DE2163522A1 - Benzodiazepine derivatives - Google Patents

Description

Br.liwJ. ™ nd, rW (srft 5T1.lfez.i971

Df.h'UiU ΙϋύδΓΘΤ PATENT Attorney I

RAN 4008/179 k-02

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

Benzodlazepine Derivatives

The present invention relates to benzodiazepine derivatives the general formula

where R and R, hydrogen or lower alkyl, R ₂ hydrogen , lower alkyl or the group «COORg and Rg are lower alkyl, B is one of the groups

209829/1168 originally inspected

CH - NH '

and

or, for the Pail that Rp means -COORg, the group

'C = N-

means,

R, hydrogen or halogen, R. hydroxy, arylsulfonyl, Arylsulfonyloxy, lower alkylsulfonyl, lower alkylsulfonyloxy, lower alkanoyl or lower Alkanoyloiy and R ^ hydrogen or with

R. together mean an additional G-N bond,

and pharmaceutically acceptable acid addition salts of these compounds.

The term "lower alkyl" as used in this specification refers to straight and branched chain hydrocarbon radicals with 1-7, preferably 1-4, carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and the like. The term "halogen" includes the four halogens chlorine, bromine and iodine and fluorine unless otherwise specified. The term "lower alkanoyl" - alone or in combination - refers to the acyl radical of a lower alkanoarboxylic acid. In the alkyl-CO radical the lower alkyl group preferably contains 1-6, very particularly preferably 1-3 carbon atoms. The acyl residue of However, formic acid should also be recorded. It is therefore a matter of residues such as formyl, acetyl, propionyl, butyryl, Valeroyl and the like. The term "arylsulfonyl" - alone or in

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Combination - includes groups such as p-toluenesulfonyl, benzenesulf onyl and the like. The term "alkylsulfonyl" - alone or in combination - includes, for example, methylsulfonyl and the like.

In a preferred embodiment, Rp is hydrogen. Compounds in which Rp is hydrogen and R is hydrogen, chlorine or fluorine, particularly preferably fluorine, are particularly preferred. Also preferred are those compounds in which R _{1 is} hydrogen or methyl and R is methyl. Very particularly preferred compounds are accordingly those in which R is methyl, R _{2 is} hydrogen and R is hydrogen, chlorine or fluorine, very particularly preferably fluorine, and R is hydrogen or methyl.

According to the present invention, compounds of the formula I and their pharmaceutically acceptable acid addition salts are prepared by a) for the preparation of compounds of the formula

Yes

R C

in which R, R ₁ and R_ have the above meaning and R _{2 is} Waeseretoff or lower alkyl, a compound of the general formula

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ORIGINAL INSPECTED

where R, R, and R "have the above meaning, R_ is hydrogen or lower alkyl and R ₇ and R _{Q are} a residue that can be removed by hydrolysis,

hydrolyzed, or that one

b) for the preparation of compounds of the formula

in which R, R ₁ and R_ have the above meaning and Rp is hydrogen or lower alkyl, a compound of the general formula

? 0 9 8 ? Sl / 1 1 6 8

III

where R, R-, R ~, R ₇ and R _{Q have the} above meaning and Rp is hydrogen or lower alkyl,

hydrolyzed, or that one

c) for the preparation of compounds of the formula

Ic

where R, R ^ and li_ have the above meaning and Rp is hydrogen or lower alkyl, a compound of the formula Ia is catalytically reduced, or that one

d) a compound for the production of preliminary compounds of the formula Ib of the formula Ia, or one can

e) for the preparation of compounds of the formula

'/ [i ^c ii \ y ⁽ / 116 8

BATH ORIGINAL

Id

where R, R-, and R "have the above meaning and Rp is hydrogen or lower alkyl,

subjects a compound of the formula Ia to photolysis, or that

f ) for the preparation of compounds of the formula

Ie

where R, R, and R, have the above meaning, Rp Vaoauratoff or lower alkyl and R 'arylsulfonyl, Arylsulfonyloxy, lower alkylsulfonyloxy, lower alkylsulfonyloxy, lower alkanoyl or lower alkanoyl-oxy mean

a compound of the formula fb or Tc with an AryläuLi'uny L-halide, elneai Nieder A Lky Laulfony! halogen Ld odor uLritüu nit »dt> r

2 [ι Π 8 2 ¹ W 1 Ί 6 8

BATH ORIGINAL

Alkanoyl delivery agent reacting _t or in that g) for the preparation of compounds of formula

Il C

where R, R ₁ and R- have the above meaning and Rp is hydrogen or lower alkyl,

a compound of the formula Ie into the corresponding 3,4-dehydro derivative convicted, or that one

h) for the preparation of compounds of the formula

COOR,

where R, R ,, R, and Rg have the above meaning, a compound of the general formula

/! J Π R ? Ί I 1 1 B 8

wherein R, R, and R, have the above meaning, cyclized, and

and that i) if desired, a product obtained in a transferred pharmaceutically acceptable acid addition salt.

Compounds of the formulas II and III can easily be converted into the corresponding compounds of the formula I using the customary hydrolysis processes at a pH below 7. As mentioned above, R ₇ and R _{Q represent} a group which can be easily removed by conventional hydrolyzing methods. Preferably, R ₇ and R _{Q are} individually lower alkyl or together are a —CH ₂ CH ₂ or a —CH ₂ —CH ₂ —CH _{2 group} . The nature of the groups represented by R ₇ and Rq is not critical for carrying out the reaction, as long as they can be easily removed by hydrolysis. If R ₇ and R _Q together represent a protecting group, compounds of the formula I can be prepared in high yields. Particularly preferred for the present invention are the compounds of the formulas II and III in which R ₇ and R 1 together denote -CHp-CHp-, ie the 1,3-dioxolan-2-yl radical.

Compounds of formulas II and III can in an aqueous medium such as aqueous lower alkanecarboxylic acids or

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aqueous lower alkanols are dissolved, z »ß. aqueous methanol, aqueous ethanol and the like. By heating the reaction mixtures obtained in this way to temperatures between and 100 °, the conversion of compounds of the formulas II and III into the corresponding compounds of the formula I can be carried out in an expedient manner.

In the most preferred aspect of the process, the hydrolysis of the compounds of formulas II and III results in the corresponding compounds of formula I by simply dissolving carried out in aqueous mineral acid. Inert organic Solvents such as dimethylformamide, lower alkanols such as methanol, dimethyl sulfoxide, ethers such as tetrahydrofuran or dioxane can be added to increase solubility. Temperature and pressure are not critical to that successful implementation of this reaction, but it is preferred to work in a temperature range between about -10 to 100, preferably 10 and 30, but very particularly preferably at about room temperature. As already mentioned above, the hydrolysis is preferably carried out in an aqueous solution of an acid, preferably in a 3N to 12N acid. The sour agent can be employed by any suitable method, such as adding to the reaction medium with the compound of formula II or III. Acidic agents suitable for this purpose are mineral acids such as nitric acid, hydrochloric acid, aqueous hydrobromic acid, Sulfuric acid and the like, or organic acids such as sulfonic acids, e.g., toluenesulfonic acid or methanesulfonic acid, trihaloacetic acids e.g. trifluoroacetic acid and other 3 strong carboxylic acids such as oxalic acid. The type of acid used is not critical and can easily be selected by those skilled in the art.

