NO130681B - - Google Patents

Description

Analogy process for the preparation of therapeutically active benzodiazepine derivatives.

The present invention relates to analog methods for the production of therapeutically active iodine-substituted benzodiazepine derivatives with the general formula,

where means hydrogen or methyl,

and acid addition salts thereof.

According to the present invention, compounds with the above-mentioned formula I and acid addition salts thereof are prepared according to the following method:

a) cyclization of a compound of the general formula,

where has the above meaning,

or

b) treatment of a compound of the general formula,

where has the meaning stated above,

with glycine or an ester thereof, or

c) carrying out a ring expansion and acid hydrolyses under aqueous conditions of a compound of the general formula,

where R1 has the meaning defined above and %

R2 means lower allcyl,

or

d) oxidation of a compound of the general formula,

where R^- has the meaning given above,

oller

e) make the diazonium salt of a compound of the general formula

where R^ has the above meaning,

subject to a Sandmeyer reaction or

f) oxidize or dehydrogenate at the 4,5 bond to a compound of the general formula, where R^ has the meaning stated above, or g) transfer one compound with the general formula,

where has the meaning stated above and

R^ means halogen or acyl,

to the corresponding 4,5-dehydro compound of formula I by treatment with a strong base, or

h) dehydrate a compound of the general formula,

where does the above anaite meaning,

to give the corresponding 4,5-dehydro compound of formula I, or

i) treatment of a compound of the general formula

where R has the above meaning and

R stands for acyl,

with a base to give the corresponding 4,5-dehydro compound of formula I, or

j) rearrangement of a compound with the general formula,

where R1 has the above meaning,

to the corresponding 4,5-dehydro compound of formula I, or

k) saponification and decarboxylation of a compound with it

general formula,

where R and R have the meanings given above, or

1) methylation of the compound of formula I, where R 1 means hydrogen, to obtain the compound of formula I, where R 1 means methyl, and

m) if desired, converts a compound of formula I into an acid addition salt.

By means of a method according to the present invention, one can consequently prepare compounds of the above formula I by cyclizing a compound of the above formula II, which in turn can be prepared from a compound of the general formula, where the above-mentioned betvdnina cg X means halogen, such as chlorine, bromine or iodine, with bromine being particularly preferred; alkyl or arylsulfonyloxy groups, such as e.g. mesyloxy and tosyloxy; a carbobenzoxyamino group or a phthalimido group,.

The intermediate amine according to formula II is preferably not isolated, but can be cyclized in situ under the reaction conditions used, thereby directly converting to the desired compound according to formula I. Optionally, the open compound according to formula II can be isolated, and then during ring formation the desired compound is obtained according to formula I. The cyclization to the compound of formula I is easily accelerated by heating the compound of formula II, which is preferably dispersed in an inert organic solvent.

When compounds of the above formula XIII, where X means halogen, alkylsulfonyloxy or arylsulfonyloxy, are used as starting material, the cyclization is carried out in the presence of ammonia. It is appropriate to cycle at a temperature in the range from approx. -35° to 100°C, and preferably in the range from approx. -35° to 35°C. The reaction can be carried out in the presence of an inert solvent. Suitable solvents for this purpose are inert organic solvents, such as lower alkanols, e.g. methanol, ethanol 0.1.5 ethers: such as e.g. ethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether 0.1.5 chlorinated hydrocarbons, such as e.g. methylene chloride and the like, and pyridine.

When using compounds of the above formula XIII, wherein

X means a carbobenzoxyamino group, as starting materials, the cyclization is carried out by first removing the amino protecting group, e.g. by treating a compound of formula XIII with hydrogen bromide in acetic acid, whereby the salt of the compound according to the above-mentioned formula II is formed. This salt is cyclized to the compound according to formula I by making the reaction mixture alkaline. It is convenient to carry out the reaction in the presence of an inert solvent. The previously discussed solvents are suitable for the cyclization of compounds of formula XIII in the presence of ammonia.

When compounds of formula XIII, where X is a phthalimido group, are used as starting materials, the cyclization is carried out by treating said compounds with hydrazine hydrate. This reaction is preferably also carried out in the presence of an inert solvent.

According to another method according to the invention, compounds of formula I can be prepared by allowing a compound of formula III, under slightly acidic conditions, to react with glycine or esters thereof, whereby methyl or ethyl esters are preferred.

