DE2050899A1 - Diarylmethane derivatives - Google Patents

Description

The present invention relates to diarylmethane derivatives, namely compounds of the general formula

N-B-CHg-NH-R,

wherein R _{1 is} halogen, nitro or trifluoromethyl, Rp is hydrogen, lower alkyl, lower hydroxyalkyl or lower dialkylaminoalkyl, R, hydrogen or lower alkoxy carbonyl, R ^, and Rp. each lower alkoxy or together a lower alkylenedioxy group or - if R, for lower Alkoxycarbonyl together represent an oxo group, A is phenyl, halophenyl or pyridyl and B is a carbonyl or methylene group

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mean,

and acid addition salts of basic compounds of the formula I.

The term "lower alkyl" refers to a straight chain or branched hydrocarbon radical with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isobutyl and like that. The term "lower hydroxyalkyl" refers to alkyl groups of 2-3 carbon atoms represented by a Hydroxy group are substituted, such as 2-hydroxyethyl, 3-hydroxypropyl etc. Under "lower dialkylaminoalkyl groups" are to be understood as meaning alkyl groups containing 2-3 carbon atoms, which carry a nitrogen atom substituted by two alkyl groups with 1-4 carbon atoms, such as diethylaminoethyl, Di-methylaminopropyl and the like. The term "lower alkoxy" - taken alone or in combination "Lower alkoxycarbonyl" - refers to an alkyloxy group having 1-4 carbon atoms such as methoxy, ethoxy etc. The term "lower alk, / xenedioxy" refers to a radical of the formula -Ö-Älkylen-O-, in which the alkylene group is straight or branched and contains 2 to 6 carbon atoms. The term "lower hydroxyalkoxy" denotes an alkoxy group having 2 to 6 carbon atoms substituted by a hydroxyl group. Unless otherwise stated, "Halogen" means the four halogens fluorine, chlorine, bromine and iodine.

Among the compounds of the formula I, preference is given to those in which R is halogen (in particular chlorine or bromine) or a nitro group. R ₂ is preferably hydrogen or a methyl, hydroxyethyl, dimethylaminoethyl or diethylaminoethyl group. A preferably denotes phenyl, o-halophenyl (in particular o-chlorophenyl or o-fluorophenyl) or 2-pyridyl, and R4 and R ^ are preferably each methoxy or ethoxy or together an ethylenedioxy or oxo group.

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2050893

If R., stands for lower alkoxycarbonyl, it is preferably a methoxycarbonyl or ethoxycarbonyl group.

Representative Examples of Preferred Compounds

of formula I.

Methyl {[(2-benzoyl-4-chlorophenyl) methyloarbamoyl] methyl} carbamate ' Methyl {[^ -benzoyl ^ -nitrophenyl) methylearbajnoyl methyl} carbamate j Methyl 5 (/ 5-chloro-2- (o-fluorobenzoyl) phenyVniethylcarbamoyl] methyli carbamate;

2-Amino-4'-chloro-2 '- (α, α-diethoxybenzyl) -N-methylacetanilidej N- [4-chloro-2 (α, α-dimethoxybenzyl) phenyl] -N-methylethylenediamine; Methyl {[/ 2- (o -chlorobenzoyl) -4-nitropheny / methylcarbamoyl] methyl} carbamate.

The compounds of the formula I and the acid addition salts of basic compounds of the formula I can according to the invention be made by one

a) for the preparation of a compound of the formula I in which R 1 is lower alkoxycarbonyl, a compound of the general formula

II

wherein R ,, R ", A and B have the meaning given in formula I and Rg is lower alkyl and R _{7 is} hydroxy, lower alkoxy or lower hydroxyalkoxy,

with aqueous acid or, if R _{7 is} lower alkoxy, under anhydrous conditions with an acid and a lower alkenol or, if R _{7 is} lower hydroxyalkoxy,

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treated with an acid under anhydrous conditions or b) for the preparation of a compound of the formula I in which R, lower alkoxycarbonyl means a compound of the general formula

III

where R,

R ₂ ,, R _r and A are indicated in formula I

,, Rp, R ₂ ,
have the same meaning
with a compound of the general formula

X_B-CHg-NH-CO

IV

where B is in formula I and R ^ is in formula II have given meaning and X stands for a halogen atom stands,

implements or

c) for the preparation of a compound of the formula I in which R 1 is hydrogen, from a compound of the general formula

Β — CH ^ -Y

wherein R ,, Rp, B and A are those given in formula I. Have meaning, Rg and R ~ each lower alkoxy or together denote a lower alkylenedioxy group and Y denotes a cleavable by one

Group protected nitrogen atom, 109822/226 ^

splits off the protective group or

d) for the preparation of a compound of the formula I in which B is a carbonyl group and Rp is lower alkyl, lower hydroxyalkyl or lower dialkylaminoalkyl, a corresponding compound of the formula I in which B is a carbonyl group and Rp are hydrogen, with a corresponding one Alkylating, hydroxyalkylating or dialkylaminoalkylating agents treated or

e) for the preparation of a compound of the formula I in which R _{2 and R 1} together represent an oxo group, in a corresponding compound of the formula I in which R 1 and R ^. each mean lower alkoxy or together a lower alkylenedioxy group, the ketal group cleaves or under acidic conditions

f) for the preparation of a compound of the formula I in which R 1 is hydrogen, a compound of the general formula

VI

wherein R ₁ , R «, A and B are those in formula I and R _Q and

Xd O

Rq have the meaning given in formula V and Z stands for the acid residue of a reactive ester,
reacts with ammonia or

g) for the preparation of an acid addition salt of a basic compound of the formula I with a corresponding free base treated with an inorganic or organic acid.

According to a first variant of the process, compounds of the formula I in which R 1 is lower alkoxycarbonyl can start from benzodiazepine derivatives of formula II above.

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If a compound of the formula II is treated for a short time at elevated temperature (for example 80 °) with aqueous acid, for example with about 4 to 8 N hydrochloric acid and the like, a compound of the formula I is obtained in which R- * lower alkoxycarbonyl and R ₂ , and R ₁ . together represent an oxo group.

If the starting material used is a compound of the formula II in which R _{7 is} lower alkoxy (eg 5-ethoxy-7-chloro-1,2,5,5-tetrahydro-1-methyl-5-phenyl-4H-1,4 -benzodiazepine-4-carboxylic acid methyl ester) and if this is treated in a ^ anhydrous lower alkenol with an anhydrous acid, such as hydrogen chloride and the like., A compound of the formula I is obtained in which R ^ lower alkoxy carbonyl and R ₂ , and Rc each mean lower alkoxy. Depending on the nature of the lower alkoxy group R ₇ in the starting product of the formula II and the lower alkanol used, compounds of the formula I can be obtained in this way in which R ₂ . and R are either the same or different lower alkoxy groups.

If a compound of the formula II in which R _{7 is} a lower hydroxyalkoxy group is used as the starting product, and this is treated under anhydrous conditions with an acid (eg hydrogen chloride), the lower alkylene glycol corresponding to the radical R "is preferably used as the solvent If an organic solvent which is inert under the reaction conditions is used, the reaction product obtained is a compound of the formula I in which R, lower alkoxy carbonyl and R ₂ , and R_ together represent a lower alkylenedioxy group, such as methyl [2- [4-chloro-N -methyl-2- (2-phenyl-1,2; 5-dioxolan-2-yl) anilino] äthyljearbaa * t.

If only very small amounts of water are present in the two last-mentioned embodiments, at least all by-products are obtained compounds of the formula I in which R- * is lower alkoxy carbonyl and R ₂ ^ and R ₅ together are an oxo group

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mean.

In a second variant of the process, compounds of the formula I in which R 1 is lower alkoxycarbonyl can thereby be prepared by reacting a compound of the above formula III with a compound of the above formula IV. The compound of formula III used is, for example, S-chloro ^ -methylaminobenzophenone diethylacetal, 5-chloro-2-methylaminobenzophenone, 2-amino-2'-fluoro-5-nitrobenzophenone, 2-amino-2'-chloro-5-nitrobenzophenone, 2-amino-5-chlorobenzophenone etc. The symbol X in formula IV stands for a leaving group in the treatment with the compound of the formula ΙΠ emerging halogen atom, preferably for chlorine, bromine or iodine. The reaction conditions for the implementation of the compounds of the formulas III and IV depend primarily on the nature of the reaction component of the formula IV.

If a compound of the formula IV is used in which B is a carbonyl group (such as N-carbomethoxyglyein chloride), so you can proceed, for example, that the compound of formula III in the presence of a suitable organic Solvent and a base, while cooling and stirring, slowly added the compound of the formula IV mentioned and after the addition has ended, the mixture is stirred for some time (e.g. for 1 to 15 hours) at room temperature. This is used as a solvent, for example, a chlorinated hydrocarbon, such as methylene chloride, and as Base e.g. sodium bicarbonate, which can be used in the form of an aqueous solution and / or in solid form. the The compound of the formula I formed is isolated by working up the reaction mixture in a customary manner. According to another embodiment, you can connect the Formula III, for example, in a chlorinated hydrocarbon such as methylene chloride, dissolve or slurry the compound mentioned add the formula IV and the mixture after addition

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small amounts (generally a few drops) of a polar aprotic solvent such as dimethylformamide, evaporate slowly, the dl * desired compound of the formula Ϊ remaining as a residue.