Compounds of the formula Ia can be controlled catalytically «; Reduction into the corresponding compounds of the formula Ic are converted. Appropriately, will hydrogenated a compound of formula Ia in the presence of platinum or a similar catalyst. To be the best possible

^209829/1168 OWGiNAL

To achieve yield of a compound of the formula Ic, the reaction is controlled so that preferably not more than 1 mol equivalent of hydrogen is taken up, and the reaction is carried out in the presence of an alkanecarboxylic acid, such as acetic acid where the acid can also serve as a solvent.

Compounds of the formula Ia can also be converted into the corresponding compounds of the formula Ib using any customary reduction process. Thus, this reduction of a compound of the formula Ia can be carried out catalytically by hydrogenation in the presence of a platinum catalyst and the like, a compound of the formula Ib being obtained. If this reduction is carried out with platinum, a compound of the formula Ic can also be formed. The mixture thus obtained can, however , be separated into its components by known methods.

Compounds of the formula Id can be prepared from compounds of the formula Ia by irradiation with UV light, which is preferably filtered with customary filters. A pressure mercury lamp is preferably used as the UV light source. The reaction is advantageous in an inert organic solvents such as tetrahydrofuran and the like. Carried out.

Compounds of the formula Ib or Ic can be converted into compounds of the formula Ie by reaction with an arylsulfonyl halide, a lower alkylsulfonyl halide or an agent which provides a lower alkBAoyl group. Suitable arylsulfonyl halides for this purpose are tosy halides, such as p-toluenesulfonyl chloride and benzenesulfonyl halides, such as benzenesulfonyl chloride. Suitable lower alkyl sulfonyl halides are methyl sulfonyl halides, such as methanesulfonyl chloride. Suitable agents which provide lower alkanol groups are acetic anhydride, acetyl chloride and the like.

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BATH

Arylsulfonyl halides are preferred in this process aspect and lower alkyl sulfonyl halides are used. Tosyl chloride and mesyl chloride are particularly preferred.

This process aspect is expedient in an inert Organic solvents such as ether, tetrahydrofuran and dioxane, dimethylformamide, dimethy! acetamide and the like. Carried out. With Advantageously, an acid acceptor is added to the reaction mixture in order to bind the hydrohalic acid which is in the reaction of a halide such as an arylsulfonyl halide or an alkyl sulfonyl halide, with a compound of formula Ib or Ic. Suitable acid acceptors are tertiary amines, pyridine and the like. Preferred the acid acceptor is added in excess in order to act both as a solvent and as an acid acceptor. In one particularly preferred process aspect, the reaction is carried out in the presence of pyridine, pyridine both as an acid acceptor as well as a solvent. temperature and pressure are not critical to this procedural aspect

The conversion of a compound of formula Ie into

a corresponding compound of the formula If can be used in counter

from a base
wart / and an inert organic solvent. Any base which can be used to effect the conversion of a compound of the formula Ie into the corresponding compound of the formula If can be used for the purpose of the present invention. Suitable bases for this are lower alkali metal alkylates, such as, for example, sodium methoxide, potassium tert-butoxide and the like, or alkali metal hydrides, such as, for example, sodium hydride. Weaker bases, such as aqueous alkali metal hydroxides, for example aqueous sodium hydroxide or aqueous potassium hydroxide, amines, such as dimethylamine, triethylamine and the like, can also be used. As mentioned above, any inert organic solvent can be used for

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BATH ORIGINAL

this reaction can be used, such as dimethylformamide, Dimethyl sulfoxide, tetrahydrofuran and the like. Temperature and pressure are not critical, but higher yields of compounds of the formula If are obtained if the reaction is carried out at temperatures between about 0 to 80 °, preferably between about 25 and is carried out. If you make a compound of the formula If by treating a corresponding compound of the formula Ie with a base, it was observed that the compound of

Formula If can be treated further with a base, preferably in a polar solvent such as water, a lower alkanol, such as ethanol and the like. For both reaction ™ steps, either the same or a different base can be used, with a corresponding 4 »5> -dehydro derivative a compound of the formula If is obtained. So you can have a compound of formula Ie with a base in the Treat the manner described above and interrupt the reaction when a compound of the formula If has formed.

A process for the preparation of compounds of the formulas II and III is shown in the following equation. In In this equation, the substituents R, R ~, R "and R" the meaning given above. Rp means hydrogen or ^ lower alkyl and X represents a group that converts into an amino group can be converted e.g. An azido or a phthalimido group, or instead a leaving group, e.g. Halogen, such as chlorine, bromine or iodine, alkyl or arylsulfonyloxy groups, e.g., meeyloxy, benzenesulfonyloxy, and tosyloxy.

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CH ₂ CN

IX

VIII

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XI

XII

III

II

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Compounds of the formula V can, as in G-isvold et al., J. Pharm. Sci, ££, 784 (1968) will.

In the first procedural stage of the formula scheme, a compound of the formula V reacted with a compound of the formula VI to give a compound of the formula VII. This reaction is preferred in the presence of an inert organic solvent carried out. Representative representatives of such solvents are alcohols, e.g. lower alkanols, such as Ethanol and methanol, dimethyl sulfoxide and dimethylformamide. Lower alkanols, especially methanol, are preferred. It is It is essential that a base be present in this reaction, any suitable base may be used. However, it is advantageous to use alkali metal hydroxides, such as sodium hydroxide. Used for this first stage of the process temperatures between about room temperature and about 100 are preferred, particularly preferably between about room temperature and about 60 °. The resulting product of formula VII needs to be converted into a compound of formula VIII not necessarily to be isolated; however, such isolation is preferred.

The second process stage of the equation relates to the conversion of a compound of the formula VII into a Compound of formula VIII by catalytic hydrogenation. Suitable catalysts for this purpose are palladium on carbon, platinum, nickel and cobalt, with palladium on Coal is particularly preferred. This catalytic hydrogenation is in the presence of a suitable inert organic solvent carried out. Suitable solvents for this purpose are tetrahydrofuran, dimethylformamide, lower alkanols, such as methyl alcohol, ethyl alcohol and the like. When converting a compound of the formula VII into a compound of the formula VIII the reaction is terminated preferably when the theoretical

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retic amount of hydrogen has been absorbed since with larger amounts of hydrogen lifting reactions can occur, which worsen the yields.

A compound of the formula VIII can be converted into the corresponding compound by a large number of preparative methods the formula, XI can be converted.

For example, a compound of formula VIII with a

Compound of the formula Halo-COCHY, wherein R _{2 is} hydrogen or

R ₂

lower alkyl and Y halogen, lower alkylsulfonyloxy or aryl

sulfonyloxy or -with an anhydride of the formula ? 2

(Halo-CH-CO) ₂ O or the formula (lower alkylsulfonyl-CH-CO) ₂ 0 or the formula (arylsulfonyl-CH-CO) ₂ 0 are implemented. Examples of such anhydrides are chloroacetic anhydride, mesyloxyacetic anhydride, tosyloxyacetic anhydride and benzenesulfonyl acetic anhydride.