A preferred method is to leave the compound with formula

III react under slightly acidic conditions with a glycine ester

with formula

for the preparation of a compound of formula,

where has the above meaning,

after which the product is cyclized in situ to the desired compound of formula I.

When carrying out the above-described reaction between a compound of formula III and an ester of glycine, it is preferred to use the hydrochloride of the ester. This reaction is conveniently carried out in the presence of an inert solvent, such as e.g. an alcohol with at least three carbon atoms in the chain, such as e.g. propanol, butanol, etc., or an aromatic hydrocarbon, such as benzene, toluene, xylene, etc. Suitable acids for making the reaction mixture slightly acidic are pivalic acid and p-toluenesulfonic acid. The reaction is preferably carried out at higher temperatures, and most preferably at the reflux temperature of the reaction mixture.

According to other methods according to the invention, compounds of the above formula I can be prepared by carrying out a ring expansion and acid hydrolysis under aqueous conditions of a compound of the above general formula IV.

Compounds according to formula IV may partly be present in the form of the corresponding, isomeric, open compounds of the general formula, where and R 2 have the above-mentioned properties.

Compounds of formula IV can also be converted into the corresponding compounds of formula I without isolation from the reaction mixture.

It is convenient to carry out the reaction in the presence of an inert solvent. Suitable inert organic solvents for this purpose include aromatic hydrocarbons, such as benzene, toluene, and the like, and chlorinated hydrocarbons, such as chloroform, carbon tetrachloride, and the like. Temperature and pressure are not critical. Consequently, the reaction can be carried out at temperatures from approx. room temperature to approx. the reflux temperature of the reaction mixture, but it is preferred to use heating, and most preferably the reflux temperature of the reaction mixture is used. Suitable acids for use in the method according to the present invention are organic and inorganic acids, e.g. alkanecarboxylic acids, such as formic acid, acetic acid, propionic acid and the like; aromatic acids, such as benzoic acid; hydrohalic acids, such as hydrochloric acid and hydrobromic acid; phosphoric acid etc. The amount of acid is not critical, but complete protonation of the amine nitrogen in the starting material must be avoided. When acetic acid is used, it can also serve as a loosening agent.

According to a further method variant according to the invention, lean compounds with the above formula i are produced by deoxidation of a compound with the above general formula V.

The deoxidation of a compound of formula V can be carried out by treating said compound with a phosphorus trihalide, such as e.g. phosphorus trichloride. It is convenient to carry out this reaction in the presence of an organic solvent, such as aromatic hydrocarbons, e.g. benzene, toluene, etc.; chlorinated hydrocarbons, e.g. carbon tetrachloride and the like, at room temperature, but also temperatures above and below room temperature can be used.

Alternatively, the oxidation of a compound of formula V can be carried out by hydrogenating in the presence of a hydrogenation catalyst, such as Raney nickel. <r>The reaction is suitably carried out in the presence of an inert organic solvent, such as e.g. dioxane, dimethoxyethane, acetic acid, etc. at room temperature,

but also temperatures above and below room temperature can be used.

In addition, the reaction can be carried out under pressure.

According to a further alternative, the deoxidation can be carried out

by treating a compound of formula V with zinc i. a smaller . amount of acetic acid. It is convenient to carry out the reaction at room temperature in the presence of an inert organic solvent, such as e.g. methylene chloride.

According to a further process variant according to the invention, compounds according to the above formula I can be prepared from the corresponding 7-amino-1,4-benzodiazepift-2-ones by using the Sandmeyer reaction. This first forms the diazonium salt

to the compound of the above formula VI.

The amino group in the compound of formula VI can be diazbted by means of conventional techniques, e.g. by treatment with some combination of reagents that produce nitric acid in situ, such as e.g. sodium nitrate-in mineral acid. e.g. hydrochloric or sulfuric acid. The diazonium salt of the compound of formula VI to then react with an iodide salt, preferably an alkali metal iodide, which e.g. sodium iodide'or - . potassium iodide, or cuprous iodide, in order to thereby obtain compounds

the part with formula I.

The diazotization of a compound of formula VI, as shown above, is carried out according to standard methods. E.g. the amine is dissolved in an aqueous solution of the mineral acid, and the mixture is cooled to a temperature between 0 and -10°. An aqueous solution of sodium nitrite is slowly added to form the diazonium salt. To avoid decomposition, the salt is allowed to react immediately with the iodide salt, whereby the iodine compound is formed.

According to a further method variant according to the invention

compounds of formula I can be prepared by dehydrogenation or oxidation of a compound of the above formula VII:.

