NO128110B - - Google Patents

Description

Analogy method for the production of

therapeutically active benzodiazepine derivatives.

The present invention relates to a process for the production of new benzbdiazepine derivatives with the general formula

where R^ means halogen or nitro,

1 * 2 phenyl or halophenyl, ;R 3 hydrogen or lower alkyl, ;R^ lower alkoxy, lower haloalkoxy or ;lower alkylsulfiny1, and ;R(. hydrogen or hydroxy, ;where R 2 means halophenyl when R^ means chlorine or nitro, R^ hydrogen, R^ methoxy and R^ hydrogen, as well as salts of these compounds. ;The term "lower alkyl" alone or in combination as "lower alkoxy" includes straight-chain and branched hydrocarbon residues 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 such as acetyl, propionyl, tert.butyryl and the like, cycloalkanecarbonyl radicals such as, cyclopropanecarbonyl and the like, aroyl or aralkanoyl radicals such as benzoyl, phenacetyl, phenylprbpionyl and the like, which may optionally also carry methoxy substituents. The term "lower halogen alkoxy" includes mono- as well as di- and tri-halogen alkoxy groups such as chloroacetyl, dichloroacetyl and the like. The term "halogen" includes all 4 halogen one, i.e. fluorine, chlorine, bromine and iodine. Preferred compounds are those where R 1 means chlorine or nitro. Furthermore, R5 is preferably hydrogen. When R2 means halophenyl, the substituent is preferably in the 2-position in the 5-phenyl ring. Further preferred compounds are those where R 2 means phenyl, 2-chlorophenyl or 2-fluorophenyl. Particularly preferred are compounds where R 1 means chlorine or nitro, R 2 phenyl, 2-fluorophenyl or 2-chlorophenyl, R 2 hydrogen, and R 2 lower alkoxy. 7-nitro-5-phenyl-1-ethoxymethyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, 7-nitro-5-phenyl-1-[(2-chloro-ethoxy)-methyl ]-1,3-dihydro-2H-1,4-benzodiazepine-2-one, 7-chloro-5-(2-fluorophenyl)-1-methoxymethyl-1,3-dihydro-2H-1,4-benzodiazepine- 2-on is particularly preferred. ;The method according to the invention is characterized by ;a) reacting a compound of the general formula ;;where R^ and R 2 have the above meanings, ;with a compound of the general formula ... ;;where R^ has the above meanings , ;Rg means lower-alkyloxy or lower-haloalkyloxy, and X halogen, ;or that one ;b) reacts a compound of the above formula II with a vinyl ether of the general formula ;;where Rg means lower-alkyl, ;or that one ;c) in a connection with the general formula ;;where R^, R2, R^°9 R5 *are the previously indicated meaning and

R18 means alkyl,

oxidizes the alkylthio group to alkylsulfinyl, or that one

d) cyclizes a compound of the general formula

where R^, R2, R3 and R^ have the above meaning,

or that one

e) hydrolyzes a compound of the general formula

where R 1 , R 2 , R 3 and R 4 have the above meaning and R 20 means an acyl group, or that one f) deoxidizes a compound with the general formula

where R 1 , R 2 , R 3 and R 8 have the above meaning

or that one

g) dehydrates a compound of the general formula

where R 1 , R 2 and R 3 have the meanings given above, and R 22 means lower alkoxy,

or that one

h) oxidizes or dehydrogenates a compound with the general formula

where R1# R2, R3 and have the meanings given above for the 4,5 bond, or that one i) saponifies and decarboxylates a compound with the general formula

where R 1 , R 2 , R 3 , R 1 and R 2 have the meanings given above and R 26 means lower alkyl,

or that one

k) transfers a compound with the general formula

where R 1 , R 2 , R 3 and R 22 have the meanings given above, and R 28 means acyl with a base to the corresponding 4,5-dehydropreparation, or that one 1) transfers a compound with the general formula

where R^, R2, and R^ have the above meaning,

R30 means a mesyl or tosyl group and R32 lower alkoxy or alkylsulfinyl,

with a strong base to the corresponding 4,5-dehydro compound, or that one m) rearranges a compound with the general formula

where R^, R2 > R3 and R4 have the above meaning,

to the corresponding 4,5-dehydro compound, and that one

if desired, transfer an obtained compound to a salt.

The reaction of a compound of formula II with a compound of formula III yields compounds of formula I, where R 1 has the meaning given for R 9 , R 5 stands for hydrogen and R 1 , R 2 and R 3 have the meanings given above. It can be carried through in an inert organic solvent or mixtures thereof such as hydrocarbons, e.g. benzene, toluene, etc., dimethylformamide, ethers such as dioxane, tetrahydrofuran, alcohols, such as tert. butanol etc. Suitable temperatures are e.g. between -50°C and 120°C. Instead of X in the sense of halogen, some equivalent leaving group such as a mesyloxy, tosyloxy group or the like can be used. It is expedient to convert a compound of formula II for the reaction with a compound of formula III first into a 1-alkali metal derivative. This 1-alkali metal derivative can, for example, be prepared using a lower alkali alcoholate such as sodium methylate, an alkali metal hydride such as sodium hydride, an alkali metal amide such as sodium amide and similar agents. . However, the reaction of a compound of formula II with a compound of formula III can also take place

in the presence of one base such as alkali hydroxides, e.g. sodium hydroxide or triethylamine.