Suitable halogen-lower-aikanoy! Halides in which Y in the formula described above denotes halogen, are chloroacetyl chloride, bromoacetyl chloride, bromopropionyl chloride and the like. It follows that the halogen functions of the "above-mentioned halogen-lower-alkanoy! halides or the The anhydrides mentioned above are preferably chlorine or bromine. This reaction step is preferred in the presence of a Acid acceptor, such as an inorganic or organic base carried out. So can bases, with a HydroxyI-ion such as alkali hydroxides, e.g. sodium hydroxide, potassium hydroxide, can be used. Other possible bases are sodium carbonate, Trläthylamine, pyridine and the like.

fr

Representatives for compounds of the formula Y-CH-CO-halogen wherein Y is lower alkylaulfonyloxy or arylsulfonyloxy, are Meeyloxyacetylchlorid and Tosyloxyacetylchlorid.

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This process aspect, namely the production of a A compound of the formula IX in which X is halogen, lower alkylsulfonyloxy or arylsulfonyloxy, "is preferred in the presence of a inert organic solvents such as benzene, ether, methylene chloride and the like. Carried out. Temperature and pressure are not critical, but temperatures below the tree temperature, e.g., between about 0 and 20, are preferred.

When performing this reaction step, one should bear in mind that the group _R _ _G ^/ "/ with moisture

or alcohols tend to convert to a lower alkanoyl group under acidic conditions. Therefore should water and Acids are avoided in this reaction step.

After the synthesis of a "compound of formula IX wherein X is halogen, lower alkylsulfonyloxy or arylsulfonyloxy, said compound is treated with ammonia and the resulting compound of formula X to the corresponding 1,4-benzodiazepin-2-one of the formula XI cyclized.

The compound of the formula X does not need to be isolated before the cyclization to give a compound of the formula XI will. The reaction does not have to be interrupted before a compound of the formula XI is obtained.

3o, for example, a haloacylamido, a tosyloxyacylamido or a mesylozyaoylamido derivative of the formula IX can be added to a solution of ammonia in a lower alkanol, such as ethanolic ammonia or methanolic ammonia, and after several hours, e.g. overnight, the corresponding l, 4-Benzodiazepin-2-one compound of the formula XI (for example a 7- (2-Rl, 3-dioxolan-2-yl) benzodiazepin-2-one is obtained if R ₇ and R "together represent an ethylene group). The cyclization can be accelerated by heating.

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In another aspect of the process, one does not work with methanol! Dimethyl sulfoxide, dimethylformamide and the like and treats the resulting solution with liquid ammonia, a compound of the formula X being obtained. The thus obtained crude or something purified compound of Formula X can be an inert organic solvent such as a lower alkanol, eg "methanol, ethanol and the like. Be added to _r where by leaving the obtained solution, and / or heating cyclisation to the corresponding compound formula XI occurs.

In a further aspect of the method, compounds of the formula IX in which X is a halogen atom other than iodine or Is bromine, or if Y is lower alkylsulfonyloxy or arylsulfonyloxy in the corresponding compounds of the formula IX in which X is iodine, are converted. The latter is particularly useful when X is a different halogen atom as iodine or bromine means. This is expediently achieved by adding a compound of the formula IX in which X is a other halogen atom than iodine or bromine, or means lower alkylsulfonyloxy or arylsulfonyloxy, with an alkali iodide in treated with an inert organic solvent. Although sodium iodide is preferably used for this purpose, it is it is clear that other iodinating agents common to those skilled in the art can also be used let apply. The iodine compound thus obtained is then preferably mixed with ammonia in the manner described above converted to a compound of formula XI.

In a further aspect of the method, compounds of the

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Formula IX, wherein X is a phthalimide group, obtained thereby that you can combine a compound of the formula VIII with a compound of the general formula

XIII

where R _{2 is} hydrogen or lower alkyl and X ^{1 is} halogen, preferably chlorine or bromine,

in the presence of an alkaline halogen acid binder. The condensation is carried out in a suitable inert solvent, such as a halogenated hydrocarbon, e.g., chloroform or methylene chloride, pyridine and the like. This reaction is preferably carried out at room temperature.

A compound of the formula IX in which X is a phthalimide group can also be obtained by a corresponding compound of the formula IX in which X is halogen, lower alkylsulfonyloxy or arylsulfonyloxy, preferably with an alkali metal salt of phthalimide (Kaliximplithalimid).

A compound of the formula IX, in which X is a phthalimide group, obtained in this way can be converted into the corresponding compound of formula X can be converted by treatment with hydrazine hydrate. This process is preferably carried out in an inert organic solvent carried out. Preference is given to working in the presence of one or more mol equivalents of hydrazine hydrate. Temperature and

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Pressures are not critical to the successful implementation of this aspect of the process, but it is preferred to work with elevated temperatures. In order to obtain good yields, the reaction is carried out in an inert organic solvent, like a lower alkenol, e.g. ethanol. A compound of the formula X obtained in this way can be used directly, i.e. without Isolation or interruption of the reaction can be converted into the corresponding compound of the formula XI.

In a further aspect of the method, a compound of the formula IX wherein X is halogen, lower alkylsulfonyloxy or Arylsulfonyloxy means treated with an azide group donating reagent. Examples of such azide groups provide Reagents are alkali azides, such as sodium azide, potassium azide, Lithium azide, alkaline earth azides such as ealzium azide, Ammonium azide and the like. Sodium azide is preferably used. In this process step, a compound of formula IX in a suitable organic solvent, such as a Alkanol such as methanol, an ether such as dioxane, tetrahydrofuran and the like. This solution is then warmed up slightly, whereby the azide compound is obtained. The thus obtained Compound is then made by catalytic hydrogenation in the presence a common catalyst such as Raney-Hickel, a noble metal catalyst , such as palladium, platinum and the like. Selectively reduced, the corresponding compound of the formula X receives. The catalytic hydrogenation is preferred in the presence of an inert organic solvent, such as ether, e.g., tetrahydrofuran. The compound of formula X thus obtained is preferably without isolation from the The reaction mixture in which it was prepared in a suitable inert organic solvent such as ethanol or methanol and the like. and then cyclized as described above for the corresponding compound of the formula XI.

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BATH ORIGINAL

In a further process aspect, the azide of the compound of the formula IX can be obtained directly from a compound of the formula VIII can be prepared by combining this compound with a compound of the formula ÜL-OHCOCI (e.g. azidoacetyl chloride) at a temperature between about 10 and about 50 in the presence of an organic solvent such as chloroform implements "

Compounds of the formula IX or of the formula XI can be converted into the corresponding compounds which are lower alkylated in the 1-position be transferred through appropriate procedures. For example, compounds of the formula IX or XI can be mixed with an alkali hydride, e.g. sodium hydride or potassium tert-butoxide and the like. be converted to the corresponding 1-alkali metal salt. This The alkali metal salt can then be mixed with an alkylating agent such as a methyl halide, e.g. methyl iodide, ethyl iodide, propyl iodide and the like, or a di-lower alkyl sulfate such as dimethyl sulfate or diethyl sulfate can be converted into the corresponding N-lower alkyl derivative. Such an N-lower alkylated compound of the formula IX can according to the method given for the corresponding unsubstituted compounds in the corresponding compound of the formula XII are converted.

Compounds of the formula XII can be reduced catalytically to the corresponding tetrahydro derivatives of the formula III using a suitable reduction system, for example by hydrogenation in the presence of platinum, Raney-Nlckel and the like. This reaction is carried out in a manner known per se in an inert organic solvent, such as an alkanol, for example ethanol, methanol and the like. Or an ether, such as diethyl ether _t tetrahydrofuran and the like. Carried out.