Dehydrogenation or oxidation of a compound with the above formula VII, can e.g. carried out with oxygen, manganese dioxide, bromine, chlorine, azodicarboxylic acid esters (e.g. diethyl ester), etc. Preferred oxidizing agents are bromine and diethyl azodicarboxylate. This reaction is conveniently carried out in the presence of an inert atmosphere. ganic solvent, "such as aromatic hydrocarbons, e.g. benzene, toluene etc.; halogenated hydrocarbons •,- such as e.g. carbon tetrachloride; alcohols, such as e.g. methanol,- an anol etc. ethers, such as e.g. dioxane , tetrahydrofuran etc., and a preferred temperature lies between approx. - icPc and the reflux temperature of the solvent.

When halogen, such as bromine or chlorine, is used as oxidizing agent, an intermediate product with the above formula VIII can be formed, where R^ means halogen, such as, for example, chlorine or bromine. Such an intermediate product can be converted to the corresponding 4,5-dehydro compound of formula I by treatment with a strong base. _-

According to a further method variant according to the invention, a compound with the above general formula VIII,.

where R^ means e.g. alkyl-sulfonyl, such as e.g. mesyl, or

arylsulfonyl, such as tosyl, is converted to the corresponding 4,5-dehydro compound of formula I by treatment with a strong base.

Cleavage of the R^-substituent from the compound of formula VIII can be achieved with a strong base, such as alkali hydrides,

like for example. sodium hydride, alkali alkoxides. like for example. sodium methoxide and potassium t-butoxide, triethylamine and alkali amides, such as e.g. sodium amide, whereby all the aforementioned substances must be in aqueous solution. It is convenient to carry out this reaction in the presence of an inert solvent. Suitable solvents are ethers, alcohols, such as e.g. ethanol, hydrocarbons, such as benzene and toluene, and dimethylformamide. The reaction is preferably carried out at temperatures between approx. 0 and approx. 120°C.

According to this process variant, an intermediate product of a compound of the above formula XI can be formed, which can be rearranged to the corresponding 4,5-dehydro compound of formula I by treatment with a base.

According to a further method variant according to the invention, water can be split off from the compound with the above formula IX, whereby a compound with formula I is obtained.

Removal of water from the compound of formula IX can be carried out by treating said formula with a suitable reagent which will dehydrate the alcohol, e.g. thionyl chloride, phosphorus oxychloride and carbodiimides, such as e.g. dicyclohexylcarbodiimide.

It is convenient to carry out this reaction at room temperature and in the presence of an inert organic solvent, such as e.g. hydrocarbons, alcohols, etc. According to the method, an intermediate product can be formed from a compound of the above formula XI, which can be rearranged to the corresponding 4,5-dehydro compound of formula I by treatment with a base.

According to a further method according to the invention, a compound of the above-mentioned general formula X can be treated with a base, whereby the corresponding 4,5-dehydro compound of formula I is obtained.

The acid cleavage of a compound of formula X can be achieved

with a strong base. Suitable bases are alkali hydrides, such as e.g. sodium hydride, triethylamines, alkali amides, such as sodium amide, alkali alkoxides, such as sodium methoxide and potassium t-butoxide, whereby all are used in an aqueous solution.

It is convenient to carry out the reaction in the presence of an inert organic solvent, such as ethers, alcohols, e.g. ethanol, hydrocarbons, e.g. benzene and toluene, dimethylformamide, etc.

at a temperature between approx. -40° and approx. 120°C. The acyl group present as R4~ substituent can be a lower alkanoyl, such as acetyl, aroyl, such as benzoyl, lower alkylsulfonyl,

such as mesyl or arylsulfonyl, such as tosyl.

In the acid cleavage of a compound of formula X, an intermediate product of a compound of the above formula XI can be formed, which can be rearranged to the corresponding 4,5-dehydro compound of formula I by treatment with a base.

After. in a further method variant according to the invention, a compound of formula XI can be rearranged to the corresponding 4,5-dehydro compound by treatment with a base, such as an alkali alkoxide, e.g. sodium methoxide, alkali hydrides, e.g. sodium hydride, triethylamine and the like. It is appropriate to carry out the reaction in an inert solvent, such as e.g. hydrocarbons, ethers, alcohols, etc. at temperatures between approx. -40° and 120°C.

According to a further method variant according to the invention, compounds of formula I can be prepared by saponification and decarboxylation of a compound of the general above formula XII.