The reaction of a compound of formula II with a vinyl ether of formula V gives a compound of formula I, where R 3 and R 4 are hydrogen > R 4 alkoxymethyl and R 1 and R 2 have the meanings given above, also a compound with an oc-alkoxyethyl residue in 1- score. The reaction is conveniently carried out in an inert organic solvent such as hydrocarbons, e.g. benzene, toluene, chlorinated hydrocarbons e.g. chloroform and the like in the presence of an acid catalyst such as glacial acetic acid. For this reaction, e.g. temperatures between room temperature and 150°C suitable.

The oxidation of a compound of formula X with an alkylthio group to the corresponding compound with an alkylsulfinyl group can take place with the aid of an oxidizing agent which peracids, e.g. peracetic acid, perbenzbic acid etc. or hydrogen peroxide. Here, too, it is appropriate to work in an inert organic solvent such as halogenated hydrocarbons, e.g. carbon tetrachloride; acetic acid etc. Suitable temperatures are e.g. between -50°C and 80°C.

The cyclization of one compound of formula XI to a compound of formula I, where R^ means hydrogen and R^, R2, R3 and R4 have the meaning given for formula I, can take place in an alkaline, neutral or acidic environment and in a 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, however it is appropriate to work at temperatures in a range of approx. 0 - 150°C.

The hydrolysis of a compound of formula XII yields compounds of formula I, where R 1 - means hydroxy and R 1 , R 2 , R 2 and R 2 have the meanings given for formula I. This hydrolysis can e.g. is carried out by alkaline or acid hydrolysis or alcohol alcoholysis. The acidic hydrolysis preferably takes place by treating the starting material with an aqueous solution of a mineral acid such as hydrochloric acid, hydrobromic acid; sulfuric acid etc., or one organic acid such as toluenesulfonic acid etc. The acid treatment is conveniently carried out at room temperature, even if this is not critical.1 Furthermore, it is convenient to work in an aqueous medium that contains an organic solvent such as dioxane, tetrahydrofuran or similar water-miscible solvents. The alkaline hydrolysis can, for example; take place with aqueous alkali hydroxides such as sodium hydroxide etc. When using a starting material which contains an acyloxyalkyl group in the molecule, a hydrolysis of this group also occurs at the same time. If one uses a starting material that exhibits carbIoxy groups, the removal of the acyl group conveniently takes place by alcoholysis, e.g. with sodium ethoxide in ethanol or triethylamine in ethanol etc.

The deoxidation of a compound of formula XIII can e.g. is obtained by hydrogenation in the presence of Raney nickel, suitably in an inert organic solvent such as hydrocarbons e.g. benzene, toluene, alcohols, ethers such as dioxane, acetic acid etc., at room temperature and normal pressure or elevated pressure or by treatment with a phosphorus trihalide, such as phosphorus trichloride, suitably in an inert organic solvent such as hydrocarbons, e.g. benzene etc., chlorinated hydrocarbons

and at room temperature, although temperatures above and below room temperature can also be used. The deoxidation can also take place with zinc and glacial acetic acid in an organic solvent such as glacial acetic acid, chlorinated hydrocarbons, ethers, alcohols etc., and suitably at temperatures between approx. -20 to 50°C. The use of a specific deoxidizing agent is largely based on the functional groups present in the molecule, in order to avoid unfavorable side reactions if possible. Deoxidation is therefore carried out in the presence of a halogeno-alkoxy- and/or nitro-group in the molecule appropriately with a phosphorus trihalide.

The dehydration of a compound of formula XIV gives corresponding compounds with a double bond in the 4,5-position and can e.g. take place with a carbodiimide such as cyclohexyl carbodiimide etc. The reaction is conveniently carried out in an inert organic solvent such as hydrocarbons, for example; benzene, toluene; ethers such as dioxane etc. Suitable temperatures are, for example, between -20 and 100°C. Frequently, in this dehydrating reaction, above all when using 3-carbon alkoxy derivatives as starting material, the formation of a corresponding isomeric 3,4-dehydro derivative with formula I is observed. This latter compound can, however, be easily isomerized to the 4,5-dehydro compound, e.g. by treatment with a base such as alkali alkoxides, e.g. sodium methoxide, triethylamine etc.

The oxidation of a compound of formula XV gives corresponding compounds with a double bond in the 4,5-position and can e.g. take place with bromine, chlorine, azodicarboxylic acid esters, e.g. the diethyl ester, halosuccinimides, e.g. bromosuccinimide, halogenamides, e.g. Chloracetamide etc. It is appropriate to work in an inert organic solvent 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 preferably at a temperature between approx. -30 and 100°C.

Compounds of formula XVI can be saponified into the corresponding 3-carboxylic acid salts, e.g. by treatment with alkali hydroxides such as sodium hydroxide, potassium hydroxide, alkaline earth hydroxides or tert. organic bases such as triethylamine. The decarboxylation of this 3-carboxylic acid salt occurs slowly on standing, faster on heating and spontaneously on acidification.