If a compound of the formula IV in which B is a methylene group is used, it can react with the starting product of the formula III take place in the presence of a base in an inert organic solvent. As bases Both inorganic bases, such as sodium acetate, and organic bases, such as triethylamine and pyridine, are suitable for this purpose and the like. Examples of suitable solvents are lower alkanols (such as methanol, ethanol, propanol and the like), aromatic ones Hydrocarbons (such as benzene, toluene, xylene and the like), open-chain or cyclic ethers (such as diethyl ether, Tetrahydrofuran, dioxane and the like), as well as amides (such as dimethylformamide and the like). If a compound of the formula IV is used in which X is chlorine or bromine, it can be as prove advantageous to add sodium iodide to the reaction mixture, to replace the chlorine or bromine atom with the more reactive iodine atom. The reaction temperature is with Advantageously in the interval between about room temperature and the reflux temperature of the reaction mixture, preferably in the upper limit of this interval.

According to a further process variant, compounds of the formula I in which R 1 denotes hydrogen can thereby be obtained be prepared that one of a compound of the above formula V, which has a protected nitrogen atom in the side chain has, splits off the protective group. Any common protective group is suitable as a protective group, which can be split off under conditions in which other groups! ■ molecule is not affected will. Protective groups that can be split off under alkaline conditions, for example lower alkoxy groups, are particularly suitable

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carboxyl groups such as methoxycarbonyl, ethoxycarbonyl and the like, or other suitable acyl groups; the protecting group can also form a ring with the nitrogen atom, such as a phthalimido or "succinimido group, etc."

An acyl group is split off by alkaline hydrolysis and is advantageously carried out, for example, that the compound of formula V in a water-miscible polar aprotic organic solvent, such as e.g. dimethyl sulfoxide and the like, treated with aqueous alkali, for example with 0.5- ^ N sodium hydroxide solution. temperature and pressure are not critical here; the reaction can be carried out, for example, at room or elevated temperature (preferably at the reflux temperature of the reaction mixture) and under normal pressure, the duration of the reaction of course largely on the reaction temperature and on the nature of the protective group to be split off and the alkaline agent used.

A phthalmido group is advantageously by Split off hydrazinolysis. Here you take a connection, for example of the formula V, in which Y is a phthalimido group, in a suitable organic solvent, such as dioxane, , add hydrazine hydrate and let the mixture stand for some time at about room temperature.

According to a further variant of the process, compounds of the formula I are obtained in which B is a carbonyl group and Rp lower alkyl, lower hydroxyalkyl or lower dialkylaminoalkyl mean by a corresponding compound of the formula I, in which Rp is hydrogen, with a corresponding Alkylating, hydroxyalkylating or dialkylamirioalkylating agents implements. Suitable alkylating agents are, for example, lower alkyl halides, such as Me thy L J od Ld etc., riLedere dialkyl sulfates, such as dimethyl sulfate

i Ci :,; 2 2 / ? 2 6 4

etc., lower alkyl esters of alkyl or aryl sulfonic acids, for example methyl p-toluenesulfonate and the like. Ethylene oxide may be mentioned as an example of a hydroxyalkylating agent. Examples of dialkylaminoalkylating agents used are lower dialkylaminoalkyl chlorides, such as diethylaminoethyl chloride, dimethylaminopropyl chloride, etc., lower dialkylaminoalkyl esters of alkyl or aryl sulfonic acids and the like. The reaction with the alkylating, hydroxyalkylating or dialkylaminoalkylating agent is carried out under those reaction conditions in which any terminal primary amino group in the side chain is not attacked or is attacked only insignificantly, advantageously under alkaline conditions, for example in the presence of alkali hydrides, such as Sodium hydride, alkali alkoxides, such as sodium methoxide and the like. In a solvent suitable for such reactions, such as dimethylformamide and the like. The temperature and pressure are not critical for this process variant, and the reaction can take place at room temperature, below this or at elevated temperature.

According to a further variant of the process, compounds can be used of formula I, wherein R, lower alkoxy carbonyl and R ^,

and Rp- each lower alkoxy or together a lower alkylenedioxy group mean, in corresponding compounds of the formula I in which Rh and R ^ together mean an oxo group, convert. For this purpose, the ketal group in the alkoxy or alkylenedioxy compounds is cleaved under acidic conditions, what after the usual methods for such ketal cleavages can be done, for example, by treatment with an aqueous mineral acid, such as dilute hydrochloric or sulfuric acid.

According to a further process variant, compounds of the formula I are prepared in which R ^ is hydrogen means by reacting a compound of the above formula VI with ammonia. The symbol Z in Formula VI stands for one at

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the treatment with ammonia as a leaving group leaving acid residue of a reactive ester, for example flir Chlorine, bromine or iodine, for an alkylsulfonyloxy group (such as methanesulfonyloxy) or for an arylsulfonyloxy group (such as Benzene, p-bromobenzene or p-toluenesulfonyloxy) etc. The The compound of the formula VI is reacted with the ammonia with advantage in an inert organic solvent e.g. in a lower alkanol such as methanol, ethanol and the like, in a high-boiling ether such as tetrahydrofuran, dioxane and the like or in methylene chloride, dimethyl sulfoxide, dimethylformamide, Diethylformamide, etc. The reaction medium does not need to be anhydrous, however, and ammonia can be used use for example in the form of a (preferably concentrated) aqueous solution. It is also possible to use the ammonia use in liquid form. If a compound of the formula VI is used as the starting product, in which Z is chlorine, bromine, Alkylsulfonyloxy or arylsulfonyloxy and the like means, so it can prove to be advantageous, the reaction mixture Add sodium iodide to replace the Z substituent with the more reactive iodine atom. When implementing the Compounds VI with ammonia release acid, which is bound by the excess ammonia used. temperature and pressure are not critical, but depend on each other and on the other reaction conditions. So you can e.g. do not exceed the boiling temperature of ammonia, if one works at normal pressure and the ammonia is to be used in liquid form without the addition of a solvent If the reaction takes place at a higher temperature, e.g. at room temperature, a suitable solvent must be added and / or work under pressure in a closed vessel.

Those compounds of the formula I which are basic substances can by generally known methods Reaction with inorganic or organic acids in

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Speaking salts are transferred, especially in pharmaceutical usable acid addition salts. Examples of inorganic and organic acids which are pharmaceutically usable Forming salts are hydrogen chloride, hydrogen bromide, sulfuric acid, acetic acid, succinic acid, maleic acid, p-toluenesulfonic acid, etc.

The compounds of the formula II used as starting materials are new and are also used by the present Invention includes. You can choose from corresponding benzodiazepine derivatives of the general formula

VII

wherein R ₁ , Rp, B and A have the meaning given in formula I,
getting produced.

If a compound of the formula VII is reacted in the presence of water (for example in a mixture of an organic solvent such as benzene, methylene chloride, etc. and an aqueous sodium bicarbonate solution) with a lower alkyl ester of chloroformic acid, a compound of the formula II is obtained in which R "means a hydroxyl group. On the other hand, if the compound of the formula VII is treated under anhydrous conditions with a lower alkyl ester of chloroformic acid and a lower alkanol or alkylene glycol, a compound of the formula II is obtained in which R ₇ is a lower alkoxy or hydroxyalkoxy group. The resulting compounds of the formula II must and cannot, however, be used in every case

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summarized or isolated, since they often directly into the under the reaction conditions used for their preparation open-chain compounds of the formula I in which IU is lower Alkoxycarbonyl means can pass over.

Compounds of the formula III in which Rj, and R, - together represent an oxo group belong to a known class of compounds. The corresponding compounds of the formula III, in which Rj, and R ₁ - each mean lower alkoxy or together a lower alkylenedioxy group, are obtained from the oxo compounds just mentioned by treating them in a known manner with an orthoformate (e.g. triethyl orthoformate) in a lower alkenol ( for example methanol or ethanol) or in a lower alkylene glycol, it being expedient that catalytic amounts of acid, for example concentrated sulfuric acid, are present. In the 2-formylaminoaryl ketal obtained, the formyl group is removed by alkaline hydrolysis, for example with sodium or potassium hydroxide solution in dimethyl sulfoxide.

One method of making compounds of Formula V is that you have a compound of the above Formula III with a compound of the formula

_z β -CH75- Y VIII

where Z and Y have the above meanings, i.e. reacts with phthalimidoacetyl chloride, for example. Compounds of the formula V are likewise obtained by reacting a compound of the above formula VI in which Z is a Halogenaton means with phthalmal potassium and the like.