Compounds of the above formula XII can be hydrolyzed by means of conventional techniques, whereby the corresponding compounds are obtained, in which the substituent in the 3-position is the group -COOA, whereby A means the cation of a base. The hydrolysis of a compound of formula XII can e.g. is carried out by treating said compound with a base, such as e.g. alkali hydroxide, such as sodium hydroxide, potassium hydroxide, etc., an alkaline earth metal hydroxide, such as calcium hydroxide, etc.,

a tertiary organic base, such as triethylamine and the like or ethanolamine. The hydrolysis of a compound of formula XII can also be carried out by treating said compound with an acid. When an acid is used as a hydrolysis agent, the hydrolysis and decarboxylation can take place simultaneously, and in this way a compound with the above formula I is obtained.

After the hydrolysis, the compound obtained is decarboxylated using conventional techniques, and thereby the desired compound of formula 1 is produced. The decarboxylation can be easily completed by leaving the solution with the hydrolyzed compound to stand, or you can heat it or acidify this compound in the solution. Decarboxylation of the hydrolysed compound proceeds slowly when the solution is allowed to stand, but decarboxylation proceeds more rapidly when heated and occurs spontaneously when acidified.

According to a further method according to the invention, the compound of formula I, where R means methyl, can be prepared from the corresponding desmethyl compound according to known methods. E.g. the 1-position can be methylated using conventional techniques. Usually, e.g. the compound of formula I, where R 1 is hydrogen, is treated with an alkali metal hydride, such as sodium hydride, potassium t-butoxide and the like, to form the 1-alkali metal salt of formula I, and then treated with a methylating agent, such as methyl halide, e.g. methyl iodide, or a methyl sulfate, to form the 1-methyl compound.

The methylation reaction is preferably carried out in the presence of a

inert organic solvent, such as tetrahydrofuran. Temperature and pressure are not critical for the method, and for the sake of simplicity the reaction is carried out at room temperature and at atmospheric pressure.

Compounds of the above formula I can be converted into the acid addition salts, preferably into pharmaceutically acceptable acid addition salts, with both organic and inorganic acids, such as e.g. hydrochloric acid, hydrobromic acid,: nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. The pharmaceutically acceptable acid addition salts can be formed using conventional techniques.

The starting materials for the method according to the invention can be produced using different preparative methods.

According to such a method, a compound of formula is treated,

where R^ has the above meaning,

R5 means hydrogen, acetyl or -COCH2X and

X has the above meaning,

with iodine monochloride in the presence of an inert organic solvent, whereby the desired iodinated benzophenone of formula,

where R, and Rj. has the above meaning,

is produced.

The treatment of a compound of the above formula XV with iodine monochloride is preferably carried out in the presence of an etherified organic solvent. Suitable solvents for this purpose include alcohols, such as methanol, ethanol and the like; hydrocarbons, such as benzene, toluene and the like; halogenated hydrocarbons, such as chloroform, carbon tetrachloride and the like; acetic acids and acetic anhydride. According to a preferred embodiment, chloroform, acetic acid or acetic anhydride is used as the solvent.

Reaction conditions, which are used when treating a compound of the above formula XV with iodine monochloride, can vary as temperature, pressure and reaction time are not critical. Consequently, temperatures in the area are from approx. 10° to approx. 100°C suitable, and the choice of temperature will primarily depend on the used release system. When chloroform is used as a solvent, it is appropriate to carry out the reaction at room temperature. If, on the other hand, acetic acid or acetic anhydride is used as a solvent, it is appropriate to carry out the reaction at higher temperatures, preferably between approx.

60° and 100°C, and most preferably at approx. 80°C. For simplicity, the reaction is carried out at atmospheric pressure.

The molar ratio of the reactants used in iodination

of ketones of formula XV, and which is carried out using iodine monochloride, will vary somewhat with the choice of reactants, especially with the choice of solvents and reaction conditions. As mono-iodination is desired, when chloroform is used as solvent, it is preferred to use 2 moles of iodine monochloride for the reaction, as the molar ratio results in optimum yield. On the other hand, if under the same conditions acetic acid is used as solvent, it is preferred to use one mole of iodine monochloride.

In the case when the R^-substituent in the compound of formula XV means haloacetyl, the treatment of said compound with iodine monochloride will, in addition to the iodination of the benzophenone, also result in a halogen exchange in the haloacetyl radical, i.e. that the chlorine, bromine or fluorine present in the haloacetyl radical can be replaced with the more reactive iodine ion.