The acid elimination from a compound of 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 anhydrous medium. One therefore works appropriately in an inert organic solvent such as ethers, alcohols, e.g. ethanol, hydrocarbons, e.g. benzene, toluene, dimethylformamide and the like and at temperatures between -40° to 120°C. The acyl group in the sense of R28 can be a lower alkanoyl, such as acetyl, aroyl, such as benzoyl, tosyl or mesyl group.

During the acid cleavage, however, a compound of formula XX can also appear as an intermediate product, which is converted in accordance with the later specified method to the final product of formula I.

The removal of a mesyl or tosyl group from a compound of formula XIX can be achieved with a strong base such as alkali hydrides, e.g. sodium hydride, alkali alkoxides such as sodium methoxide, triethylamine and alkali amides such as sodium amide etc. in anhydrous medium. One therefore works appropriately in an inert organic solvent such as ethers, alcohols such as ethanol, hydrocarbons such as benzene, toluene, dimethylformamide etc. and at temperatures between 0° and 120°C. Also in this reaction, an isomeric compound of formula XX can occur, which isomerizes to the final product of formula I.

The isomerization of a compound of formula XX can be achieved

by treatment with a base such as alkali alcoholates, e.g. sodium methoxide, alkali hydrides, such as sodium hydride, triethylamine etc. The reaction suitably takes place in an inert organic solvent such as hydrocarbons, ethers, alcohols etc. and at temperatures between -40° and 120°C.

With regard to the starting materials used in the method according to the invention, the following can be said:

The compounds with the formulas II, III and V are known respectively

can be easily produced in analogy to known methods.

The 4-deoxy compounds with the formulas X and XVI which do not exhibit any hydroxy group in the 3-position can be obtained by using the above-mentioned method variant d) or in analogy to this. The 4-oxides of formula XXIII can be obtained, provided they are not available in analogy to the method variant defined above under a), by oxidation of the corresponding 4-deoxy compound, e.g. by treatment with peracids, such as peracetic acid in an organic solvent which

acetic acid, chlorinated hydrocarbons such as methylene chloride, etc.

The 3-hydroxy compounds with the formulas X and XVI can be prepared j e.g. when treating a compound with the general

in Formula I

where R^, R2, R3 and R4 have the above meaning, and Rg means hydrogen or COOR2g, where R2g has before

stated meaning,

with an anhydride, sulfide or halide of an aliphatic, aromatic or araliphatic carboxylic acid. The reaction causes a splitting off of the oxygen atom in the 4-position while simultaneously acyloxylating the carbon atom in the 3-position. The reaction is conveniently carried out in a common inert organic solvent such as hydrocarbons, e.g. toluene, benzene etc., halogenated hydrocarbons such as carbon tetrachloride

etc., dimethylformamide etc. When using an acid anhydride or a diacyl sulphide as an acylating agent, this acid anhydride or diacyl sulphide can also serve directly as a reaction medium. Subsequent hydrolysis of the 3-acyloxy derivatives obtained in the manner specified for a compound of formula XII gives 3-hydroxy derivatives.

Compounds of formula XI can be prepared in a known manner, e.g. by reaction of a carbobenzoxyglycylamido-benzophenone with the general formula

or a 2<1->benzoyl-phthalimido-acetanilide of the general formula or a tert-butoxy-glycylamidobenzophenone of the general formula

where in the formulas XXIV, XXV and XXVI R 1 and R 2 have the above meaning, with a compound of formula III or a corresponding alkyl-;

thio compound and subsequent cleavage of the carbobenzoxyl residue, resp. the phthalimide residue or the tert.-butoxycarbonyl residue, j whereby, if necessary for the cleavage, an alkylthio group in j

oxidized to an alkylsulfinyl group.

The reaction of a compound of the formulas XXIV, XXV or

XXVI with a compound of formula III or a corresponding alkylthio compound can take place in the manner indicated for the reaction of a compound of formula II with a compound of formula III.

The cleavage of the carbobenzoxyl residue can e.g. is carried out by catalytic hydrogenation or with the help of a halohydrogen acid in the presence of acetic acid.

The catalytic hydrogenation can take place in glacial acetic acid/HCl or ethanol/HCl etc. The cleavage using a halogen-hydrogen acid in glacial acetic acid can take place in the presence of an inert organic solvent such as chlorinated hydrocarbons, e.g. methylene chloride, etc. and at temperatures between -20°

and room temperature. The cleavage of the phthalimide residue is conveniently carried out by hydrazinolysis in an inert organic solvent such as alcohols, ethers such as dioxane, dimethylformamide etc. and at temperatures between room temperature and 150°C. The cleavage of the tert.-butoxycarbonyl residue can be carried out with trifluoroacetic acid and in an organic solvent such as hydrocarbons, chlorinated hydrocarbons, glacial acetic acid or trifluoroacetic acid and suitably at room temperature.

Thus obtained compounds of formula XI can be cyclized

without isolation to benzodiazepine derivatives of formula I.

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

where R^^ means halogen and

R2 has the above meaning,

with a compound of the general formula III, reduces an obtained compound of the general formula

where R 2 , R 3 / R 8 and R 8 have the above meaning, oxidizes a compound obtained with the general formula

where R2, R^, Rg and R^^ have the above meaning,

to the corresponding 2-carboxaldehyde, oxidises this compound" and reduces a compound obtained with the general formula

where R 2 , R 31 / R 3 and RQ have the above meaning, then to a compound of the general formula

where R 2 , R 3 ^/ R 3 °<3 R 8 have the above meaning, and oxidize this compound to a compound of formula

XI.

