromine or nitro, trifluoromethyl and methylsulfonyl radicals, and S * is hydrogen, lower alkyl or the acyl radical of a carboxylic acid. Among the acyl radicals of carboxylic acids, which

30 may be suitable, mention may be made of acetyl, propionyl, caproyl, benzoyl, toluyl, phenacetyl, betaphenyl propionyl and cinnamoyl radicals, aminoacyl radicals such as amino cetyl., Aminobenzoyl and morpholinoacetyl, and haloacyl radicals such as chloracetyl ,

5bromobenzoyle, etc. E is preferably hydrogen or a methyl radical, Ar is a phenyl or chlorophenyl radical,

X and T respectively represent hydrogen and a substituent 7-chloro and R 'is hydrogen.

In the patent of the Union of South Africa N ° 60/4931 10 of November 9, 1960 and in the patent application of the United States of America N ° 87.102 of February 6, 1961, entitled: Novel 1,4-benzodiazopines and Intermediates therefor .

There are described 1,3-dihydro-1,4-benzodiazepine-2-one-4-oxides which can be represented by the formula (IX) below:

<img file="OA2171A_D0008.tif" />

0=0

<img file="OA2171A_D0009.tif" />

(ix) in which R represents hydrogen or a hydrocarbon radical and X, Y and nr have the meaning indicated above, as well as processes for their preparation.

By gently heating a 1,3-dihydro-2H-1,4-benzodiazepine-2-one-4-oxide corresponding to the formula (IX) with a halide or a carboxylic acid anhydride, it forms with a very high yield a product corresponding to formula (X) below.

<img file="OA2171A_D0010.tif" />

<img file="OA2171A_D0011.tif" />

in which X, Y, R and Ar have the meaning already indicated and X 'represents the halide or ncyloxy radical of this halide or anhydride of carboxylic acid. When the reagent used is an organic acid anhydride, the product · is a 3-acyloxy-1,3-dihydro-2H-1,4, benzodiazepine-2 "* one of the formula (XI) below:

<img file="OA2171A_D0012.tif" />

When the reagent is a hydrocarbon carboxylic acid halide, the product is usually a mixture of

205-acyloxy-1,3-dihydro-2H-1,4-benzodiazepine-2-one and a

5-halo-1,3-dihydro-2H-1,4-benzodiazepine-2-one of the formula (XII) below

<img file="OA2171A_D0013.tif" />

(XII) the first being predominant. However, in the special case where the reagent is an alkyl haloformate, the product recueil501i is a 3-halo ~ l, 3-dihydro-2H-l, 4-benzodiazepine ~ 2-one (XII).

The products of formula XI, being esters, can be saponified by treating them with sodium hydroxide, which gives compounds corresponding to the formula VII in which R 'is hydrogen. The compounds having the formula XI in which the acyl radical is a haloacyl radical (for example chloracetyl), can be transformed, by reaction with an amine (for example with morpholine), into aminoacylic esters, such as morpholinoacetates.

It is possible, if desired, to transform the compounds 10 of the formula VIII in which. R is hydrogen, into compounds of the formula VIII in which R is a hydrocarbon substituent by treating them with an alkaline substance such as 1 ' sodium or potassium hydroxide and an alkylating agent such as dimethyl sulfate, sulfate

15 of ethyl, methyl iodide, allyl bromide or benzyl chloride.

Compounds having formula (VIII) in which

R ′ is hydrogen, that is to say compounds VII can be transformed into 3-chloro-1,3-dihydro-2H-1,4 ~ benzodiazè20pine-2-ones (formula XII) treating with thionyl chloride. These 3-chloro derivatives are valuable intermediates for the preparation of the corresponding 3-alkoxy compounds (Formula VIII, R = alkylated), because they react easily with alcohols to form the latter; outraged

25our formation by reaction between thionyl chloride and the 3-hydroxy compounds, they occur simultaneously in some cases during the acylation by an acid chloride of the 2-one-4-oxides, as has been exposed above, and as shown in Example 8 below. These 3-chlo30ro compounds can also be transformed into 3-hydroxy compounds

- 24 correspondents (Formula VIII, R '= H) by heating with water and a mutual solvent, such as acetone and dioxane.

The active products of this invention, often in the form of acid addition salts, can be administered parenterally or perorally, and can be mixed as desired with diluents, solvents, suspending agents , fillers, excipients, o-adhesives, coloring or flavoring materials, for the preparation of convenient dosage forms.

The following nonlimiting examples are intended to illustrate the preparation of the compounds of this invention:

-25 EXAMPLE 1

To a mixture of 2.1 g of hydroxylamine hydrochloride and 5 ml of 4N sodium hydroxide in 75 ml of alcohol and 25 ml of e · ·, 3.6 g of 5-chloro- 2 ~ (2'-iodo-acetamido)

5bensophenone and the mixture is heated to reflux for 20 minutes. Sodium hydroxide is added to the resulting solution to neutralize any hydrochloride which may not have reacted. The solution is diluted with 100 ml of water. After removing the impurities by filtration, acidify

101a solution by means of acetic acid, the resulting solid is collected and it is recrystallized from ethanol to obtain the 4-oxide of 7-chloro ~ 1,3-dihydro-5-phenyl-2H-1,4- benzo · diazepine-2-one, which melts at 235 ° -237 ° C.

EIZEMPLE 2

We manufacture as in Example 1 the 4-oxide of 7bromo-5 ~ (p-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2one (which melts at 260 ° -261 ° C with decomposition ), from

5-bromo-2- (2'-bromo-acetamido) -4 '' - chlorobenzophenone and hydroxylamine.

EXAMPLE 5

The 4-oxide of 7-chloro-1,3-dihydro-1-methyl -5-phenyl- 2H-1, 4-benzodiazepine-2-one, melting at 178 ° 180 ° C, is produced from the 5 -chloro-2 ~ (2'-iodo-N-methylacetamido) benzophenone and hydroxylamine following the operating mode of Example 1.

