DE2005508A1 - Benzodiazepine derivatives - Google Patents

Description

ί). ! iiq. A. van der Werftiv.FrciÄtedflier

PAlENIANWALIi /

4008/148

F. HofFmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Benzodiazepln derivatives

The invention relates to new benzodiazepine derivatives general formula

wherein R, halogen or nitro, R ₂ phenyl, halophenyl or pyridyl, R_ hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, haloalkyl, carbalkoxy, monoalkylaminoalkyl or dialkylaminoalkyl, R ^ alkoxy, haloalkoxy,

00 98 3.5 / 19 57

Monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkyloxy, alkoxyalkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, R _{5 is} hydrogen or hydroxy and Rg is hydrogen or carbalkoxy and. where in the case of R ^ is hydrogen, the nitrogen atom in the 4-position can carry an oxygen atom,
and salts of these compounds.

The term "alkyl" alone or in combination such as "Alkoxy" includes straight-chain and branched hydrocarbon radicals with 1-6, preferably with 1-4 carbon atoms such as methyl, ethyl, isopropyl and the like. The term "acyl" includes acyl groups such as alkanoyl radicals, e.g. acetyl, propionyl, tert. Butyryl and the like, cycloalkanecarbonyl radicals such as cyclopropanecarbonyl and the like, aroyl or aralkanoyl radicals such as benzoyl, phenacetyl, phenylpropionyl and the like, the given * if they can also carry methoxy substituents. The term “haloalkoxy” includes mono- and di- and tri-haloalkoxy groups such as chloroacetyl, dichioracetyl and the like. The term "halogen" includes all 4 halogens, i.e. fluorine, chlorine, bromine and iodine.

Preferred compounds are those in which R is chlorine or nitro. Furthermore, R, - and Rg are preferably hydrogen. If R _{3 is} halophenyl, then the substituent is preferably in the 2-position of the 5-phenyl ring.

009835/1957

When R _{3 is} pyridyl, the pyridyl 2 group is preferred. Further preferred compounds are those in which Rp is phenyl, 2 ^ chlorophenyl or 2-fluorophenyl. If R-, acyloxyalkyl, then acyloxymethyl is preferred, acetyl, cyclopropionyl, tert. Butyryl are preferred as acyl radicals. Compounds in which Rj, chlorine or nitro, Rp phenyl, 2-fluorophenyl or 2-chlorophenyl, R ₁ - and R ^ are hydrogen, R, hydrogen or alkyl, and Rj, alkoxy are particularly preferred. 7-Nitro-5-phenyl-1-methoxymethy1-1,3-dihydro-2H-1, k -benzodiazepine- are particularly preferred. 2-one, 7-nitro-5-phenyl-l-ethoxymethyl-l, 3-dlhydro-2H-l, 4-benzodlazepin-2-one, 7-nitro-5-phenyl-l - ((2-chloroethoxy) methyl] -1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-chloro-5- (2-fluorophenyl) .l-methoxyethyl-1,3-dihydro-2H-1,4 -benzodiazepin-2-one, 7-chloro- (2-cyclopropionyloxy-1-methoxy-ethyl) -l, 3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one.

The method according to the invention is characterized in that that a) a compound of the general formula

II

0G9835 / 1S57-

BATH

wherein R ₁ , R ₂ and Rg above meaning is a 4-oxide thereof, with a compound aäes?

implements,

X — CH-Rg IESTiE

where R _{7 is} hydrogen, alkyl, haloalkyl * or acyl oxy alkyl, Rg is alkoxy, haloalkoacy * or alkoxyalkoxy and X is halogen «

or that one b) a compound of the general formula

fe where R ₁ and R _{2 have the} above meaning,

with a vinyl ether of the general formula

wherein R _{q is} alkyl, reacts,
or that one c) a compound of the general formula

00 9 8 35/1957 BADOR ₁ G ₁ NAL

wotfin R., Rp and H ₁ . have the above meaning and R _{10 is} hydrogen, alkyl, hydroxyalkyl, haloalkyl, monoalky! aminoalkyl, dialkylarainoalkyl or aeyloxy alkyl and R _{11 has} the meaning given for R ₁ ^, but at least one of the substituents R _o and I _{11 is} monohaloalkyl or _{a is a} monohaloalkoxy group and where in the case of R ₁ - is hydrogen, the nitrogen atom in

4-position can carry an oxygen atom Reacts with a monoalkylamine or dialkylamine, or that one d) a compound of the general formula

wherein R ₁ and Rg have the above meaning, R _{12 is} alkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio or aminoalkoxy, R ₁ , hydrogen, 0Q983B7 19S7

Alkyl, monoalkylaminoalkyl, dialkylaminoalkyl or aminoalkyl mean, however, at least one of the substituents R ₂ and R ,, means an aminoalkoxy, monoalkylaminoalkoxy, aminoalkyl or monoalkylaaino · alkyl group,

or a corresponding 4-oxide alkylated, or that nan e) from a compound of the general formula

R ₁ -JT- CH-R.,

VIII

wherein R ^ and R _{2 have the} above meaning, R ₁ ^ alkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio or a slotted monoalkylaminoalkoxy group, R ,, - hydrogen, alkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyloxyalkyl or a protected monoalkylaminoalkyl group means at least one of the Substituents R ₁ ^ and R ,, - a protected Monoalkylaminoalkpxy or Monoalkylaminoalkylgruppe,

or splits off the protective group from a corresponding 4-0'xyd,
or that one f) in a compound of the general formula

009835/1957

where isn

it Uaaeei-afeolf

"in

l., iliial ^^ aittätn®aiacylL

ässr

fe ^ zw ,. i

; Eäl © aib: oiae

. _t oäer that mm ^

GH — 1

e3; nser

wherein R ₁ , R ₂ , R ₅ and Rg have the above meanings «R ₁ Q is alkylthio and R _{19 is} hydrogen, alkyl, hydroxyalkyl, haloalkyl, carbalkoxy or aoyloxyalkyl and in the case of R _{c being} hydrogen, the nitrogen atom in the 4-position can carry a Saueretoffatob,

the alkylthio group to alkylsulfinyl or alkylsulfonyl group oxidized,

or that one h) a compound of the general formula

Sa where R ₁ , R ₂ * R -, * R ^ and Rg have the above meaning,

cyclized, or that «an i) a compound of the general formula

009835/1957

wherein R ₁ , R-, R · »» Rj. and Rg have the above meaning

and R ₂₀ denotes an acyl group, hydrolyzed, or that aan J) is a compound <er general formula

XIII

in which R 1, Rg, R, and Rg have the above meanings and Rg _{1 is} alkoxy, haloalkoxy, monoalkylaminoalkoxy, dialkyl-ainoalkoxy, hydroxyalkoxy. Mean alkoxyalkoxy or alkylthio

deoxidized,

or daas mank) a compound of the general formula

XIV

wherein R ₁ , R ₂ and Rg have the above meanings, alkoxy, dialkylaminoalkoxy, alkoxyalkoxy or alkyl · 009835/1957

thio and R ₂ -J are Waae »» etoff, alkyl, carbalkoxy, dialkylaminoalkyl or acyloxyalkyl,

dehydrated,

or the · nan 1) a connection of the general pore ·! .

wherein R ₁ , R ₂ and Rg have the above meaning and R ₂ ^ alkoxy, nonoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy or alkoxyalkoxy and Rp ₁ . Denotes hydrogen, alkyl, hydroxyalkyl, carbalkoxy, monoalkylaminoalkyl, P dialkylaminoalkyl or acyloxyalkyl,

oxidized or dehydrogenated at the 4,5 bond, or that m) a compound of the general formula

009835/1957

" ^U "

wherein R ₁ , Rg, R ^ and R _{5 have the} above meaning, Rgg alkyl and R ₂ - hydrogen, alkyl, hydroxyalkyl, haloalkyl / monoalkylaalnoalkyl, dialkylaminoalkyl or aoyloxyalkyl and where the case R _{5 is} hydrogen «the nitrogen of fatoii in ^ -Position can carry an oxygen atom

saponified and decarboxylated,

or that nan η) is a compound of the general formula

CH COOR

26th

XVII

where R ,, R ₂ * R · »· R ^ and R_g have the above meaning sur 3-hydroxy compound is oxidized,.

or that o) a compound of the general formula

XVIII

009835/1957

wherein R ₁ , R ₂ , Rg and R _{35 have the} above meanings,

^R 28 ^{acyl and R} 29 ^alkoxy * are monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy or alkylthlo,

■ with a base into the corresponding 4,5-dehydro compound convicted,

or that p) a compound of the general formula

XIX

where R ₁ , R _g and Rg have the above meaning, R is a mesyl or tosyl group, R ^ _{1 is} hydrogen, alkyl, Hydroxyalkjrl, Carbalkoxy, Dialkylamino-

P alkyl or acyloxyalkyl and R, ₂ alkoxy, dialkyl

aainoalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkylthio, alkylsulphonyl or alkylsulphonyl mean, ■ converted into the corresponding 4,5-dehydro compound with a strong base, or that q) a compound of the general formula

009835/1957

xx

in which R ₁ , Rg, R, | Bjj and Rg have the above meanings rearranged into the corresponding 4,5-dehydro compound, or that r) a compound of the general formula

XXI

where R ₁ , R ₂ and Rg have the above meaning and R ^ _{0 is} hydroxyalkyl, RjJ _{1 is} alkoxy, haloalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl,

or a corresponding 4-oxide dayon with an acylation medium treated,

or that one s) in a compound of the general formula

009835/1957

XXII

wherein R ₁ , R ₂ and Rg have the above meaning and

Rj ^ ₂ haloalkyl and R ^, alkoxy »dialkylauino-

alkoxy, alkoxyalkoxy "alkylthio" alkylsulfinyl or alkylsulfonyl mean «

or a »corresponding 4-oxide the aliphatically bonded one Halogen atom is converted into an acyloxy group and that t), if desired, a compound obtained is converted into a salt.

The reaction of a compound of the formula II or a W 4 oxide thereof with a compound of the formula III provides Compounds of the formula I (including 4-oxides thereof), in which R ~ have the _{meaning given for R 7} and R ^ the meaning given for Rg «R ₁ . stands for hydrogen and R ₁ * R ₂ and Rg have the above meaning. It can be used in an inert organic solvent or mixtures thereof such as hydrocarbons, such as benzene, toluene and the like, dimethylformamide, ethers such as dioxane, tetrahydrofuran, alcohols such as tert. Butanol and the like. Be carried out. Suitable temperatures are, for example, between -5O ⁰ C and 120 ⁹ C. Instead of X meaning halogen, any

009835/1957

equivalent leaving group such as a mesyloxy, tosyloxy group or the like * can be used. It is twofold to first convert a compound of the formula II into a 1-alkali metal derivative before reacting it with a compound of the formula III. This 1-alkali metal derivative can be produced, for example, with the aid of a lower alkali metal alcoholate such as sodium ethylate, an alkali metal hydride such as sodium hydride, an alkali metal amide such as sodium amide and similar agents. The reaction of a compound of the formula II with a compound of the formula III ( can, however, also be carried out in the presence of a base such as alkali metal hydroxides, for example sodium hydroxide or triethylamine.

The reaction of a compound of the formula IV with a vinyl ether of the formula V yields a compound of the formula I in which R ,, Rc and Rg are hydrogen, R ^ alkoxymethyl and R. and RgObige have meanings, i.e. a compound with an α-alkoxyKthylreet in 1 -Position. This reaction is conveniently carried out in an inert organic solvent such as Hydrocarbons such as benzene, toluene, chlorinated hydrocarbons such as chloroform and the like. Carried out in the presence of a SCure catalyst such as glacial acetic acid. For example, temperatures between room temperature and 15O ^# C are suitable for this reaction.

The implementation of a compound of formula VI with a Monoalkylamine or a dialkylamine provides compounds of

Formula I, in which R, hydrogen, alkyl, hydroxyalkyl, monoalkyl

³ 0 09 835/1957

2ÖÖ5508

aminoalkyl, dialkylaminoalkyl or acyloxyalkyl, E ^ alkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy. Hydroxyalkoxy, alkoxyalkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl and R ^ are hydrogen and R ₁ , R and R, - have the meaning given for formula I, where in the case of R ₁ . Is hydrogen, the nitrogen atom in the 4-position can carry an oxygen atom, and where bed: use of a monoalkylamine as a reagent at least one of the substituents R, and Rl is a mono-

"alkylaminoalkyl or monoalkylaminoalkoxy group and, if a dialkylamine is used as the reagent, at least one of the Substituents R, and Rl represents a Dlalkylaminoalkyl- or dialkylaminoalkoxy group. This implementation can be done in one or several inert organic solvents such as ethers, e.g. Dloxan, dimethylformamide, hydrocarbons such as benzene, Toluene, ketones such as acetone, methyl ethyl ketone and the like. Be carried out. The temperatures and pressures to be used are not critical and the reaction can take place at room temperature or

"be carried out at elevated temperature and / or under pressure.

The alkylation of a compound of the formula VII gives compounds of the formula I (including 4-oxides thereof) in which R- is hydrogen, alkyl, monoalkylaminoalkyl or Dlalkylaminoalkyl, Rh alkoxy, monoalkylaininoalkoxy, dialkylaminolealkoxy, alkoxyalkoxy or alkylthio and Rj and Rg are hydrogen and R ₁ and R _{2 have} the meaning given for formula I, where at least one of the substituents R_ and R ^ is a monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylaininoalkoxy or

0Q9S35 / 1957

BATH

Represents dialkylaminoalkoxy group. This alkylation can take place, for example, by reductive alkylation with formaldehyde. It is expedient to work in methanol, for example in the presence of Raney nickel, and at room temperature, although temperatures above and below room temperature can also be used. You can also work under pressure. Furthermore, a compound of the formula VtI can be alkylated with an alkyl halide such as methyl iodide and the like. Zweckmässlgerweise is carried out at room temperature to 120 ⁰ C and in the presence of an organic solvent .as dioxane, dimethylformamide, "alcohols such as ethanol, hydrocarbons such as benzene," toluene, and the like. They reaction can also be carried out at elevated pressure.

The splitting off of a protective group from a compound of the formula VIII or a corresponding 4-oxide gives compounds of the formula I (including the corresponding 4-oxides) in which R is hydrogen, alkyl, monoalkylaminoalkyl, dialkylaminoalkyl or acyl oxyalkyl, Rj. Alkoxy, monoalkyl aminoalkoxy, DiälkylaminoalkGOcy, alkoxyalkoxy or alkylthio and R, - and Rg are hydrogen and R, and R «have the meaning given for formula I, where at least one of the substituents R- and R ₁ , a monoalky1 aminoalkyl · * or«. Represents monoalkylaminoalkoxy group. The choice of the protective group in a compound of the formula VIII and its elimination is based on the particulars of the molecule. Suitable protective groups are e.g. carbobenzoxy, -obaikoxy and the like

00 & 835/19571 1

The protective group can be carried out, for example, by alkaline hydrolysis or hydrogenolysis. The hydrolysis is expediently carried out in an inert organic solution such as ether. Alcohols and at temperatures from room temperature to 10O ⁰ C carried out. Bases suitable for this are, for example, alkali or alkaline earth metal hydroxides such as sodium hydroxide and the like.