However, a compound of formula XXIX can also be transferred

in a known manner to an amide of the general formula

and reduce this compound to a compound of formula

XXXII.

The reduction of a compound of formula XXIX and XXXI conveniently takes place with a reducing agent such as lithium aluminum hydride and in an inert organic solvent such as ethers, e.g. tetrahydrofuran etc.

The oxidation of a compound of formula XXX conveniently takes place 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 the reflux temperature of the reaction mixture. The oxidation of the 2-carboxaldehyde obtained is achieved with hydroxylamine. It is also appropriate to work here in a solvent such as water, alcohols, ethers, triethylamine, pyridine etc. and at temperatures between room temperature and the reflux temperature of the reaction mixture.

The oxidation of a compound of formula XXXII can find

place with an oxidizing agent such as chromium trioxide in glacial acetic acid. Compounds of formula XXXII are oxidized and cyclized appropriately without isolation of a compound of formula XI.

Compounds of formula XIV can be obtained by reduction of the corresponding 4-oxide of the general formula

where R^, R2, R3 and R22 have the above meaning,

in the presence of platinum oxide.

One works appropriately in an organic solvent such as glacial acetic acid, alcohols and at a temperature between approx. 0° and 50°C, preferably at room temperature.

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

where R 1 , R 3 and R 22 have the meanings given above, with a compound of the general formula

where Z means Li, MgJ or MgBr.

It is appropriate to work in an inert organic solvent such as ethers, hydrocarbons, and at temperatures between -60°C and the reflux temperature for the reaction mixture. Compounds of formula XXXV can in turn be prepared by introducing the substituent in the 1-position of a compound unsubstituted in the 1-position according to reaction a).

Compounds of formula XV can be prepared by reacting

a corresponding 1-unsubstituted compound with a compound of formula III according to variant a).

Compounds of formula XVIII can be prepared by acylation

of a corresponding 4-hydroxy-substituted compound of formula XIV. Suitable acylating agents are e.g. acid anhydrides

such as acetic anhydride, acid halides etc. One works towards

: termly in the presence of a base as an acid acceptor such as pyridine etc. and in an organic solvent such as hydrocarbons, chlorinated hydrocarbons, ethers and the like. at temperatures between -50° and 100°C.

Compounds of formula XIX can be prepared by acylation

of a corresponding 4,5-dihydro compound of formula XV

or analogues thereof, which are obtained in analogy to the preparation of the compounds of formula XV, e.g. with a tosyl or mesyl halide. One works appropriately in an inert organic solvent such as hydrocarbons, e.g. benzene, chlorinated hydrocarbons, etc. and in the presence of an acid acceptor such as pyridine and the like. and at temperatures between 0°C and the reflux temperature of the reaction mixture.

Compounds of formula XX can be prepared from corresponding compounds of formula XVIII or XIX in the manner described herein. Furthermore, compounds of formula XX can be prepared by introducing a substituent into a 1-unsubstituted compound according to method a). In this reaction, however, an isomerization to a 4,5-dehydro compound can also take place.

It is hereby pointed out that the relevant starting materials do not necessarily have to be used in an isolated state, but can also be reacted further without isolation from the reaction mixture in which they were prepared.

Compounds with the general formula I, which have a basic character, form acid addition salts with inorganic 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, etc.

Compounds of the general formula I as well as their pharmaceutically usable salts can be used as anticonvulsants, muscle relaxants, sedatives and anxiolytics. The anticonvulsant activity is demonstrated when mice, which have been administered the compounds of formula I or their salts, are subjected to the pentamethylenetetrazole test. E.g. shows 7-nitro-5-phenyl-1-ethoxymethyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

that an LD5Q of 1200 - 2500 mg/kg (p.o.) shows in the test for anticonvulsant activity in the pentetrazole test in accordance with the method of Orloff (Proe. Soc. Exptl. Biol. Med. 70 254-257 1949) an APR of 2.0 of 0.2 mgAg (p.o.) [APR 2.0 means the dose in mg/kg of an anticonvulsant which causes

the double pentetrazole consumption compared to the untreated control group] and 7-nitro-5-phenyl-1-[(2-chloroethoxy)-methyl]-1, 3-dihydro-2H-1, 4-benzodiazepine-2-one (LD ^Q >5000 mg/kg p.o.) an APR 2.0 of 1.8 mg/kg (p.o.). In contrast, phenobarbital, a common anticonvulsant, shows an APR of 2.0 at 30 mg/kg. The muscle-relaxing activity can be demonstrated in the test vein on the rotary rod. E.g. shows the aforementioned 7-nitro-5-phenyl-1-ethoxymethyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one an HD5q of 5 mg/kg (p.o.) and 7-nitro-5- phenyl-1-[(2-chloroethoxy-methyl)]1,3-dihydro-2H-1,4-benzodiazepine-2-one an HD^Q of 0.5 mg/kg (p.o.).