Compounds of the formula II can be prepared from the corresponding compounds of the formula XII by a compound of formula XII in an inert organic

2 0 9 8 2 9/1168 ^ ^{0 pRlGiNAL}

Solvents treated with an oxidation system, which converts this compound to IT oxide. Suitable organic Solvents are halogenated hydrocarbons such as methylene chloride, weak peracids, such as chloroperbenzoic acid, peracetic acid and the like. Serve.

The compounds of the formula IV can be prepared by using a benzophenone of the general formula

R-C

where R, R-, and R, have the above meaning, with an acid ester halide of the general formula

0 NH-carbobenzoxy halo-6-CH-COO-lower alkyl converts, whereby a compound of the general formula

XV

R-. 0

I ¹ I!

N — C — CII-COO-

M-carbobenzoxy

lower alkyl

XVI

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wherein R ₁ R-, and R "have the above meaning, receives ·

The reaction of a benzophenone of formula XIV with a Acid ester halide of the formula XV is advantageous in the presence of a inert organic. Solvent carried out. Suitable solvents for this purpose are hydrocarbons, such as Benzene, toluene and the like, chlorinated hydrocarbons such as methylene chloride and the like. And ethers such as dioxane and the like. The Reaction can take place at temperatures between -40 and the reflux temperature of the reaction mixture carried out ".

In addition, the reaction between compounds of the formulas XIV and XV in the presence or absence of a Acid acceptor are carried out. Acid acceptors suitable for this purpose are, for example, bicarbonates, such as sodium bicarbonate and the like. And triethylamine.

The compound of formula XVI thus obtained is then treated with a hydrohalic acid in the presence of acetic acid treated. The crude product obtained is then neutralized and heated in benzene, whereby cyclization to a compound of the formula Ig occurs. Hydrobromic acid is preferably used as the hydrohalic acid. The reaction can carried out at room temperature or below.

Compounds of the formula I are anticonvulsant, muscle relaxant and sedative. Such compounds can be incorporated into pharmaceutical preparations with the use of suitable ones pharmaceutical carriers are transferred and can be enterally or parenterally according to the requirements of the pharmacological situation either in the form of the free base or as an acid addition salt with a pharmaceutical applicable oii acids, such as hydrochloric acid, hydrobromic acid and the like. Can be applied.

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BATH

The new compounds of formula I can be incorporated into pharmaceutical Gebrauohsformen, which about Contain 100 to 200 mg of active ingredient, the dosage of the species to be treated and the individual requirements Barenteral formulations are commonly used contain less active substance than preparations for oral administration. The new connections according to this Invention can be used alone or in combination with pharmaceutically acceptable carrier materials in many dosage- forms are used. As mentioned above, where indicated, they can be in the form of pharmaceutically acceptable acid addition salts be used.'

For example, one can use solid preparations for oral use Administration such as tablets, capsules, powders, granules, emulsions, suspensions and the like. Use. Solid preparations can contain an inorganic carrier such as talc, or an organic carrier such as lactose, starch. Additives such as magnesium stearate (a lubricant) can also be used. Liquid preparations, such as solutions, Suspensions or emulsions can contain the usual diluents, such as water, a suspending agent such as polyoxyethylene glycols, vegetable oils and the like. They can also contain other additional ingredients, such as preservatives, Stabilizing agents, wetting agents, salts for changing the oesmotic pressure or buffers. You can also they contain other therapeutically valuable substances in combination.

The following examples illustrate the invention · All temperatures are in ⁰ C.

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example 1

A solution of 847 mg (2.6 mmol) of 7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-1,3 »4,5-tetrahydro-2H-1,4-benzodiazepine -2-one in 20 ml of 3N aqueous hydrochloric acid is allowed to stand at room temperature for 10 minutes. Mach neutralization with a saturated aqueous HatriumbicarbonatlÖsung and extraction with methylene chloride, one can Aoetyl _{7-phenyll-5-f} 3f4,5-tetrahydro-2H-l, 4-'benzodiazepin-2- "on isolate. Crystallization from acetonitrile gives a product with a melting point of 184-186 °.

The starting material can be produced as follows:

To a solution of 330 g (2.0 mol) of p-nitroacetophenone in 2.5 liters of benzene, 160.0 g (2.5 mol) of ethylene glycol " "and 5.0 g of p-toluenesulfonic acid were added. The clear solution reflux with a Dean-Stark trap for 3 hours heated until no more water is separated out. After cooling, the cloudy benzene solution turns from a small one alcoholic Sohioht decanted and dried over anhydrous sodium sulfate. The solution is then made up to about 1 liter concentrated and poured onto 4 liters of hexane. The colorless flakes of 2-methyl-2- (4-nitrophenyl) -l, 3-dioxolane will be separated and washed with hexane, melting point 71-73. Analytical results are obtained by recrystallization from methyl chloride / hexane Material as colorless flakes with a melting point of 73-74 °.

58.6 g (0.50 mol) of phenylacetonitrile are added to a solution of 100 g (2.5 mol) of sodium hydroxide in 500 ml of methanol and then 104 g (0.50 mol) of 2-methyl-2- (4-nitrophenyl) -1,3-dioxolane added at room temperature, the temperature rising to about 55 ° in the harvest half hour. To The reaction mixture is filtered after stirring vigorously for 16 hours and the residue with water and then with small por-

209829/1168 _BAD ORIGINAL

washed cold methanol, 5- (2-methyl-1,3-dioxolan-2-yl) -3-phenyl-2,1-benzisoxazole obtained as a light yellow powder, melting point 137-138 °.

A solution of 2.81 g (10 mmol) 5- (2-methyl-1,3-dioxolan-2-yl) -3-phenyl-2,1-benzisoxazole in 35 ml of tetrahydrofuran in the presence of 200 mg of palladium on carbon at atmos- hydrogenated spherical pressure and room temperature for 2 hours. Then the catalyst is filtered off and the filtrate to Evaporated dry. The remaining oil is crystallized from benzene / hexane, crude 2-amino-5- (2-methy1-1,3-dioxolan-2-yl) benzophenone obtained as slightly yellow needles, melting point 97-99 °. The crude product will continue through Chromatography on 50 g aluminum oxide (neutral, Woelm activity I) cleaned. By eluting with 20% diethyl ether / methylene chloride and crystallization from methylene chloride / hexane gives 2-amino-5- (2-methyl-1,3-dioxolan-2-yl) benzophenone as yellow prisms, melting point 112-114

A mixture of 14.2 g (50 mmol) of 2-amino-5- (2-methyll, 3-dioxolan-2-yl) benzophenone and 10.4 g (50 mmol) of chloroacetic anhydride in 150 ml of benzene is flattened to stand calmly. The benzene solution is washed with saturated sodium bicarbonate solution and then with water, dried and evaporated to dryness. Crystallization of the residue from ethanol gives 2 ¹ -benzoyl-2-chloro-4 '- (2-methyl-1,3-dioxolan-2-yl) aoetanilide as colorless needles, melting point 131-133 °.

In an analogous manner, from 2-amino-5- (2-methy1-l, 3-dioxolan-2-yl) benzophenone and Mesyloxyacetylchlorid 2 '-benzoyl ^ -mesyloxy ^ ^l - (2-methyl-l, 3-dioxolan -2-yl) acetanilide and from 2-amino-5- (2-methyl-1,3-dioxolan-2-yl) benzophenone and tosyloxyacetylohlorid 2 ^f -Benzoyl-2-tosyloxy-4 '- (2-methy1-1 , 3-dioxolan-2-yl) aoetanilide.