EXAMPLE 4

A mixture of 5.0 g of 5-chloro-2- (2'-iodoacetamido) -benzophenone, 7.0 g of hydroxylamine hydrochloride, 20 ml of water, 20 ml of 4M solution is stirred at room temperature. sodium hydroxide and 60 ml of dimethylformiamide

- 26 during half an hour during which a clear solution is formed. 100 ml of water are added, the resulting solid is collected and it is recrystallized from benzene to obtain 5-chloro-2- (2'-hydroxylamino-acetamido) -benzophenone, which melts at 129 ° -131 ° C . Analysis: Calculated for C₁₅H₁₃C1ïï₂O₃ : C, 59.10; H, 4.30; Cl, 11.64; h, 9.21% Found: G, 59.38; H, 4.16; 01, 11.70; N, 9.00%.

EXAMPLE 5

A mixture of 4.0 g of 5-chloro-210 (2'-chloro-acetamido) -benzophenone, of 7.0 g of hydroxylamine hydrochloride, 10 ml of water, 20 ml is stirred at 50 ° C. of a 4N solution of sodium hydroxide, 100 ml of dimethylformamide and 0.2 g of sodium iodide, for half an hour during which a clear solution is formed. 100 ml of water are added while cooling, the precipitate is recrystallized from alcohol and then from benzene to obtain 5-chloro-2- (2'-hydroxyamino-acetamido) -benzophenone, which melts at 129 °. -131 ° C.

EXAMPLE 6

In the reaction of Example 5, acidification

20 of the clear solution by means of hydrochloric acid, and heating precipitate the 4-oxide of 7-ohloro-1, 3-dihydro-5phenyl-2H ~ 1,4-benzodiazepine-2-one, which melts at 235 ° - 237 ° 0.

EXAMPLE 7

To a suspension of 1.0 g of 5-chloro-2- (2'-hydroxy25amino-acetamidc) -benzophenone in 30 ml of 50% alcohol, 2 ml of 6N hydrochloric acid is added and the mixture is then heated on the boiling water bath for 10 minutes. The solution is diluted with an equal volume of water and cooled; the solid 7-chloro-1, .3-dihydro-5-phenyl-2H301,4-benzodiazepine-2-one 4-oxide is collected and washed with ether.

- 27 EXAMPLE 8

A solution of 5-chlor0-2- (2'-hydroxyamino-acetamido) -benzophenone in acetic acid containing hydrochloric gas is heated on a boiling water bath.

5 dilute with water to obtain the 4-oxide of 7-chloro-1,5-dihyb.ro5-phenyl-'2H-1,4-benzodiasepine-2-one.

EXAMPLE 9

To a suspension of 1.0 g of 5-chlor0-2- (2'-hydroxyamino-acetamido) -benzophenone in 30 ml of 50% alcohol,

Add 2 ml of sodium hydroxide solution. The solution is diluted with an equal volume of water and acidified with acetic acid. The solid 7-chloro-1,3-dihydro-5-phenyl 2H-1,4-benzodiazepine-2-one 4-oxide is collected and washed with ether.

EXAMPLE 10

5 We heat on a boiling water bath a mixture of

5 ~ chloro-2- (2'-hydroxyamino-acetamido) -benzophenone in acetic anhydride for 10 minutes until all the solid has dissolved, then the mixture is cooled. The resulting precipitate is collected, 2- (2'-N-acetoxy-N-acetylamino-acetamido) -5-chlo20robenzophcnone, which melts at 151-153 ° C. Analysis: calculated for C_lgII₁₇Key₂0₅ : C, 5S, 7O; H, 4.41; h, 7.41; Cl, 9.12 /.

Found: C, 58.68; H, 4.42; M, 7.11; Cl, 9.1 /.

In pharmacological tests, this compound shows sedative activity.

EXAMPLE 11

2- (2'-K-acetoxy-1-acetylamino-acetamido) 5-chloro-benzophenone is suspended in ethyl alcohol to which an excess of hydrochloric acid is added. The mixture is boiled for a few minutes and allowed to cool. The resulting precipitate, the 4-oxide, is collected.

-287-chloro-1,3-dihyàro-5-phenyl-2ïï-1, 4-benzodiazepine-2-one, melting at 238 ° -239 ° C.

MELE 12

À We heat on a boiling water bath a solution

5of 1.0 g of 5-chloro-2- (2'-hydroxyamino-a.cetamido) -benzophenone and 10 ml of acetic acid, for half an hour, then 1 ml of acetic anhydride and the heating is continued for half an hour. The reaction mixture is cooled and diluted with 10 ml of water; the solid which precipitates is collected to obtain 3-acetoxy-7-chloro ~ 1,3-dihydroxy-5-phe ~ hyl-2H-1,4-benzodiazepine-2-one, which melts at 241 ° -243 ° 0 .

B This procedure is also carried out by adding the anhydridqâcétique to a reflux solution of 5-chloro2- (2'-hydroxyamino-acetamido) -bensophenone in acetic acid, heating for an additional 30 minutes.

By following the procedure of Example 1 or the procedure of Example 4 followed by that of Example 9, the intermediates and products obtained below are obtained (The abbreviation PE indicating the melting point):

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<td></td><td> '0</td><td>d</td><td>d</td><td></td>

<td>Oi</td><td>o</td><td>-P</td><td> 0</td><td></td>

<td> 0</td><td rowspan="2">d 1</td><td> '0</td><td> 1</td><td></td>

<td> 0</td><td>at</td><td> —</td><td></td>

<td>d</td><td> 0</td><td> 0</td><td>CM</td><td></td>

<td>d</td><td>ri</td><td>ri</td><td></td><td> 0</td>

<td>-P</td><td> 0</td><td> 0</td><td> 1</td><td>d</td>

<td>œ</td><td>ri</td><td>d</td><td>CM</td><td> 0</td>

<td>d</td><td>d</td><td>ri</td><td> 1</td><td>d</td>

<td>d</td><td> 0</td><td>ri</td><td> 0</td><td> '0</td>

<td>ra</td><td> 1</td><td>• ri</td><td>ri</td><td>d</td>

<td></td><td>CM</td><td>ri</td><td>O</td><td>P-</td>

<td></td><td>O |</td><td>-P have</td><td> 0</td><td>0 t &lt;3 d</td>

<td></td><td> 1</td><td> 1</td><td> 1</td><td> 0</td>

<td></td><td>\ l</td><td>\ l</td><td>LT3</td><td>d</td>

- 32 Following the procedure of Example 5, 5-chloro-2- (2'-hydroxyamino-acetamido) -ben2D phenone is produced from 5-chloro-2- (2'-bromo-acetamido). ) -benzophenone; we manufacture the o- (2-hydroxyamino-acetamido) -benzophenone