Alternatively, compounds of the above formula XIV can be prepared by treating a compound of the above formula XV with iodine in the presence of a suitable oxidizing agent.

In effecting the iodination of a compound of formula XV with iodine, any suitable oxidizing agent may be used. Representative oxidizing agents, which can be used for this purpose, include sodium persulfate, nitric acid, iodic acid, mercury solvoxide, lead oxide, solvoxide and the like. According to a preferred method, sodium persulfate is used as oxidizing agent.

It is possible that the iodination of the compound of the above formula XV with iodine under oxidizing conditions is the result of the removal of formed iodide ions, which are formed as a by-product of the oxidation reaction. Consequently, any oxidizing agent, which thus oxidizes the hydroiodic acid or iodine ions formed by the reaction to iodine, is suitable for the present purpose. While the above-mentioned oxidizing agents are representative of those that are preferred, this does not preclude that other oxidizing agents may also be used. All that is required of the oxidizing agent is that it causes the formation of iodine under the reaction conditions used.

In the case of the substituent R 2 in a compound of formula XV

means haloacetyl, then the treatment of this compound can

with iodine under oxidation conditions, and in addition to the iodination ' "~ åv béhzofénbnét, also eftérfolgés -av et halbgeneutbytté" i'~ : the halogenacetyl residue, i.e. that the chlorine, bromine or fluorine present in the halogenacetyl residue can be replaced with iodine, which is more reactive.

The treatment of a compound of formula XV with iodine under oxidizing conditions is preferably carried out in the presence of an inert organic solvent. Solvents suitable for this purpose include alcohols, such as methanol, ethanol and the like; hydrocarbons, such as benzene, toluene and the like; halogenated hydrocarbons, such as chloroform, carbon tetrachloride etc. acetone,

ether, petroleum ether, carbon disulfide and acetic anhydride. In a preferred embodiment, acetic anhydride is used as a solvent.

Reaction conditions for iodination of a compound with

formula XV with iodine in the presence of an oxidizing agent may vary,

as temperature, pressure and reaction time are not critical. Thus, temperatures in the area are from approx. 10° to approx. 100°C suitable.

In order to achieve optimal yield, however, temperatures above room temperature are preferably used. In the same way, reaction times are used, which enable the reaction to be completed, usually between 12 and 36 hours. For simplicity, the reaction is carried out at atmospheric pressure. Compounds with the above formula XXV, as well as methods for their preparation, which consist in treating a compound with the above formula XV either with iodine monochloride or with iodine in the presence of an oxidizing agent, are also included

of the present invention.

They used compounds with the above as starting products

Formula XV are known compounds, or they can be prepared

according to known analogy methods.

In the event that the substituent in the compound with the above formula XIV means hydrogen, these compounds can be transferred to compounds with the formula XIII by bringing a compound with the formula

where X' means halogen and

X has the above meaning,

to reaction.

In the event that the substituent R^ in a compound of formula XIV denotes an acetyl group, the conversion of this compound to a compound of formula XIII can take place by hydrolyzing this compound in order to remove the acetyl group, and reacting the compound obtained therein with a compound of formula XVIII .

2'-fluoro-5-iodo-2-methylaminobenzophenone can be prepared from 2-amino-2'-fluoro-5-iodobenzophenone by tosylation, methylation and removal of the tosyl group by acid hydrolysis.

Compounds of formula IV can be prepared by bringing a benzophenone of the general formula,

where has the above meaning,

for reaction with a compound of the general formula,

where R^ and X' have the above meanings and R6 means a carbobenzoxy group, and either treats a compound obtained with the general formula, where R1? R 2 and R fe have the above-mentioned reactions, with a hydrohalic acid, such as hydrobromic acid, and acetic anhydride or, treating this compound with a base and treating the compound thus obtained with the general formula,

where R 1 , R 2 and R 2 have the meanings given above, with a halogen hydrogen acid.

Compounds of formula IV can also be prepared by treating a benzophenone of formula XIX with a compound of the general formula,

where R 2 and X' have the meanings given above, nitrates or nitrosates an obtained compound with the general formula, where R n and R 1 have the meanings given above, and reduces an obtained compound with the general formula,

where R, and R^ have the above-mentioned meanings.

Compounds with the above formula V can be prepared according to the following reaction scheme, which shows the procedure:

It is appropriate to carry out method step a in the presence of an inert organic solvent, e.g. in the presence of alcohols, such as methanol, ethanol etc.