Compounds of formula I as well as their pharmaceutically acceptable salts can therefore find use as pharmaceuticals, e.g. in the form of pharmaceutical preparations, which contain them or their salts in admixture with a pharmaceutical organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, rubber, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. such as • tablets, dragées, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and resp. or contains auxiliary substances, such as preservatives, stabilisers, wetting agents or emulsifiers, salts to change the osmotic pressures or buffers. They may also contain other therapeutically valuable substances. The dosage takes place according to individual requirements, however a dosage of 0.1 mg/kg - 10 mg/kg/day is preferred.

The following examples illustrate the invention:

EXAMPLE 1

A solution of 7.5 g of 7-chloro-§-(o-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one in 75 ml of dimethylformamide is cooled to -10° and 2 g of sodium methylate are added . After stirring for 15 minutes at -10° to 0° under a nitrogen atmosphere, it is cooled to -40° and 3.1 g of chloromethyl methyl ether is added dropwise. After the addition, the temperature is allowed to rise to 0° over the course of 30 minutes. The reaction mixture is poured into 500 ml of water and the separated substance is separated. This is taken up in methylene chloride, the solution is washed with water, dried over sodium sulphate and evaporated. 8.6 g of crude product is obtained. Crystallization from ether and recrystallization from methanol gives 4.4 g of pure 7-chloro-5-(o-chlorophenyl)-1, 3-dihydro-1-(methoxymethyl)-2H-1,4-benzodiazepine-2-one with s.p. 139-140°.

EXAMPLE 2

According to the method described in example 1, 7.9 g of 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepine-2-

on with 2 g of sodium methylate and 3.1 g of chloromethyl methyl ether in 50 ml of dimethylformamide 9.5 g of crude product. This is chromatographed on 200 g of silicon 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-chloro-phenyl)-1,3-dihydro-1-(methoxymethyl)-7-nitro-2H-1,4-benzodiazepine-2-one with m.p. 136 - 137°.

EXAMPLE 3

The reaction of 7.2 g of 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one with 2 g of sodium methylate and 3.1 g of chloromethyl methyl ether in 50 ml of dimethylformamide gives after normal processing 7.5 g raw product. From there can by chromatography on

200 g of silicon gel with 20% ethyl acetate in methylene chloride 4.4 g of uniform 7-chloro-1,3-dihydro-5-(o-fluorophenyl)-1-(methoxymethyl)-2H-1,4-benzodiazepine-2-one are isolated , as crystallized from ether and recrystallized from methanol melts at 113 r- 114°c.

EXAMPLE 4

To a cooled to -20° solution of 14 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one in 150 ml of dimethylformamide, 4 g of sodium methylate are added. After stirring for 10 minutes at -10, it is cooled to -50 and over the course of 5 minutes, 7 g of chloromethylethyl ether are added dropwise. After the addition, the temperature is allowed to rise over 30 minutes to -20°. The reaction mixture is stirred in with water, the precipitated resin is separated, dissolved in methylene chloride and the solution is washed with bicarbonate solution and water, dried over sodium sulphate and evaporated. The residue (17 g) is chromatographed on 300 g of silicon gel with 10% ethyl acetate in methylene chloride.

The uniform fractions crystallized from ether give, after recrystallization from alcohol, 6.5 g of 1-(ethoxymethyl)-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 105 - 107°.

EXAMPLE 5

A cooled to -10° solution of 13.5 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 150 ml of dimethylformamide is added with 5.4 g of sodium methylate and stirred for 10 minutes at -10° to 0°. It is then cooled to -40° and 9.5 g of 1-chloroethylmethyl ether is added dropwise over the course of 5 minutes. The temperature is allowed to rise over the course of 40 minutes to 0°. The usual work-up yields 15.5 g of crude product, which is chromatographed on 300 g of silicon gel with 10% ethyl acetate in methylene chloride. The uniform fractions crystallize from ether-hexane. Recrystallization from methylene chloride-hexane gives 7.5 g of 7-chloro-1,3-dihydro-1-(1-methoxyethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 131 - 132°.

EXAMPLE 6

A solution of 14 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one in 100 ml of dimethylformamide is cooled to -20° and 4 g of sodium methylate are added. After 10 minutes of stirring at -10°, the mixture is cooled to -50° and 7 g of 1-chloroethyl methyl ether is added dropwise over the course of 5 minutes. The temperature rises in the course of 30 minutes to -20° and the reaction mixture is prepared in the usual way. The obtained 1,3-dihydro-1-(1-methoxyethyl)-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one crystallizes from ether (8.5 g) and melts after recrystallization twice from methanol at 189 - 190°C.

. EXAMPLE 7

According to the method described in example 6, the alkylation of 28 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one in

200 ml of dimethylformamide with 8 g of sodium methylate and 16 g of 1-chloroethylethyl ether 13.5 g of product with a melting point of 170 - 173°. After recrystallization from alcohol, 1-(1-ethoxyethyl)-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one melts at 17 2 - 174°C.

EXAMPLE 8

In an analogous manner to example 6, one obtains by reacting 28.1 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one in 200 ml of dimethylformamide with 8 g of sodium methoxide and 16.2 g of chloromethylpropyl ether after chromatography of the crude product on 500 g of silicon gel with 5% ethyl acetate in methylene chloride 17.1 g of 1,3-dihydro-7-nitro-5-phenyl-1-(propoxy-methyl)-2H-1 ,4-benzodiazepine-2-oh, which after recrystallization from alcohol melts at 73 - 76°C.