5from the o- (2-chloroacetamido) -benzophenoiie; / 5-chloro-2- (2'-hydroxyamino-acetamido) -phenyl7 / 2thienyl7-ketone is produced from / 2- (2'-chloro-acetamido) -5ehlorophenyl7 / 5-thienyl7-ketone; / 5-chloro-2 (2'-hydroxy-amino-acetamido) -phenyl7 / ~ o-chlorophenyl7-ketone

10a from the / 2- (2'-chloro-acetamido) -5-chlorophenyl7 / ~ ocbloropbenyl7-ketone; 4,5-dichloro-2- (2'-hydroxyamino-acetamido) -benzophenone is made from 4,5 ~ dichloro-2 (2'-chloro-acetamido) -benzophenone, and 5chlor0 is manufactured -2- (2'-hydroxyamino-E-methyl-acetamido) -benzophenone to

15Start from 5-chloro-2- (2'-chloro-R-methyl-acetamido) -benzophenone.

EXAMPLE 15

To a solution, heated to reflux, of 1.0 g of 5chlor0-2- (2¹-hydroxyamino-acetamido) -benzophenone in 10 ml

20 of dioxane containing hydrochloric acid, 1 ml of acetic anhydride is added and the mixture is then heated for 30 minutes. The reaction mixture is cooled and diluted with 10 ml of water to precipitate 3-acetoxy-7- chloro-1,3-dihydro-5phényl-2H-1,4-benzodiazepine-2-one.

EXAMPLES 14 to 21

By following the procedure of Example 12B, the following products are obtained from the intermediaries mentioned below:

-33Exem-

<td>pie n °</td><td>Intermediate</td><td>Product</td>

<td> 14</td><td>2- (2'-hydroxyamino acétami-</td><td>3-acetoxy-1,3-dihydro-5-</td>

<td></td><td>do) benzophenone</td><td>phenyl-2H-1, 4-benzodia-</td>

<td> 5</td><td></td><td>zépine-2-one. PF229-</td>

<td></td><td></td><td>231 ° C.</td>

<td> 15</td><td>/ 5-chloro-2- (2'-hydroxy</td><td>3-acetoxy-7-chloro-1,3</td>

<td></td><td>amino-acet amido) -phenyl7</td><td>dihydr0-5- (2-thienyl) -2H</td>

<td></td><td>/ 5-thiényl7 ketone</td><td>1,4-benzodiazepine-2-one</td>

<td> 10</td><td></td><td>Mp 269 ° C.</td>

<td> 16</td><td>/ 5-chloro-2- (2'-hydroxy</td><td>3-acetoxy-7-chloro-1,3-</td>

<td></td><td>amino-acetamido) -phényl7</td><td>dihydro-5-o-chlorophenyl</td>

<td></td><td>/ "O-chloro-phényl7cétone</td><td>2II-1,4-benzodiazepine-2-</td>

<td></td><td></td><td>one, mp 262-264 ° C.</td>

<td> 15 17</td><td>4,5-dichloro-2- (2'-hydro</td><td>3-acetoxy-7,8-dichloro-</td>

<td></td><td>xy-amino-acetamido) -Ben-</td><td>1,3-dihydro-5-phenyl "2H-</td>

<td></td><td>zophénone</td><td>1,4-benzodiazepine-2-one</td>

<td> 18</td><td>5-chloro-2- (2'-hydroxyami-</td><td>7-chloro-1,3-dihydro-5-</td>

<td></td><td>no-acetamido) benzophenone.</td><td>phenyl-3-propionoxy-2H-</td>

<td> 20</td><td>Treat with anhydride</td><td>1,4-benzodiazepine-2-one</td>

<td></td><td>propionic acid.</td><td></td>

<td> 19</td><td>5-chloro-2- (2¹-hydroxamino-</td><td>3-benzyloxy-7-chloro-1,3</td>

<td></td><td>acetamido) benzophenone.</td><td>dihydro-5-phenyl-2H-1,4</td>

<td></td><td>Treat with anhydride</td><td>benzodiazepine-2-one.</td>

<td> 25</td><td>benzoic.</td><td>Mp 251-2 ° C.</td>

<td> 20</td><td>5-chloro-2- (2¹hydroxy</td><td>7-chloro-1,3-dihydro-3-</td>

<td></td><td>amino acétarido) -benzophé-</td><td>chloroacetoxy-5-phenyl-</td>

<td></td><td>none.</td><td>2H-1,4-benzodiazepine-2-</td>

<td></td><td>Treat with anhydride</td><td>one. Mp 230-231 ° C.</td>

<td> 30</td><td>chloroacetic acid.</td><td></td>

-34 Example no.

Intermediate

Product, 5 ~ dichloro-2- (2'-hydro- 3-chloroacetoxy-7,8xy-amino-ac and amido) - benzodichloro-1,3-dihydr o · phenone.

5-phenyl-2H-1,4-benzo Treat with diazepine-2-one chloride.

of chloraeetyl.

EXAMPLE 22

To a solution of 40 g of 2-amino-5-chlorobenzophenone

10in 150 ml of chloroform; a solution of 26 g of acetylglycolyl chloride in 60 ml of chloroform is added dropwise. The solution heats up during the addition, and when the addition is complete, the reaction mixture is heated on a boiling water bath for 15 minutes. The solvent is removed

15 under reduced pressure and the residue is recrystallized from ethanol, in order to obtain 2- (2 '-s.cétoxy-acetamido) -5-chlorobenzophenone, which melts at 121 ° -123 ° C. Analysis. Calculated for:

<img file="OA2171A_D0014.tif" />

(B) A solution of 100 g of 2- (2'iodo-acetamido) -5-chlorobenzophenone, 75 g of sodium acetate and 600 ml of glacial acetic acid is heated to reflux for 2 hours. The reaction mixture thus obtained is diluted and the product is crystallized from ethanol to obtain 2- (2'-acetoxy25acetamido) -5-chloro-benzophenone, melting at 121-123 ° C.