The conversion of quinazoline compound 2 into benzodiazepine compound 3 takes place by treating the quinazoline with a base. Suitable bases for this purpose include alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide. The reaction preferably takes place in the presence of an inert organic solvent, such as ethanol.

The optional methylation of benzodiazepine 3 to benzodiazepine

4 can be done according to the methods described above.

Compounds of the above formula VI can be prepared by reduction of the corresponding 7-nitro compound of the general formula,

where has the above meaning,

by means of e.g. tin(II) chloride in aqueous hydrochloric acid.

Compounds of the above formula VII can be prepared by deoxidation and reduction of a compound of formula V using an excess of zinc in acetic acid.

Compounds of the above formula VIII, where R 3 means acyl. can be obtained by treating a compound of formula VII with a suitable acylating agent.

Compounds of the above formula IX can be prepared by treating the corresponding compound of formula V with sodium borohydride.

Compounds of the above formula X can be obtained by treating a compound of formula IX with a suitable acylation moiety.

Compounds of the above formula XII can be prepared according to the following reaction scheme, which shows the procedure with regard to the preparation of compounds of formula XII, where R2 means methyl: Compound 1 is transferred by reaction with N-benzyloxy;Y carbonyl--2-carbmethoxyglycine chloride to compound 5. Compound 5 is treated in order to cleave the benzyloxycarbonyl group with hydrobromic acid. Compound 6 is cyclized to benzodiazepine derivative 7, which can be methylated to benzodiazepine derivative 8.

Compounds of the above formula I, as well as their pharmaceutically acceptable salts, have good anticonvulsant, sedative

and muscle relaxant properties. Thus, these compounds and their pharmaceutically acceptable salts can be used as pharmaceuticals.

They can e.g. find application in the form of pharmaceutical preparations, which contain these or their salts in admixture with a pharmaceutical or organic or inorganic inert organic material suitable for enteral or parenteral administration.

When administering compounds of formula I or their pharmaceutically acceptable salts, the dosage is adapted to individual needs. The dosage is appropriate in the range from approx. o.o5 mg to approx. 1 mg per day.

As mentioned above, compounds of formula I and their pharmaceutically acceptable salts have useful sedative, muscle relaxant and anticonvulsant properties. The usability of the compounds according to the invention can be observed by numerous experiments.

In the experiments described below, compounds with the above formula I are used as test substances, i.e. 5(2-fluorophenyl)-7-iodo-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2- one (compound A) and 5-(2-fluorophenyl)-7-iodo-1,3-dihydro-2H-1,4-benzodiazepine-2-one (compound B).

The sedative and muscle-relaxing effect of the compounds according to the invention can be observed in the following experiments:-

Forsbk on an inclined plane:

The test substance is administered up to a maximum of 5oo mg/kg p.o. to male mice. The animals are brought over to an inclined plane, where they are observed for at least 4 hours with regard to whether they slide down from the plane due to paralytic syrptones. You decide

PD^o according to Behren's method (Arch. Exp. Pathol. Pharmacol. JL4o,

237 (1929)) and on the basis of 6 mice per dose and at least 2 points between loo and o%. In this experiment, compound A shows a PD^Q of 1 mg/kg and compound B a PD^Q of 3.5 mg/kg.

Forsbk on awake cat: ............... •..;._...;................

You treat normal cats orally and observe whether significant changes occur. The minimally effective dose (M.E.D.) is the lowest dose with which symptoms can be observed.

In this experiment, compound A showed an M.E.D. of about 5 mg/kg

and compound N a M.E.D. of o.1 mg/kg.

Kampforsbk:

One brings 2 mice into one. upside down 1 liter beaker, whereby the mice are on a grid through which they are knocked on their feet. Pairs of mice are chosen which, under these conditions, fight at least 5 times during a 2-minute test period. The mice are administered the test substance orally, and

the attempt is repeated after an hour. In this way, logarithmically increasing doses are used up to a maximum of loo mg/kg. A loo% inhibitory dose (<p>Di00) is defined as a dose which prevents any fight between pairs of mice within one hour, whereby 3 different pairs of mice are used. In this case, a PD^00 is displayed in connection A

of l.o mg/kg and compound B a PD^oo^a ^ mg/kg.