EXAMPLE 9

The alkylation of 28.1 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one dissolved in 200 ml of dimethylformamide with 8 g of sodium methoxide and 22.6 g of chloromethylhexyl ether gives, after chromatography on 600 g silica gel with 10% ethyl acetate in methylene chloride 18.6 g 1,3-dihydro-1-(hexyloxymethyl)-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one, as crystallized from ether

melts at 108 - 109°C.

EXAMPLE 10

To a cooled to -20° solution of 28.1 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one in 150 ml of dimethylformamide, 8 g of sodium methoxide are added. In the course of 5 minutes, it is stirred at this temperature and cooled to -50°. At -50° to -40°, 19.3 g of chloromethyl-2-chloroethyl ether are added dropwise. After the addition, the temperature is allowed to rise over 15 minutes to -20°. While stirring, 500 ml of water is poured in, the precipitated material is separated and taken up in methylene chloride. The methylene chloride solution is evaporated after drying over sodium sulphate and the residue is crystallized from alcohol. The aspirated crystals are washed with alcohol and ether and dried. After recrystallization from alcohol, 1-[(-2-chloroethoxy)-methyl]-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 97 - 99 is obtained °C.

EXAMPLE 11

The reaction of 27.1 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 300 ml of dimethylformamide with 8 g of sodium methoxide and 19.3 g of chloromethyl-2-chloroethyl ether gives under the conditions described in Example 10, 15 g of 7-chloro-1-[(2-chloroethoxy)methyl J-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 96 crystallized from methanol - 98°C.

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

EXAMPLE 12

A solution of 14.5 g of 7-chloro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-one in 50 ml of dimethylformamide is cooled to -20° and 4 g of sodium methoxide are added . It is stirred for 5 minutes at this temperature and then cooled to -50°. After dropping in 7 g of chloromethyl-2-chloroethyl ether, the temperature is allowed to rise within 15 minutes to -20° and worked up as usual. The crude product is chromatographed on 250 g of silicon gel with 10% ethyl acetate in methylene chloride. The uniform fractions give, after crystallization from ether, 8.6 g of pure 7-chloro-1-[(2-chloro-ethoxy)-methyl']-5-(o-chlorophenyl)-1,3-dihydro-2H-1, 4-benzodiazepine-2-one with melting point 92 - 93°. Another crystal modification melts at 131 - 133°C.

EXAMPLE 13

25 ml of 15% peracetic acid is added dropwise to a solution cooled to -10° of 7 g of 1,3-dihydro-1-]_(methylthio)methyl]-7-nitro-5-phenyl-2H-1,4-benzodiazepine -2-one in 80 ml of methylene chloride. After addition, stir for 15 minutes at -10°. The reaction mixture is washed with 10% soda ash solution, the methylene chloride phase is separated, dried and evaporated. Crystallization of the residue from ethyl acetate gives 5.5 g of 1,3-dihydro-1-[(methylsulfinyl)-methyl]-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 190-192 °C.

EXAMPLE 14

A solution of 10 g of 7-chloro-1,3-dihydro-1-[(methylthio)-methylj-5-phenyl-2H-1,4-benzodiazepine-2-one in 100 ml of methylene chloride is cooled to -10° and added dropwise with 15 ml of 40% peracetic acid. After 15 minutes, the reaction mixture is washed with 10% soda ash solution, dried and evaporated. Chromatography of the residue on 200 g of silicon gel with 10% alcohol in ethyl acetate gives, after crystallization from ethyl acetate/hexane, 7.5 g of 7-chloro-1,3-dihydro-1-[(methylsulfinyl)methyl]-5-phenyl-2H-1 ,4-benzodiazepine-2-one with melting point 158 - 159°C.

EXAMPLE 15

To a solution cooled to -20° of 7.5 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-1-[(methylthio)methyl]-2H-1,4-benzodiazepine-2- 5 ml of 40% peracetic acid is added dropwise to 50 ml of methylene chloride. After 10 minutes, the reaction solution is washed out with a 10% soda solution, dried over sodium sulfate and evaporated. Crystallization of the residue from ethyl acetate ether gives 4 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-1-[(methylsulfinyl)methyl]-2H-1,4-benzodiazepine-2-one, which after recrystallization from ethyl acetate-ether melts at 150 - 15 2°C.

The starting products used in examples 13, 14 and 15 can be prepared as follows: a) To a solution cooled to -10° of 28 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine- 2-one in 100 ml of dimethylformamide is added 8 g of sodium methoxide. It is stirred for 15 minutes