Compounds of the formula V in which Y is benzyloxycarbonyl are also obtained according to that described above

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205C899

Process using compounds of formula VII and benzyl chloroformate as starting materials.

Compounds of the above formula VI are obtained, for example, by reacting a compound of the above formula III with a compound of the formula

X ¹¹ B CHp Z IX

wherein X and Z have the above meanings.

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.- ■ ** .- 2Ü5C899

Suitable compounds of the formula IX are, for example, 1,2-dichloroethane, chloroacetyl chloride, bromoacetyl bromide, methanesulf onyloxyacetyl chloride, benzenesulfonyloxyacetyl bromide, p-toluenesulfonyloxyacetyl chloride and the like. In the preparation of a compound of the formula VI, in which Z is a carbonyl group, can be used in place of a compound of Formula IX also an anhydride of a carboxylic acid of the formula

HOOC-CH ₂ -ZX

wherein Z has the above meaning, use, for example, chloroacetic anhydride.

The compounds of general formula I and their pharmaceutically acceptable salts are distinguished by sedative, anticonvulsant, muscle relaxing and / or anxiolytic properties.

The anticonvulsant activity is demonstrated when mice which have been administered compounds of the formula I or their salts are subjected to the pentamethylenetetrazole test. For example, the methyl shows | [(2-benzoyl-4-chloropheny 1) -me thy lc arbamoyl] me thy lj; carbamate, which in the mouse has an LD ^ ₀ between 1250 and 2500 mg / kg Ρ · ο. (24 hour value) has an APR 2.0 of 5 mg / kg pol under APR 2.0 is the dose in mg / kg of an anticonvulsant which causes double the pentetrazole consumption compared to the untreated control group]. In the same experiment, 2-Amino-4 ^! -chlor-2 '- (a, a-diethoxybenzyl) -N-methylacetanilide, which has an LD, - ₀ of 2500 mg / kg (po), an APR 2.0 of 8 mg / kg (po). In contrast, phenobarbital, a common anticonvulsant, shows an APR 2.0 of 30 mg / kg.

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-> * ■ - 205CÖ99 ·

The muscle-relaxing effectiveness can be demonstrated in a test on a rotating rod. For example, the above-mentioned methyl {((2-benzoyl-4-chlorophenyl) -methylcarbamoyl] -methyl ^ -carbamate when administered to mice shows an HD ™ of 5 mg / kg po and the 2-amino-4'-chloro 2 ^l - (a, a-diethoxybenzyl) -N-methylacetanilide a Ηϋ _ΚΓ . Of 15 mg / kg (po)

Compounds of the formula I and their pharmaceutically applicable salts can therefore be used as medicaments, for example in the form Pharmaceutical preparations find use, which they or their salts in a mixture with a for the 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, rubber, polyalkylene glycols, petroleum jelly, etc. contain. The pharmaceutical preparations can be in solid form, e.g. as tablets, coated tablets, suppositories, capsules, or in in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries such as preservatives, stabilizers, Wetting or emulsifying agents, salts to change the osmotic appearance Pressure or buffer. They can also contain other therapeutically valuable substances. Appropriate pharmaceutical Dosage forms contain approximately 1 to 200 mg of a compound of the formula I. Dosage is individual Requirements, however, when administered to mammals, a dosage of about 0.1 mg / kg to 5 mg / kg p.o. and 0.01, respectively mg / kg to 0.5 mg / kg i.v. per day preferred.

The following examples illustrate the invention. All temperatures are given in degrees Celsius (uncorrected).

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example 1

24.4 g of 7-1H-1,4-benzodiazepine are dissolved in 200 ml of benzene and are added at room temperature 28 ml of methyl chloroformate are added and the mixture is stirred for 5 minutes at room temperature. The mixture is then cooled in an ice bath, treated with 200 ml of an approximately 10 # strength aqueous sodium bicarbonate solution and then overnight at room temperature touched. Sodium hydroxide solution is then added to the mixture until it has an alkaline reaction, and the benzene layer is separated from, the aqueous phase extracted with methylene chloride and combined these methylene chloride phases with the above Benzene layer. The combined organic phases are dried over magnesium sulfate, filtered and evaporated, whereby 32 g of a crude residue remain.

This residue is heated to 80 ° for a short time with 100 ml of 6N hydrochloric acid. The mixture is then cooled in an ice bath, add sodium carbonate until an alkaline reaction and extract with methylene chloride. The organic phase is dried over magnesium sulfate and evaporated, whereby methyl (2- (2-benzoyl-4-chloro-N-methylanilino) ethyl] carbamate remains as a residue; the compound is made from methanol / water recrystallizes and then melts at 82-83 °.

Example 2

48.6 g of 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine are dissolved in 400 ml of benzene. 56 ml of methyl chloroformate are then added and the mixture is stirred 5 minutes at room temperature, then leaves under ice cooling Add dropwise 400 ml of 10% sodium bicarbonate solution and stir the mixture over Naoht at room temperature. Afterward the benzene layer is separated off, once with 10% sodium bicarbonate solution and washed twice with water, then over

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Dried magnesium sulfate, filtered and evaporated. The residue is treated with absolute ether and the undissolved solid is filtered off; the pilter residue is washed 4-5 times with absolute ether and dried in vacuo. T-chloro-l ^^^ - tetrahydro-S-hydroxy-l-methyl-S-phenyl-4H-1,4-benzodiazepine-4-carboxylic acid methyl ester is obtained in the form of colorless crystals of melting point II5-II6 ⁰ .

By heating with hydrochloric acid and subsequent work-up in the manner described in Example 1, paragraph 2, methyl [2- (2-benzoyl-4-chloro-N-methylanilino) ethyl] carbamate of melting point 82-83 ° (according to Crystallization from methanol / W water).

Example 3

10 g of 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine, 30 ml of methanol and 11.5 ml of methyl chloroformate are mixed, the mixture is stirred at room temperature and obtained after 5 minutes a dark red solution. This solution is cooled in an ice bath, 6 ml of triethylamine are added, the mixture is stirred for one hour at room temperature, then 5 ml of methyl chloroformate are added and the mixture is then stirred for a further hour at room temperature. The mixture is then again cooled in an ice bath and slowly neutralized by adding about 20 ml of trimethylamine. For working up, the reaction mixture is poured into 400 ml of ice water, stirred for one hour and the crystalline product is filtered off. The crude methyl [2- [4-chloro-2- (a, a-dimethoxybenzyl) -N-methylanilino] ethyl} carbamate obtained in this way is recrystallized twice from methanol and then melts at 128-130 ×.

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Example 4

According to the information in Example 3, 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine is obtained by reaction with methyl chloroformate in ethylene glycol Methyl {2- ^ -chlor-N-methy 1-2- (2-phenyl-1,3-dioxolan-2-yl) anilino] ethyl carbamate. The obtained crude product is subjected to chromatography Purified on silica gel (elution with methylene chloride) and then recrystallized from methanol / water; Melting point 117-120 °.

Example 5

According to the information in Example 2, 7-ChIOr ^, ^ - dihydro-l-methyl-ij-phenyl-lH-l ^ -benzodiazepine, Ethanol and methyl chloroformate 5-ethoxy-7-chloro

carboxylic acid methyl ester, which after recrystallization Ethenol / dfasser melts at 126-128 °.

1.5 g of the above 5-ethoxy-7-chloro-1 ^, 3,5-tetrahydro-1-methyl-S-phenyl ^ H-1 ^ -benzodiazepine ^ -carboxylic acid methyl ester are dissolved in 20 ml of absolute ethanol, add 2 ml of saturated ethanolic hydrogen chloride solution and allow stand for half an hour. Ether is then added to the mixture by adding 10% aqueous sodium bicarbonate solution neutralized and shaken. The organic phase is separated off, washed with water, over Magnesium sulfate dried and evaporated. The remaining as residue methyl {2- (4-chloro-2- (a, a-diethyoxybenzyl) -N-methylanilino] ethyl carbamate is recrystallized from ethanol and then melts at 100-103 °.

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Example 6

.1 * 5 g S-

phenyl- ^ Hl ^ -benzodiazepine - ^ - carboxylic acid methyl ester (prepared according to the information in Example 5 from 7-chloro-l, 3-dihydro-5-phenyl-2H-l, 4-benzodiazepin-2-one, ethanol and chloroformic acid methyl ester) are stirred in 21 ml of absolute ethanol and 2.1 ml of saturated ethanolic hydrogen chloride solution at room temperature overnight, a clear solution gradually forming. This solution is treated with methylene chloride, neutralized with sodium bicarbonate 10 # ψ and shaken. The organic phase is separated off, washed with water, dried over magnesium sulfate and evaporated, leaving ethyl [{/ 4-chloro-2- (a, a-diethoxybenzyl) phenyl / carbamoyl} methyl] carbamate as a residue. For purification, the crude product is placed on a column containing 40 g of silica gel, eluted with methylene chloride and then recrystallized from ether; Melting point 138-140 °.