(c) To a 66.6 g suspension of 2- (2'-acetoxy-acetamido)

5-chlorobenzophenone in 550 ml of ethanol, a solution of 8 g of sodium hydroxide in 60 ml of water is added while stirring. Stirring is continued until the solution of the old solution is clear. 750 ml of water are added to precipitate the pro-35duit which is recrystallized from ethanol to obtain 55 g of 2- (2'-hydroxy-acetamido) -5-chlorobenzophenone, melting at 15C ° -152 ° C. Analysis. Calculated for C ^ 2CIRO3; C, 62.18;

H, 4.18; F, 4.84; Cl, 12.24% - Found: C, 62.25; H, 4.15;

5R, 4.72; Cl, 12.30%.

(d) To a solution of 15 g of 2 - (2 '-hydroxy-acetamido) ~ 5chloro-benzophenone in 200 ml of triethylamine, 28 g of jo-br chloride omophenyl tallow onyl are added. The reaction mixture is heated on a boiling water bath for 30 minutes

About 10, it is cooled and diluted with ice water; the resulting precipitate is collected and recrystallized from acetonitrile to obtain 17 g of 2- (2'-p-bromophenyl-sulfonoxyacetamido) -5-chlorobenzophenone, melting at 150 ° -152 ° C. Analysis: Calculated for C ^ H., ^ BrClRO ^: C, 49.58, · H, 2.97; R, 2.75;

15Br, 15.71; Cl, 6.97; S, 6.30% - Found: C, 49.98; H, 2.84; R, 2.93 -, Br, 15.6 5 Cl, 6.80; S, 6.30%.

(e) To a solution of 15 g of 2- (2'-hydroxyacetamido) -5chlorobenzophenone in 200 ml of triethylamine, 21 g of p-toluene-sulfonyl chloride are added. We isolate the product

20as described above and recrystallized from acetonitrile to obtain 13 g (76%) of 2- (2'-para-toluene-sulfonoxy-acetamido) -5-chloro-benzophenone, melting at 148 ° -150 ° C. Analysis. Calculated for C ^^ B ^ CIRO ^ S. C, 59.52; H, 4.09 -, Cl,, 7.99; S, 7.22% - Found: C, 59.57; H, 3.97; Cl, 8.0;

25S, 7.2%.

(f) Similarly, 2- (2 * -methylsulfonoxyacetamido) -5-chlorobenzophenone, melting at 120 ° -122 ° C, is produced from 2- (2'-hydroxy-acetamido) -5- chlorobenzophenone and methyl-sulfonyl chloride. Analysis: Calculated for

3OC₁₆H_uO1RO₅S: C, 52.24; H, 3.84; R, 3.81; C, 9.64;

- 36 S, 8.70 0 - Found: C, 52.30; H, 3.78; N, 3.83; Cl, 9.7;

S, 9.0%.

(g) Following the procedure of paragraph (a) above, a solution of 2-p-toluenesulphonylacetyl chloride (Bull. Soc. Chim. France, .1.94.8, 995) in chloroform is treated with 2-amino-5-chloro-henzophenone in chloroform to obtain 2- (2'- £ -toluenesulfonoxy-acetamido) ~ 5chloro-benzophenone, which melts at 148 ° -15O ° C after recrystallization from acetonitrile.

(H) Following the procedure of paragraph (a) above, a 2-amino-5- (chlorobenzophenone in 50 ml of chloroform) solution is added to a solution of 14 g of 2-phenylsulfonoxy-acetyl chloride (Bull Soc. Chim. France, 1948, 995) in chloroform. The mixture is heated on a boiling water bath for 20 minutes and the solvent is removed in vacuo, the residue solidifies and it is crystallized from about 800 ml of ethanol to * obtain 21 g (81 /) of 2 - (2'-phenylsulfonoxy-acetamido) -5-chlorobenzophenone melting at 130 ° 0-132 ° C. Analysis: Calculated for C ^ H ^ gClEC ^ S - C, 58.67; H, 3.75;

20C1, 8.25; E, 3.26; S, 7.46% - Found: C, 58.56; H, 3.6.2; Cl, 8.56; E, 3.56; S, 7.5 / ·.

(i) To 5.1 g of 2- (2'-bromophenylsulfonoxy-acetamido) -5 chlorobenzophenone in 150 ml of methyl cellosolve heated to 85 ° C., a solution of 10 g of hydrochloride hydrochloride is added.

251amine, 5 g of sodium hydroxide and 20 ml of water. The temperature is maintained at 80 ° -90 ° C for 15 minutes, the mixture is then cooled and diluted with water. The product is collected and recrystallized from benzene to obtain 2- (2'-hydroxyamino-acetamido) -5 ~ chlorobenzophenone (fondant

30 to 129-131 ° C).

EXAMPLE 25

To a solution of 4.4 g of 2- (2'-p-toluenesulfonoxyacetamidc) -5-chloro-benzophenone in 150 ml of methyl cellosolve at 85 ° 0, a solution of 10 g of hydroxylamine hydrochloride and of 5 g sodium hydroxide in 20 ml

5d'eau. After 15 minutes at 85 ° C., the mixture is cooled, diluted with water, the product is collected and it is recrystallized from benzene to obtain 1.6 g of 2 (2'-hydroxyamino- acetamido) -5-chlorobenzophenone, melting at 1290-151 ° C.

By following the same procedure, the

2- (2'-hydroxyamino-acetamido) -5-chlorobenzophenone from 2- (2'-phenyl-sulfonoxy-acetamido) -5-chlorobenzophenone and hydroxylamine.

EXAMPLE 24

To 100 ml of ethanol saturated with ammonia, 1.0 g of 2- / 5- (K-acetoxy-acetamido) acetamido-75-chlorobenzophenone is added, with stirring. The mixture is left to stand for approximately 12 hours, then it is concentrated in vacuo and the

20 residue in benzene. Cooled and collected in the form of a white solid product 0.65 g of 5-ketanido-7 ~ chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one.

Melting point 272-273 ° 0.

Calculated for C ^ H ^ Clh ^ O ^: C 62.29; H 4.30; N $ 12.8

25Found: G 62.24; H 4.51; N 12.3

EXAMPLE 25

1 g of 5-acetamido-7-chloro-1,3-dihydro-5phenyl-2H-1,4-benzodiazepine-2-one is dissolved in ethanol containing an excess of hydrochloric acid. Leave to stand for 18 hours.

300n spreads the solution with water and makes it alkaline at

- 38 means ammonium hydroxide. The solid product which precipitates is collected and recrystallized from ethanol to obtain 0.45 g of 3-amino-7-chloro-1,3 “dihyoro-5-phenyl-1,4benzodiazepine-2-one. Melting point: 202-205 ° C.