The hydrogenolysis is conveniently carried out in glacial acetic acid in the presence of palladium and at room temperature, although temperatures above and below room temperature can also be used.

A compound of the formula IX can be converted into a corresponding compound in which the aliphatically bonded halogen atoms are replaced by hydroxyl groups, for example, by hydrolysis or alcoholysis with catalytic amounts of a base fc of the corresponding acetate. It is expedient to work in an organic solvent such as alcohols, ketones, for example acetone, ethers, for example dioxane, dimethylformamide, dimethyl sulfoxide and the like. And at a temperature between room temperature and the reflux temperature of the reaction mixture. <

The oxidation of a compound of the formula X with an alkylthio group to the corresponding compound with an alkylsulfinyl or alkylsulfonyl group can be carried out with the aid of an oxidizing agent such as peracids, e.g. peracetic acid, perbenzoic acid acid and the like. Or hydrogen peroxide. One works

009835/1957

2ÖÖBSÖ8

here, too, expediently in an inert organic Solvents such as halogenated hydrocarbons, e.g., carbon tetrachloride; Acetic acid and the like. Suitable temperatures are, for example, between -50 * 0 and 80 * C.

The cyclization of a compound of the formula XI to a compound of the Foreel I (excluding the 4-oxides) in which R_ is hydrogen and R ₁ , R ₀ , R ,, Rj ₁ BBd R ^ have the meaning given for formula I, can in an alkaline, neutral or acidic medium and in any inert organic solvent such as hydrocarbons, chlorinated hydrocarbons, ethers, glacial acetic acid, alcohols, dimethylformamide and the like. Temperature and pressure are not critical factors, but it is advisable to work at temperatures in the range of approx. 0-15 ° C.

The hydrolysis of a compound of formula XIl provides

,; ■ ' .. ■ ■ ■; ■■,. - - "■ - .-., ·." ■ I compounds of Foreel I (excluding the 4-oxides), where R * Waisserstöff, alkyl, hydroxyalkyl, haloalkyl, carbalicoxy, monoalkylaalnoalkyl or dialkylaminoalkyl and R _{5 is} hydroxy and R, , R «, R ^ and Rg have the meaning given for formula I. This hydrolysis can be carried out, for example, by alkaline or acidic hydrolysis or alcoholysis. The acid hydrolysis is preferably carried out by treating the starting material with an aqueous solution of a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like. Or an organic acid such as toluenesulfonic acid

009835/1957

acid and the like. The acid treatment is expediently at Carried out at room temperature, although this is not critical. In addition, one works expediently in an aqueous one Medium.as an organic solvent such as dioxane, tetrahydrofuran or similar solvents that can be mixed with water contains. The alkaline hydrolysis can for example be carried out with aqueous alkali hydroxides such as sodium hydroxide and the like. at When using a starting material which contains an acyloxyalkyl group in the molecule, hydrolysis of this group also occurs at the same time. If a starting material is used which has carbalkoxy groups, the acyl group is split off in two ways by alcoholysis e.g. with sodium ethoxide in ethanol or triethylamine in ethanol and the like.

The deoxidation of a compound of the formula XIII gives corresponding 4-deoxides and can, for example, by Hydrogenation in the presence of Raney Niokel, conveniently in an inert organic solvent such as hydrocarbons e.g. benzene, toluene, alcohols, ethers such as Dioxane, ethyl acetate and the like. At room temperature and normal pressure or elevated pressure or by treatment with a Phosphorus trihalide, such as phosphorus trichloride, conveniently In an inert organic solvent as hydrocarbons, e.g. benzene and the like, chlorinated hydrocarbons and at room temperature, although temperatures

009835/1957

-2X-

above and below room temperature can also be used. The deoxidation can be carried out up to 50 ⁰ C with zinc and glacial acetic acid in an organic solvent such as glacial acetic acid, chlorinated hydrocarbons, ethers, alcohols and the like., And conveniently at temperatures between about -20. The use of a certain deoxidizing agent depends largely on the functional groups present in the molecule in order to avoid unfavorable side reactions | to report if possible. If a haloalkyl, haloalkoxy, alkylthio and / or nitro group is present in the molecule, it is therefore advisable to deoxidize with a phosphorus trihalide, whereas if a hydroxyalkyl and / or hydroxyalkoxy group is present, Raney nickel or zinc / glacial acetic acid is advantageously used.

The dehydration of a compound of Formula XIV

provides corresponding compounds with a double bond in | 4,5-position and can, for example, be carried out with a carbodiimide such as cyclohexylcarbodiimide and the like. The reaction is usually carried out in an inert organic solvent such as hydrocarbons, for example benzene, toluene, ethers such as dioxane and the like. Oeeignete temperatures are, for example * -20 to 100 ⁰ C. It is often observed in this Dehydratislerungsreaktion, especially when using 3rCajTb alkoxy derivatives as a starting material, the formation of a corresponding isomeric 3f4-dehydro derivative of formula I * This latter

009835 / 19S7

Connection Jedooh can easily become 4,5-dehydro connection be isomerized, for example by treatment with a base such as Alkali alkoxides such as sodium methoxide, triethylamine and the like.

The oxidation of a compound of formula XV provides corresponding compounds having a double bond in ^, IS-position and can, for example, with bromine, chlorine, _k azodicarboxylic esters, such as the Diäthy-lester, halosuccinimides such as bromine

suciinimld, haloamides such as chloroacetamide and the like. One works in two ways in an inert organic Solvents such as hydrocarbons, e.g. benzene, toluene and the like, halogenated hydrocarbons such as carbon tetrachloride, ethers such as dioxane, tetrahydrofuran and the like. and advantageously at a temperature between about. -30 and 100 · 0.

fc compounds of the formula XVI can be added to the corresponding

3-carboxylic acid salts are saponified, for example by treatment with alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxides or tert. organic bases such as triethylamine. The decarboxylation of this 3-carboxylic acid salts occurs long 'sam on standing, faster on heating and spontaneously upon acidification.

009835/1957

2Q05508

Compounds of the formula XVII can with air

or oxygen in the presence of a base ---- - -

oxidized to the corresponding ^ -HydroaEy - ^ - carbalkoxy derivatives will. The oxidation is expediently carried out in one inert organic solvents such as ethane, e.g. tetrahydrofuran « Dioxane, alcohols, e.g., lower alcohols, dimethylformamide and the like. Suitable bases are e.g. alkali alkoxides such as sodium methoxide, alkali hydrides, alkali amides and Alkali hydroxides such as sodium hydroxide. When using However, alkali hydroxides can simultaneously saponify a existing Garbalkoxygruppe in j-position or an exchange of a halo atom versus a hydroxy group in a haloalkyl and / or haloalkoxy-substituted compound occur. The use of alkali hydroxides is for the same reason Presence of a carbon alkoxy group in the substituent in the 1-position feu avoid.

The elimination of acid from a compound of the formula |

XVIII can be achieved with a base such as alkali hydrides such as sodium hydride, triethylamine, alkali amides such as sodium amide, alkali alkoxides such as sodium methoxide and the like in an anhydrous medium. It is expedient to work in an inert organic solvent such as ether, alcohols, for example ethanol, hydrocarbons, for example benzene, toluene, dimethylformamide and the like, and at temperatures between -40.degree. C. and 120.degree. The ^acyl: group in the meaning of R ₂ Q may be a lower alkanoyl, such as acetyl, aroyl such as benzoyl, tosyl, or mesyl.

009835/1957.

When the acid is split off, however, a compound of the formula XX can also occur as an intermediate, which accordingly the method given later is converted into the end product of formula I.

A mesyl or tosyl group can be split off from a compound of the formula XIX with a strong base such as alkali hydrides, for example sodium hydride, alkali alkoxides such as sodium methoxide, triethylamine and alkali amides such as sodium amide and the like in an anhydrous medium. It operates zwvokmässigerweise in an inert organic solvent such as ethers, alcohols such as ethanol, hydrocarbons such as benzene, toluene, dimethylformamide and the like., And at temperatures between 0 ^e 120 ° C. An isomeric compound of the formula XX, which is isomerized to the end product of the formula I, can also occur in this reaction.

The isomerization of a compound of the formula XX can be achieved by treatment with a base such as alkali metal alcoholates, for example sodium methoxide, alkali hydrides such as sodium hydride, triethylamine and the like. The reaction is conveniently effected in an inert organic solvent such as hydrocarbons, ethers, alcohols and the like., And at temperatures between -40 ° to 120 ^# C.

009835/1957

Compounds of the formula I (including 4-oxides thereof) in which R, acyloxyalkyl, R ^ alkoxy, haloalkoxy, dialkylaninoalkoxy, alkoxyalkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl and R ^ are hydrogen and R ₁ , R ₂ and Rg are the ones given for formula I. Have meaning can be prepared from corresponding compounds of the formula XXI by reaction with an acylating agent. Esterification can be accomplished with any suitable acylating agent such as an acid anhydride such as acetic anhydride, and the like, an acid halide such as acetyl chloride, benzoyl chloride, and the like. The reaction conditions are not critical and can be selected by any person skilled in the art depending on the esterification agent chosen. It is possible, for example, to work at room temperature or above or below room temperature, depending on the reagent chosen. In addition, it is expedient to work in a customary organic solvent such as hydrocarbons such as benzene, toluene and the like, chlorinated hydrocarbons such as methylene chloride and the like, dimethylformamide, pyridine and the like

The introduction of an acyloxy radical into a compound of the formula XXII provides compounds of the formula I (including 4-oxides thereof), wherein R, acyloxyalkyl, R ^ alkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio, alkylsulfinyl or Alkylsulfonyl and R ,, R «and Rg have the meanings given for formula I, and is conveniently carried out with a silver, sodium or potassium salt of a corresponding one

009835/1957

Acid, such as potassium acetate and the like. It is expedient to work in an organic solvent such as hydrocarbons, e.g. benzene, toluene and the like, dimethylformamide, ketones such as Acetone, Methyläthylkiton and the like. Depending on the The chosen reagent can be used at temperatures between room temperature and reflux temperature of the reaction mixture.

fc With regard to the method according to the invention

The following can be said of the raw materials used

The compounds of the formulas II, III, IV, V are known or can easily be prepared in analogy to known processes.

The 4-deoxy compounds of the formulas VI, VII, IX, X, XVI and XVII which have no hydroxyl group in the J5 position, fc can be obtained by using the process variant h) defined above. The corresponding 4-oxides of Formulas VI, IX, X, XVI and XXIII, if they are not accessible by using the process variant defined above under a), can be obtained by oxidation of the corresponding 4-deoxy compound, e.g. by Treatment with peracids such as peracetic acid in an organic solvent such as acetic acid, chlorinated hydrocarbons such as methylene chloride and the like.

009835/1957

3-Hydroxy compounds of the formulas VI> IX, χ and XVI can, for example, by treating a compound of the general formula

Rj-CH-R ₄ .

XXIII

wherein R ₁ , R ₂ , R, R ₁ ^ and Rg have the above meaning

with an anhydride, sulfide or halide of an aliphatic, aromatic or araliphatic carboxylic acid. The reaction causes the oxygen atoms in the 4-position to be split off with simultaneous acyloxylation of the carbon atom in the 3-position. The reaction is expediently carried out in a customary inert organic solvent such as hydrocarbons, for example toluene, benzene and the like, halogenated hydrocarbons such as carbon tetrachloride and the like, dimethylformamide and the like. If an acid anhydride or a diacyl sulfide is used as the aylating agent, these acid anhydrides or diacyl sulfides can also serve directly as the reaction medium. Subsequent hydrolysis of the 5-acyloxy derivatives obtained in the manner indicated for a compound of the formula XII gives 3-hydroxy derivatives.

009835/1957

^ -Hydroxy compounds of the formula VI can also be obtained from corresponding compounds unsubstituted in the 3-position by treatment with a halogenating agent which has an -NX group, in which X is halogen and a 3-halo compound obtained is reacted with, for example, an acetate or a Alcohol to the 4-acetoxy or 3-alkoxy compound obtained, which can be converted into J5-hydroxy compounds by hydrolysis, for example treatment with a base in a solvent, for example methanolic NaOH. Suitable shark generation

medium are e.g. N-chlorosuccinimide, N-bromosuccinimide, N-halo-lower Alkanoylamide and the like. The halogenation is expediently carried out in an inert organic solvent such as hydrocarbons, e.g. Benzene, toluene, chlorinated hydrocarbons of fm such as carbon tetrachloride and the like. Temperature and pressure are not critical in this process step and it can therefore be at room temperature and atmospheric pressure or work above room temperature. The reaction is also conveniently carried out in the presence of a radical forming catalyst, for example azo-bis-lower alkyl nitriles such as azodiisobutyronitrile and the like.

Compounds of the formula VII are all obtained by using the process variant defined above under c) accessible. Compounds of the formula VIII can be prepared in analogy to the process variant defined above under c) using a suitable amine with a protecting group. Q09835 / 1957

Pre-bindings of the formula XI can be used in known catfish " e.g. by reaction of a carbobenzoxyglycylamido-benzophenone of the general formula

—CO— CH ₂ —NH-COO -CH ₂ -

XXIV

or a 2 V-benzoyl-phthalimido-acetanilide of the general formula

N— CO—

C = O

XXV

or of a tert-butoxy-glycylamidobenzophenone of the general formula

009835/1957

LcO-CH ₂ -HH-COO-C (CH ₃ ,,

XXVI

in which in the formulas XXIV, XXV and XXVI R ₁ and R _{2 have} the meaning given above, with a compound of the formula III and subsequent cleavage of the carbobenzoxy radical or the phthalinide radical or the tert-butoxycarbonyl radical are prepared, if necessary before the cleavage an aliphatically bonded halogen atom is exchanged for a hydroxy group or a monoalkylamino or dialkylamino group or an alkylthio group is oxidized to an alkylsulfinyl or alkylsulfonyl group.

The reaction of a compound of the formula XXTV, XXV or XXVI with * iner compound of the formula III can be used in the reaction of a compound of the formula II with a compound the formula III specified manner take place.

The cleavage of the carbobenzoxy radical can be carried out, for example, by catalytic hydrogenation or by means of a hydrohalic acid in the presence of acetic acid.