Example 7

A mixture of 10 g of 1,3-dihydro-7-nitro-5-phenyl-2H-

"1,4-benzodiazepin-2-one, 10 ml of methanol, 10 g of methyl chloroformate, 50 ml of methylene chloride, 15 ml of a 10 ^ igen aqueous Sodium bicarbonate solution and 12 g of solid sodium bicarbonate are stirred vigorously at room temperature overnight. Afterward are added 50 ml of methylene chloride and 50 ml of 10 # ige Sodium bicarbonate solution is added, the methylene chloride phase is separated off and the aqueous phase is extracted with methylene chloride} the methylene chloride phases are combined, dried over magnesium sulfate, filtered and evaporated, whereby 11 g of a crude product remain as a residue. This product is added to a column containing 250 g of silica gel and eluted with methylene chloride / ethyl acetate in a ratio of 9: 1 and then 5: 1. Methyl £ [(2-benzoyl-4-nitrophenyl) - is isolated

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carbamoyljmethylj carbamt, which after recrystallization from Methanol melts at 144-146 °.

Example 8

Following the procedure described in Example 3 is obtained a crude product is obtained from 2,3-dihydro-7-nitro-5-phenyl-lH-l, 4-benzodiazepine, which is obtained by chromatography on a silica gel column and elution with methylene chloride. Methyl [2- [2- (a, a-dimethoxybenzyl) -4-nitroanilinojäthylj] is isolated carbamate with a melting point of 164-165 ° (from methanol) and methyl (2- (2-benzoyl-4-nitroanilino) ethyl] carbamate from Melting point 122-124 ° (from methanol).

Example 9

Following the procedure described in Example 3 is obtained from 2,3-dihydro ~ l-methyl-7-nitro-5-phenyl-lH-1,4-benzodiazepine a crude product, which by chromatography on a Silica gel column and elution using methylene chloride / ethyl acetate (10: 1) is separated. Methyl f2- [2- (cc, adimethoxybenzyl) -N-methyl-4-nitroanilino] ethyl is isolated carbamate with a melting point of 146-148 ° (from methanol) and methyl [2- (2-benzoyl-N-methyl-4-nitroanilino) ethyl] carbama1; . From melting point 106-108 ° (from methanol).

Example 10

From 7-chloro-5- (o-fluorophenyl) -2,3-dihydro-1-methyl-1H-1,4-benzodiazepln obtained by the method described in Example 3, methyl {2- [4-chloro-2- (o-fluoro-a, a-dimethoxybenzyl) -N-methylanilino] ethyl} carbamate, which is recrystallized from methanol / water and then at 124-125 ° melts.

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Example 11

100 mg ^ -Aethoxy-T-chloro-l ^^^ - tetrahydro-l-methyl-2-oxo-5-phenyl-4H-1,4-benzodiazepine-4-carboxylic acid ethyl ester (prepared according to the information in Example 5 from 7 -Chlor-l, 3-dihydro-l-methyl-5-phenyl-2H-l, 4-benzodiazepin-2-one, ethanol and ethyl chloroformate) are dissolved in 0.5 ml of saturated ethanolic hydrogen chloride solution and left to stand for half an hour. It is then evaporated in a rotary evaporator, sodium bicarbonate solution is added to the residue until an alkaline reaction is achieved and the mixture is extracted with methylene chloride, whereupon the organic phase is dried over magnesium sulfate, filtered and evaporated. The ethyl - \ [ (2-benzoyl-4-chlorophenyl) methylcarbamoyl] methyl | remaining as residue carbamate is crystallized from ether-petroleum ether and then melts at 95-97 °.

Example 12

According to the process described in Example 7, a crude product is obtained from 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiaze.pin-2-one, which by chromatography on a silica gel Column and elution using methylene chloride containing 20 # ethyl acetate. To give methyl {((2-benzoyl-4-chlorophenyl) methylcarbamoyl] methyl carbamate _v ^s of melting point 110-112 °.

Example 13

According to the method described in Example 11, by treating S-ethoxy ^ -ehlor-l ^^ S-tetrahydro ^ - oxo-5-phenyl-4H-1,4-benzodiazepine-4 ~ carboxylic acid ethyl ester with ethanolic hydrogen chloride solution, a reaction mixture which is chromatographed on a silica gel column. It is eluted with methylene chloride and ethyl £ [ (2-benzoyl-

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4-chlorophenyl) carbamoyl] methyl ^ carbamate, which according to Crystallization from ether / n-hexane melts at 93-95 °.

Example 14

3 g of 7-bromo-1,3-dihydro-1-methyl-5- (2-pyridiyl) -2H-1,4-. benzodiazepin-2-one with 2.6 g of potassium carbonate and 2.6 ml of ethyl chloroformate in 30 ml of methyl en chi or id during Stirred for 24 hours. Another 2.6 g of potassium carbonate are then added and 2.5 ml of ethyl chloroformate are added and stirred for a few days at room temperature. The mixture is poured into ice water and extracted with methylene chloride, whereupon the organic phase is separated off, dried over magnesium sulfate, filtered and evaporated. By recrystallization the residue from ethyl acetate can be 5-ethoxy-7-bromo-1,2,3,5-tetrahydro-1-methyl-2-oxo-5- (2-pyridyl) -4H-1,4-benzodiazepln-4- ethyl carboxylate obtained from melting point 220 °.

By chromatography of the crude product on silica gel and elution using methylene chloride / ethyl acetate (10: 1) you can in addition to the benzodiazepine carboxylic acid derivative mentioned above, also ethyl {[(4-bromo-2-picolinoylphenyl) methylcarbamoynmethyl] carbamate isolate which, after crystallization from ether, melts at 143 °.

Example 15

3 * 6 g 1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one are in 60 ml abs. Benzene with 1.4 g of ethyl chloroformate and 5 drops of ethanol during Boiled under reflux for 3 hours. The reaction mixture is adjusted to a pH of 7-8 with triethylamine and four days left to stand, the pH being checked from time to time and kept at 7-8 by means of triethylamine. On that it is poured into water and extracted with methylene chloride; the

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organic phase is dried over magnesium sulfate and filtered and evaporated. The residue is purified by chromatography on silica gel and crystallized from ligroin methylene chloride * one receives ethyl [(2-benzoyl-4-nitrophenyl) methylcarbamoylJmethylS carbamate with a melting point of 95-97 °.

Example 16

150 g T-

2-one are stirred in 600 ml of methylene chloride with 120 g of potassium carbonate and at 40 ° dropwise with 120 ml of methyl chloroformate offset. The reaction mixture is 3 hours on Boiled under reflux, left to stand for a few days and poured into ice water. Extract with methylene chloride, whereupon the organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is taken in a little methylene chloride and the starting product which has crystallized out is filtered off. When the crystallization has ended, the Mother liquor over aluminum oxide and wash with methylene chloride until the piltrate is colorless. The resulting piltrate is evaporated; the residue is crystallized from ether, 7-chloro-1,2,3 * 5-tetrahydro-5- »methoxy-2-oxo-5-pheny1-4H-1,4-benzodiazepine-4-carboxylic acid methyl ester obtained with a melting point of 240 °.

According to the method described in Example 5, paragraph 2, a crude product is obtained from this compound, which is chromatographed on silica gel. It is eluted with methylene chloride / ethyl acetate (10: 1) and isolates methyl ([(2-benzoyl-4-chlorophenyl) carbamoyl] methyl] carbamate, which melts at 112-115 ° after crystallization from ether.

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Example 17

64 g of 7-chloro-1,2,3> 5-tetrahydro-5-hydroxy-1-methyl-5-phenyl-4H-1,4-benzodiazepine-4-carboxylic acid methyl ester 400 ml of aqueous hydrochloric acid (1: 1) are added and the mixture is heated to 80 ° for 10 minutes. The solution is cooled in ice and concentrated with Sodium hydroxide solution neutralized. The precipitated oil is extracted with methylene chloride; the organic phase becomes dried over magnesium sulfate, filtered and evaporated. The remaining methyl [2- (2-benzoyl-4-chloro-N-methylanilino) ethyl] carbamate is crystallized from methanol-water and then melts at 80 °.

Example 18

From 7-chloro-1,3-dihydro-1- (2-hydroxyethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one obtained by the method described in Example 7, a crude product which on silica gel with Methylene chloride / ethyl acetate (10: 1) is chromatographed. That methyl ^ [(2-benzoyl-4-chlorophenyl) - (2-hydroxyethyl) carbamoyl methyl carbamate obtained shows characteristic bands at 1730, 1670 and 1525 cm "in the infrared spectrum.