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A) A mixture of 14.0 g (39 mmol) of 2-benzoyl-2-chloro-4 '- (2-methyl-1,3-dioxolan-2-yl) acetanilide and 11.6 g (78 mmol) Sodium iodide in 500 ml of acetone is refluxed for half an hour. After cooling, the reaction mixture is filtered and the solvent is evaporated off under reduced pressure. The residue consisting of crude 2'-benzoyl-2-iodo-4 ^l - (2-methyll, 3-dioxolan-2-yl) acetanilide is dissolved in 150 ml of tetrahydrofuran and this solution is added to 400 ml of liquid ammonia in a stirred vessel Dry ice cooler. The reaction mixture is then stirred under reflux for 5 hours, the excess ammonia is evaporated off overnight and the inorganic salts are removed by filtration. The tetrahydrofuran is then removed under reduced pressure and an oil of crude 2 ^l -benzoyl-2-amino-4 '- (2-methyl-1,3-dioxolan-2-yl) acetanllide is obtained, which is dissolved in 200 ml of ethanol and heated to reflux for 2 hours. On cooling, colorless prisms of 1,3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5-pheny1-2H-1,4-kenzodiazepin-2-one crystallize out, melting point 250- 252 °. After recrystallization from ethanol, the melting point remains unchanged.

B) A mixture of 2.0 g (5.6 mmol) of 2'-benzoyl-2-chloro-4 '- (2-methyl-1,3-dioxolan-2-yl) acetanilide and 1.68 g (11.2 mmol) of sodium iodide in 100 ml of acetone is added for half an hour heated to reflux. After cooling, the insoluble inorganic salts are filtered off and the filtrate evaporated to dryness. The residue is then partitioned between methylene chloride and water, the organic phase separated, dried and evaporated to dryness. The residue obtained in this way is crystallized from methanol, whereby one 2 · -Benzoyl-2-iodo -4 '- (2-methyl-1,3-dioxolan-2-yl) acetanilide obtained as colorless prisms, melting point 117-119 ° · The crystals are dissolved in 150 ml of tetrahydrofuran and the so obtained solution to 400 ml of liquid ammonia in a 1000 ml three-necked flask equipped with a stirrer and a Trooke ice cooler

209829/1168

given. The reaction mixture is then stirred under reflux for 5 hours, then the excess is added Ammonia evaporated over Naoht and the inorganic salts filtered off. The tetrahydrofuran is evaporated off under reduced pressure and the remaining oil in 200 ml of ethanol dissolved and the resulting solution heated to reflux for 2 hours. On cooling, 1,3-dihydro-7- (2-me thy 1-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one as colorless prisms, melting point 250-252 °.

C) To a solution of 8.4 mmol of 2 »-Benzoyl-2-chloro-4 '- (2-methyl-1,3-dioxolan-2-yJ.) Acetanilide 16.8 mmol of sodium azide are added all at once in 120 ml of methanol. the The reaction mixture is then heated on a steam bath for 15 minutes. The reaction mixture is then used to Evaporated dry and the residue partitioned between water and methylene chloride. The organic phase is separated washed with water, dried and evaporated. Crystalline * - Sation of the residue from ethanol gives 2-azido-2'-benzoyl-4 '- (2-methyl-1,3-dioxolan-2-yl) aoetanilide

By reacting 2 'benzoyl-2-mesyloxy-4' - (2-methyl-1,3-dioxolan-2-yl) acetanilide or 2'-benzoyl-2-toxyloxy-4 '- (2 -methyl-1,3-dioxolan-2-yl) acetanilide with matrium azide 2-azido-2 ^l -benzoyl-4 ^l - (2-methyl-1,3-dioxolan-2-yl) acetanilide.

A solution of 6.2 mmol of 2-azido-2'-benzoyl-4 ^l - (2-methyll, 3-dioxolan-2-yl) acetanilide in 125 ml of tetrahydrofuran are at atmospheric pressure for two hours in the presence of 350 mg of 10 ^ hydrogenated pure palladium on carbon, 2-amino-2'-benzoyl-4 ^l - (2-methyl-1,3-dioxolan-2-yl) acetanilide being obtained. When the hydrogenation has ended, the catalyst is filtered off through Oelit and the piltrate is evaporated to dryness. The slightly yellow residue is dissolved in 125 ml of ethanol and the resulting

209829/1168

Solution heated to reflux for 2 hours «, then is the solvent is evaporated off, l, 3-dihydro-7 ~ (2-methyl-1,3-dioxolan-2 ~ yl) -5-phenyl-2H-l, 4-benzodiazepin-2-one obtained as colorless prisms, melting point 250-252 °.

In a manner analogous to that described above, the following compounds can be prepared: 1,3-Dihydro-7- (2-ethy1-1,3-dioxolan-2-yl) -S-phenyl- ^ Hl, 4-benzodiazepine-2 -on; 1,3-dihydro-7- (2-propyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one; 1,3-Dihydro-7- (2-butyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

A solution of 3.0 g (9.3 mmol) 1,3-dihydro-7- (2-methy1-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepine-2 -on in 150 ml of tetrahydrofuran is hydrogenated in the presence of 2.0 g of platinum oxide at atmospheric pressure for 8 hours. Thereafter the catalyst is filtered off and washed with tetrahydrofuran. The filtrate is evaporated under reduced pressure and the residue crystallized from acetonitrile, 7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2 -on Obtained as colorless prisms, melting point 181-182 °.

Example 2

A warm solution of 76 mg (0.40 mmol) of p-toluenesulfonyl chloride in 5 ml of absolute pyridine slowly becomes a boiling solution of 107 mg (0.38 mmol) of 7-aoetyl-5-phenyl-1,3.4.5 -tetrahydro-2H-1,4-benzodiazepin-2-one given in absolute pyridine. The reaction mixture is then heated to reflux for 15 hours with exclusion of moisture and then poured into 10 ml of ice water. This mixture is then left to stand overnight at 5 °, the deposited precipitate is filtered off, washed with water, followed by ethanol and ether and recrystallized from acetonitrile _s whereby 7-acetyl-

209829/1168

5-phenyl-1,3,4 »5-tetrahydro-5-p-toluenesulfonyl-2H-1,4-benzodiazepin-2-one Obtained as yellow prisms, melting point 265-266 °.

Example 3

To a stirred solution of 9.65 g (30 mmol) 1,3-dihydro-7- (2-methyl-1,3-diozolan-2-yl) -5-phenyl-2H-1,4-benzodiazepine-2 6.0 g (30 mmol) of 85% m-chloroperbenzoic acid are added to 150 ml of methylene chloride. The reaction mixture is then stirred until a clear solution is obtained

* which is then left to stand at room temperature for 24 hours. The reaction solution is then concentrated to a smaller volume and the precipitated m-chlorobenzoic acid is filtered off. The filtrate is evaporated to dryness and the crude 1,3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one obtained in this way 4-Oxide dissolved in 50 ml of tetrahydrofuran and treated with 30 ml of 3N aqueous hydrochloric acid. The reaction mixture is then stirred for 20 minutes at room temperature, adjusted to pH 7 with aqueous sodium hydroxide solution, diluted with water and extracted with methylene chloride. The methylene chloride extracts are washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and

W concentrated to a smaller volume. By slowly adding ether, crude crystalline 7-acetyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazpin-2-one 4-oxide precipitates, melting point 193-195. Recrystallization from acetone gives yellow needles with a melting point of 208-209 °.