EXAMPLE 26

A suspension of 2 g of 2- / 2 (N-acetoxy-acetamido) -acetamido7-5-chlorobenzophenone in 20 ml of methanol is slowly added to 100 ml of methanol saturated with ammonia, at 50 ° -60 ° C. The mixture is heated at reflux for 2 1/2 hours.

1OOn the solution is evaporated in vacuo and the procedure is as in Example 24 to obtain the same product (1.1 g).

EXAMPLE 27

1 g of 2- / 2- (N-acetoxy-acetamido) acetamido7 · 5-chlorobenzophenone at 0 ° C. is added to 100 ml of alcohol saturated with amI

15monia and stirred for 15 hours. After evaporation of the solvent in vacuo, the residue is dissolved in benzene and cooled. The resulting precipitate is collected having a melting point of 125-130 ° C (0.31 g) and is quickly recrystallized from acetonitrile to constant boiling point

20gal at 140-142 ° C to obtain 2- (2 ~ acetamido-2-aminoacetami do) -5-chloro-benzophenone (0.13 g).

Calculated for:

C, 59.05; H, 4.67; N, 12.15; Cl, 10.25.

Found: C, 58.76; H, 4.40; N, 11.87; 01, 10.4.

By heating in xylene for 2 1/2 hours, this compound is transformed into 3-acetamido-7-chloro-1,3-dihydro-5phenyl-2H-1,4-benzodiazepine-2-one, melting point: 272 273 ° vs.

EXAMPLE 28

By the method of example 25, the 730 is transformed

- 39 chloro-1,3-dihydro-3-formamido-5-phenyl-2H-1,4-benzodiazepine2-one with melting point 243 ~ 245 ° C in 3-araino-7-chloro-1,3dihydro-5 -phenyl-1,4-2II benzodiazépins-2-one.

EXAMPLE 29 ^:

To 2 liters of methanol saturated with ammonia at 25 ° C., 1.5 liters of methanol and 70 g of 2- / 2- (N-acetoxyacetamido) aeetamido7-5 chlorobenzophenone are added and the resulting solution is heated to 60 ° C for 2 hours. The mixture is then heated at reflux for 1 hour 1/2. Concentrate to 350 ml

10 at atmospheric pressure and cooled to 40 ° C. We add

8.4 ml of glacial acetic acid; cooled slowly with stirring to 20 ° C and stirred further for 4 hours. Cool to 0 ° 0 for 1 hour; the filtered solid product is filtered and washed three times with 20 ml of methanol, in order to obtain 38.4 g of 3-acetamido-7-chlorO “1,3-dihydro-5-phenyl-2H1,4-benzodiazepine-2- one, m.p. 272-275 ° C (with decomposition). This compound has anticonvulsant properties when tested on laboratory animals.

EXAMPLE 30

To 50 ml of concentrated hydrochloric acid is added per portion ^ 0 g of product of Example 29, this in 5 minutes and at 25 ° C. Stir for 19 hours and cool to 15 ° C.

20 g of ice and 120 ml of water are added, and then carefully 35 ml of ammonium hydroxide (partial neutralization 251e); stirred for 1 hour at 10 ° C and separated by filtration 8.6 g of 3-amino-7-chloro-1,3-dihydro-5phenyl-2H-1,4-benzodiazepine-2-one hydrochloride melting point 204-205 ° C (with decomposition). After recrystallization from water, the melting point of the product rises to 211-212 ° C.

- 40 EXAMPLE 51

A mixture of 5.0 g of 7-chloro-3-hydroxy ~ 5-phen3rl-1,3-dihydro-2H-1,4benzodiazepine-2-one and 50 ml of thionyl chloride is heated at reflux for 30 minutes. ,

5 after which the unreacted thionyl chloride is removed by evaporation under reduced pressure. Ether is added to the redisu, the 3,7-dicliloro-5-phenyl-1,3-dihydro2l-1,4-benzodiazepine-2-one is collected, it is dissolved in dimethyl ether. ethylene glycol and separated by filtration

10 a small amount of undissolved material. The solution is then added to an excess of ammonia dissolved in ethylene glycol dimethyl ether and the mixture is stirred at room temperature for 20 minutes. The mixture is filtered and the filtrate is concentrated by evaporating it under video. We dissolve the residue

15in cold acetonitrile, and treated with an excess of alcoholic hydrochloric acid, which determines the precipitation of the hydrochloride. By recrystallization from alcohol, the semi-alcohol hydrochloride of 3-amino-7-chloro-5-phenyl-1, 3-dihydro-2ïï-1, 4-benzodiazepine-2-one is obtained, which melts at 22520226 ° C.

Analysis: Calculated for C ^ ÏÏ ^ Clh ^ O, IïCl, 1/2 C₂H ^ 0H:

C, 55.66; H, 4.07; M, 12.12; Cl, 20.54

Found: C, 55.62; H, 4.57; N, 12.36; Cl, 20.51.

The hydrochloride can be dissolved in water and

Treat with a sodium carbonate solution to precipitate the free base which, recrystallized from alcohol, melts at 205-206 ° C.

Analysis: Calculated for C ^ gClN ^ O ·

C, 63.05 d H, 4.23; N, 14.71; Cl, 12.41

30Trcuvé; C, 63.20; H, 4.36; h, 14.86; Cl, 12.20.

i

I t - 41

EXAMPLE 32

To a hot solution of 1.0 g of 3-amino-7-cbloro1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 3 equivalents of hydrochloric acid, is added dropwise a

5 aqueous solution of sodium nitrite 5 fi · The solid which precipitates is filtered and recrystallized from alcohol, which gives 7-ch.loro-1,3-dihydro-3-hydroxy-5-phenyl-2H -1,4benzodiazepine-2-one; melting point: 204-205 ° C.

EXAMPLE 33

A solution of 1.0 g of 3-amino-7-chloro-1,3- * dihydro-5-phenyl-2H-1,3-benzodiazepine-2-one is acidified in hot ethanol with 2 equivalents d aqueous hydrochloric acid and treated with butyl nitrite. The solid which precipitates is filtered and recrystallized from alcohol, which

15 gives 7-chloro-1,3-dihydro-3-bydroxy-5-phenyl-2H-1,4-benzodiazepine-2-one; melting point: 204-205 ° C.