• *

Example 19

To 12 g of 2-methylamino-5-chlorobenzophenone, 8.3 g of triethyl orthoformate and 15 g of absolute ethanol, a drop of concentrated sulfuric acid is added and that is left Mixture for 3 weeks in a closed vessel Stand room temperature. For working up, the solution is evaporated to dryness, the residue is taken up in ether and extracted the resulting solution with aqueous sodium bicarbonate solution. The essential solution is washed with water, over Magnesium sulfate dried and evaporated. The 4'-chloro-α, a-diethoxy-N-methyl-a-phenyl-o-formotoluidide remaining as residue is converted from petroleum ether and from ether / petroleum ether

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ν *

crystallizes and then melts with decomposition at 1O4 ~ 1O6 °.

6 g of the above 4'-chloro-α, a-diethoxy-N-methyl-oc-phenylo-formotoluidide are heated with 50 ml of dimethyl sulfoxide and 13 ml of 28 # strength (g / g) aqueous sodium hydroxide solution for two hours while stirring at 120 ° . For working up, the mixture is poured into 500 ml of ice water and extracted with ether. The ethereal extract is _{dried over MgSO 1} ^ and evaporated, 5-chloro-2-methylaminobenzophenone diethyl acetal remaining as a residue. The product is recrystallized from ethanol / water and then melts at 77-80 °.

4.8 s N-carbomethoxyglycine, 50 ml methylene chloride and 7 * 5 g phosphorus pentachloride are stirred at -20 ° (dry ice cooling) until a clear solution is formed (approx. 15 minutes). This solution is then added dropwise to a mixture, cooled to 0 °, of 9 »6 g of 5-chloro-2-methylaminobenzophenone diethyl acetal, 50 ml of methylene chloride and 250 ml of 10% aqueous sodium bicarbonate solution. When the addition is complete, the solution is stirred vigorously for 15 minutes at 0 ° and then for one hour at room temperature. The phases are then separated} the organic phase is washed with water, dried over magnesium sulfate and evaporated, methyl {j ^ / 4-chloro-2- (α, a-diethoxybenzyl) phenyl / methylcarbamoylmethyl] oarbamate remaining as a residue. The compound is recrystallized from ethanol and then melts at 161-162 °.

Example 20

A solution of N-carbomethoxyglycine chloride is prepared by adding 24 g of N-carbomethoxyglycine in 250 ml of absolute methylene chloride, then cooling to -20 °, then 37 * 5 g of phosphorus pentahonide are added and then the mixture is stirred at -20 ° until it is clear after about 1-2 hours

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Solution emerges.

A solution of 56.8 g of 5-chloro-2-methylaminobenzophenone in 250 ml of methylene chloride is mixed with 1 liter of a 10 ^ strength sodium bicarbonate solution stirred and cooled to 0 °. Then let the · slowly with vigorous stirring and cooling to 0 °. Add the above N-carbomethoxyglycine chloride solution dropwise, decreases When the addition is complete, the temperature of the mixture rises to room temperature and the mixture is stirred for a further hour at room temperature. The methylene chloride phase is then separated off and the aqueous phase is extracted with methylene chloride the combined methylene chloride phases are dried over magnesium sulfate, filtered and evaporated, whereby Methyl i [(2-benzoyl-4-chlorophenyl) methylcarbamoyl] methyll carbamate remains as a residue. The compound is crystallized from ether and shows after recrystallization from ethanol a melting point of 110-111 °.

Example 21

According to the information in Example 20, 670 mg of N-carbomethoxyglycine and 1.1 g of phosphorus pentachloride are prepared in 5 ml Methylene chloride, an N-carbomethoxyglycine chloride solution.

520 mg of 2-amino-2'-fluoro-5-nitrobenzophenone are then dissolved in 20 ml of methylene chloride, add a drop of dimethylformamide and then the above N-carbomethoxyglycine chloride solution and then slowly evaporates the mixture at a temperature of. The residue left is methyl £ [^ 2- (2-fluorobenzoyl) -4-nitropheny ^ 7carbamoyl] methyl carbamate, which is recrystallized from ethanol / ether and then at 142 ° melts.

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Example 22

According to the information in Example 20, from 5 6 N-carbomethoxyglycine and 7.5 6 phosphorus pentachloride in 50 ml Methylene chloride, an N-carbomethoxyglycine chloride solution.

8 g of 2-amino-2'-chloro-5-nitrobenzophenone are then slurried in 50 ml of methylene chloride, 3 drops of dimethylformamide are added and the slurry is added to the above N-carbomethoxyglycine chloride solution. The mixture is on a rotary evaporator slowly evaporated at a temperature of 40 °. The remaining residue is with methylene chloride and 10% sodium bicarbonate solution was added; the methylene chloride phase is dried over magnesium sulfate, filtered and evaporated, whereby methyl {[/ 2- (2-chlorobenzoyl) -4-nitrophenyl / carbamoyl] methylj carbamate remains as a residue. After recrystallizing twice from ethanol, the melts Connection at 177-178 °.

Example 23

According to the information in Example 20, methyl {l (2-benzoyl-4-chlorophenyl) carbamoyl] methy] | is obtained from 2-amino-4-chlorobenzophenone and N-carbomethoxyglycine chloride carbamate, which is recrystallized from ethanol / ether; Doppe1-melting point LLJ ^o / l30 °.

Example 24

4 g of N-carbomethoxyglycine in 10 ml of methylene chloride are stirred vigorously with 6.2 g of phosphorus pentachloride at -20 ° until a clear solution is formed. Then dissolve 5.6 g of 5-chloro-2-methylamino-2 ^l -chlorobenzophenone in 20 ml of methylene chloride, add 10.6 g of sodium carbonate in 20 ml of water, cool to 0 ° and leave the above acid chloride with vigorous stirring. Add solution dropwise. After half an hour it will

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separating the aqueous solution; the methylene chloride solution is washed with water, dried over magnesium sulfate, filtered and evaporated. Crystallization from ether and recrystallization from methanol gives methyl H / JI 2- (o-chlorobenzoyl) phenyl 7methylcarbamoyl _i] methyl5 carbamate of melting point 115-114 °.

Example 25

First, make up 1.5 g of N-carbomethoxyglycine following the procedure described in Example 24, an N-carbanethoxyglycine chloride solution here.

2.6 g of 2-methylamino-5-nitrobenzophenone are dissolved in 20 ml of methylene chloride. Thereupon 5 drops of dimethylformamide are added and the above acid chi or id solution was added. It is evaporated at 40 ° in vacuo and the residue is dissolved in methylene chloride. The solution is washed with aqueous sodium carbonate solution, dried over magnesium sulfate and filtered and evaporated. By chromatography on silica gel with methylene chloride / ethyl acetate (9s1) and crystallization Ether gives methyl [(2-benzoyl-4-nitrophenyl) methylcarbamoyl] methyl | carbamate with a melting point of 112-113 °.

Example 26

From 2 ^l -chloro-2-methylamino-4-nitrobenzophenone, by the method described in Example 25, methyl {1- (o-chlorobenzoyl) -4-nitrophenyl / methylcarbamoyl] methyl carbamate is obtained which, after chromatographic purification on silica gel and crystallization, is obtained Methylene chloride / ether melts at 90-92 °.

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Example 27

From 4-chloro-2 ^! -fluoro-2-methylaminobenzophenone is obtained by the method described in Example 25, methyl {[/ 4-chloro-2- (o-fluorobenzoyl) phenyl7methylcarbamoyl] methyl carbamate, which is recrystallized from ether / petroleum ether and then melts at 100 °.

Example 28

Of 4-chloro-2- (2-diäthylamlnoäthy1) -2'-fluorobenzophenone w is obtained by the method described in Example 25 methyl {{/ ^J l-chloro-2- (o-fluorobenzoyl) phenyl] _i 7 <2- diethylaminoethyl carbamoyl methyl carbamate. The compound shows characteristic bands at 1727 and 1676 cm "in the IR spectrum. Nuclear magnetic resonance spectrum: triplet of 6 protons at 1 ppmj multiplet of 6 protons at 2.6 ppmj multiplet of 2 protons at 3 # 2 ppmj etc.

Example 29

From 2- (2-amino-5-bromobenzoyl) pyridine one obtains after. the procedure described in Example 25 Methyl £ [(4-bromo-2-picolinoylphenyl) carbamoyl] methylj carbamate, which melts, after crystallization from ethanol at I63 ^0th

Example 30

From 2- (5-bromo-2-methylaminobenzoyl) pyridine is obtained following the procedure described in Example 25, methyl {[(4-bromo-2-pioolinoylphenyl) methylcarbamoyl] methylif carbamate, which after crystallization from ether / petroleum ether at 111-112 ° melts.