Example 4

A suspension of 1.61 g (5.0 mmol) 1,3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepine-2 -on in 10 ml of absolute dimethylformamide with stirring in a nitrogen atmosphere with 288 mg (6 mmol) of 50% sodium hydride dispersion in oil in small portions within 1 minute added, whereby initially hydrogen evolves. Inner

209829/11 68 ™ _IM *.

BATH ORIGINAL

half past ten minutes the heat mix becomes solid G-elatin mass After 15 minutes, 0.5 nil (8 mmol) of methyl iodide added all at once, the whole solid dissolving within 10 minutes. After 30 minutes the reaction mixture becomes Poured into 100 ml of ice-cold water and extracted with ether. The ether extracts are washed with water, dried over anhydrous sodium sulfate and concentrated to a smaller volume. 1,3-Dihydro-imethyl-7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one crystallizes on cooling off, melting point 122-124 °. Recrystallization from Acetone / hexane provides colorless prisms, melting point 122-24 °.

Example 5

To a solution of 44 »Q g (1.10 mol) of sodium hydroxide 26.0 g (0.22 mol) of benzyl cyanide and 43 »0 g (0.22 mol) of p-nitrophenyl-1,3-dioxolane are added in 200 ml of methanol. the The reaction mixture is stirred vigorously for 30 minutes, The solution initially takes on a dark red color and then silky yellow needles crystallize out Crystals are filtered off, washed with water and methanol and recrystallized from methanol, 5- (l »3-dioxolan-2-yl) -3-phenyl-2,1-benzisoxazole obtained as colorless needles, melting point 134-135 °.

A solution of 26.7 g (0.1 mole) 5- (l # 3-dioxolan-2-yl) -3-phenyl-2,1-benzisoxazole in 350 ml of tetrahydrofuran is in the presence of 2.0 g of lO ^ igem palladium on charcoal Hydrogenated atmospheric pressure and room temperature for one hour. The catalyst is then filtered off and the filtrate is evaporated to dryness. The crystalline residue is then up recrystallized from benzene / hexane to a constant melting point, taking 2-amino-5- (1,3-dioxolan-2-yl) benzophenone as easily yellow flakes obtained, melting point 95-97 °.

209829/1168

A solution of 2.69 g (10 mmol) of 2-amino-5- (1,3-dioxolan-2-yl) benzophenone and 2.08 g (10 mmol) of chloroacetic anhydride in 30 ml of benzene will stand at 5 ° overnight calmly. The reaction mixture is then washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfate free from water and evaporated to dryness. Crystallization of the residue from ethanol yields 2; '- Benzoyl-2-chloro-4 ^f - (1,3-dioxolan-2-yl ) acetanilide as colorless needles, melting point 152-153 °.

A mixture of 5.2 g (15.0 mmol) of 2'-benzoyl-2-chloro-4 '- (1,3-dioxolan-2-yl) acetanilide and 4.45 g (30 mmol) of sodium iodide in 250 ml Acetone is refluxed for 30 minutes. The insoluble inorganic salts are then filtered off and the piltrate is evaporated to dryness. Crystallization of the residue from ethanol to a constant melting point gives 2 ^l -Benzoyl-4 '- (1,3-dioxolan-2-yl) -2-iodoacetanilide as colorless needles, melting point 110-112 °.

A solution of 5.0 g (11.4 mmol) of 2'-benzoyl-4 ^l - (1,3-dioxolan-2-yl) -2-iodoacetanilide in 50 ml of tetrahydrofuran is added to 250 ml of ammonia. The reaction mixture is stirred under reflux for 5 hours and the excess ammonia is evaporated off overnight, 2-amino-2 ^l -benzoyl-4 ^l - (l, 3-dioxolan-2-yl) acetanilide being obtained. The tetrahydrofuran is evaporated off under reduced pressure and the residue is partitioned between methylene chloride and water, the methylene chloride phase is separated off, dried and evaporated to dryness and the residue is dissolved in 25 ml of ethanol. This solution is then heated to gentle reflux on a steam bath for 15 minutes. When the ethanol solution cools, 1,3-dihydro-7- (1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one crystallizes out as slightly yellow prisms, melting point 153- 154 °.

V Ü 0 8 2 9/1 1 B 8

Example 6

A solution of 1.4 g (5 mmol) of 7-acetyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-Oxide in 45 ml of acetic acid is present at room temperature and atmospheric pressure hydrogenated by 0.4 g of prehydrogenated platinum oxide. After 1 hour the absorption is slightly more (137 ml) than 5 mmoles of hydrogen completed. The catalyst is filtered off and the filtrate is evaporated to dryness under reduced pressure. Crystallization of the residue from methylene chloride and recrystallization from the same solvent gives 7-acetyl-4-hydroxy-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepin-2-one as colorless crystals, melting point 201-203 °.

Example 7

A suspension of 0.5 g (16.9 mmol) of 7-aoetyl-4-hydroxyl, 3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 5 ml of acetic anhydride is heated on a steam bath for 10 minutes so that a clear solution is obtained. When cooling down 4-Acetozy-7-acetyl-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepin-2-one crystallizes as a pure colorless crystalline product with a melting point of 187-188.

Example 8

A mixture of 0.6 g of 4-acetoxy-7-acetyl-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 0.6 ml of triethylamine and 15 ml of ethanol is on a for 10 minutes Steam bath heated. Then the reaction mixture is under concentrated under reduced pressure to a smaller volume and slowly diluted with petroleum ether. The crystalline reaction product is filtered off and recrystallized from methylene chloride and petroleum ether, with 7-acetyl-l, 5-dihydro-5-phenyl-2H-l, 4-benzodiazepin-2-one obtained as colorless prisms, melting point 200-201.

^209829/1168

Example 9

A solution of 1.0 g of T-1,4-benzodiazepin-2-one 4-oxide in 150 ml of tetrahydrofuran is under nitrogen atmosphere with a 250 watt Hanovia medium pressure mercury lamp with the connection of a Pyrex filter irradiated

After 1 hour, thin-layer chromatography can no longer detect any starting material and the solution gives a strong positive starch iodide test. Then we will find a solution evaporated to dryness at tree temperature. Crystallization of the remaining oil from benzene gives 7-acetyl-1,3-dihydro-4,5-epoxy-5-phenyl-2H-1,4-benzodiazepin-2-one, Melting point 134-136 ° (decomp.).

Example 10

A) To a solution of 1.0 g (3.54 mmol) of 2-amino-5- (2-methyl-1,3-dioxolan-2-yl) benzophenone 14 ml IM HOlO- are given in 30 ml of ethanol. The mixture is left overnight at room temperature touched. Then the ethanol-insoluble fraction becomes filtered off and the piltrate made basic with 3 N sodium hydroxide solution and distributed between methylene chloride and water. The organic phase is dried and evaporated to dryness. The residue is combined with the Aethano! -Insoluble portion and crystallized from benzene / hexane to give 2-amino-5-acetylbenzophenone obtained as a yellow tuft of needles, melting point 152-154 °.