The anticonvulsant effect of compounds according to the invention can be demonstrated in the following experiments:

Maximum electric shock:

This experiment is carried out according to the method of Swinyard, Goodman and

Brown (J. Pharmacol. Exp. Ther. lo6, 319 (1952)), however with

following modifications: One uses a male mouse and puts it in shock in the same way and for the same time as in the method described above. However, the current is not 5o mA, but 3o mA. One hour after the administration of the test substance, the animals are exposed to the aforementioned electric shock. A criterion of

The effect of the test substance is the absence of stretch cramp in the hind foot. In this experiment, compound A showed an ED, Cbo.

of 1.6 mg/kg and compound N an ED^Q of 1.3 mg/kg.

7-halo-1,4 benzodiazepine-2-one belongs to a known class of compounds. The particularly pronounced sedative, muscle relaxant and anticonvulsant properties of 5-(2-fluorophenyl) 7-iodo-1,4-benzodiazepine-2-one of formula I, which make these compounds unusually good sedatives, have not been known until now . The invention of these hitherto undescribed compounds, which can be classified in a known compound-

class, and their unusual properties, and especially the sedative properties, form the main part of the present invention.

The following examples illustrate the invention without it

to limit it. All temperatures are given in degrees Celsius.

EXAMPLE 1

A mixture of 27 g (58.5 mmol) of 2-bromo-2'-(2-fluoro-benzoyl)-4'-iodoacetanilide and 750 ml of liquid ammonia is stirred for 5 hours under an ice-filled mantle, after which the ammonia is allowed to evaporate over the night. The residue is heated under stirring and heating for 2 hours with 1.2 liters of pyridine. The pyridine is then distilled in a vacuum, and the residue is distributed between methylene chloride and water. The residue, which is triturated over sodium sulfate, crystallizes in ether to give 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepine-2-one with m.p. 221 - 223°. By recrystallization i

o

ethanol, one obtains colored solvents with m.p. 222 - 224 . In the course of the reaction described above, 2-amino-2'-(2-fluorobenzoyl)-4'-iodoacetanilide is formed as an intermediate product, which is not isolated.

The starting product can be produced as follows:

To a stirred solution of 43 g (0.2 mol) of 2-amino-2'-fluoro-benzophenone in 1 liter of chloroform, 65 g (0.4 mol) of iodine monochloride in 50 ml of chloroform are added at room temperature. This mixture is stirred for 1 hour at room temperature, and then the excess of iodine monochloride is destroyed by adding 1 liter of saturated sodium bisulphite solution. It is then neutralized with concentrated ammonium hydroxide. The chloroform layer is separated, dried over sodium sulphate and evaporated in vacuo. Crystallization of the residue with hexane yields 2-amino-2'-fluoro-5-iodobenzo-phenone with m.p. 93 - 96°. Recrystallization in ethanol/water gives orange-colored needles with m.p. 102 - 105°. A mixture of 32.1 g (94.3 mmol) 2-amino-2-fluoro-5-iodobenzophenone, 40.2 g (0.2 mol) bromoacetyl bromide and 500 ml benzene is heated for 2 hours under reflux, after which it is cooled and neutralized with dilute ammonium hydroxide. Methylene chloride is then added and the organic phase is separated. The organic phase is washed with water, dried over sodium sulphate and evaporated in vacuo to a volume of 200-300 ml. Addition of petroleum ether gives 2-bromo-2'-(2-fluorobenzoyl)-4'-iodoacetanilide with m.p. 148 - 151°. Recrystallization in ethanol gives white needles with a m.p. of 150 - 151°. 2-amino-2'-fluoro-5-iodobenzophenone can be prepared as follows: A mixture of 12 g (55 mmol) 2-amino-2'-fluoro-benzophenone, 125 ml acetic anhydride, 12.7 g (50 mmol) iodine and 47.6 g (200 mmol) of sodium persulfate are stirred for 3 days at 20 - 25°. It is then diluted with 500 ml of water, and this is extracted with 3 x 100 ml of methylene chloride. The combined organic phases are shaken with 200 ml of 10% sodium bisulphite solution. The aqueous phase is made alkaline with concentrated ammonium hydroxide and shaken once more with the organic phase. The organic phase is separated, dried over sodium sulphate and evaporated in vacuo. The residue is crystallized in hexane, whereby crude is obtained. 2-amino-2'-fluoro-5-iodobenzophenone. On recrystallization from mixtures of ethanol and water obtains

one a pure product with m.p. 102 - 105°.