By operating as explained above, but by replacing 3-amino-7-chloro-1,3-dibydro-5-phenyl-2H-1,4benzodiazepine-2-one with 3-amino-7 -chloro-1,3-dihydro-12ümetbyl-5-phenyl-2H-1,4-benzodiazepine-2-one and gar 3-amino7-chloro-5- (o-chloro-phenyl) -1,3-dib .hydro-2H-1,4-benzodiazepine2-one, 3-amino-7-ehloro-5- (o-chlorophenyl) ~ 1,3-dihydro-1métbyl-2H-1,4-benzodiazepine-2-one, we obtain :

7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl ~ 2H-1,425 benzodiazepine-2-one; melting point: 11 S-121 ° C; 7 ~ chloro-5- (o-chlorophenyl) -1,3-dihydro-3-hydroxy-2H-1,4benzodiazepine-2-one; melting point: 166-168 ° C; 7 ~ chloro-5- (o-chlorophenyl) -1,3-dihydro-3-hydroxy-1-methyl2H-1,4-benzodiazepine-2-one; melting point: 192 ~ 194 ° 0,

- 42 EXAMPLE 34

Heated on a boiling water bath, with stirring, a suspension of 20 g of 7-ehloro-1,3-dihydro-5-phenyl-2H1,4-benzodiazepine-2-one-4-oxide in 150 ml of acetic anhydride until all of the solid product is dissolved. After cooling, 1? Analytically pure, analytically pure 3-acetoxy-7-chloro1,3-dihydro-5-phenyl-2H-1,4-benzoaziazepine-2-one; melting point: 242-243 ° 0.

Analysis - Calculated for C ^ H ^ CIE ^ O ^:

C, 62.09; H, 3.98; E, 8.52

Find ; C, 62.06; H, 4.13; E, 8.30.

EXAMPLE 35

3-acetoxy ~ 1,3-dihydro ~ 5-phenyl-2E-1,4benzûdiazépine-2-one, melting at 229-231 ° C, is prepared from 1,3-di15hydro-5-phenyl-2II- 1,4-Benzodiazepine-2-one-4-oxide, according to the method of Example 1.

Analysis - Calculated for C ^ ÏÏ ^ E ^ O ^:

C, 69.39; ïï, 4.80; E, 9.51 Found: C, 69.30; H, 4.91; E, 9.64 "

EXTiMPLE 36

Preparing 3-acetoxy-7-chloro-1,3-dihydro-1-methyl-5-nhenyl-2H-1,4-benzodiazepine-2 ~ one, melting at 262-263 ° C, from 7- chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1, 4benzodiazepine-2-one-4-oxide, according to the process for

251 example 34.

Analysis - Calculated for C ^ gH ^ ClE ^ O ^:

C, 63.07; H, 4.41; E, 8.17; Cl, 10.34 Found; C, 63.16; H, 4.57; E, 8.22; Cl, 10.25 /

EXAMPLE 37

3-acetoxy-7-bromo-5- (p-chlorophenyl) is prepared

I

- 43 1,3-dihydro-2H-1,4-benzodiazepine-2-one, melting point: 256-257 ° C, from 7-bromo-5- (p-chlorophen.yl) -1.3 -dihydro 2K-1,4-benzodiazepine-2-one-4x, yu, according to the method of Example 34.

5Analysis - Calculated for C_&lt;] γΗ ^^ BrClN ^ O ^:

C, 50.07; H, 2.97: N, 6.86; Cl, 8.70; Br, 19.60 Found: C, 50.08; H, 3.08; N, 6.77; Cl, 8.51; Br, 19.18

EXAMPLE 38

3-acetoxy-7-ohloro-1,3-dihydro-5-210 (thienyl) -2ïï-1,4-benzodiazepine-2-one, melting point 269 ° C, is prepared from 7-chloro- 1,3-dihydro-5- (2-thienyl) -2H-1,4-benzodiazepine-2-one-4-oxide, according to the method of Example 34.

Analysis - Calculated for C ^ ClN ^ O ^ S:

C, 53.80; H, 3.31; N, 8.37

Found: C, 53.95; H, 3.41; N, 8.17.

EXAMPLE 39

7-chloro-3- (alpha-chloroacetoxy) -1,3dihydro-5 ~ phenyl-2H-1,4-benzodiazepine ~ 2-one is prepared, melting point

20230-231 ° C, from 7-chloro-1,3-dihydro-5-phenyl ~ 2fi-1,4benzodiazepine-2-one-4-oxide, and an alpha-cloroacetic anhydride, in accordance with the process for example 34 ·

Analysis - Calculated for C ^ γΗ ^ 2 ^ 2 ^ 2 ^ 3 '

C, 56.06; H, 3.32; N, 7.70; Cl, 19.47

25Found: C, 56.08; H, 3.42; M, 7.43; Cl, 19.40.

EXAMPLE 40

7-chloro-3- (alpha-ch.loroacétox.y) -1,3dihydro-5-phenyl-2ïï-1,4-benzodiazepine-2-one is prepared by making acetyl chloride act on 7- chloro-1,3-dihydro-5-phényl302II-1,4-benzodiazepine-2-one 4-oxide. The compound is the same

- 44 than that prepared in Example 39 *

EXAMPLE 41 (a) A suspension of 5.0 g of 7-chloro-1,3dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one ~ 4-ox is heated^:'- from in 20

5ml of benzoyl chloride until all the solid product is dissolved. By adding cyclohexane, a solid product is precipitated which is suspended in hot ethanol and the 3-benzoxy-7-chloro-1,3-dihydro-5phenyl-2H-1,4-henzodiazepine is collected. -2-one crystalline and colored

10white; melting point: 251-252 ° C.

Analysis - Calculated for C22S-J 5θ1 ^ 2θ3 ^:

C, 67.63; H, 3.87; h, 7.17; Cl, 9.07

Found: C, 67.57; H, 4.05; N, 6.93; Cl, 9.05.

(b) water is added to the alcoholic filtrate above,

The solid product which precipitates is collected and recrystallized from acetonitrile, to give 7-chloro-1,3oihydro-3-ethoxy-5-phenyl-2H-1,4-benzodiazepine-2-one; melting point: 225-227 ° C.

Analysis - Calculated for C ^ H ^ Clî ^ O2 ·

C, 64.87; H, 4.80; h, 8.90; Cl, 11.25

Found: C, 64.45; H, 4.69; N, 8.88; Cl, 11.20.