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Example 31

4.3 g of [2- (2-methylamino-5-bromobenzoyl) pyridine 7.5 ml abs. Ethanol, 2.6 g of ethyl orthoformate and 3 drops of concentrated sulfuric acid are 5 hours on Heated to reflux, left to stand overnight at room temperature and then in aqueous, ice-cold sodium carbonate solution given. It is extracted with ether, whereupon the ethereal layer is washed with water, dried over magnesium sulfate, is filtered and evaporated. The residue is placed on a silica gel column and with methylene chloride and then with 4o # ethyl acetate containing methylene chloride eluted. Man receives 4 '-Brom-2' - (diethoxy-2-pyridyl-methyl) -N-methylformanilide, which is crystallized from petroleum ether and then melts at 113-115 °.

According to the method described in Example 19 *, second paragraph, this gives <$ - bromo-2-methylaminophenyl) -2-pyridyl ketone diethylacetal, which is crystallized from petroleum ether and then melts at 106-108 °.

According to the third paragraph described in Example 19 * Process is obtained from this methyl £ ^ T4-bromo-2- (dieth0xy-2-pyridyl-methyl) phenyl] methylcarbamoyl / methyls carbamate, which is crystallized from ether / petroleum ether and then melts at 132-134 °.

Example 32

Obtained from 5-chloro-2- (2-hydroxyethylamino) benzophenone

using the method described in Example 24, methyl

-pTienyr

{[(4-chloro-2-benzoy $ 0- (2-hydroxyethyl) carbamoyl] methyl carbamate which is chromatographed on a silica gel column with methylene chloride / ethyl acetate (3: 1) and then with ethyl acetate. The compound obtained shows characteristic characteristics in the IR spectrum

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Bands at 1726 and 1672 cm "

Example 33

15 g methyl £ 2- (4-chloro-2- (a, a-dimethoxybenzyl) -N-methylanilinojäthyljcarbamat, 240 ml of dimethyl sulfoxide and 6O ml 2N sodium hydroxide solution are stirred to 100 ° (oil bath temperature) heated, whereby a clear solution is formed after a short time. This solution is heated with stirring for 2 hours 80 ° (oil bath temperature), then pour it into 3500 ml of ice water and extract several times with ether. The United essential extracts are washed three times with water, dried over magnesium sulfate and evaporated, whereby a crystalline residue with a melting point of 81-85 ° remains. The N- [4-chloro-2- (a, a-dimethoxybenzyl) phenyl] -N-methylethylenediamine thus obtained is recrystallized from methanol / water without changing the melting point.

By neutralizing the free base with an equimolar amount of a 0.1 η solution of hydrogen chloride in abs. Methanol the corresponding hydrochloride is obtained, which after crystallization from methanol / ether at 100 ° with decomposition melts.

Example 34

From methyl {2- [4-chloro-2- (a, a-diethoxybenzyl) -N-methylanilinojäthyl} carbamate, N- [4-chloro-2- {a , a-diäthoxybenzyl) phenyl] N-methyläthylendiamin which water is recrystallized from ethanol / and then melts at 65 ^0th

The hydrochloride prepared as indicated in Example 33 this compound melts after crystallization from ethanol / ether at 170 ⁰ with decomposition.

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Example 35

14.8 g of methyl ^ f [4-chloro-2- (a, a-diethoxybenzyl) phenyl] methylcarbamoyl] methyl / carbamate, 120 ml of dimethyl sulfoxide and 30 ml of 2N sodium hydroxide solution are stirred at 80 ° for one hour. For working up, the mixture is poured into 200 ml of ice water and extracted twice with 100 ml of methylene chloride each time; the combined methylene chloride extracts are washed 5-6 times with water, dried over magnesium sulfate and evaporated. The 2-amino-4'-chloro-2 ^f - (a, a-diethoxybenzyl) -N ~ methylacetanilide remaining as residue is recrystallized from ethyl acetate and then melts at 158-159 °.

Example 36

From methyl {2- [4-chloro-N-methyl-2- (2-phenyl-1,3-dioxolan-2-yl) anilino] ethyl carbamate obtained by the process described in Example 33 N- [4-chloro-2- (2-phenyl-1,3-dioxolan-2-yl) -N-methylethylenediamine, which after crystallization from ether / petroleum ether melts at 82-84 °.

Example 37

From methyl £ 2- [2- (a, oc-dimethoxybenzyl) -4-nitroanilino] ethyl} carbamate obtained by the process described in Example 33 N- [2- (α, α-dimethoxybenzyl) -4-nitrophenyl] ethylenediamine, which after crystallization from methanol / water melts at 150-152 °.

Example 38

From methyl £ 2- [4-chloro-2- (o-fluoro-a, a-dimethoxybenzyl) -N-methylanilino] ethyl carbamate obtained by the process described in Example 33 N- [4-chloro-2- (o-fluoro-a, a-dimethoxybenzyl) phenyl] -N-methylethylenediamine, which in the IR spectrum shows a characteristic band at 1057 cm ~.

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Example 39

From methyl [2- [2- (a, a-dimethoxybenzyl) -N-methyl-4-nitroanilino] äthylj carbamate is obtained by the method described in Example 33 N- [2- (a, <x-dimethoxybenzyl) -4-nitrophenyl] -N-methylethylenediamine, which shows characteristic bands in the IR spectrum at 1110 and 1054 cm ~.

Example 40

From phthalimidoacetyl chloride and 5-chloro-2-methyl-

"Aminobenzophenone-diethylacetal obtained by the process described in Example 19 {[/ 4-chloro-2- (a, a-diäthyloxybenzyl) phenyl _/ 7methylcarbamoyl] methylj phthalimide which melts after crystallization from ether at I76 ^0th

10 mg of / 4-chloro-2- (a, a-diethoxybenzyl) phenyl / methylcarbamoyl] methyljphthalimide are dissolved in 1 ml of dioxane and 2 drops of hydrazine hydrate are added. The mixture is left to stand for 3-4 hours at room temperature, the reaction mixture is poured into water and extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulfate and filtered. and evaporated. By crystallization of the residue from ether there is obtained 2-amino-4'-chloro-2 '- (a, a-diäthoxybenzyl) -N-methylacetanilide of melting point I56 ^0th

Example 41

From methyl £ 14-bromo-2- (diethoxy-2-pyridyl-methyl) -phenyl] methylcarbamoyl / methyl carbamate is obtained by the process described in Example 35 2-amino-N- [4-bromo-2- (diethoxy-2-pyridyl-methyl) phenyl-N-methylacetamide, which is crystallized from ether and then melts at 148-150 °.

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Example 4la

100 g ^

2-one, 500 ml of methylene chloride, 50 ml of ethanol and 80 g of g are stirred at room temperature and 100 ml of benzyl chloroformate are added dropwise. Stir overnight at room temperature, the mixture is then poured into ice water and extracted with methylene chloride. The methylene chloride extract is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue is on silica gel with Methylene chloride diromatographed. 5-Aethoxy-7-chloro-1,2 is isolated Benzyl 3,5-tetrahydro-2-oxo-5-phenyl-4H-1,4-benzodiazepine-4-carboxylate which is crystallized from ether / petroleum ether and recrystallized and then melts at 210-212 °.

According to the process described in Example 6, benzyl 1 ^ -chloro-2- (a, a-cliäthoxybenzyl) phenyl 1-carbamoyl / methyl 1 is obtained therefrom carbamate which after chromatography on a silica gel column with methylene chloride / ethyl acetate (20: 1) and Crystallization from ether-petroleum ether melts at 120-123 °.

150 mg of benzyl {(/ 5-chloro-2- (α, oc-diethoxybenzyl) phenyl] carbamoyl7methyl carbamate are dissolved in 15 ml of absolute ethanol, 50 mg of palladium carbon (5%) are added and the mixture is hydrogenated at room temperature and normal pressure After 1 hour, the palladium carbon is filtered off, the piltrate is evaporated and the residue is taken up in methylene chloride. The solution is washed with 10 # sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from ether / petroleum ether and then melts at 124-126 ° j. The product obtained shows characteristic bands in the IR spectrum at 3414, 3294, 1677, 1527 and 1077 cm " ^1. According to the mass spectrum, it is 2-amino-4 ^l -chlor-2'- (a, adiäthoxybenzyl) acetanilide, which is contaminated by the corresponding '4' unsubstituted compound.

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Example 42

1 g of methyl [[(2-benzoyl-4-chlorophenyl) carbamoyl] methyll carbamate is dissolved in 7 ml of dimethylformamide, 200 mg of sodium methylate are added at -4o ° C. and half an hour touched. 500 mg of methyl iodide are then added and left over Stand in the freezer at night. The reaction mixture is neutralized with glacial acetic acid and in about 10 ^ ige aqueous sodium bicarbonate solution poured, whereupon extracted with ether. The ether solution is washed three times with water, over Dried magnesium sulfate, filtered and evaporated. Most of the unreacted starting material is through Crystallization removed. The residue remaining when the mother liquor is evaporated is treated with methylene chloride on a Chromatographed silica gel column. Methyl | [(2-benzoyl - ^ - chlorophenyl / methylcarbamoyl / methyll carbamate, which is recrystallized from ethanol and then melts at 106-107 °.