0 0 9835/1957

The catalytic hydrogenation can be carried out in glacial acetic acid / HCl or ethanol / HCl and the like. The cleavage by means of a hydrohalic acid in glacial acetic acid can be carried out in the presence of an inert organic solvent such as chlorinated hydrocarbons, for example methylene chloride and the like, and at temperatures between -20 ° and room temperature. The cleavage, the Phthalimidrestes.wird conveniently carried out by hydrazinolysis in an inert organic solvent such as alcohols Aethem such as dioxane, dimethylformamide and the like., And at temperatures between room temperature and 150 ⁰ C. "The cleavage" of the tert-butoxycarbonyl radical can be carried out with trifluoroacetic acid and in an organic solvent such as hydrocarbons, chlorinated hydrocarbons, glacial acetic acid or trifluoroacetic acid, and conveniently at room temperature.

Compounds of the formula XI obtained in this way can be used without Isolation to benzodiazepine derivatives of the formula I are cyclized.

Furthermore, compounds of the formula XI can be obtained, by making a compound of the general formula, "

009835/1957

XXVII

where R ,, signifies halogen and R «has the meaning given above, with a compound of the general formula

X-CH-R

XXVIII

wherein X has the meaning given above and R-J.J. Hydrogen, alkyl or haloalkyl and R ,,. Alkoxy, Alkoxy-alkoxy or haloalkoxy mean

converts, in a "obtained compound, a haloalkoxy group converted into a mono- or dialkylaminoalkoxy group or a haloalkyl group converted into a mono- or dialkylaminoalkyl group, a compound obtained of the general formula

009835/19 5 7

Ik COOG ₂ H ₅

XXIX

wherein R ₂ Wd ** · *! ^obl 8 · have meaning and R, g

Alkyl ~

Hydrogen, mono- or dialkylaminoalkyl,

and R__ alkoxyj alkoxy-alkoxy or mono * or dialkylaminoalkoxy, reduced, a compound of the general formula obtained

XXX

wherein R ₂ , R ,,, R_g and R, ~ have the above meaning to. the corresponding 2-carboxaldehyde is oxidized, this compound is oxidized and a compound of the general formula obtained

00 98 35/1957

CH-NOH

wherein R ₂ * R ₅₁ , R, g and R, ~ have the above meaning, followed by a compound of the general formula

XXXII

and R, _{7 have the} above meaning,

wherein R, R ,, R.
reduced and this compound oxidized to a compound of formula XI.

However, one can also use a compound of the formula XXIX in a known manner into an amide of the general formula

CH-R.

"N-CQHH

XXXIII

^l 37

009835 / 19B7

Transfer and this connection to a connection of the Reduce Formula XXXII.

The reaction of a compound of formula XXVII with a Compound of the formula XXVIII can be used in the implementation of a Compound of the formula II «with a compound of the formula III specified catfish are made '

The preferred leadership of a haloalkoxy or haloalkyl group In a mono- or dialkylaminoalkoxy or mono- or dialkylaminoalkyl group, in the for a compound of the formula VI specified catfish take place "

A compound of the formulas XXIX and XXXI is reduced in two ways instead of a reducing agent such as lithium aluminum hydride and in an inert organic solvent such as ethers, e.g. tetrahydrofuran and the like.

The oxidation of a compound of the formula XXX is expediently carried out with an oxidizing agent such as Manganese dioxide and in an inert, organic solvent such as hydrocarbons e.g. benzene, toluene, chlorinated hydrocarbons such as methylene chloride and at temperatures between Room temperature and reflux temperature of the reaction mixture. The oximation of the 2-carboxaldehyde obtained is with

Q09835 / 19S7

Reached hydroxylamine. One also works expediently in a solvent such as water, alcohols, etherp, Triethylamine, Pyridln and the like. And at temperatures between Room temperature and fluid temperature of the reaction solution.

The oxidation of a compound of the formula XXXII can with an oxidizing agent such as chromium oxide in glacial acetic acid. Compounds of the formula XXXII become two-component catfish

"

oxidized and cyclized without isolating a compound of the formula XI.

Compounds of the formula XII can be obtained by treating a corresponding 4-oxide with an acid anhydride, sulfide or halide in the catfish described for the reaction of a compound of formula XXXIV.

^ Compounds of the formula XIII can by application

of the process variants defined under a) c) d) e) €) g).

Compounds of the formula XIV can be prepared by reducing the corresponding 4-oxide of the general formula

009835/1957

CH-R

XXXIV

wherein R ^, Rg, Rg, R ₂ - have the above meaning and R_q is alkoxy, dialkylaminoalkoxy or alkoxyalkoxy, are obtained in the presence of platinum oxide.

Zweckmässigerwe1se carried out in an organic solvent such as glacial acetic acid, alcohols, and at a temperature between approximately 0 ° and 50 ⁰ C., preferably at room temperature.

Compounds of the formula XIV can also by reaction a compound of the general formula

N-CO

JCH,

XXXV

CH = N

wherein R, and R ₂ - have the above meaning, R-.g hydrogen,

00 9835 / 195t

Alkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkyl aminoalkyl or acyl mean oxyalkyl , with a compound of the general formula

XXXVi

wherein Z is Li, MgI or NgBr .

Conveniently carried out in an inert organic solvent such as ethers, hydrocarbons, and at temperatures of between -6O ^e C and Rlickflusstemperatur the reaction mixture. Compounds of the formula XXXV can in turn be prepared by introducing the substituent in the 1-position or a compound unsubstituted in the 1-position according to reactions a) c) d) e) f).

When using a starting compound of the formula XXXV which has a substituent with an acyloxyalkyl group in the 1-position, this group is simultaneously converted into a hydroxyalkyl group. >

Compounds of the formula XV can be prepared by reacting a corresponding 1-unsubstituted compound with a compound of the formula III according to variant a) and possibly subsequent reactions according to the processes described in variant ce). The oxidation of the alkylthio group to the alkylsulfinyl or alkylsulfonyl group, however, takes place after a protective group such as a carbobenzoxy-

009835/1957

BAD OR »GIN ^AL

introduces a group, a carbethoxy group and the like in the 4-position, those for the preparation of a compound of the formula XV conclusively can be removed again hydrogenolytically or hydrolytically in the manner described herein.

Compounds of the formula XVIII can be prepared by acylation of a corresponding 4-hydroxy-substituted compound of the formula XIV or analogs thereof which are obtained in analogy to the preparation of compounds of the formula] XIV. | Suitable acylating agents are, for example, acid anhydrides such as acetic acid anhydride, acid halides and the like. It is expedient to work in the presence of a base as acid acceptor such as pyridine and the like and in an organic solvent such as hydrocarbons, chlorinated hydrocarbons, ethers and the like at temperatures between -50 ° and IQO ⁰ C.

In the case of a monalkylamino group as a substituent

is present in the 1-position, this group is more expedient before acylation, e.g. by a carbobenzoxy group or slotted an equivalent protecting group. The carbobenzoxy group can be removed again in the manner described herein will.

Compounds of the formula XIX can be prepared by acylation of a corresponding 4,5-dihydro compound of the formula XV or analogs thereof, which are obtained in analogy to the preparation of compounds of the formula XV, for example with a tosyl or mesyl halide. One works for purpose—— -> - - ^ -——

carried out in an inert organic solvent such as hydrocarbons, for example benzene, chlorinated hydrocarbons and the like., and in the presence of an acid acceptor such as pyridine and the like., and at temperatures between 0 ⁰ C and reflux temperature of the reaction mixture.

Compounds of the formula XX can be prepared from corresponding compounds of the formula XVIII or XIX in the Written way can be established. In addition,

bonds of the formula XX by introducing a substituent into a 1-unsubstituted compound according to those described herein Methods a) c) d) e) f). In this reaction, however, an isomerization can also occur at the same time to a 4,5-dehydro compound. It should be noted that the respective starting materials are not necessarily must be used in the isolated state, but also without isolation from the reaction mixture in the they have been produced, can be further implemented.

Compounds of the general formula I which are basic in character form acid addition salts with inorganic ones or organic acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, citric acid, sulfuric acid, Acetic acid, formic acid, succinic acid, maleic acid, p-toluenesulfonic acid and the like

Compounds of general formula I and their

- 009835/1957

pharmaceutically acceptable salts can be used as anticonvulsants, muscle relaxants, sedatives and anxiolytics. The anticonvulsant activity is demonstrated when Mäuae, soft compounds of the formula I or their salts are administered to the pentamethylene tetrazole test. For example, the T-Nitro-5-phenyl-l-methoxymethy1-1,3-dihydro-2H-1,4-benzodiazepin-2-one, which has an LD, - ₀ of 600-1200 mg / kg (po) has an APR 2.0 of 0.5 mg / kg when tested for anti-convulsive effectiveness in the pentetrazole test based on the method of Orloff (Proc. Soc. Exptl. Biol. Med. £ 0 254-257 19 * 1-9) (po) [under APR 2.0 one understands that dose in mg / kg of an anticonvulsant3 which causes twice the pentetrazole consumption compared to the untreated control group], the 7-nitro-5-phenyl-l-ethoxymethyl-l, 3-dihydro- 2H-l, 4-benzodiazepin-2-one (LD ₅₀ 1200-2500 mg / kg po) an APR 2.0 of 0.2 mg / kg (po) and the 7-nitro-5-phenyl-l- [ (2-chloroethoxy) methyl] -1,3-dihydro-2H-1,4-benzodiazepin-2-one (LDc _n > 5000 mg / kg po) an APR 2.0 of 1.8 mgAs (po). In contrast, phenobarbital, a common anticonvulsant, shows an APR 2.0 of 30 mg / kg. The muscle-relaxing effectiveness can be demonstrated in a test on a rotating rod. For example, the above-mentioned 7-nitro-5-phenyl-1-methoxymethyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one shows an HD, _ _n of 2 mg / kg (po) the. 7-nitro-5-phenyl-l-ethoxymethyl-l, 3-dihydro-2H-l, 4-benzodiazepin-2-one an HD, ₀ of • 5 mg / kg (po) and the 7-nitro-5- phenyl-l - [(2-chloroethoxymethyl)] 1,3-dihydro-2H-1,4-benzodiazepin-2-one has an HD ₅₀ of 0.5 mg / kg (po). .009.835 / 1957-

Compounds of the formula I and their pharmaceuticals Applicable salts can therefore be used as medicaments, e.g. in the form of pharmaceutical preparations, which they or their salts mixed with one for enteral or parenteral Application of suitable pharmaceutical, organic or inorganic inert carrier material, such as water, Gelatine, milk sugar, starch, magnesium stearate, talc, vegetable oils, gum, polyalkylene glycols, petroleum jelly, etc. contain. The pharmaceutical preparations can be in solid form, e.g. as tablets, coated tablets, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or or contain auxiliaries such as preservatives, stabilizers, Wetting or emulsifying agents, salts to change the osmotic pressure or buffers. You can also do others therapeutically contain valuable substances. The dosage is based on individual requirements, however, a dosage of 0.1 mg / kg-10 mg / kg / day preferred.

009835/1957

The following examples illustrate the invention: example 1

8.1 g (0.15 mol) of sodium methylate are stirred into a solution, cooled to -15 °, of 28 g (0.1 mol) of 1, J5-dihydr oT-nitro-S-phenyl-SH-l ^ -behzodiazepine ^ -one given in 150 inl dimethylformamide. After 10 minutes at -15 ° to -10 ° | was stirred, is cooled to -50 ° and at -50 ° to -4o ° 12 ml (P, 16 mol) of chloromethyl methyl ether are added dropwise. After the addition, the temperature is allowed to rise to -20 ° within 15 minutes. The dark brown reaction mixture is poured into 1 l of water and the flocculated material is separated off. This is taken up in methylene chloride, the methylene chloride solution is washed with water, dried over sodium sulfate and evaporated. The residue is crystallized from ether and from benzene-Alkoholumkristallisiert> wobei_ d 14.5 gl, 3-dihydro-l- (methoxymethyl) -7-nitrö-5-phenyl-2H-l, 4-benzodiazepin-2-one from M.p. 139-1 ^ 1 °.

00903571957

Example 2

A solution of 13.5 β 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 150 ml of dimethylformamide is brought to -10 ° cooled and mixed with 4 g of sodium methylate. After stirring for 15 minutes at -10 ° to 0 ° under a nitrogen atmosphere

^ was cooled to -4o ° and 6 ml of chloromethyl methyl ether added dropwise. After the addition, the temperature is allowed to rise to 0 ° within 30 minutes. The reaction mixture is Poured into 1 l of water and separated the precipitated resin. This is taken up in methylene chloride, the solution with Washed water, dried over sodium sulfate and evaporated. The residue is chromatographed on 300 g of silica gel using the solvent system methylene chloride: ethyl acetate 9: 1. The non-crystalline, chromatographically pure 7-chloro

* 1,3-dihydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one shows the following spectroscopic data.

Mass spectrum: M i | 314

Main fragments at f 286 (iP-CO) 269 (M ^ -CHpO NMR spectrum: 7 * 8-7.1 ppm (multiplet), 8 aromatic protons! [CDCl ₃ ] 5.40 ppm (doublet) and 4.88 ppm (doublet), AB system with 3-10 cps, N-CjJ ₀ -O;

BATH

009835/1957

4.84 ppm (doublet) and 3.83 ppm (doublet), AB system with J * 10.5 ops, C_-protonsi 3.37 ppm (singlet), OGEy

Example 3

According to the manner described in Example 2, 7.5 g of 7-chloro-5- (o-chlorophenyl) -i, 3-dihydro-2H-1,4-benzo-

-2-0 / 7

diazepine /, 2 g of sodium methylate and 3.1 g of chloromethyl methyl ether, 8.6 g of crude product were obtained. Crystallization from ether and recrystallization from methanol yields 4.4 g of pure 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-1- (methoxymethyl) -2H-1,4-benzodiazepin-2-one of mp . lj9-l40 ^o .

Example 4

According to the manner described in Example'2, 7.9 g of 5- (o-chlorophenyl) -l, 3-dlhydro-7-nitro-2H-1,4-benzodiazepin-2-one with 2 g of sodium methylate and 3 are obtained * 1 β chloromethyl methyl ether in 50 ml dimethylformamide 9.5 S crude product. This is chromatographed on 200 g of silica gel with 20 # ethyl acetate in methylene chloride. The uniform fractions are crystallized from ether and recrystallized from methanol. 3.9 g of 5- (o-chlorophenyl) -1, 3-dihydro-1- (methoxymethyl) -7-nitro-2H-1,4-benzodiazepin-2-one with a melting point of 136-137 ⁰ are obtained .