-10° and then cooled to -30°. At this temperature, 17 g of chloromethyl-methylsulphide are added dropwise and stirred after addition without cooling for 4 hours. The reaction mixture is poured into 500 ml of water and 25 ml of 2-n acetic acid. The aqueous solution is decanted from the precipitated resin. This is taken up in methylene-

chloride, the solution is washed with water, dried over sodium sulphate and evaporated. After chromatography on 500 g of silicon gel with the solvent system methylene chloride:ethyl acetate 4:1, the residue gives 8 g of 1,3-dihydro-1-[(methylthio)methyl]-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2 -on with melting point 139 - 140°C. After recrystallization from alcohol, the sulfide melts at 142 - 143°C. b) To a solution cooled to -10° of 27 g of 7-chloro-1,3-dihydro^-phenyl-2H-1,4-benzodiazepine-2-one in 300 ml of dimethylformamide, 8 g of sodium methoxide are added. After 10 minutes, 17 g of chloromethyl-methylsulphide are added dropwise. After it has been stirred for 2 hours without cooling, 8 g of sodium methylate and 17 g of chloromethyl-methyl sulphide are added in sequence at -10°. The solution is allowed to stir for a further 2 hours without cooling and the reaction mixture is poured into 1 liter of water and 50 ml of 2-n acetic acid. The crude product obtained after normal work-up is chromatographed on 500 g of silicon gel with 10% ethyl acetate in methylene chloride. It is obtained by crystallization of the homogeneous fractions from ether-hexane 9.5 g 7-chloro-1,3-dihydro-1-[(methyl-thio)methyl]-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 115 - 117 °C. c) A solution cooled to -10° of 15 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one in 150 ml of dimethylformamide is added with 5 g of a 50% suspension of sodium hydride in mineral oil. The solution is allowed to stir for 15 minutes and then 10 g of chloromethyl-methyl sulfide is added. After 1 hour, the mixture is poured into 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 silicon gel with 20% ethyl acetate in methylene chloride. The uniform fractions give, after crystallization from ether, 12.2 g of 7-chloro-. 5-(o-chlorophenyl)-1,3-dihydro-1-[(methylthio)methyl]-2H-1,4-diaze-pin-2-one, which melts after recrystallization from ethyl acetate hexane at 127 - 129°C .

E X E M P E L 16

A) Production of output products

A solution of 28.7 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one-4-oxide in 200 ml of dimethylformamide is added at -20° with 8.1 g sodium methoxide and stir for 5 minutes. By

-20°, 12 ml of chlorodimethyl ether are added dropwise while stirring. After the addition, the solution is allowed to stir for a further 30 minutes without cooling. The reaction mixture is poured onto 1 1 water and processed as usual. Crystallization of the crude product by grafting methanol-ether yields 11.5 g of 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one-4- oxide, which after recrystallization from alcohol melts at 164 - 166°C. Seed crystals are obtained by chromatography on silicon gel with the solvent system methylene chloride:ethyl acetate 1:1. 75 ml of 40% peracetic acid is added to a solution of 50 g of 1,3-dihydro-1-(methoxymethyl-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one in 300 ml of methylene chloride. After After standing for 24 hours at room temperature, the solution is washed out with 10% soda ash solution, dried over sodium sulfate and evaporated. Crystallization of the residue from methylene chloride-ethyl acetate gives 40 g of 1,3-dihydro-1-(methoxymethyl)-7-nitro-5-phenyl-2H -1,4-benzodiazepine-2-one-4-oxide, which after recrystallization from the same solvent mixture exhibits a melting point of 212 - 215° C. B) Further processing of the above-mentioned starting products.

17.5 g of 1,3-dihydro-1-(methoxymethyl)-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one-4-oxide are heated in a mixture of 180 ml of acetic anhydride and 300 ml of toluene 'for boiling. It is distilled from 200 ml of the solvent mixture within 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-benzodiazepine-2-one, as recrystallized from ethyl acetate-hexane melts at 163 - 165°C.

A solution of 26 g of 3-acetoxy-1,3-dihydro-1-methoxymethyl)-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one in 400 ml of tetrahydrofuran and 200 ml of methanol is added dropwise at -20° with 70 ml of 2-n caustic soda. After the addition, it is stirred for 15 minutes, the addition of glacial acetic acid at pH 6 is debuffered and concentrated in vacuo. The residue is distributed between water and methylene chloride, the methylene chloride phase is dried and evaporated. Crystallization of the crude product from methylene chloride-ether gives 20 g of 1,3-dihydro3-hydroxy-1-(methoxymethyl)-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 160 - 162°C .

The above carried out reaction of 3.3 g of 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one-4-oxide with 30 ml of acetic anhydride in 50 ml of toluene and crystallization of the crude product from ether gives 2.6 g of 3-acetoxy-7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 130 - 132°C. After recrystallization from ether, the product melts at 131 - 133°C.

6.3 g of 3-acetoxy-7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one are dissolved hot in 200 ml of methanol. After cooling, 1.8 g of sodium methoxide is added. After 15 minutes, add 2.5 ml of glacial acetic acid and evaporate in a vacuum. The remainder is distributed between methylene chloride and bicarbonate solution,

the methylene chloride solution is dried and evaporated. Crystallization from alcohol gives 4.4 g of 7-chloro-1,3-dihydro-3-hydroxy-1-(methoxy-methyl)-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 138 - 139 °C-.

EXAMPLE 17

0.8 g of sodium hydride suspension (50% in mineral oil) is introduced into a solution cooled to -10° of 3.42 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2 -one-3-carboxylic acid ethyl ester in 30 ml of dimethylformamide. After stirring for 30 minutes at -10°, cool to -40° and add 1.3 ml of chlorodimethyl ether.