B) A solution of 1.18 g (5.0 mmol) of 5-acetyl-3-phenyl-2,1-benzisoxazole in 25 ml of tetrahydrofuran is at atmospheric pressure in the presence of 200 mg of lO ^ igem palladium on carbon hydrogenated. The uptake of hydrogen has ended after 30 minutes and the catalyst is filtered off. The tetrahydrofuran is then evaporated off and the residue is crystallized from benzene, 2-amino ~ 5-acetylbenzophenone being obtained as yellow prisms

^209829/1168

obtained, melting point 153-154 °.

Example 11

3 ml of 6Π hydrochloric acid are added to a solution of 270 mg (1.01 mmol) of 2-amino-5- (1,3-dioxolan-2-yl) benzophenone in 5 _f 0 ml of tetrahydrofuran and the mixture is added for 5 minutes " The reaction mixture is then diluted with 15 ml of water, made basic with 10M potassium hydroxide solution and extracted with methylene chloride. The organic phase is separated off, dried and evaporated to dryness. Crystallization of the residue to a constant melting point from benzene / hexane gives 2- Amino-5-formyl-benzophenone as yellow microprisms, melting point 134-136 °.

Example 12

To a suspension of 4 »8 g (18 mmol) of 2-carbomethoxy-N- (benzoyloxycarbonyl) glycine in 30 ml of methylene chloride, 3.78 g (18 mmol) of phosphorus pentachloride are added all at once at 0 °. Further stirring at 0 ° forms a clear solution, to which 2.79 g (11.7 mmol) of 5-acetyl-2-aminobenzophenone are added after 20 minutes are given. After stirring for a further 20 minutes at 0 °, 150 ml of a saturated aqueous Sodium bicarbonate solution was slowly added with vigorous stirring. The two-phase reaction mixture is then left to stand at -5 ° overnight. Then methylene chloride is added and the two layers separated. The methylene chloride phase is washed with aqueous sodium bicarbonate solution and dried and evaporated. Crystallization of the gummy residue from methanol gives 4'-acetyl-2'-benzoyl-2- £ (benzyloxycarbonyljaminoj ^ -carbomethoxyacetanilide as white prisms with a melting point of 123-126. After repeated recrystallization from methanol the melting point rises to 127-128 °.

2 0 9829/1168

A solution of 1.60 g (3.28 mmol) 4 ^l -acetyl-2 ^l -benzoyl-2-f (benzyloxycarbonyl) aminoJ-2-carbomethoxyacetanilide in a mixture of 10 ml 30 # hydrobromic acid in acetic acid and 15 ml glacial acetic acid are left to stand at room temperature for 16 hours. Then the solvent is evaporated off under reduced pressure and the residue is partitioned between water and ether. The aqueous phase is washed again with ether and then adjusted to about pH 10 with sodium hydroxide solution. Extraction of the basic aqueous solution with methylene chloride gives a crude mixture, which is dissolved in a mixture of 50 ml of benzene and 5 ml of glacial acetic acid and refluxed under moisture for 4 hours, after which the solvent is removed under reduced pressure and the crude product mixture by thin-layer chromatography at 20 cm χ 20 cm silica gel plates cleaned, elution with ethyl acetate yields a product which crystallizes from benzene / hexane rd, recrystallization from benzene gives 7-acetyl-3-oarbomethoxy-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one as lends yellow prisms, melting point 195-196 °.

Example 13

A mixture of 1.24 g (4.0 mmol) 1,3-dihydro-7- (1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one and 240 mg (5.0 mmol) of sodium hydride (λ, 50 # dispersion in OeI) in 10 ml Dimethylformamide is stirred in an ice bath for 5 minutes. Then 660 mg (5.28 mmol) of dimethyl sulfate are added and the mixture was stirred at 0 ° for 15 minutes. The mixture is then added to 100 ml of ice water and extracted with ether. The ether extracts are dried and evaporated to dryness under reduced pressure. Crystallization of the A residue from ether / pentane gives 1,3-dihydro-7- (1,3-dioxolan-2-yl) -1-methyl-5-phenyl-2H-1,4-benzodiazepine as yellow prisms, melting point 138-139 °.

209829/1168

Any of the following compounds can be used as the active ingredient in any of the following examples;

7-acetyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-0xyd;

7-Acetyl-5-phenyl-1,3,4,5-te trahydro-2H-1,4-benzodiazepin-2-one;

7-acetyl-4-hydroxy-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepin-2-one;

4-Acetozy-7-acetyl-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepin-2-one;

7-acetyl-1,5-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one;

7-acetyl-3-carbomethoxy-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one j

7-acetyl-1,3-dinydro-4,5-epoxy ~ 5-pnenyl-2H-1,4-benzodiazepin-2-one and

7-acetyl-5-pnenyl-1,3,4,5-tetranydro-4-p-toluenesulfonyl-2H-1,4-benzodiazepin-2-one.

Example 14 Tablets are produced with the following composition:

Active ingredient lactose corn starch corn starch as a 10 ^ ige paste Talk

Magnesium stearate corn starch

Total weight 200.0 mg

The active ingredient, lactose and corn starch are mixed in a suitable mixer and then the starch paste is slowly added until a thick, moist mass is obtained, which can be replaced by a coarse Sieve guides «The moist granulate is discharged onto trooken plates ·

209829/1168

Per tablet mg 25.0 mg 98.0 mg 61.0 mg 5.0 mg 4.5 mg 1.5

spread and dried at 45 °. The dry granules will passed through a sieve and then in a suitable mixer with talc, with magnesium stearate and the second serving of cornstarch mixed together. Mix well and compress to tablets weighing 200 mg each.

Example 15

Capsules are made with the following composition:

Per capsule

Active ingredient 10 mg

Milk sugar 165 mg

Corn starch 30 mg

Talc 5 mg

Total weight 210 mg

The active ingredient, lactose and corn starch are mixed in a suitable mixer. The mixture is then passed through a grinding machine. The mixed powder is returned to the mixer, mixed with the talc and mixed well again. The mixture obtained is packed in hard gelatin capsules bottled on a capsule filling machine.

Example 16

A parenteral use form is made accordingly the following composition:

Per ml

Active ingredient 5.0 mg

Propylene glycol 0.4 ml

Benzyl alcohol (benzaldehyde free) 0.015 ml

Ethanol 95 # ig 0.10 ml

Sodium benzoate 48.8 mg

209829/1 168

Benzoic acid 1.2 mg

Water for injections q.s. 1.0 ml

The active ingredient is dissolved in 150 ml of benzyl alcohol whereupon φ liter of propylene glycol and 1 liter of ethanol clogs. 12 g of benzoic acid are dissolved in this solution, whereupon 488 g of sodium benzoate are dissolved in 3 liters of water for Injections added. The solution is brought to the final volume of 10 liters with water for injections. the Solution is filtered through a candle filter, into suitable Ampoules filled, gassed with nitrogen and sealed. It is then autoclaved at 0.7 atmospheres for 30 minutes.