009835/1967

Example 5

The reaction of 7 * 2 g of 7-chloro-5- (o-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one with 2 g of sodium methylate and 3.1 g of chloromethyl methyl ether in 50 ml of dimethylformamide gives 7.5 g of crude product after customary work-up. From this, by chromatography on 200 g of silica gel with 20 # ethyl acetate in methylene chloride, 4.4 g of uniform 7-chloro-1,3-dihydro- ™ 5- (of luorophenyl) -l-methoxymethyl> -2H-1,4-benzodiazepine- 2-one are isolated, which crystallizes from ether and recrystallizes from methanol at 113-H ^ ⁰ C melts. '

Example 6

To a solution, cooled to -20 °, of 14 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one 4 g of sodium methylate are added in 150 ml of dimethylformamide. After during Was stirred at -10 ° for 10 minutes, the mixture was cooled to -50 ° and 7 g of chloromethyl ethyl ether were added dropwise over the course of 5 minutes. To the addition, the temperature is allowed to rise to -20 ° within 30 minutes. The reaction mixture is stirred into 1 1 of water, separated the precipitated resin, dissolved in methylene chloride and washed the solution with bicarbonate solution and water, over Dried sodium sulfate and evaporated. The residue (17 g) is poured onto 300 g of silica gel with 10 # ethyl acetate in methylene chloride chromatographed.

00 88 3 B / f IS »BAD ORIGINAL

The uniform fractions crystallized from ether give after uncrystallization from alcohol 6.5 g of 1- (ethoxymethyl) -10-dihydro-nitro-S-phenyl-Hl, 4-benzodiazepin-2-one of melting point 105-107 ^e «

Example 7

A solution of 15.5 6 7-chloro-1,> dihydrQ-5-phenyl "2H-1,4-benzodiazepin-2-one, cooled to -10 ° in 150 ml of dimethylformamide is mixed with 5.4 g of sodium methylate and during Stirred for 10 minutes at -10 ° to 0 °. This will turn to -4o ° cooled and 9.5 g of 1-ChI or ät hy line thy lather within 5 minutes added dropwise. The temperature is left within after the addition Increase to 0 ° for 40 minutes. The usual work-up delivers -15 * 5. g of crude product, which on 300 g of silica gel with 10 # ethyl acetate is chromatographed in methylene chloride. The uniform fractions crystallize from ether-hexane. Recrystallization from methylene chloride-hexane gives 7.5 g 7-chloro-1,3-dAhydro-1- (1-methoxyethy1) -5-pheny1-2H-1,4-benzodiazepih-2-one of m.p. 131-132 °.

Example 8

A solution of 14 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodlazepin-2-one in 100 ml of dimethylformamide is cooled to -20 ° and mixed with 4 g of sodium methylate. After 10 minutes Stirring at -10 ° is cooled to -50 ° and 7 g of 1-chlorine-

009835/1957

ethyl methyl ether was added dropwise within 5 minutes. The temperature is increased to -20 ° within 20 minutes and the reaction mixture is worked up as usual. The received 1,3-Dihydro-1- (1-methoxyethyl) -7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one crystallizes from ether (8.5 g) and, after recrystallizing twice from methanol, melts at 189-19O ° C.

Example 9

According to the manner described in Example 8 gives the alkylation of 28 g of l, J-dihydro-7-nitro-5-phenyl-2H-l, 4-benzodiazepin-2-one in 200 ml of dimethylformamide with 8 g of sodium methylate and 16 g of 1-chloroethyl ethyl ether 13.5 g of product from m.p. 170-173 °. Melts after Umkriätalllsation from alcohol the l- (l-ethoxyethyl) -l, 3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one at 172-174 °.

P example 10

In a similar manner as in Example 8, 28.1 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one are obtained by reaction in 200 ml of dimethylformamide with 8 g of sodium methoxide and 16.2 g of chloromethyl propyl ether after chromatography of the crude product on 500 g of silica gel with 5 # ethyl acetate in Methylene chloride 17.1 g l, 3-dihydro-7-nitro-5-phenyl-l- (propoxymethyl) -2H-l, 4-benzodiazepin-2-one, which melts after recrystallization from alcohol at 73-76 °.

0 09 835/19 57 bad original

.- 49 -

Example 11

The alkylation of 28 ^ 1 g of 10-dihydro-T-nitro-S-phenyi-2H-1,4-benzodiazepin-2-one dissolved in 200 ml of dimethylforaamide, with 8 g of sodium methoxide and 22.6 g of chloromethylhexyl ether gives after chromatography on 600 g of silica gel with 10 $ ethyl acetate in methylene chloride 18.6 g 1,3-dihydro-1- (hexyloxymethyl) -7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one , the

• 'i

crystallized from ether at 108-109 ° melts.

Example 12

By reacting 28.1 g of I, J-Dihydro-T-nitro - ^ - phenyl-2H-1,4-benzodiazepin-2-one with 8 g sodium methoxide and 18.6 g Chloromethyl (2-methoxy) ethyl ether is obtained according to the information in Example 8 l,> - Dihydro-l - [(2-methoxyethoxy) -, methyl] -7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one Crystallization from methanol. After recrystallization from ^ Methanol gives a product with a melting point of 120-121 ° ♦

Example 13 ,

A solution of 28.1 g of 1,5-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepih-2-one in 200 ml of dimethylformamide is cooled to -10 ° and treated with 8 g of sodium methoxide. After stirring for 10 minutes at -10 °, are at -40 ° 20.7 g of methyl 2-chloro-2-methoxy acetate were added dropwise. Man

009835 / 19S7

lets the temperature rise to −10 ⁰ within 30 minutes and pour the reaction mixture into 300 ml of water with stirring. The flocculated product is filtered off with suction, washed with water and taken up in methylene chloride. The methylene chloride solution is dried over sodium sulfate, filtered and evaporated. Crystallization of the residue from methanol gives 17 g of 1- (carbomethoxy-methoxy-methyl) -l, 3-dihydro-7-nitro-5-phenyl- |. 2H-l, 4-benzodiazepin-2-one which, after recrystallization from methanol, melts at 157-159 °.

Example 14

In a manner analogous to Example 13, 27.1 g of Y-chloro-lO-dihydro-S-phenyl-iM-l ^ -benzodiazepin ^ -one in 400 ml of dimethylformamide, 8 g of sodium methoxide and 20.7 g of methyl 2-6hlor-2-methoxy-acetate 1- (carbomethoxy-methoxy-methyl) - Wk 7-chloro-1,3-dihydro-5-phenyl-2H «1,4-benzodlazepin-2-one, which after recrystallization from Methanol / methylene chloride melts at 195-196 °.

Example 15 '

8 g of sodium methoxide are added to a solution, cooled to -20 °, of 28.1 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one in 150 ml of dimethylformamide. During 5 minutes is stirred at this temperature and then cooled to -50 °. At -50 ° to -4o ° 19 # 3 g of chloromethyl-2-chloroethyl ether

009835/1957

added dropwise. After the addition, the temperature is allowed to rise to -20® within 15 minutes. While stirring, it is increased to 500 ml Poured water, separated the precipitated material and taken up in methylene chloride. The methylene chloride solution is evaporated after drying over sodium sulfate and the residue crystallized from alcohol. The extracted crystals are washed with alcohol and ether and dried. To Recrystallization from alcohol gives 1- ((2-chloroethoxy) methyl] -1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one I with a melting point of 97-99 °.

Example l6

The reaction of 27 * 1 g of 7-chloro-1,3-dihydro-5-phenyl-2H-i, 4-benzodiazepin-2-one in 300 ml of dimethylformamide with 8 g of sodium methoxide and 19.3 g of chloromethyl-a-chloroethyl ether under the conditions described in Example 15, 15 g of 7-chloro-1 - [(2-chloroethoxy) methyl] -1,3- I crystallized from methanol dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one of m.p. 96-98 °.,

A second crystal modification shows a melting point of 128-130 °.

Example 17

A solution of 14.5 g ^ -Chlor-lj ^ -dihydro-S- (o-chloro phenyl) -2H-1,4-benzodiazepin-2-one in 50 ml of dimethyl

00 98 35 / 19B7

formamide is cooled to -20 ° and mixed with 4 g of sodium methoxide. It is stirred for 5 minutes at this temperature and then cooled to -50 °. After 7 g of chloromethyl-2-chloroethyl ether have been added dropwise, the temperature is allowed to rise to -20 ° over the course of 15 minutes and the work is carried out as usual. The crude product is chromatographed on 250 g of silica gel with 10 # ethyl acetate in methylene chloride. The uniform fractions yield, after crystallization from ether, 8.6 g of pure ψ 7-chloro-1- [(2-chloroethoxy) raethyl] -5- (o-chlorophenyl) -1, 3-dihydro-2H-1,4-benzodiazepine -2-one with a melting point of 92-93 ° · A second crystal modification melts at

Example 18

A solution, cooled to -20 °, of 14 g of 3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one in 100 ml of dimethylformamide is mixed with 4 g of sodium methoxide and stirred for 5 minutes . After cooling to -50 °, 9.7 g of 1,2-dichloro-1-methoxy-ethane are added dropwise. The temperature is allowed to rise to -10 ° within JO minutes. After the usual work-up, the crude product is crystallized from methanol.

After recrystallization from methylene chloride-methanol, pure 1- (2-chloro-1-methoxy-ethyl) -l, 3-dihydro-7-nitro-5-phenyl-2H ~ 1,4-benzodiazepin-2-one is obtained from the melting point. 162-164 °.

009835/1957

Example 19

The reaction of 27 * 1 g of 7-chloro-1,3-dihydro-5-phenyr-2H <-l, 4-benzodiazepin-2-one, as described in Example 18 with 8 g of sodium methoxide and 19 * 5 g of 1,2-dichloro-1-methoxyethane results after recrystallization from methylene chloride-methane oil 17 * 5 g of pure 7-chloro-1- [2-chloro-1-methoxy-ethyl] -l, 3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one of melting point "-152-155 °

Example 20 - .-

A stirred suspension of 36 * 3 S 7-chloro-1 - [(2-chloroethoxy) methyl] -1, 3-dihydro-5-phenyl-2H-1, 4-benzodiazepin-2-one and 22.4 g of phthalimide potassium in 300 ml of dimethylformamide is refluxed for 20 minutes under a nitrogen atmosphere. After cooling, it is filtered and the filtrate is evaporated in a high vacuum. The residue is taken up in benzene, the solution is filtered and evaporated again. The residue dissolved in 100 ml of methanol is mixed with 10 ml of ether and, after inoculation, crystallized with stirring. Seed crystals can be obtained by chromatographic purification. After recrystallization from methylene chloride-methanol, 29 g of 7-chloro-1,3-dihydro-5-phenyl-l - [(2-phthalimidoethoxy) methyl] -2H-1,4-benzodiazepin-2-one with a melting point of 138 are obtained -I39 ⁰ .

0 0 9 8 3 5? T 9 S 7-

14.7 g of 7-chloro-1,3-dihydro-5-phenyl-1,3-[(2-phthalimidoethoxy) »ethyl] -2H-1,4-benzodiazepin-2-one are in 200 ml of alcohol in the presence of 3.5 g of hydrazine hydrate for 2 hours refluxed. After cooling to 0 °, the phthalazine which has crystallized out is filtered off with suction and the piltrate is evaporated. The residue is partitioned between 2N acetic acid and ether. The aqueous phase is washed with ether and filtered and made alkaline with 2N sodium hydroxide solution. The unusual one

^ Base is extracted with ether. The extracts are made with water washed, dried over sodium sulfate and evaporated. Of the The residue is taken up in alcohol and adjusted to pH 5-5 * 5 with ethanolic hydrochloric acid. After evaporation leaves the residue is crystallized from ethyl acetate-methanol. 5 g of l - [(2-aminoethoxy) methyl] -7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one hydrochloride are obtained from m.p. 147-150 °.

~ Example 21

A solution of 3.63 g of 7-chloro-1- [2-chloroethoxy) methyl] -l, 3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 30 ml of dimethylformamide is mixed with 1.65 g of potassium acetate and in Boiled under reflux in a nitrogen atmosphere for 15 minutes. After cooling to room temperature, 50 ml of water are added dropwise. The precipitated resin is separated off in methylene chloride recorded. The solution, washed with water and dried over sodium sulfate, is evaporated and the residue by chromatography on 100 g of silica gel with the solvent

009835/1957

system methylene chloride, thylacetate 4s1 purified. You get X - [(2-Acetoxyethoxy) methylJ-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one # das crystallized from ether-hexane, melts at 92-94 °,

8 g of l - [(2-acetoxyethoxy) ynethyl3-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepln-2-one are dissolved warm in 100 ml of absolute methanol. The mixed with 0.2 g of sodium methoxide

The solution is left to stand for 1 hour. After adding © of 0.4 ml ~ Glacial acetic acid is concentrated in vacuo, the residue is partitioned between methylene chloride and water and the organic phase dried and evaporated. The residue crystallizes at Rub on with ether. 6 g of 7-chloro-1,3-dihydro-l - [(2-hydroxyethoxy) methylJ-5-phenyl-2H-1,4-benzodiazepin-2-one are obtained from m.p. 129-131 *

Example 22

A suspension of 16 g of anhydrous potassium acetate in 300 ml of toluene and 500 ml of dimethylformamide are heated with stirring. After distillation of 400 ml of solvent will be 36 g of 7-chloro-l-l (2-chloro-l-methoxy) ethyl] -!, ^ - dihydro-S-phenyl-2H-1,4-benzodiazepin-2-one added. The reaction mixture is refluxed for 5 minutes under a nitrogen atmosphere warmed up. After cooling to 5 °, 800 ml of water are added and separated the precipitated resin. This will taken up in methylene chloride, the solution washed with water,

0Q9835 / 19S7

Dried over sodium sulfate and evaporated. From the Solution of the residue in ether initially crystallizes 4 g of 7-chloro-1,3-dihydro-l - [(2-hydroxy-l-methoxy) ethyl] -5-phenyl-2H-1,4-benzodlazepin-2-one. The mother liquor comes with something Boiled activated charcoal, filtered, mixed with hexane and crystallized after seeding. Seed crystals of pure

2H-1,4-benzodiazepin-2-one with melting point 110-111 ° (from alcohol) W- can be obtained by chromatography on silica gel with 20% ethyl acetate in methylene chloride.

Which crystallized from the seeded solution ■ Product (14 g) melted by Urakristallisatlon of alcohol at 110-111 °.

3 g of l - [(2-acetoxy-l-methoxy) ethyl] -7-chloro-l,>

"-I dihydro-5-phenyl-2H-1,4-benzodia2epin-2 ~ one are dissolved in 30» 1 methanol

** Dissolved hot and mixed with 0.1 g of sodium ethoxide. The end The material which crystallizes overnight from the cooled solution is filtered off with suction, washed with methanol and dried. To Recrystallization from alcohol gives 7-chloro-1,3-dihydrol-i (2-hydroxy-1-methoxy) ethyl-5-phenyl-2H-1,4-b «n * odiazepin-2-one with a melting point of 157 -159 *.