The temperature is allowed to rise over the course of 30 minutes to -10°

and rather the reaction mixture of 100 ml of water and 10 ml of 2-n acetic acid. The precipitated product is separated and taken up in methylene chloride. The dried methylene chloride solution is evaporated and the residue crystallized from methylene chloride ether, (1.6 g). 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one-3-carboxylic acid ethyl ester is obtained, which after recrystallization from methylene chloride-ether melts at 161 - 164°C. ■

EXAMPLE 18

To a solution of 0.5 g of sodium in 50 ml of absolute alcohol is added a solution of 9.7 g of 7-chloro-1,3-dihydro-1-(methoxy-methyl)-5-phenyl-2H-1,4 -benzodiazepine-2-one-3-carboxylic acid ethyl ester in 50 ml abs. tetrahydrofuran. At 10 - 15°, a dry stream of air is introduced into the stirred solution for 4 hours. After adding 2 ml of glacial acetic acid, concentrate in vacuo and the remainder is distributed between water and methylene chloride. The methylene chloride phase is separated, dried over sodium sulphate and evaporated. The residue yields on crystallization from alcohol 7.7 g of 7-chloro-1,3-dihydro-3-hydroxy-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one-3-carboxylic acid ethyl ester with melting point 187 - 189°C.

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

0.5 g of this salt is boiled in 10 ml of glacial acetic acid for 10 minutes under reflux. After evaporation in a vacuum, the residue is distributed between bicarbonate solution and 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-3-hydroxy-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 136 - 138 °C.

EXAMPLE 19

To a solution cooled to -10° of 28 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one in 150 ml of dimethylformamide is added 10.8 g of sodium methoxide. 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, the temperature is allowed to rise for 30 minutes to 0° and the reaction mixture is poured into 1 liter of water. The separated resin is decanted from. This is taken up in methylene chloride, the solution is washed with water, dried over sodium sulphate and evaporated. The residue is taken up in ether, as the starting material crystallizes out. The evaporated mother liquor is chromatographed on 500 g of silicon gel with 5% acetate in methylene chloride. Crystallization of the uniform fractions from alcohol yields 10.6 g of 1,3-dihydro-7-nitro-5-phenyl-1-[(2,2,2-trichloroethoxy)methyl]-2H-1,4-benzodiazepine -2-one with melting point 113 - 118°C.

EXAMPLE 20

A mixture of 14 g of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one, 50 ml of glacial acetic acid and 20 ml of ethyl vinyl ether is boiled for 5 hours under reflux. The reaction mixture is evaporated in vacuo and the residue is dissolved in methylene chloride. This solution is washed out with a 10% soda solution, dried and evaporated. Crystallization of the residue from methylene chloride-ether returns 10 g of starting material. The mother liquor is evaporated and the residue is chromatographed on 100 g of silicon gel with 20% acetate in methylene chloride. Crystallization from ether yields 0.65 g of 1-£(1-ethoxy)ethyl]-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one with melting point 170 - 173°C.

Claims (1)

Analogy method for the production of therapy tically active benzodiazepine derivatives of the general formula where R^ means halogen or nitro, 1*2 phenyl or halophenyl, R_ hydrogen or lower alkyl, R^ lower alkoxy, lower haloalkoxy or lower alkylsulfinyl, and R^ hydrogen or hydroxy, wherein R2 means halophenyl when R^ means chlorine or nitro, R^ hydrogen, R^ methoxy and R^ hydrogen, as well as salts of these compounds, characterized by a) reacting a compound with the general formula where and R2 has the above meaning, or a 4-oxide thereof, with a compound of the general formula where R^ has the above meaning, Rg means lower- alkoxy or lower-halo- alkoxy and X is halogen, or that one b) reacts a compound of the preceding formula II with a vinyl ether of the general formula where Rg means lower alkyl, or that one c) in a compound with the general formula where R^, R^, R^ and R^ have the meaning stated above and R18 Detvr a-alkylthio, oxidizes the alkylthio group to alkylsulfiny, or that one d) cyclizes a compound with the general formula where R^, R2/R3 and R^ have the meanings indicated above, or that one e) hydrolyzes a compound with the general formula where Rlf <R>2, R3 and <R>4 have the meanings indicated above and R20 means an acyl group, or that one f) deoxidizes a compound with the general formula where R^, R2 < R^ and Rg have the meanings indicated above, or that one g)' dehydrates a compound with the general formula where R^, R 2 and R 3 have the above meaning and R 22 means lower alkoxy, or that one h) oxidizes or dehydrogenates a compound with it , general formula where R^-, R2/R3 and R22 have the meanings given above, at the 4,5-bond, or that one i) saponifies and decarboxylates a compound with the gene- real formula where R 2 , R 2 , R 2 , R 2 and R 2 have the above meanings and R 26 is lower alkyl, or that one k) transfers a compound with the general formula .: where R^, R 2 , R 3 and R 22 have the above meaning and <R> 28 means acyl, with a base to the corresponding 4,5-dehydro compound, or that one 1) transfers a compound with the general formula . where R^, R 2 and R 3 have the above meaning, R 3 Q means a mesyl or tosyl group and R 2 lower alkoxy or alkylsulfinyl, with a strong base to the corresponding 4,5-dehydro compound, or that one m) rearranges a compound with the general formula where R^, R2, R^ and R^ have the meanings given above, to the corresponding 4,5-dehydro compound, and that one if desired, converts an obtained compound into a salt.