Example 43

From methyl {[(2-benzoyl-4-nitrophenyl) carbamoyl] methyl carbamate methyl {[(2-benzoyl-4-nitrophenyl) methylcarbamoyl 1-methyljf] is obtained by the process described in Example 42 carbamate, which after chromatography on silica gel with methylene chloride and crystallization from ether at 110-112 ° melts.

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Example 44

10 mg of methyl {[/ 5-chloro-2- (a, a-diethoxybenzyl) phenyl7-methylcarbamoylmethyl} carbamate are dissolved in 1 ml of ethanol and 2 drops of ethanolic hydrochloric acid are added. The mixture is warmed gently, shaken, mixed with water and extracted with methylene chloride, whereupon the extract is dried over magnesium sulphate, filtered and evaporated. This gives methyl {[ (2-benzoyl-4-chlorophenyl) methylcarbamoyl1-methyl ^ carbamate which is crystallized from ethanol and then melts at 110 °.

Example 45

1 g of 5-chloro-2- (methylamino) benzophenone diethyl acetal is dissolved in 10 ml of methylene chloride, covered with 10 ml of about 10% sodium carbonate solution and, with vigorous stirring, with 0.6 ml Bromoacetyl bromide added. After half an hour, the organic phase is separated off, washed with water, over Dried magnesium sulfate, filtered and evaporated. The 2-bromo-4'-chloro-2 '- (α, α-diethoxybenzyl) remaining as residue N-methylacetanilide is crystallized from ether and melts then at 14l °.

300 mg of 2-bromo-4'-chloro-2 ¹ - (α, α-diethoxybenzyl) -N-methylacetanillide are dissolved in 2 ml of dimethylformamide and a trace of sodium iodide is added. Then, at room temperature and with stirring, gaseous ammonia is passed in and left to stand overnight. The reaction mixture is poured

0 9 8 Γ? '/ ": B A

in water and extracted with methylene chloride. The methylene chloride solution is washed twice with water, dried over magnesium sulfate, filtered and evaporated. The residue is mixed with ether, the product which has crystallized out is filtered off, the mother liquor is concentrated and the residue is treated with cyclohexane, whereupon it solidifies. Recrystallization from ethyl acetate gives 2-amino-4 ^! -chlor-2 '- (a, a-diethoxybenzyl) -N-methylaeetanilide of melting point 156-158 °.

Example 46

960 mg of 5-chloro-2- (methyiamino) benzophenone diethylacetal are dissolved in 10 ml of abs. Benzene dissolved. 96 ml of triethylamine and 570 mg of chloroacetic anhydride are added at room temperature and the mixture is left to stand overnight. It is then evaporated, the residue is taken up in benzene, whereupon the solution obtained is treated with activated charcoal, filtered and evaporated. Chromatography of the residue on silica gel eluting with methylene chloride to obtain 2-chloro-4'-chloro-2 '- (a, a-diäthoxybenzyl) -N-methylacetanilide, which is crystallized from ether and then melts at 170 ^0th

From 2-chloro-4'-chloro-2 '- (α, α-diethoxybenzyl) -N _r methy1-acetanilide, treatment with ammonia according to the process described in Example 45 gives 2-amino-4'-chloro-2' - (a, a-diethoxybenzyl) -N-methylacetanilide, which is recrystallized from ethyl acetate and then melts at 158-159 °.

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205Ö8IS

Per tablet mg 10 mg 53 mg 150 mg 6th

Example A.
Tablets are made with the following composition:

Methyl [[(2-benzoyl-4-chlorophenyl) -methylcarbamoyljmethylj carbamate

Corn starch lactose gelatin ($ 10 solution)

The active ingredient, the corn starch and the milk sugar are thickened with a 10% gelatin solution. The paste will crushed, the granules put in a suitable pan and dried at 4} °. The dried granules are through a shredder and mixed in a mixer with the following ingredients:

Talc 6 mg

Magnesium stearate 6 mg

Corn starch 9 mg and then compressed into tablets of 240 mg.

Example B.

Suppositories are made with the following ingredients:

per 1.3 g of suppository

Methyl {[(2-benzoyl-4-chloro-

phenyl ) methylcarbamoyl] -

methyl ^ carbamate 10.0 mg

Hydrogenated Coconut Oil 1245.0 mg

Carnauba wax 45.0 mg

The hydrogenated coconut oil and the carnauba wax are placed in a suitable container with a glass insert.

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"melted and cooled to 45 °. The active ingredient is under Stir added and stirred until completely dispersed. The mixture is poured into suppository molds on top ensure a suppository weight of 1.3 g.

Example C

A parenteral form of use is made with the following Components manufactured:

per ml

Methyl {[(2-benzoyl-4-chlorophenyl) methylcarbamoyl] methyl carbamate 5 mg Dimethylacetamide

Benzyl alcohol

Ethanol

Water for injections ad 1 ml

The active ingredient is dissolved in dimethylacetamide and mixed with benzyl alcohol, ethanol and water. It is filtered through a candle filter, filled into suitable ampoules, sealed and sterilized.

Example D

According to Examples A to C, tablets or suppositories or a parenteral usable form are produced, but instead of methyl [(2-benzoyl-4-chlorophenyl) methylcarbamoyl / methyl carbamate, one of the following compounds is used as the active ingredient: methyl [[(2 -benzoyl-4-nitrophenyl) methylcarbamoyl] methyl} carbamate methyl £ (/ 4-chloro-2- (o-fluorobenzyl) phenyl / methylcarbamoyl] methy1 \ carbamate j 2-amino-4'-chloro-2 '- (α, α-diethoxybenzyl) -N-methylacetanilide / N- (4-chloro-2- (α, α-dimethoxybenzyl) phenyl] -N-methylethyenediamine / methyl [i / 2- (ochlorbenzoyl) -4-nitrophenyl / methylcarbamoyl / methyl carbamate.

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Claims (1)