009835/1967

Example 23

To a solution, cooled to -10 °, of 28 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-behzodia «epin-2-one θ g of sodium methoxide are added to 100 ml of dimethylformamide. It will be during Stirred for 15 minutes at -10 ° and then cooled to -30 °. 17 g of chloromethyl methyl sulfide are added dropwise at this temperature and after the addition, the mixture is stirred without cooling for 4 hours. The reaction mixture is made up of 500 ml of water and 25 ml of 2N Poured acetic acid. The aqueous solution is decanted from the precipitated resin. This is taken up in methylene chloride, the solution washed with water, dried over sodium sulfate and evaporated. The residue yields after chromatography on 500 g silica gel with the solvent system methylene chloride: Ethyl acetate 4: 18 g 1,3-dihydro-1- [(methylthio) methyl] -7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one of m.p. 139-140 °. After recrystallization from alcohol, the sulfide melts

Example 24

To a solution, cooled to -10 °, of 27 g of 7-chloro, 3-dihydro-5-pheiiyT'-2H-1,4-benzodiazepin-2-one 8 g of sodium methoxide are added to 300 ml of dimethylformamide. To 17 g of chloromethyl methyl sulfide are added dropwise for 10 minutes. After stirring for 2 hours without cooling, are at -10 ° again 8 g of sodium methyl ether and 17 g of chloromethyl methyl sulfide added one after the other. The mixture is stirred for a further 2 hours without cooling and the reaction mixture is poured into 1 liter

009835/1957

Water and 50 ml of 2N acetic acid. The crude product obtained after customary work-up is chromatographed on 500 g of silica gel with 10 # ethyl acetate in methylene chloride. By crystallizing the homogeneous fractions from ether-hexane, 9.5 g of 7-chloro-1,3-dihydro-l - [(methylthio) methyl] -5-phenyl-2H-1,4-benzodiazepin-2-one from M.p. 115-117 °.

Example 25

A solution, cooled to -10 °, of 15 g of 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one in 150 ml of dimethylformamide is mixed with 5 g of a 50 # -igen suspension of sodium hydride in mineral oil. The mixture is left to stir for 15 minutes, and then 10 g of chloromethylmethyl sulfide are added. After 1 hour, it is poured onto ice water and the product is extracted with ether. The extracts, washed with water and dried over sodium sulfate, are evaporated. The residue obtained is chromatographed on 400 g of silica gel with 20 # ethyl acetate in methylene chloride. The uniform fractions yield after crystallization from ether 12.2 g of 7-chloro-5- (o-chlorophenyl) -l, 3-dihydro-l- [(methylthio) methyl] -2H-l, _{4-benzodiazepin-2-one>} the after recrystallization from ethyl acetate-hexane melts at 127-129 °.

009835/1957

Example 26

25 ml of 15% peresalgic acid become one -10 ° cooled solution of 7 gl, 3-pihydro-1- ((methylthio) methyl] -7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one in 80 ml of methylene chloride was added dropwise is for 15 minutes stirred at -10 ·. The reaction noise is 10 # Washed soda solution »the methylene chloride phase separated, dried and evaporated. Crystallization of the residue from ethyl acetate gives 5 * 5 g of 1, ^ dihydro-1-f (methylsulfinyl) -methylJ - T-nltro-S-phenyl - ^ - li ^ -benzodiazepin-S-one vom Srap. 190-192 °.

Belaplel 27

A solution of 10 g of 7-chloro-1,> d. <. Hydro-1 - [(methylthio) -methyl-5-phenyl-2H-1 # 4-benzodiazepin-2-one in 100 ml of methylene chloride is cooled to -10 ° and dropwise with 15 ml of I 40) i-iger pere "8 acetic acid. After 15 minutes it will be Waxed reaction odor with 10ji-strength soda solution, dried and evaporated. Chromatography of the residue on 200 g Kieaelgel with 105 <alcohol in ethyl acetate results after crystallization from ethyl acetate He; w ^ I ^ ((i ^^ l «ui ^ nyl) wit ^ ll ^^ - | ^ ny ^ V Srap. 8i *

009835/1957

Example 28

To a solution, cooled to -20 °, of 7.5 g of 7-chloro-5- (o-chloropheny1) -1,3-dihydro-1- ((methylthio) methyl] -2H-1 , k benzodiazepin-2-one crystallization in 50 al of methylene chloride 5 ml 4o # peracetic acid was added dropwise. After 10 minutes the reaction solution with 10 # sodium carbonate solution is washed, dried over sodium sulfate and evaporated. of ψ residue from ethyl acetate-ether yields 4 g of 7-chloro-

5- (o-chlorophenyl) -l, 3-dihydro-l - [(methylsulfinyl) raethyl] -2H-l, 4-benzodiazepin-2-one, which melts after recrystallization from ethyl acetate-ether at I50-152 ^0th

example 29

A solution of 3.75 g of 1,5-Dlhydro-l - [(methylsulfinyl) -

_ / - 7-nitro-5-phenyl-2H-l. ^ - benzodiazepin-2-one methyiy in 50 ml of methylene chloride is added after adding 6 ml

P 40jf-lger Pereeelgetture stirred for 2 hours at room temperature. The crude product obtained after customary work-up crystallizes from alcohol-methylene chloride. 2.8 g of 1, 1-dihydro-1-methylsulfonyl-methyl-1 -tro-S 2H-1, 4-benzodlazepin-2-one are obtained, which after recrystallization from the same solvent mixture melts at 190-192 °.

009835/1957

Example 30

The analogous oxidation as in Example 29 of 3.5 g of 7-chloro-l, 3-dihydro-l - [(methylsulfinyl) methyl] -5-phenyl-2H-l, 4-benzodiazepin-2-one with 6 ml of 4o # -iger peracetic acid in 50 ml of methylene chloride gives 2.6 g of 7-chloro-1,3-dihydrol- [(methylsulfonyl) methyl] -5 "-phenyl- ^ Hl ^ -benzodiazepin-2-one, which after recrystallization from Ethyl acetate-ether i

has a m.p. of 162-164 °.

Example 31

In the same way as in Example 29, oxidation of 7-chloro-5- (o-chlorophenyl) -1,3-dihydrol- [(methylsulfinyl) methyl] -2H-1,4-benzodiazepin-2-one is obtained 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-l - [(methylsulfonyl) methyl] -2H-1,4-benzodiazepin-2-one, that crystallizes from alcohol with a J molecule solvent and at 110-115 ° melts with decomposition.

Example 32

A solution of 28.7 S 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-4-oxide 8.1 g of sodium methoxide are added to 200 ml of dimethylformamide at -20 ° and during Stirred for 5 minutes. At -20 °, 12 ml of chlorodimethyl ether are stirred added dropwise. After the addition, it is left without cooling

009835/1957

continue stirring for 30 minutes. The reaction mixture is poured into 1 liter of water and worked up as usual. Crystallization of the crude product by inoculation from methanol-ether gives 11.5 g of 7-chloro-1,3-dihydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one-4-oxide, which melts ^{at 164-166 e} after recirculation from alcohol. Seed crystals are obtained by chromatography on silica gel with the solvent system methylene chloride / ethyl acetate 1: 1.

Example 33

75 ml of 40 # peracetic acid become a solution of 50 g of 1,3-dihydro-1- (methoxymethyl) -T-nitro-S-phenyl- ^ H-1,4-benzodiazepin-2-one in 300 ml of methylene chloride. After standing for 24 hours at room temperature, the solution is washed out with 10% soda solution, dried over sodium sulfate. ~ dries and evaporates. Crystallization of the residue from methylene chloride-ethyl acetate gives 40 g of 1,3-dihydro-1- (methoxymethyl) -7 -nitro-S-phenyl ^ Hl ^ -benzodiazepine - ^ - one-4-oxide, which after recrystallization from the same solvent mixture has a melting point of 212-215 °.

Example 34

17 # 5 g lO

2H-1,4-benzodiazepin-2-one-4-oxide are in an Oemisoh from 180 ml of acetic anhydride and 300 ml of toluene heated to the boil. It

009835/1957

200 ml of the solvent mixture are distilled off over the course of 4 hours. The remaining solution is evaporated in vacuo, the residue is taken up in methylene chloride, the solution is washed with soda solution, dried and evaporated. Crystallization of the crude product obtained from methylene chloride ether gives 15 g of 3-acetoxy-1,3-dihydro-1- (methoxymethyl) -7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, which is obtained from ethyl acetate -Hexane recrystallized at I63-I65 ⁰ melts.

A solution of 26 g of 3-acetoxy-1,3-dihydro-1- (methoxymethyl) -7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one in 400 ml of tetrahydrofuran and 200 ml of methanol is added -20 ° dropwise v 70 ml of 2N Natronlau ^. After the addition , the mixture is stirred for 15 minutes, buffered to pH 6 by adding glacial acetic acid and concentrated in vacuo. The residue is partitioned between water and methylene chloride, and the methylene chloride phase is dried and evaporated. Crystallization of the crude product from methylene chloride-ether gives 20 g of, S-Hydro-J-hydroxyl- (methox3niethylj-7-nitro-5-phenyl-2H-1,4-benzodiazepln-2-one from Sap. 160-162 ⁰ .

example 35

The reaction, described in Example J> k , of 3.3 g of 7-chloro-1,3-dihydro-1- (methoxymethyl) -5-phenyl-2H-1,4-oenzodi * zepin-2-one-4-oxide with 30 ml of acetavhydride in ^ O ml of toluene and crystallization of the crude product from ether gives 2.6 g of 3-acetoxy-7-chloro

009835/1957

1,3-dihydro-l- (me thoxymethy1) -5-phenyl-2H-l, 4-benzodiazepin-2-one, mp. 120-132 ° "After Umkriatallisation from ether sohnllzt the product at I3I-I33 ^0th

6.3 g of 3-AcOtOXy-T-ChIor-1,3-dlhydro-1- (inethoxyinethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one are dissolved in 200 ml of warm methanol. After cooling, 1.8 g of sodium methoxide are added. After 15 minutes, add 2.5 ml of glacial acetic acid and evaporate Ψ in a vacuum. The residue is between methylene chloride and carbonate solution distributed, the methylene chloride solution dried and evaporated. Crystallization from alcohol results 4.4 g of 7-chloro-1,3-dihydro-3-hydroxy-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one with a melting point of 138-139 °.

Example 36

0.8 ml of phosphorus trichloride become a solution of 1 g 1,3-Dihydro-1- (methoxymethyl) -7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-orv in 15 ml of methylene chloride. After a Standing at room temperature for one hour, the solution is obtained with 10% -lger Washed soda solution. Dried over sodium sulfate and evaporated. Crystallization of the residue from alcohol results 0 # 6 g 1,3-dihydro-1- (methoxymethyl) -7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one of m.p. 139-141 °.

009835/1957

Example 37

To a solution, cooled to -10 °, of 0.95 g of 7-chloro-1- (methoxymethyl) -5-phenyl-1,3 * 4,5-tetrahydro-2H-1,4-benzodiazepin-2-one 12 ml of a 0.5 molar solution of bromine in chloroform are added to 15 ml of chloroform. After during Was stirred for 30 minutes at 0 ° -5 °, 25 ml of 2N sodium hydroxide solution are added and the mixture is stirred for 30 minutes. The chloro- j form phase is separated off, washed with dilute sodium hydroxide solution and water, dried and evaporated. The residue will on 30 g of silica gel with 10 # ethyl acetate in methylene chloride chromatographed. 0.63 g of 7-chloro-1,3-dihydro-l- ■ are obtained (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

The starting material can be prepared as follows: 4.5 g of zinc dust are poured into a solution in portions

of 3.3 g of 7-chloro-l, 3-dihydro-l- (methoxymethyl) -5-phenyl-2H-l, 4-benzodiazepin-2-one-4-oxide in 40 ml of methylene chloride and Λ 10 ml of glacial acetic acid entered . When the addition is complete, the mixture is stirred for 30 minutes, filtered off, the piltrate is washed with aqueous ammonia and with water, the methylene chloride solution is dried and evaporated. Crystallization of the residue from alcohol gives 2.4 g of 7-chloro-1,3,4,5-tetrahydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodlazepln-2-one of melting point I35- I36 ⁰ . The melting point rises by recrystallization from alcohol I36-138 ^0th

009835/1957

Example 38

0.67 g of 7-chloro-4-hytooxy-1- (inethoxymethyl) -5-phenyl, 3> 4,5-tetrahydro-2H-1,4-benzodlazepin-2-one and 0.63 g Dioyclohexylcarbodiimld be in 20 ml of toluene during Boiled under reflux for 16 hours. The dicyclohexylurea is filtered off with suction and the filtrate is extracted three times with 2N hydrochloric acid. The extracts are made alkaline with ammonia and extracted with methylene chloride. The dried extracts are evaporated and the residue on 15 g of silica gel with 10 $ Ethyl acetate in methylene chloride chromatographed, giving 0.25 g of pure 7-calor-1,3-dihydro-1- (iiiethoxy-ethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one with those given in Example 2 spectroscopic properties can be obtained.

The starting material can be prepared as follows: 3.3 g of 7-chloro-1,3-dihydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one-4-oxide are in 30 ml of glacial acetic acid hydrogenated in the presence of 0.3 g of platinum oxide at atmospheric pressure and room temperature. After taking up 400 ml of hydrogen is separated from the catalyst and evaporated. The residue is taken up in benzene and the solution with 2N hydrochloric acid extracted. The benzene phase then washed with water is dried and evaporated. Crystallization of the residue from methanol gives 1.1 g of 7-chloro-4-hydroxy-1- (methoxymethyl) -5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepln-2-one vom

168-172 °. The pure product melts after recrystallization

009835/19 5 7

_ΒΛ0 owe »» ¹ -

from methanol at 173-175 °.

The hydrochloric acid extracts become alkaline with soda solution placed and extracted with methylene chloride. The dried extracts are evaporated and the residue is also removed Methanol crystallizes. 1.4 g of 7-chloro-1- (methoxymethyl) -5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one are obtained.

Example 39 '

An aqueous solution of 0.37 g of 2-amino-2'-benzoyl-4'-chloro-N- (methoxymethyl) -acetanllid-hydrochlorld is with made alkaline with dilute ammonia and extracted the precipitated base with methylene chloride. But the sodium sulfate dried extracts are evaporated and the residue is boiled in 10 ml of methanol. Obtained after renewed evaporation 0.28 g of 7-chloro-1,3-dihydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepine- ™ which is uniform in thin-layer chromatography 2-one with the -in Example 2 specified spectroscopic Data.