EXAMPLE 42

To a slightly hot suspension of 3.0 g of 3-acetoxy-7-chloro-1,3-d.ihydro-5-phenyl-2H-1,4-benzodiazepine-2-one

In 150 ml of ethanol, 4 ml of 4N sodium hydroxide solution are added while stirring. All the solid product dissolves and soon it precipitates a thick white solid product. This solid product is filtered, washed well with water and recrystallized from ethanol, which gives 7-chlo30ro-1,3-dihydro-3-hydroxy-5-phenyl ~ 2H-1 , 4-benzodiazepine-2-one;

- 45 melting point: 203 ° C.

Analysis - Calculated for C ^ CINgOg;

<td>C, 62.81</td><td>; H</td><td>3.84; NOT,</td><td> 9,27 ;</td><td>Cl,</td><td> 12,37</td>

<td>5Found: C, 62.57</td><td>; H</td><td>3.93; NOT,</td><td> 9,59 ;</td><td>this,</td><td> 12,30</td>

<td></td><td></td><td>EXAMPLE</td><td> 43</td><td></td><td></td>

6 ml of hydroxide are added to a suspension of 3.4 g of 3-acetoxy-7-chloro-1,3dihydro-5-phenyl-2H-1,4-benzodiazepine ~ 2-one in 80 ml of alcohol 4N sodium. After complete

10dissolution, it precipitates a solid body which redissolves by adding 80 ml of water. The solution is acidified with acetic acid, which gives white crystals. After recrystallization from alcohol, the compound melts at 203-204 ° C and it is identical to the product of Example 42.

EXAMPLE 44

It is heated to reflux for a few minutes from the

7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepine2-one with a 5 to 10-fold excess of thionyl chloride, then evaporated to dryness. the residue is a hydrochloride

Partial of 3,7-dichloro-1,3-dihydro-5-phenyl-2I-1,4-benzodiazepine-2-one; Fusion point ; 151-153 ° C. As a free base, it melts at 179 ° C (with decomposition).

Analysis - Calculated for Ο ^ Η ^ θΟΙ ^^ Ο:

C, 59.03; H, 3.30; Cl, 23.24; N, 9.18

25Found: C, 59.57; H, 3.22; Cl, 22.05; N, 9.51.

EXAMPLE 45

3,7-Dichloro-1,3-dihydro-5-phenyl2Ξ-1,4-benzodiazepine-2-one is dissolved in hot ethanol. After a few minutes, water is added, which precipitates the 730chloro-3-ethoxy-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-46 one; it is filtered off, dried and washed. recrystallizes from acetonitrile. The product melts at 224 225 ° 0 and it is the same as that described in Example 41 h.

EXAMPLE 46

Dissolve one gram of 3,7-dichloro ~ 5-phenyl-1,3dihydro-2K-1,4-henzodiaaépine-2-one in. 20 ml of aqueous acetone at 50 μl and heat on a water bath until so that after a few minutes it precipitates a solid product. This substance is recrystallized from alcohol, which gives

101a 7-chloro-3-hydroxy-5-phenyl-1,3-dihydrΟ-2Η-1,4-benzodiazepine-2-one, identical to the products of Examples 42 and 43.

EXAMPLE 47

A solution of 3.0 g of 7-chloro-3- (alpha-chloro-acetoxy) -1,3-dihydro-515phenyl-2H-1, 4-benzodiazepine-2-one, of 2.2 ml of morpholine and 75 ml of ethanol. After cooling, the solution is acidified with alcoholic hydrochloric acid. The hydrochloride is separated from the 7-chloro-1,3-dihydro-3- (morpholino-acetoxy) -5-phenyl-2H-1,4-benzodiaepine-2-one by filtration; point of

20 fusion 223-224 ° C, and washed with ethanol.

Analysis - Calculated N, 9.33

Found: E, 9.02 for C₂₁H_2OC1₂NOT₅O₄; Cl, 15.75; Cl, 15.70.

EXAMPLE 48

1 gram of 7-chloro-5-phenyl-1,3-dihydro2H-1,4-benzodiazepine-2 ~ one-4-oxide is added to 20 ml of ethyl chloroformate and the mixture is heated for 15 minutes on the boiling water bath. The excess reagent is removed by evaporation under vacuum, which leaves a residue of 3,7-dichloro-530phenyl-1,3-dihydro-2ïï-1,4-benzodiazepine-2-one, identical to

- 47 product of example 44.

EXAMPLE 49

7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1, 4-benzodiazepine-2-one, melting at 1195121 ° 0, is prepared from 3-acetoxy -7-chloro ~ 1,3-dihydro-1-methyl5-phenyl-2ïI-1,4-benzodiazepine-2-one and an equivalent of sodium hydroxide, in accordance with the process of example 43. Analysis - Calculated for C ^ gH ^ ClE ^ O ^:

C, 63.92; H, 4.36; N, 9.32 lOT Found: C, 63.78; H, 4.64; N, 9.26.

EXAMPLE 5Q

A mixture of 3.4 g of 7chloro-3-hydroxy-5-phenyl-1,3 ~ dihydro-2H ~ 1,4-benzocliazepine2-one, 4 ml of 4N sodium hydroxide solution is stirred for 2 hours and 1.4

15 ml of dimethyl sulphate in 200 ml of 50% alcohol and then evaporated under vacuum until dry. Water and ether are added and the ethereal layer is separated. The solvent is eliminated and the residue is recrystallized from cyclohexane, which gives 7-chloro-1,3-dihydro ~ 3-hydroxy ~ 1-methyl-5-phenyl-2ïï-l_f3_

20benzodiazepine-2-one; melting point: 119—121 ° C.

EXAMPLE 51

3-acetoxy-7-chloro-5- (o-chlorophenyl) 1,3-dihydro-2H-1,4-benzodiazepine-2-one, melting point 262 264 ° 0, is prepared from 7-chloro- 5- (o-chlorophenyl) -1,3-dihydro-525phenyl-2H-1,4-benzodiazepine-2-one-4-oxide, according to the process of Example 34.

Analysis - Calculated for C ^ gClglïgO ^:

C, 56.21; H, 3.33 5 N, 7.71 Found: C, 56.21; H, 3.54; N, 7.40.