Claims 1. Process for the preparation of diarylmethane derivatives the general formula wherein R, halogen, nitro or trifluoromethyl, Rp hydrogen, lower alkyl, lower hydroxyalkyl or lower dialkylaminoalkyl, R., hydrogen or lower alkoxy carbonyl, R ^. and R ₁ - each lower alkoxy or together a lower alkylenedioxy group or - if R stands for lower alkoxycarbonyl - together an oxo group, A is phenyl, halophenyl or pyridyl and B is a carbonyl or methylene group, and of acid addition salts of basic compounds of the formula I, characterized in that one a) for the preparation of a compound of the formula I in which R 1 is lower alkoxycarbonyl, a compound of the general formula II COOR, 109822/2264 wherein R ₁ , R ₃ , A and B have the meaning given in formula I and R _{6 is} lower alkyl and R is hydroxy, lower alkoxy or lower hydroxyalkoxy, with aqueous acid or, if R is lower alkoxy, under anhydrous conditions with an acid and a lower alkanol or, if R is lower hydroxyalkoxy, treated with an acid under anhydrous conditions or b) for the preparation of a compound of the formula I in which R-, lower alkoxyoarbonyl means a compound of the general formula III ^R 2 * ^R 4 * R ₁ - and A are those indicated in formula I where R
have the same meaning
with a compound of the general formula X_B-CHg-NH-CO-OR ₆ IV in which B has the _{meaning given in formula I and R 6} and X stands for a halogen atom, implements or c) for the preparation of a compound of the formula I in which R 1 is hydrogen, from a compound of the general formula 109822/2264 NB-CH ₂ -Y wherein R ₁ , R ₂ , .B and A have the meaning given in formula I, Rg and R each mean lower alkoxy or together a lower alkylenedioxy group and Y stands for a nitrogen atom protected by a group which can be split off, splits off the protective group or d) for the preparation of a compound of the formula I in which B is a carbonyl group and Rp is lower alkyl, lower hydroxyalkyl or lower dialkylaminoalkyl, a corresponding compound of the formula I in which B is a carbonyl group and R _? Are hydrogen, treated with a corresponding alkylating, hydroxyalkylating or dialkylaminoalkylating agent or e) for the preparation of a compound of the formula I, wherein Ji ^ and R ₁ - together denote an oxo group in a corresponding compound of the formula I in which Ru and R ₁ . each denotes lower alkoxy or together a lower alkylenedioxy group which cleaves the ketal group under acidic conditions or f) for the preparation of a compound of the formula I in which R 1 denotes hydrogen, a compound of the general formula NB-CH ₂ -Z VI 109822/2264 wherein R ,, R ", A and B are those in formula I and R _Q and Ld O Rg have the meaning given in formula V and Z stands for the acid residue of a reactive "ester, reacts with ammonia or g) for the preparation of an acid addition salt of a basic compound of the formula I with a corresponding free base treated with an inorganic or organic acid. 2. The method according to claim 1, characterized in that for the preparation of a compound of the formula I in which R-, lower alkoxycarbonyl and Rj. And R ₁ . each is lower alkoxy or together is lower alkylenedioxy, a compound of the formula II in which R _{7 is} lower alkoxy or lower hydroxyalkoxy, if R _{7 is} lower alkoxy, under anhydrous conditions with an acid and a lower alkanol, or _{if R 7 is} lower hydroxyalkoxy means treated with an acid under anhydrous conditions. 3. The method according to claim 1, characterized in that for the preparation of a compound of the formula I in which R, lower alkoxycarbonyl and Rh and R ₁ . together denote the oxo group, a compound of the formula II in which R ₇ denotes hydroxy, treated with aqueous acid. 4. The method according to claim 1, characterized in that aan for the preparation of a compound of formula I, wherein R, lower alkoxycarbonyl and R ₁ ^ and R ₅ each mean lower alkoxy or together a lower alkylenedioxy group, a compound of formula III, wherein Rj , and R ₁ . Each is lower alkoxy or together a lower alkylenedioxy group, reacted with a compound of the formula IV. 5. The method according to claim 1, characterized in that for the preparation of a compound of the formula I, wherein ^109822/2264 2Ö508S§ FL lower alkoxycarbonyl and Eu and R ₁ . together denote an oxo group, a compound of the formula III, in which R4 and R ₁ - together denote an oxo group, are reacted with a compound of the formula IV. . 6. The method according to claim 1, characterized in that that for the preparation of a compound of the formula I in which R 1 is hydrogen, from a compound of the general Formula V, in which Y stands for a nitrogen atom which is protected by a group which can be split off under alkaline conditions, splits off the protective group. y. Process according to Claim 1, characterized in that, for the preparation of a compound of the formula I in which B is a carbonyl group, R _{2 is} lower alkyl, lower hydroxyalkyl or lower dialkylaminoalkyl and R_ is hydrogen, a corresponding compound of the formula I in which Rp is hydrogen, with a corresponding alkylating, hydroxyalkylating or dialkylaminoalkylating agent. 8. The method according to claim 1, characterized in that for the preparation of a compound of formula I in which R, lower alkoxycarbonyl and R ₁ , and Rj- together before oxo group, in a corresponding compound of formula I in which R ₁ , and R ₁ . each mean lower alkoxy or together a lower alkylenedioxy group which cleaves the ketal group under acidic conditions. 9. The method according to claim 1, characterized in that that for the preparation of a compound of the formula I in which R, denotes hydrogen, a compound of the formula VI with Ammonia converts. 10. The method according to any one of claims 1-9 »thereby 109822/2264 ■ Nt characterized in that R _{1 is} halogen or nitro. 11. The method according to claim 10, characterized in that R, is chlorine or bromine. ..-. '. ·. 12. The method according to any one of claims 1- £ and 8'-H, characterized in that R _{p is} hydrogen. 13. Process according to one of Claims 1-11, characterized in that R ₂ denotes a methyl, hydroxyethyl, dimethylaminoethyl or diethylaminoethyl group. 14. The method according to any one of claims 1-13, characterized characterized in that A is phenyl, o-halophenyl or 2-pyridyl means. - 15. The method according to claim 14, characterized in that that A is o-chlorophenyl or o-fluorophenyl. 16. The method according to any one of claims 1, 2, 4, 6, 7 » and 9-15 »characterized in that R ^ and R ^. each methoxy or ethoxy or together represent an ethylenedioxy group. 17. The method according to any one of claims 1 and iO-15 »characterized in that Rj, and R ₁ - together represent an oxo group. 18. The method according to claim 1, characterized in that R, chlorine, Rp methyl, R-, methoxy carbonyl, R ^ and R ₁ - together represent an oxo group, A is phenyl and B is a carbonyl group. 19. The method according to claim 1, characterized in that R _{1 is} nitro, R _{2 is} methyl, R-, methoxy carbonyl, R ₁ ^ and R ₅ together are an oxo group, A is phenyl and B is a carbonyl group 109822/2264. interpret. 20. The method according to claim 1, characterized in that R, chlorine, R ^ methyl, R, methoxycarbonyl, R ^ and R, - together is an oxo group, A is o-fluorophenyl and B is a carbonyl group mean. 21. The method according to claim 1, characterized in that R, chlorine, Rp methyl, R-, hydrogen, R ₁ ^ and R ₁ - each is ethoxy, A is phenyl and B is a carbonyl group. 22. The method according to claim 1, characterized in that R, chlorine, R _{2 is} methyl, R, hydrogen, R ₁ ^ and R ^ are each methoxy, A is phenyl and B is a methylene group. 23 · Process according to claim 1, characterized in that R. Nitro, R ₂ methyl, R, methoxycarbonyl, R ₁ ^ and R, - together represent an oxo group, A is o-chlorophenyl and B is a carbonyl group. 109822/2264 24. Process for the production of preparations with sedative, anticonvulsive, muscle relaxant and / or Anxiolytic properties, characterized in that one or more of the compounds defined in claim 1 of the general formula I or a pharmaceutically acceptable salt thereof for therapeutic administration suitable, non-toxic, inert solid and liquid carriers which are customary in such preparations and / or Mixed excipients. . 25. A pharmaceutical preparation with sedative, anticonvulsive, mush-relaxant and / or anxiolytic properties containing one or more of the compounds of general formula I defined in claim or a pharmaceutically usable salt thereof and suitable pharmaceutical carrier material. 109822/2264 M3 26. The method according to claim 1, characterized in that one of a compound of the general formula ^R 2 VII where R ,, R _? , B and A have the meaning given in formula I, a compound of formula II by reaction with a lower alkyl ester of chloroformic acid in the presence of water or by treatment with a lower alkyl ester of chloroformic acid and a lower alkanol or alkylene glycol under anhydrous conditions and converts this into a compound of the formula I. 27 · Compounds of the general formula ■ wherein) FL halogen, nitro or trifluoromethyl, R "hydrogen, lower alkyl, lower hydroxy-""alkyl or lower dialkylaminoalkyl, R, hydrogen or lower alkoxy carbonyl, Rn and Rp- each lower alkoxy or together a lower alkylenedioxy group or if R, stands for lower alkoxycarbonyl - together an oxo group, A is phenyl, halopftenyl or pyridyl and B is a carbonyl or methylene group,
and acid addition salts of basic compounds of the formula 109822/22 ^ 4 - «.- 20S0399 28. Compounds according to claim 27, wherein R, lower alkoxycarbonyl and R ^ and R ₁ - each mean lower alkoxy or together a lower alkylenedioxy group. 29. Compounds according to claim 27, wherein R-, lower alkoxycarbonyl and R ₁ . and Rp. together represent an oxo group. 30. Compounds according to claim 27, wherein R ^, hydrogen and R ^ and R ₁ - each mean lower alkoxy or together a lower alkylenedloxy group. "31 · Compounds according to claim 27, wherein R, hydrogen, R_ lower alkyl, lower hydroxyalkyl or lower dialkylaminoalkyl and R ^ and R each lower alkoxy or together mean a lower alkylenedioxy group. 32. Compounds according to any one of claims 27-31, V " wherein R is halogen or nitro. 33 · Compounds according to claim 32, in which R is chlorine or bromine. 3 ^. Compounds according to any one of claims 27-30 and 31-3 5, where Rp is hydrogen. \ 35 '·· Connection MEe ^ according to any one of claims 27-33, wherein Rp a methyl, hydroxyethyl, dimethylaminoethyl or Diethylaminoethyl group meant. 36. Compounds according to any one of claims 27-35, wherein A is phenyl, o-halophenyl or 2-pyridyl. 37.Verbindungen according to claim 36, wherein A is o-chlorophenyl or is o-fluorophenyl. 109822/2264 2050699 38. Compounds according to any one of claims 27, 28 07, wherein R ^ and R ₁ . each methoxy od together mean an ethylenedioxy group. and 30-07, wherein R ^ and R ₁ . each methoxy or ethoxy or to 39. Compound according to one of claims 27 and 32-37 »* wherein Ru and Rf-. together represent an oxo group. 40. Methyl {(2-benzoyl-4-chlorophenyl) methylcarbamoy1] methyl carbamate. 41. Methyl j | [(2-benzoyl-4-nitrophenyl) methylcarbamoyl] me thy lj carbamat. 42. Methyl {{/ 5-chloro-2- (o-fluorobenzoyl) phenyl7methylcarbamoyl] methyl ^ carbamate. 43. 2-Amino-4'-chloro-2 '- (α, α-diethoxybenzyl) -N-methylacetane IIIide. 44. N- [4-Chlorine ^ - (α, α-dimethoxybenzyl) phenyl] -N-methylethylenediamine. 45. Methyl {(/ 2- (o-chlorobehzoyl) -4-nitrophenyl / -methyl carbanoyl] M * ^ 109822/2264