The starting material can be produced as follows:

2.2 g of sodium hydride suspension are added to a solution, cooled to -10 °, of 12.7 g of 2'-benzoyl-2- (benzyloxyearbonyl) amino-4 ^{l -chloroacetanilide in 150 ml of dimethylformamide}

3 5/1957

in mineral oil). After stirring for 15 mm, 3.6 g of chlorodimethyl ether are added dropwise at -10 °. After the addition, stirring is continued for 1 hour without cooling. The reaction mixture is poured into 1 liter of water and extracted several times with ether. The dried ether extracts are evaporated and the residue obtained is chromatographed on 300 g of silica gel with 10 # ethyl acetate in methylene chloride. The 2'-Benzoy1-2- (benzyloxycarbonyl) amino-4 ^l -chloro-N-methoxymethyl-acetanilide obtained, which is uniform by thin-layer chromatography, shows the following spectroscopic properties:

Mass spectrum: M ^: 466, Main fragments: bei-J 274, 244, 214, 180, 108, 105 »91, 77 NMR spectrum in CDCi: 3.05 ppm »singlet, OgH-.

3.9 ppm. Doublet J «5 Hz, -CH,., - NH

4.87 ppm, center of an AB system, N-CJ ₂ -O

5.08 ppm, singlet, -OCJJg-CgH ₅

5.72 ppm, broad triplet, J »5 Hz, -NH-

7.1-8 ppm, aromatic protons

2.4 g of 2 ^l -benzoyl-2- (benzyloxycarbonyl) amino-4'-chloro-N- (methoxymethyl) acetanilide are hydrogenated in the presence of 500 mg of palladium carbon (5 #) and 360 mg of hydrogen chloride. After 30 minutes, the hydrogen uptake comes to a standstill. The catalyst is filtered off and the filtrate is evaporated at 30 ° in vacuo. The residue crystallizes on trituration

009835 / 19S7

with methylene chloride-ethyl acetate-ether. After dissolving from methylene chloride / ethyl acetate, 2-amino-2 ^? Benzoyl-4'-chloro-N- (methoxymethyl) acetanilide hydrochloride, melting point 117-125 °.

Example 40 1 g of 2 ^l -benzoyl-4 ^l -chloro-N- (methoxymethyl) -2-phthalimido-

acetanilide are dissolved in 30 ml of alcohol in the presence of 0.4 ml Hydrazine hydrate boiled under reflux for 1 1/2 hours.

After cooling, the phthalazine which has crystallized out is g

suctioned off, the filtrate evaporated, the residue in ether taken up, the resulting solution filtered again and the residue remaining after evaporation on 15 g of silica gel chromatographed with 10 # ethyl acetate in methylene chloride. Man This gives 0.6 g of pure 7-chloro-1,3-dlhydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

The starting material can be produced as follows:

To a cooled to -10 ° solution of 8.4 g of ^{2-benzoyl-f f} 4-chloro-2-phthalimido-acetanilide (SNP 218-220 °.) In 150 ml of dimethylformamide are added 1.5 g Natriiimhydridsuspension (50 # - ig in mineral oil). After stirring for 15 minutes, 2.3 ml of chlorodimethyl ether are added dropwise at -10 °. After the addition, the mixture is allowed to rise to room temperature within JO minutes and the reaction mixture is poured into 500 ml of water and 10 ml of 2N acetic acid. The flocculated material is separated off, taken up in methylene chloride, the solution dried and evaporated. The residue is on 200 g of silica gel with 10 # ethyl acetate

009835/1957

chromatographed in methylene chloride. The homogeneous »fractions crystallize when rubbed with ether. 5.8 g of pure 2'-benzoyl-4'-chloro-N- (methoxymethyl) -2-phthalimidoacetanilide with a melting point of 150 ° -152 ° are obtained.

Beiaplel »1

A solution of 1.5 g of chromium trioxide in 1.5 ml of water is diluted with 15 ml of glacial acetic acid and at 20 ° in portions with 1.8 g 2-aminomethyl-5-chloro-1- (methoxymethyl) -3-phenylindole hydrochloride was added. After the addition, it takes 1 1/2 hours stirred at room temperature. With the addition of ice, cone. Made ammonia alkaline and extracted the bases with methylene chloride. The extracts are dried with sodium sulfate evaporated and the residue chromatographed on 40 g of silica gel with £ 10 ethyl acetate in methylene chloride, giving 0.25 g pure 7-chloro-1,3-dihydro-1- (methoxyeethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one is obtained.

The starting material can be produced as follows:

8.1 g of sodium thyate are cooled to -20 ° Solution of 5-chloro-3-phenylindole-2-carbqneic acid ethyl ester given in 150 ml of dimethylformamide. After 10 minutes it will open Cooled -40 ° and added dropwise 12 ml of chlorodimethyl ether, Maji lets the temperature rise to 10 ° within jJO minutes, Poured into water, separates the precipitated oil, extracted

009835/1957

the aqueous phase with hexane and combined the extracts with the OeI. The dried solution is evaporated and the residue is dissolved in 100 ml of ether. This solution is at 0-5 ° in a? Suspension of 17 g of lithium aluminum hydride in 150 ml Aether dripped in. After the addition, the mixture is stirred for 15 minutes without cooling and hydrolyzed by dropwise addition of 35 ml of water. The precipitate is filtered off with suction and the filtrate dried with sodium sulfate and evaporated. Crystallization of the residue from ether-hexane gives 18.6 g of 5-chloro-l- *

(Methoxymethyl) -3-phenylndol-2-nethanol, which, after recrystallization from ether-hexane, melts at 135-136 °.

37 g of manganese dioxide are added to a solution of 6.7 g of 5-chloro-1- (n> ethoxymethyl) -3-phenyl-indol-2-ethanol in 150 ml Methylenohlorld given. A further 30 g of manganese dioxide are introduced into this stirred suspension after 1 hour. then is woken up for 20 hours. After filtration through Celite, the filtrate is concentrated and the residue from alcohol " crystallized. 5.9 g of needles of 5-chloro-1- (methoxymethyl) -3-phenyl-indol-2-carboxaldehyde are obtained from the sap. 104-105 °.

A mixture of 5.8 g of 5-chloro-1- (ethoxymethyl) -3-phenylindole-2-carboxaldehyde, 3.9 g of potassium hydroxide, 4.2 g Hydroxylamine hydrochloride, 60 ml of alcohol and 6 ml of water are refluxed for 45 minutes. When moving of the reaction mixture with water, the 5-chloro-1 - (- methoxymethyl) -3-phenylindole-2-earboxaldehyde-oxime precipitates in crystalline form

009835/1957

Shape. After cooling to 0 °, the crystals are filtered off with suction, washed with cold water and dried (5.7 g). After recrystallization from alcohol 155-156 ⁰ .

5.5 g of 5-chloro-1- (methoxymethyl) -3-phenyl-indol-2-carboxaldoxlm are poured into a stirred suspension in portions 3 g Llthlumalumlumhydrld entered in 150 ml of ether. That The reaction mixture is refluxed for 2 hours and then left to stand overnight. By dropping 15 ml Water is hydrolyzed. The inorganic material is filtered off with suction, the filtrate is dried with sodium sulfate and evaporated. The solution of the residue in alcohol is with alcoholic hydrochloric acid adjusted to pH 4-5. In a vacuum concentrated and until the beginning of crystallization with ether offset. 3.9 g of 2-aminomethyl-5-chloro-1- (methoxy- «ethyl) -3-phenylindole hydrochloride are obtained, which after recrystallization from methanol-ether melts at 186-187 °.

Example 42

0.8 g sodium hydride suspension (50Ji-Ig In mineral oil) In a solution, cooled to -10 °, of 3 * 42 g of 7-chloro, 3-dlhydro-5-phenyl-2H-l, 4-benzodlazepln-2-one-3-carboxylic acid ethyl ester Added to 30 ml of dimethylformamide. After during Was stirred for 30 minutes at -10 x, it is cooled to -40 ° iind 1.3 ml of chlorodimethyl ether is added. The temperature is allowed to rise to -10 ° within 30 minutes and poured

009835/1957

the reaction mixture to 100 ml of water and 10 ml of 2N acetic acid. The flocculated product is separated and in Methylene chloride added. The dried methylene chloride solution is evaporated and the residue from methylene chloride-ether crystallized. (1.6 g) 7-chloro-1,3-dihydrol- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one-3-carboxylic acid ethyl ester is obtained after recrystallization from methylene chloride-ether melts at 16-164 °.

Example 43

3 * 9 g of 7-chloro-1,3-dihydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one-3-carboxylic acid ethyl ester are dissolved in 4o ml of dioxane and in the presence of 6 ml of 2N sodium hydroxide solution and 30 ml of water for 6 hours at room temperature Stirred in a nitrogen atmosphere. The reaction mixture is extracted with ether, the aqueous phase is separated off and treated with 2N Hydrochloric acid acidified until the precipitated material goes into solution again. Then it is made alkaline with ammonia and the base extracted with methylene chloride. After purifying the crude base by chromatography, 2.1 g of 7-chloro, 3-dlhydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one are obtained.

Example 44

To a solution of 0.5 β sodium in 50 ml of absolute 009835/1957

Alcohol is a solution of 9.7 g of 7-chloro-1,3-dihydro-1- (methoxymethyl) -5-pheny1-2H-1,4-benzodlazepln-2-one-3-carboxylic acid ethyl ester in 50 ml of abs. Given tetrahydrofuran. at 10-15 °, a stream of dry air is passed into the stirred solution for 4 hours. After adding 2 ml of glacial acetic acid, im Concentrated in vacuo and the residue is partitioned between water and methylene chloride / The methylene chloride phase is separated off, dried over sodium sulfate and evaporated. The back

^{By crystallization from alcohol, w} stand yields 7.7 g of 7-chloro, 3-dihydro-3-hydroxy-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one ~ 3-carboxylic acid ethyl ester with a melting point of 187 -189 °.

Example 45

A solution of 9 g of 7-chloro-l, 3-dihydro-3-hydroxy-l- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one-3-carboxylic acid ethyl ester in 75 ml of dioxane is with 14 ml of 2N sodium hydroxide solution and 60 ml of water are added and the mixture is stirred at 26-28 ° for 20 hours. The reaction mixture is shaken out with 150 ml of ether, the aqueous phase is separated off and treated with 2N acetic acid pH 7-8 adjusted, washed twice with 50 ml of ether each time, separated off and concentrated in vacuo at 40-50 ° to 25 g. By Addition of 50 ml of acetone gives 7.5 g of crystalline sodium salt.

0.5 g of this salt are refluxed in 10 ml of glacial acetic acid for 10 minutes. After evaporation in

009835/1957

The residue is between bicarbonate solution and vacuum Distributed methylene chloride. The methylene chloride phase is dried and evaporated. Crystallization of the residue from alcohol gives 0.2 g of 7-chloro-1,3-dihydro-) -hydroxy-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one of mp. 136-138 °.

Example »6

10.8 g of sodium methoxide are added to a solution, cooled to -10 °, of 28 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one in 150 ml of dimethylformamide. The reaction mixture is stirred for 5 minutes and then cooled to -40 °. At this temperature, 29.7 g of chloromethyltrichloroethyl ether are added dropwise. After the addition, it is allowed to rise to 0 ° within 30 minutes and the reaction mixture is poured into 1 liter of water. Separated resin is decanted off. This is taken up in methylene chloride, the solution washed with water, dried over sodium sulfate and evaporated. The residue is taken up in ether, the starting material crystallizing out. The evaporated mother liquor is chromatographed on 300 g of silica gel with 5% ethyl acetate in methylene chloride. Crystallization of the uniform fractions from alcohol gives 10.6 g of 1,3-dihydro-7-nitro-5-phenyl-l - [(2,2,2-trichloroethoxy) methyl] -2H-l, 4-benzodiazepine- 2-one of m.p. II3-II8 ⁰ .

009835/1957

Example 47

A solution of 6.4 g of 7-chloro-1- [(2-chloro-1-methoxy) ethyl] -l, 3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ^ _n Methylenehlorid 200 ml is mixed with 50 ml 400 peracetic acid. The solution is left to stand for 2 days at room temperature and then washed out with 10 l sodium carbonate solution. The dried methylene chloride phase is evaporated and, after the addition of ether, crystallized. This gives} 6.5 β 7-chloro-l - ((2-chloro-l-methoxy) ethyl] -l,> dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-4- oxide with a melting point of 213 ° -215 °. The product, which is crystallized from ethyl acetate-alcohol, melts at 214 ° -215 °.

Example 48

A mixture of J> 0 g of 7-chloro-l- [2-chloro-l-methoxy) ethyl] -1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-4- oxide, 200 ml of acetic anhydride and 250 ml of toluene are heated for 4 hours, sodaes toluene slowly distilled. After evaporation in vacuo, the residue is crystallized from methylene chloride and recrystallized from alcohol. 21.5 g of> acetoxy-7-chloro-1- [(2-chloro-1-methoxy) ethyl] -l, 3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one from M.p. 193-195 °

009835/1957

Example 49

A mixture of 18 g of 3-acetoxy-7-chloro-l - [(2-chloro-methoxy) ethyl] -l, 3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one , 200 ml of methanol and 2 ml of triethylamine is added for 7 hours refluxed. The solution is up to the onset Crystallization concentrated and then cooled. 10.5 g of 7-chloro-l - [(2-chloro-l-methoxy> ethyl] -l, 3-dihydro-> are obtained hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, which is made from ethyl acetate recrystallized at 191-193 ° melts.

Example 50

A mixture of 10 g of 7-chloro-l - [(2-chloro-ethoxy) methyl] -l, 3-dihydro-5-phenyl-2H-l, 4-benzodiazepin-2-one, 20 ml of pyrrolidine, 2 g of sodium iodide and 100 ml of dioxane are added for 5 hours refluxed. The one after evaporation in vacuo

obtained residue is between ether and 10Jfc-iger soda solution distributed. The ether phase is separated off, dried and evaporated. The residue is added to 150 g of silica gel the solvent system benzene: acetone: triethylamine l6: j5: l chromatographed. The pure ones according to thin-layer chromatography Fractions (7j 2 g) are combined and treated with alcoholic hydrochloric acid adjusted to pH 6. After evaporation in vacuo, the residue is crystallized from acetone-ether. You get 6.5 g of 7-chloro-1,3-dihydro-5-phenyl-l- £ [2- (l-pyrrolidinyl) -

* thoxy] methyl} -2H-1,4-benzodiazepin-2-one hydrochloride of m.p. 165-166 ⁰ . 009835/1957

Example 51

1 g of l - ((2-amino-ethoxy) methyl-7-chloro-l, 5-dihydro-5-phenyl-2H-l, 4-benzodiazepln-2-one hydrochloride we * in 5 ml 300 iger Pormaldehydlöaung dissolved and for 2 hours at Left to stand at room temperature. Then it is with 20 al of methanol diluted and in the presence of 1 g of Raney-Nlekel during Hydrogenated for 3 hours. After filtering off the catalyst, it is Evaporated in vacuo and the residue between ether and lOjf-iger soda solution distributed. The ether phase is separated, dried and evaporated, finally after the addition of benzene. The residue is dissolved in ether and brought to pH 6 with methanolic hydrochloric acid. After renewed evaporation, the residue is crystallized from acetone-ether. 0.4 g of 7-chloro-1,3-dihydro-l {[2- (dimethylamine) ethoxy] -methy1-} 5-phenyl-2H-1,4-benzodiazepin-2-one hydrochloride is obtained Dissolve from acetone-ether at 175-177 ° melts.