209829/1 168

Claims (1)

Claims (l) Process for the preparation of benzodiazepine derivatives the general formula wherein R and R, hydrogen or lower alkyl, Rp Hydrogen, lower alkyl or the group -COORg and Rg are lower alkyl, B is one of the groups ■ CH - N- and or, for the Pail that R _{2 is} -COORg, the group means, H- hydrogen or halogen, R. hydroxy, arylsulfonyl, arylsulfonyloxy, lower alkylsulfonyl, lower alkylsulfonyloxy, lower alkanoyl or lower alkanoyloxy and R ₅ denotes hydrogen or with R. together an additional CN bond, and pharmaceutically acceptable acid addition salts thereof, thereby 209829/1168 marked that one a) for the preparation of compounds of the formula Ή R, Yes where R, IL and R, have the above meaning and R _{2 is} hydrogen or lower alkyl,
a compound of the general formula ■ R. wherein R, R, and R, have the above meanings, hydrogen or lower alkyl and R ₇ and R _Q mean a radical which can be removed by hydrolysis, hydrolysed, or that one 209829/1 168 ORIGINAL INSPECTED b) for the preparation of compounds of the formula in which R, R- and R, have the above meanings and R _{2 is} hydrogen or lower alkyl, a compound of the general formula wherein R, R ₁ , JL, R ₇ and R _{Q have the} above meaning and R _{2 is} hydrogen or lower alkyl, hydrolyzed, or that one c) for the preparation of compounds of the formula 209829/1 168 Io wherein R, IL and R, have the above meaning and R _{2 is} hydrogen or lower alkyl, a compound of the formula Ia is catalytically reduced, or that one d) for the production of. Compounds of the formula Ib a compound of formula Ia reduced, or that one e) for the preparation of compounds of the formula Id where R, R-, and R "have the above meaning and R _{2 is} hydrogen or lower alkyl, subjects a compound of the formula Ia to photolysis, or that f) for the preparation of compounds of the formula 209829/1168 ORIGINAL INSPECTED Ie where R, R, and R_ have the above meaning, Rp is hydrogen or lower AUsyl and R .1 is arylsulfonyl, arylsulfonyloxy, lower alkylsulfonyl, lower alkyl _T sulfonyloxy, lower alkanoyl or lower alkanoyloxy, a compound of the formula Ib or Ic with an arylsulfonyl halide, a lower alkylsulfonyl halide or a lower alkanoyl group-producing agent, or that one g) for the preparation of compounds of the formula wherein R, R ₁ and R- have the above meaning and R _{2 is} hydrogen or lower alkyl, a compound of the formula Ie into the corresponding 3,4-dehydro- 209829/1 1 68 ORIGINAL INSPECTED derivative, or that one h) for the preparation of compounds of the formula COOR, where R, H-, R, and Rg have the above meaning, a compound of the general formula CH — COO lower alkyl IV where R, R, and R- have the above meaning cyclized, and that i) if necessary, a product obtained in a transferred pharmaceutically acceptable acid addition salt. 2. The method according to claim 1, characterized in that a compound of formula II or III in claim 1 as Starting material is used. 209829/1168 ORIGINAL INSPECTED 3. The method according to claim 1, characterized in that a compound of formula Ia, Ib, Ic, Ie or IV in Claim 1 used as a starting material. 4. The method according to any one of claims 1-3, characterized in, that R «is hydrogen. 5. The method according to any one of claims 1-4, characterized in that that R is hydrogen, chlorine or fluorine. 6. The method according to any one of claims 1-5, characterized in that that R is hydrogen or methyl. 7. The method according to any one of claims 1-6, characterized by that R is methyl. 8. Method according to Claim 2 or 3, characterized in that that 7-acetyl-5-phenyl-1,3 »4,5-tetrahydro-» 2H-1,4-'benzodiazepin-2-one manufactures. 9. Ancestors naoh claim 3, characterized in that that 7-acetyl-5-phenyl-1,3 »4,5-tetrahydro-4-P-toluenesulfonyl-2H-1,4-benzodiazepin-2-one manufactures 10. The method according to claim 2, characterized in that nan 7-acetyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-Oxide produces. 11. The method according to claim 3 »characterized in that 7-acetyl-4-hydroxy-1,3,4» 5-tetrahydro-5-phenyl-2H-1,4-benzodiazepin-2-one manufactures. 12. The method according to claim 3, characterized in that 4-acetoxy-7-acetyl-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepin-2-one manufactures. 209829/1168 13. The method according to claim 3 »characterized in that 7-aoetyl-l, 5-dihydro-5-phenyl-2H-l, 4-benzodiazepin-2-one manufactures. 14. The method according to claim 3 »characterized in that 7-acetyl-1,3-dihydro-4» 5-epoxy-5-phenyl-2H-1,4-l5enzodiazepin-2-one manufactures. 15. The method according to claim 3 »daduroh characterized, that 7-acetyl-3-carlDometho: sy-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one manufactures. 209829/1168 lf>. Process for the production of preparations with anticonvulsant »muscle relaxing and sedative properties, characterized in that one is a benzodiazepine derivative of the formula I in claim 1 or a pharmaceutically usable acid addition salt thereof as an active ingredient Suitable for therapeutic administration, non-toxic, inert, solid and conventional per se in such preparations liquid carriers and / or excipients. 17. A pharmaceutical preparation with anticonvulsant, muscle relaxant and sedative properties _m, characterized in that it contains a Benzodiazepinderivfct of the formula I in claim 1 or a pharmaceutically acceptable acid addition salt thereof and a carrier material. 209829/1168 18. Benzodiazepine derivatives of the general formula where R and IL are hydrogen or lower alkyl,
Hydrogen, lower alkyl or the group -g and Rg are lower alkyl, B is one of the groups 'CH - NH' other or, in the event that R _{2 is} -OOORg, the group means, R- hydrogen or halogen, R. hydroxy, arylsulfonyl, arylsulfonyloxy, lower alkylsulfonyly, lower alkylsulfonyloxy, lower alkanoyl or
lower alkanoyloxy and R _{5 is} hydrogen or with
R ^, together denote an additional ON bond, and pharmaceutically acceptable acid addition salts thereof. 19. Benzodiazepine derivatives of the formula I according to claim 18, characterized in that R2 is hydrogen or lower alkyl 209829/1168 BATH ORIGINAL R _n - hydrogen .iiiid B one of the groups
5 C = N. rSo mean and R, R, and R ~ have the meaning given in claim 18
to have. 20. Benzodiazepine derivatives of the formula I according to claim 18, characterized in that B is one of the groups and or in the event that group ^^ ^ R, the group -GOORg means the means and R, R _{1 , R 2} , R_, R., R 1 - and Rg have the meaning given in claim 18. 21. Benzodiazepine derivatives of the formula I according to claim 18 in which Rp is hydrogen. 22. Benzodiazepine derivatives of the formula I according to claim 18 wherein R_ is hydrogen, chlorine or fluorine. 2 0 9 8 2 9/11 68 23. Benzodiazepine derivatives of the formula I according to claim. 18, in which. R _{1 is} hydrogen or methyl. 24. Benzodiazepine derivatives of the formula I according to claim. where R is methyl. 25. 7-Acetyl-5-piienyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one. 26. 7-Acetyl ~ 5-plienyl-1,4,5-tetrahydro-4-p-toluenesulfonyl-2H-1,4-benzodiazepin-2-one. 27 · 7-Acetyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide, 28. 7-Acetyl-4-hydroxy-1,3 »4,5-tetrahydro-5-ph.enyl ~ 2H-1,4-tenzodiazepin-2-one. 29. 4-Acetoxy-7-acety1-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepin-2-one. 30. 7-Acetyl-1,5-dihydro-5-phenyl-2H-1,4-13enzodiazepin-2-one. 31 7-acetyl-l, 3 ~ dihydro-4,5-epoxy-5-ph.enyl-2H-l, A- benzodiazepin-2-one. 32. 7-Acetyl-3-carbomethoxy-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one. \
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