- 48 EXAMPLE 52

7-c] aloro-5- (o-chlorophenyl) -1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one is prepared from 3acetoxy-7 ~ chloro "5- (o-chlorophenyl) -1,3-dihydro-2ïï-1,4-benzo5diazepine-2-one, according to the method of Example 43 and it is isolated in the form of solvate with 1 mole of ethanol. When heated, it loses the solvating ethanol and it melts at 166-168 ° C. .

Analysis - Calculated for C ^ g01₂®2% *

C, 55.60; H, 4.39; N, 7, '63

Find ! C, 55.68; H, 4.20; N, 7.93.

EXAMPLE 53.

7-chloro-5- (o-chlorophenyl) -1,3-dihydro-3 ~ hydroxy-1-methyl-2E-1,4-benzodiazepine-2-one is prepared from

151a 3-acetoxy-7-chloro-5- (o-chlorophenyl) -1,3-dihydro-1-methyl2H-1,4-benzodiazepine-2-one according to the method of Example 43.

EXAMPLE 54

7-chloro-5- (o-chlorophenyl) -1,3-dihy20dro-3-hydroxy-1-methyl-2H-1,4-benzodiazepine-2-one is prepared from 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-3-hydroxy-2H-1,41 benzodiazepine-2-one according to the method of Example 50; melting point 192-194 ° C.

Analysis - Calculated for 2θ · ^ 2 ^ 2θ2 ^:

0.57.33; H, 3.61N, 8.36; Cl ,. 21.15 Found: C, 57.42; E, 3.44; N, 8.69; Cl, 21.15.

EXAMPLE 55

1,3-dihydro-3-hydroxy-5-phenyl7-trifluoromethyl-2H-1,4-benzodiazepine-2-one can be prepared from

303-acetoxy-1,3-dihydro-5-phenyl-7-tri £ luor omethyl-2ïï-1,4-benzo-49 diazepine-2-one in accordance with the process of Example 43. · The latter is easily manufactured compound by the method of Example 34 from 1,3-dihydro-5-phenyl-7-trifluoromethyl-2ïï-1,4-benzodiazepine-2 ~ one-4-oxide, described in the patent of the Union South African, n ° 60/4938 dated 29 November 1960. EXAMPLE 36

3-acetoxy-7 “Chloro-1,3-dihydro1-ethyl-5-phenyl-2H-1,4-benzodiazepine-2-one can be prepared from 7chloro-1,3-dihydro-1-ethyl- 5-phenyl-2II-1,4 ~ benzodiazepine-21Oone-4-oxide according to the method of example 34.

EXAMPLE 57

7,8-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepine-2-one can be prepared from 3-acetoxy-7,8-dichloro-1 , 3-dihydro-5-phenyl-2H-1,4-benzodiazepine

15 in accordance with the method of Example 43 ·

EXAMPLE 58

1,3-dihydro-3-hydroxy-5- (mfluoroph.enyl) -7-chloro-2l-1,4-benzodiazepine-2-one can be prepared from 3-acetoxy-1,3-dihydro -5- (m-fluorophenyl) -7-chloro-2H201,4-benzodiazepine-2-one according to the method of Example 43.

EXAMPLE 59

1,3-dihydro-3-hydroxy-7-nitro5-phenyl-2H-1,4-benzodiazepine-2-one can be prepared from 3-acetoxy251,3-dihydro-7-nitro-5-phenyl -2H-1,4-benzodiazepine-2-one, in accordance with the method of Example 10. The last compound can be prepared by the method of Example 34 from 4-oxide, as described in the patent of l Union Africaine N ° 60/4938 cited above

- 50 EXAMPLE 60

1-allyl-7-chloro-1,3-dihydro-3hydroxy-5-phenyl-2H-1,4-benzodiazepine-2 ~ one can be prepared from 7-chloro-1,3-dih.ydro '-3-h.ydroxy-5-ph.enyl-2ïï-1,4-benzodiazepine52-one and allyl bromide according to the method of Example 50.

EXAMPLE 61

1,3-dihydro-3 - hydroxy-7-chloro5- (o-tolyl) -2H-1,4-benzodiazepine-2 ~ one can be prepared from 3-acé1Otoxy-1,3-dihydro- 7-cbloro-5- (o-tolyl) -2H-1,4-benzodiazepine-2one according to the method of Example 43.

EXAMPLE 62

1,3-dih.ydro-3-hydroxy-7-methylsulfonyl-5-phenyl-2H-1,4-benzodiazepine-2-one can be prepared from acetoxy-1,3-aihydro-7- methyl-sulfonyl-5 ~ pb.enyl-2'H-1,4-benzodiazepine-2-one according to the method of Example 43.

EXAMPLE 65

1,5-dihydro-3-h.hydroxy-7-chloro5- (p-trifluoromethylphenyl) -2ïï-1,4-benzodiazepine-2-one can be prepared from

20de 3-acetoxy-1,3-dih.ydro-7-ciLLorO “5- (p-trifluoromethylphenyl) -2H-1,4-benzodiazepine-2-one according to the method of Example 43.

EXAMPLE 64

5-acetoxy-7,9-dichloro-1,3-di25bydro-5-pbenyl-2ïï-1,4-benzodiazepine-2-one can be prepared from 7,9dichloro-1,3-dihydro-5- phenyl-2ïï-1,4-benzodiazepine-2-one-4oxide according to the process of example 34,

EXAMPLE 65

6-chloro-1,3-dihydro-3-hydroxy3O5-phenyl-2H-1,4-benzodiazepine-2-one can be prepared from 3-acetoxy-51 6-chloro-1,3-dihydro- 5-phenyl-2I-1,4-benzodiazepine-2-one in accordance with. procedure of Example 43.

EXAMPLE 66

1-Benzyl-7-chloro-1,3-dihydro3-hydroxy-5-phenyl-2l-1,4-benzodiazepine-2-one can be prepared from 7chloro-1,3-dihydro-3-hydroxy- 5-phenyl-2H-1,4-benzodiazepine-2one and benzyl bromide, according to the method of Example 50.

EXAMPLE 67

3-acetoxy-7-chloro-1,3-dihydro5- (p-methoxyphenyl) -2H-1,4-benzodiazepine-2-one can be prepared from 7chloro-1,3-dihydro-5- (p -methoxyphenyl) - 2H-1, 4-benzodiazepine2-one-4-oxide according to the method of Example 34