Example 52 A mixture of 14 g of 1,3-dihydro-7-nitro-5-phenyl - «- 1,4

benzodlazepin-2-one, 50 ml of glacial acetic acid and 20 ml of ethyl vinyl ether

will

refluxed for 5 hours. The reaction '

mixture is evaporated in vacuo and the residue is dissolved in methylene chloride. This solution is washed out with 10 pounds of soda solution, dried and evaporated. Crystallization of the Residue from methylene chloride ether yields 10 g of starting material back. The mother liquor is evaporated and the

RUokstand on 100 κ silica gel with 200 Bsslgester in methylene

009835/1957

Chloride chromatographed. By crystallization from ether one receives 0.65 g of l-Ul-ethoxy) a * thyl] -l, 3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one with a melting point of 170 ° -173 °. ·

Example 53

A mixture of 10 g of 7-chloro-l - [(2-chloroethoxy) -methyl]-l ^ -dihydro ^ -phenyl ^ H-l ^ -benzodiazepin ^ -one, 2 g Sodium iodide, 20 ml of Dinetnylamin and 100 ml of dioxane is Im I.

Autoclave heated to 110-115 ° for 4 hours. After evaporation in vacuo, the residue is partitioned between 10% soda solution and ether. The ether phase becomes with water washed. Dried over sodium sulfate and evaporated, finally after the addition of benzene. The residue is in alcohol solved. The pH of the solution is adjusted to 6 with alcoholic hydrochloric acid. The solvent is removed in vacuo and the residue is crystallized from acetone-ether. Man receives 9.5 g of 7-chloro-1- {12- (dimethylamino) ethoxy] methyl} -l, 3-. | dihydro-5-phenyl-2H-l, 4-bβnzodiazepin-2-one hydΓochlorid, the after recrystallization from acetone-ether melts at 174-176 °.

Example 54

A mixture of 10 g of 7-chloro-l - [(2-chloroethoxy) methyl] -l, 3-dihydro-5-phenyl-2H-l, 4-benzodiazepin-2-one, 2 g of sodium iodide, 20 ml of methylamine and 100 ml of dioxane is used for 4 hours

Heated to 110-115 ° in the autoclave. After the evaporation

009835/1957

volatile components in vacuo, the residue is between 10 £ -iger soda solution and ether-benzene mixture distributed. the organic phase is extracted three times with 2N acetic acid. The extracts are washed with ether, made alkaline with 2N sodium hydroxide solution and extracted with a benzene-ether mixture. The extracts dried over sodium sulphate deliver! after evaporation, 5 g of a yellow oil. By chromatography on 120 g of silica gel (Merck 0.05-0.2 mm) with the Solvent system benzene: ethanol: triethylamine 7: 2: 1 gives 2.8 g of thin-layer chromatographically pure product. At the If an alcoholic solution of the base is mixed with an equivalent of oxalic acid in alcohol, crystalline 7-chloro, 3-dihydro-l - {[2- (methylamino) ethoxy] methyl} -5-phenyl-2H-l, 4-benzodiazepine-2- on-oxalate from m.p. 208-210 °.

Example 55

2 g of 4-acetoxy-7-chloro-1- (methoxymethyl) -5-phenyl, 3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one are in 30 ml Alcohol and 5 ml of triethylamine boiled under reflux for 30 minutes. The one obtained after evaporation in vacuo The residue is chromatographed on 50 g of silica gel with 10 $ ethyl acetate in methylene chloride. First 1.3 g of 7-chloro-1,5-dihydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one are eluted. This compound shows off after crystallization Ether-hexane has a melting point of 126-129 °. After that, 0.4 g of the isomeric 7-chloro-1,3-dihydro-l- (methoxymethyl) -5-phenyl-2H-

009835/1957

1,4-benzodiazepin-2-one eluted.

The starting material can be produced as follows:

A solution of 3.3 g of 7-chloro-1- (methoxymethyl) -4-hydroxy-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one 10 ml of acetic anhydride are added to 20 ml of pyridine and the mixture is left to stand at room temperature for 48 hours. To after evaporation in vacuo, the residue is partitioned between ™ Ether and 2N hydrochloric acid. The ether phase is washed with bicarbonate solution and water, dried and evaporated. Crystallization of the residue from ether-hexane yields 3.1 g 4-Acetoxy-7-chloro-1- (methoxymethyl) -5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one of m.p. 95-103 °. The melting point is improved by recrystallization from methanol to 103-106 °.

Example 56 '

0.3 g of 7-chloro-1,5-dihydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one are in a solution of 0.1 g of sodium in 10 ml of alcohol for 30 minutes at room temperature ditched. The reaction mixture is neutralized by adding glacial acetic acid and evaporated in vacuo. The residue is distributed between 10 # soda solution and methylene chloride. That after evaporation of the dried methylene chloride solution The residue obtained is added to 20 g of silica gel

009835/1957

Ethyl acetate chromatographed in methylene chloride. Nan receives 0.23 g of 7-chloro-1,3-dihydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

Example 57

0.4 g of sodium methoxide are added to a solution of 1 g of 7-chloro-l- {methoxymethyl) -5-phenyl-4- (p-toluenesulfonyl) -l, 3,4,5-tetrahydro-2H-l, 4- benzodiazepin-2-one in 20 ml of dimethylformamide given. The mixture is stirred for 30 minutes under a nitrogen atmosphere, then neutralized with glacial acetic acid and evaporated in vacuo. The residue is taken up in ether and three times extracted with 2N hydrochloric acid. The extracts washed with ether are made alkaline with concentrated ammonia and extracted three times with methylene chloride. The dried methylene chloride extracts leave 0.6 g after evaporation yellow oil, which after chromatography on 20 g of silica gel with 10 $ Ethyl acetate in methylene chloride 0.4 g of 7-chloro-1,3-dihydro-1- (methoxymethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one 1ie fert.

The starting material can be produced as follows:,

A solution of 3.2 g of 7-chloro-1- (methoxymethyl) -5-phenyl, 3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one in 20 ml of pyridine 2.3 g of tosyl chloride are added and the mixture is left to stand for 3 hours at room temperature. After removing the pyridine the residue is partitioned between methylene chloride and 2N hydrochloric acid in vacuo. The methylene chloride phase is then with

009835 / 19E7

Washed 110 gallons of soda solution and water, dried and evaporated. The crystalline residue is recrystallized from methanol-methylene chloride. 7-Chloro-1- (methoxymethyl) -5-phenyl-4- (p-toluenesulfcnyl) -l, 3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one of melting point 218 is obtained. 220 °.

Example 58

A solution of 10.3 g of 7-chloro-1,3-dihydro-ll-ynethoxy ^ HthylJ ^ -phenyl ^ H-l ^ -benzodiazepin - ^ - one in 125 «1 Pyridine is added dropwise at 30-35 ° with 9.6 g of pivaloyl chloride offset. After the addition, the reaction mixture is 1 hour stirred at room temperature and then evaporated under reduced pressure. The residue is taken up in methylene chloride, the solution was washed with water, dried over sodium sulfate and concentrated. The remaining oil crystallizes on trituration with hexane and gives a crude product with a melting point of 95-100 °. Recrystallization from an Oemlsch of ether-hexane results 7-chloro-1,3-dihydro-1- (1-methoxy-2-p ± raloyloxy-tlthy]) -5-phenyl-2H-1,4-benzodiazepin-2-one of m.p. 101-103 °.

Example 59

Oem & ss in the manner described in Example 58 is obtained from 10.3 S 7-chloro-l, 3-dihydro-l - [(2-hydroxy-l-methoxy -) - ethyl] -5-phenyl-2H-l, 4-benzodiazepin-2-one and 18 , 4 g 3 * 4.5-

Trimethoxy-benzoyl chloride 19.9 g of crude product. This will be on

009835/1957

600 g of Kieeelgel with 20 $ ethyl acetate in Mttahylenchlorld chromatographed. The unified parliamentary groups will be united, concentrated and recrystallized from methylene chloride-hexane.

There are 7-chloro-l, 3-dihydro-l- (l-methoxy-2- (3,4,5-trimethoxy-

benzoyloxy) ethyl] -5-phenyl-1H-1, ^ «» benzodiazepin-2-one from

M.p. 146-148 ° obtained. Example 60

Duroh is obtained in a manner analogous to Example 59 Reaction of 10.3 g of 7-chloro-1,3-dihydro-1,3-dihydro-1,3-[(2-hydroxy-imethoxy) -ethy]) -5-phenyl-2H-1,4-benzodlazepin-2-one with 7,8 G Cyolopropanecarboxylic acid chloride after chromatography of the crude product on 450 g of silica gel with ethyl acetate in methylene chloride 7-chloro-1- (2-cyclopropanecarbonyloxy-1-methyloxy-ethyl) -l, 3-dihydro-5-phenyl-2H-1,4-benzodiazepine -2-one, which melts after recrystallization from ethanol at 113-115 °.

Example 6l

A slurry of 8.0 g of N, N'-carbonyl-di-imidazole in 40 ml of tetrahydrofuran is after the addition of 7 * 8 g of p-methoxyphenylacetic acid for 2 hours under nitrogen at room temperature touched; a clear solution of p-methoxyphenylesslgsäure-imidazolld is obtained. In the meantime, a solution of imidazole sodium is made from 0.16 g sodium with 1.6 g imidazole in 20 ml tetrahydrofuran by heating under reflux at peuohtlgkeit-

009835/1957

Exclusion prepares and after cooling down to tree temperature with a suspension of 8.1 g of 7-chloro-1,3-dihydro-1,3-dihydro-1,3 [(2 * hydroxyl-methoxy) ethyl] -5-phenyl-2H-1,4-benzodiazepin-2-one added in 50 ml of methylene chloride. The solution of the imidazolide which has been prepared is then added at room temperature and stirring is continued Night. The precipitate is then filtered off and the filtrate evaporated in vacuo. The oily residue is taken up in methylene chloride, the solution with bicarbonate solution and Washed with water, dried over sodium sulfate and concentrated. The remaining oil is chromatographed on 200 g Purified silica gel with 30 # ethyl acetate in methylene chloride. the After recrystallization from ether-hexane, uniform fractions yield 7-chloro-1,3-dihydro-1- [l-methoxy-2- (p-methoxyphenylacetoxy) ethyl] -5-phenyl-2H-1,4-benzodiazepine-2 -on of m.p. 95-97 °.

Example 62

1.6 g (0.03 mol) of sodium methylate are added with stirring to a solution, cooled to -20 °, of 6.4 g (0.02 mol) of 1,3-dihydro-7-bromo-5- (2-pyridyl ) -2H-1,4-benzodiazepin-2-one given in 30 ml of dimethylformamide. After stirring for 5 minutes at -20 °, the mixture is ^{cooled to -4o e} and 2.6 g (0.032 mol) of chloromethyl methyl ether are added dropwise. The reaction mixture is then poured into water and shaken, the aqueous phase is separated off and taken up in methylene chloride. The methylene chloride phase is dried over sodium sulfate and

009835/1957

evaporated. The residue is chromatographed over 200 g of silica gel (methylene chloride / ethyl acetate 4: 1) whereby 1,3-dihydro-1- (methoxymethyl) -T-bromo-5- (2-pyridyl) -2H-1,4-t? üzodiazepin-2-one receives the following spectroscopic Data has: Mass spectrum: 359/361, 314/316, 28o, 208, 45

Nuclear magnetic resonance spectrum: 6OMHz in CDCl ,:

1) -OCH ₃ : (s, 3H) 3 ^ 3 ppm

2) -N-CH ₂ * -: (AB.2H) 3.92 ppmj _Igeffl

3) -N-CH ₂ -O: (AB, 2H) 4.80 ppm) _τ ^^

** ty ( ppmj

4) H arom (m, 6H) approx 7.25-8.25 ppm

5) H_ (pyridine) 8.67 ppm

Example 63 Tablets are made with the following composition:

per tablet

1,3-Dihydro-1- (methoxymethyl) -7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one 10 mg

Corn starch 53 ng Milk sugar 150 mg Gelatin ($ 10 solution) 6 mg

The active ingredient, the corn starch and the lactose are thickened with a 10 # oelatine solution. Di- paste will Shredded, put the granules in a suitable pan

009835/1957 BAD

and dried at 43 °. The dried granules will passed through a crusher and in a blender mixed with the following ingredients:

Talc 6 mg

Magnesium stearate 6 mg Corn starch 9 mg

and then compressed into tablets of 240 mg.

Example 64

Suppositories are made with the following ingredients:

per 1 g of suppository

1,3-Dihydro-1- (nethoxymethyl) -7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one 10 * 0 mg

Vfecobee M (hydrogenated coconut oil) 97 * 5 mg Carnauba wax 1.5 mg %

The Wecobee M and the carnauba wax are made in one a suitable vessel with a glass insert melted and cooled to 45 °. The active ingredient is added with stirring and stirred until completely dispersed. The mixture is then poured into suppository molds which ensure a suppository weight of 1 g.

009835/1957

Example 65

A parenteral brewing form is made with the following Beetandteile produced

per ml

1,3-Dlhydro-1- (methoxymethyl) -T-nltro-S-phenyl-SH-l. ^ - benzodlazepin-2-one 5 ng

Dlmethylaoetanld Propylene glycol Benzyl alcohol

AethanOl

Water for injections ad 1 nl

The active ingredient is dissolved in Dinethylaoetamld and mixed with benzyl alcohol, propylene glycol, ethanol and water. Filter through a candle filter, fill in suitable Ampoules, worn and sterilized.

009835/1957

Claims (1)

Claims 1. Process for the preparation of benzodiazepine derivatives of the general formula CH-R ₄ wherein R, halogen or nitro, R _g phenyl, halophenyl or pyridyl, R, hydrogen, alkyl, hydroxyalkyl, acyloxy alkyl, haloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carbalkoxy, R ₁ , alkoxy, haloalkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkyloxy, alkyl, alkoxy , Alkylsulfinyl or alkylsulfonyl, R_ hydrogen or hydroxy and Rg hydrogen or λ Carbalkoxy mean, and where, in the case of R is hydrogen means that the nitrogen atom in the 4-position can carry an oxygen atom, and salts of these compounds, characterized in that a) a compound of the general form I 009835/1957 II where R., Rp and Rg have the above meaning, or a 4-oxide thereof, with a compound of the general formula X-CH-Rg III wherein R _{7 is} hydrogen, alkyl, haloalkyl, carboalkoxy or acyloxyalkyl, Rq is alkoxy, haloalkoxy, alkylthio or alkoxyalkoxy and X is halogen, implements, or that one b) a compound of the general formula 009835/1957 IV wherein R ₁ and Rp have the above meaning, with a vinyl ether of the general formula where Rg is alkyl, implements, or that c) a compound of the general formula VI where R ₁ , R ₀ and R_ have the above meaning and R _{10 is} hydrogen, alkyl, hydroxyalkyl, haloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, or acyloxyalkyl and R _{11 has} the meaning given for R ₁ ^, but at least one of the substituents 009835/1957 R ₁₀ and R ₁₁ denote a monohaloalkyl or monohaloalkoxy group, and in the case of R ₁ . Hydrogen, carrying the nitrogen atom in position 4 an oxygen atom can Reacts with a monoalkylamine or dialkylamine , or that one d) a compound of the general formula VII where R ₁ and R- have the above meaning, R _{12 is} alkoxy, monoalky1aminoalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio or aminoalkoxy, R ₁ - is hydrogen, alkyl, monoalkylaminoalkyl, Dlalkylaninoalkyl, or aminoalkyl, but at least one of the substituents R ₁₂ and R ₁ - an aminoalkoxy, monoalky 1 aminoalkoxy, aminoalkyl or monoalkylaminoalkyl group or a corresponding 4-oxide alkylated, or that one e) from a compound of the general formula 009835/1957 VIII wherein R ₁ and R _{g have the} above meaning, R ₁₄ alkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio or a slotted monoalkylaminoalkoxy group, R ₁ , - hydrogen, alkyl, monoalkylaminoalky 1, dialkylaminoalkyl, acyloxyalkyl or a protected monoalkylaminoalkyl group, where at least one of the substituents R ₁₄ and R ₁₁ - a slotted monoalkylaminoalkoxy or JO Means monoalkylaminoalkyl group or splits off the protective group from a corresponding 4-oxide or that one f) in a compound of the general formula IX 009835/1957 wherein R ₁ , R ₃ , R ₅ and Rg have the above meaning, and where, in the case of R _{c is} hydrogen, the sticky Substance atom in the 4-position can carry an oxygen atom, R, / - alkoxy, monohaloalkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy or alkylthlo and R _{17 is} hydrogen, alkyl, hydroxyalkyl, monohaloalkyl, carbalkoxy, monoalkylaninoalkyl, dialkylaminoalkyl or at least a alkylaminoalkyl one of the two substituents R, g and R _{17 is} monohaloalkoxy or monohaloalkyl, the aliphatically bound halo atoms through hydroxyl groups replaces, or that one g) in a compound of the general formula wherein R ,, Rp, R- and R ^ have the above meanings, R ^ alkylthio and Rg are hydrogen, alkyl, hydroxyalkyl, haloalkyl, carbalkoxy or acyloxyalkyl and in the case of R _{c is} hydrogen, that Nitrogen atom in position 4 is an oxygen atom 009835/1957 can carry the alkylthio group is oxidized to the alkylsulfinyl or alkylsulfonyl group, or that h) a compound of the general formula - * 4 ^rows * 4 ^R 6 -CO-CH-NH XI C = O wherein R _1, Rg, R ,, R ^ and Rg have the above meaning, is cyclized, or in that i) a VerbinJ.t; ~ of the general formula XII wherein R ,, Rp, R ,, R ₁ . and Rg have the above meaning and R _{20 is} an acyl group, hydrolyzed,
or that one j) a compound of the general formula 009835/1957 in which R., R ₃ , R and Rg have the above meanings and R _{21 is} alkoxy, haloalkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy or alkylthio _; deoxidized, or that one k) a compound of the general formula XIV where R ,, R_ and R, - have the above meaning, R_p is alkoxy, dialkylaminoalkoxy, alkoxyalkoxy or alkylthio and R ₂ -, hydrogen, alkyl, carbalkoxy, dialkylaminoalkyl or acyloxyalkyl, dehydrated, or that 1) a compound of the general formula 009835/1957 where R-, R ₂ and Rg have the above meaning and R ₂₂ , alkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy or alkoxyalkoxy and R ₂ - hydrogen, alkyl, hydroxyalkyl, carbalkoxy, monoalkylaminoalkyl, dialkylaminoalkyl or acyloxyalkyl, on the 4,5 bond oxidized or dehydrated, or that m) a compound of the general formula OOR wherein , R ₂ , and R _{5 have the} above meaning, Alkyl and R _{37 are} hydrogen, alkyl, hydroxyalkyl, haloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or acyloxyalkyl and where in the case of Rj. 009835/1957 ^D Hydrogen means the nitrogen atom in the 4-position can carry an oxygen atom,
saponified and decarboxylated,
or that n) a compound of the general formula COOR XVII wherein R ,, R ₃ , R ,, R ^ and R ₃ ^ have the above meaning oxidizes to the 3-hydroxy compound,
or that o) a compound of the general formula CH-R, OR ₂₈ XVIII where R ,, and R _{35 have the} above meaning, R ₂ D is acyl and R _{39 is} alkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy or alkylthio,
with a base in the corresponding '. 009835/1957 4,5-dehydro compound transferred, or that ρ) is a compound of the general formula XIX wherein, R, Rp and Rg have the above meanings, R, alkyl _{Q represents} a mesyl or tosyl group, R ,, is hydrogen, alkyl, hydroxyalkyl, carbalkoxy, dialkylamino or acyloxyalkyl and R, ₂ alkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkylthio, Mean alkylsulfinyl or alkylsulfonyl, with a strong base in the corresponding 4,5-dehydro compound transferred, or that q) a compound of the general formula R · = -CH-R 009835/1957 wherein R ₁ , R-, R-, R ₄ and Rg have the above meaning, stored in the corresponding 4,5-dehydro-connection, or that nan r) a compound of the general Pornel CH-R XXI where R ₁ * R ₂ and Rg have the above meanings and R _{4 is} hydroxyalkyl, R _{41 is} alkoxy, haloalkoxy, alkylalkoxyalkoxy, alkoxyalkoxy, alkylthio, alkylsulphonyl or alkylsulphonyl, or a 4-hydroxy thereof ■ treated with a) training aid, or that «an s) in a combination of the general formula XXII in which R ₁ , R ₂ and Rg have the above meaning and R _{42 is} haloalkyl and R _{4 is} alkoxy, dialkylanolalkoxy, alkoxyalkoxy, alkylthio, alkylsulphonyl or alkylsulphonyl, or a corresponding 4-oxide the aliphatically bonded halogen atom into an acyloxy group convicted, and that t) if desired, a compound In a salt transferred. . 009835/1957 2. The method according to variants a) to q) and t) in claim 1, characterized in that R _{2 is} phenyl or 2-halophenyl. 3. The method according to claims 1 or 2, characterized in that R _{1 is} chlorine or nitro. 4. The method naoh claim 1, 2 or 3, characterized in that R _{2 is} 2-chlorophenyl, 2-fluorophenyl ^ or phenyl. 5. The method according to any one of claims 1-4, characterized in that R _{e is} hydrogen. 6. The method according to any one of claims 1-5, characterized in that Rg is hydrogen. 7. The method according to any one of claims 1-6, characterized in that Rb is alkoxy. 8. The method according to any one of claims 1-7, characterized in that R is hydrogen or alkyl. 9. The method according to any one of claims 1-7, characterized in that R, denotes acyloxyalkyl. 009835/1957 10. The method according to claim 9 »daduroh characterized, that R, denotes aoyloxynethyl. 11. The method according to claim 10, characterized in that R, alkanoyloxymethyl, aroyloxymethyl or Cycloälkanoarbonyloxynethyl means. 12. The method according to any one of claims 1-8, characterized in that 7-nitro-5-phenyl-1-bethoxyeethyl-1,3-dihydro-2H-1,4-benzodlazepln-2-one is prepared. 13. Process according to one of Claims 1-8, characterized in that 7-nitro-5-phenyl-1-ithoxymethyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one is produced. 14. The method according to any one of claims 1-6, and 8, characterized in that 7-Witro-5-phenyl-li (2-chloroethoxy) methyl] -l, 3-dihydro-2H-l, 4-benzodiazepine 2-on manufactures. 15. The method naoh one of claims 1-8, characterized in that 7-chloro-5- (2-fluorophenyl) -l-methoxymethyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one is prepared . 16. The method according to any one of claims 1-7 and 9-11, characterized in that 2 ~ (7 ~ chloro-2,3-dih7dro-2-oxo-5-phenyl-lH-1,4-bensodiR3sepin-l -yl) / »- s propanoarboxyl & t manufactures. 009835 / * 957 BAD ORIGINAL 17 · Process cur Production of preparations with anticonvulsant, sedative, muscle relaxant and anxiolytic pools Properties, daduroh characterized that nan a benzodiazepine Derlvat gealss claim 1 or a salt thereof as active component old "non-toxic" inert "ones suitable for therapeutic administration per se. Solid and liquid carriers and / or exoiplsntlen customary in solo preparations. | 18. Preparations of old anticonvulsant »muscle relaxants, sedative and anxiolytic properties, characterized in that they contain a benzodlazepine derivative according to claim 1 or a salt thereof and a carrier material. 009835/1957 19 · Benzodiazepine derivative · the general Forael wherein R _{1 is} halogen or nitro, R _{2 is} phenyl, halophenyl or pyridyl, R, hydrogen, alkyl, hydroxyalkyl, aoyloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, haloalkyl or carbalkoxy, R 1 is alkoxy, haloalkoxy, monoalkylaminoalkoxy, Dlalkylaninoalkoxy, hydroxyalkoxy, alkylthioalkoxy, alkylthioalkoxy or alkylsulfonyl, R. hydrogen or hydroxy and R. 20. Benzodlazepine derivatives according to claim 10, word * Rg denotes phenyl or 2-halophenyl. 21. Benzodlazepine derivatives genttss one of the claims and 20 wherein R-, chlorine or nitro. 009835/1957 22. Benzodiazepine derivatives according to one of claims 19-21 in which R _g denotes phenyl, 2-chlorophenyl or 2-fluorophenyl. 23 · Benzodiazepine derivatives according to one of claims 19-22, wherein R _{5 is} hydrogen. 24. benzodiazepine derivatives genXss a 19-23 »wherein Rg is hydrogen of the claims. 25. Benzodiazepine derivatives vegetable one of the claims 19-24, wherein R 1 is alkoxy. $ 2. Benzodiazepine derivative according to one of the claims 19-25, where R is hydrogen or alkyl. 2f. Benzodiazepine derivatives according to one of the claims 19-25, in which R 1 is acyloxyalkyl. 28. Benzodiazepine derivatives genKss claim 27, wherein R, denotes aoyloxyethyl. 29. Benzodiazepine derivatives vegetables claim 28, wherein R, Alkanoyloxyethyl, aroyloxyethyl or cycloalkanecarbonyloxymethyl means. 009835 / 19B7 30. T-1,4-benzodiazepin-2-one. 31. 7-Nitro-5-phenyl-1-ethoxyethyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one. 32. 7-Mitro-5-phenyl-l - [(2-chloroethoxy) methyl] -1, 3-dihydro-2H-1,4-benzodiazepin-2-one. 33. 7-ChIor-S- (2-fluorophenyl) -l-methoxynewthyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one. 34. 2- (7-Chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepln-1-yl) -2-methoxyXthyl-cyclopropanecarboxylate. 009835/1957 35 · Beneophenone derivatives of the general formula CO-CH ^ -NH, where R _{1 is} halogen or nitro, Rg is phenyl, halophenyl or pyridyl, R, is hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, monoalkylaalnoalkyl, dialkylino * ls * l, haloalky 1 or carbalkoxy, R ^ is alkoxy, haloalkoxy, monoalkylalkoxyalkoxy, dialkylaalnoalkyl oxy, Alkoxy-alkoxy, alkylthlo, alkylsulfinyl. Or alkyl .and R _{c is} hydrogen or carbalkoxy sulfonyl /. 36. Benrodlazepine derivatives of the general formula wherein R. is halogen or nitro, R _{2 is} phenyl, halophenyl or pyridyl, Rg is hydrogen or carbalkoxy, R _{22 is} alkoxy, dialkyl alkoxy. Alkoxyalkoxy or alkyl-009835/1957 thlo and R ₂ , hydrogen, alkyl, carbalkoxy, Dlalkylaminoalkyl or Aoylmxyalkyl. 37 · Benzodiazepine derivatives of the general formula CH-R ₆ wherein R _{1 is} halogen or nitro, R _{2 is} phenyl, halophenyl or pyridyl, Rg is hydrogen or carbalkoxy, Rl is alkoxy, monoalkylaminoalkoxy, Dlalkylaminoalkoxy, hydroxyalkoxy or alkoxyalkoxy and R _2,. Mean hydrogen, alkyl, hydroxyalkyl, carbalkoxy, monoalkylaminoalkyl, dialkylaminoalkyl or aoyloxyalkyl. 36. Benzodiazepine derivatives of the general formula wherein R _{1 is} halogen or nitro, R _{2 is} phenyl, halophenyl or pyridyl, R ^ is hydrogen or carbalkoxy, R _2,. , 009835/1957 Hydrogen, alkyl, hydroxyalkyl, carbalkoxy, monoalkylaminoalkyl, dialkylaminoalkyl or acyloxyalkyl, R ₂ Q aoyl to R ₃₉ alkoxy, nonoalkylaminoalkoxy, dialkylaminoalkoxy. Hydroxy alkoxy, alkoxyalkoxy, or alkylthlo mean. 39 · Benzodiazepine derivatives of the general formula where R _{1 is} halogen or nitro, R _{2 is} phenyl, halophenyl or pyridyl, Rg is hydrogen or carbalkoxy, R _{50 is} a mesyl or tosyl group, R_, hydrogen, alkyl, hydroxyalkyl, carbalkoxy, dialkylaminoalkyl or acyloxyalkyl and R, _{2 is} alkoxy, dialkylanlnoalkoxy, hydroxyalkoxy , Alkoxyalkoxy, alkylthlo, alkylsulfinyl or alkylsulfonyl. 009835/1957 4O. Benzodlazepln derivatives of the general formula wherein R, halogen or nitro, Rp phenyl, halophenyl or pyridyl, Rg hydrogen or carbalkoxy, R, Hydrogen, alkyl, hydroxyalkyl, carbalkoxy, monoalkylaminoalkyl, Dlalkylaminoalkyl, acyloxyalkyl or haloalkyl, R ^ alkoxy, haloalkoxy, mono- alkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, Alkoxyalkoxy, alkylthlo, alkylsulfonyl or alkylsulfonyl mean. 009835/1957