EXAMPLE 2

A mixture of 1 g of 2-bromo-21-(2-fluorobenzoyl)-4'-iodo-N-methyl-acetanilide, 10 ml of dimethylformamide and 2 ml of concentrated ammonia is heated for 3 minutes under reflux. After cooling, the solution is diluted with water and extracted with ether. The combined ether extracts are washed with water, dried over sodium sulphate and evaporated. Chromatography of the residue using 8 g of silica gel and with ethyl acetate/methylene chloride 1:1 gives 5-(2-fluoro-phenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine- 2-one, which after crystallization in ether/hexane melts at 106 - 109°. During the reaction described above, 2-amino-2'-(2-fluorobenzoyl)-4'-iodo-N-methylacetanilide is formed as an intermediate, which is not isolated.

The starting product can be produced as follows:

A mixture of 34.1 g (0.1 mol) of 2-amino-2'-fluoro-5-iodobenzophenone, 22.9 g (0.12 mol) of p-toluenesulfonyl chloride and 250 ml

dry pyridine is heated for 1 hour under reflux, and the solution is then evaporated in vacuo. 500 ml of methylene chloride and 500 ml of water are added to the residue. The pH of the aqueous phase is brought to 7 by means of concentrated ammonium hydroxide. The methylene chloride phase

separated, dried over sodium sulfate and filtered through 300 g of aluminum oxide. In this way, one liter of methylene chloride is used as eluent. The eluate is evaporated in vacuo, the residue is crystallized in ether and 2'-(2-fluorobenzoyl)-4'-iodo-p-toluene-sulfonanilide is obtained with m.p. 146 - 149°. For further purification, 1 g is dissolved in methylene chloride and the solution is filtered through 20 g of aluminum oxide. The residue remaining after evaporation of the eluate is crystallized in ether. It is then recrystallized by dissolving this substance in methanol and methylene chloride to distill off the methylene chloride. White prisms with m.p. 151 - 153°.

To a solution of 9.9 g (0.02 mol) of 2'-(2-fluoro-benzoyl)-4'-iodo-p-toluenesulfonanilide in 125 ml of dry dimethylformamide is added 0.6 g (0.0125 mol) sodium hydride (50% in mineral oil). Mon

stir the mixture 10 minutes and then add 1.87 ml

(0.03 mole) of methyl iodide. The mixture is stirred for 18 hours at room temperature and then poured into 300 ml of water and 75 ml of ether.

The crude 2'-(2-fluorobenzoyl)-4<1->iodo-N-methyl-p-toluenesulfonanilide obtained as a solid is collected, and it melts at 162 - 164°. By recrystallization in chloroform/petroleum ether, colorless prisms with a m.p. of 146 - 148°.

100 ml of 70% sulfuric acid is heated to 105° and added

5 g of 2'-(2-fluorobenzoyl)-4<1->iodo-N-methyl-p-toluenesulfonanilide. The temperature is increased over the course of 10 minutes to 145°. At 125°

a purplish vapor is obtained, indicating loss of iodine. The solution is poured into 1 kg of finely powdered ice. The mixture is extracted with 3 x 250 ml of methylene chloride. The extracts are dried over sodium sulphate and evaporated to dryness in vacuo. By recrystallization of the residue in 100 ml of boiling hexane, crude 2'-fluoro-5-iodo-2-methylaminobenzophenone is obtained with m.p. 93 - 96°. Recrystallization in hexane gives yellow needles with m.p. 97 - 100°.

A mixture of 3.6 g of 2'-fluoro-5-iodo-2-methylamino-benzophenone,

30 ml of methylene chloride and 3 g of bromoacetyl bromide are stirred for 1 hour at room temperature. The mixture is then washed with water and then

with saturated sodium bicarbonate solution, then dried with sodium sulphate and evaporated. The residue is crystallized in methanol and recrystallized in methylene chloride/hexane, whereby 2-bromo-2'-(2-fluorobenzoyl)-4'-iodo-N-methylacetanilide with m.p. 90 - 93°.

EXAMPLE 3

A solution of 16.2 g (40 mmol) of 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepine-2-one in 500 ml of dry tetrahydrofuran is treated with 6.72 g (60 mmol) of potassium t-butoxide and then with 11.4 g (80 mmol) of methyl iodide. Stir at room temperature overnight, filter the mixture through diatomaceous earth and evaporate the filtrate in a vacuum. The residue is taken up in 650 ml of ether. The solution is filtered and saturated with dry hydrogen chloride. The solid is collected and recrystallized in methanol/ether, whereby 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one hydrochloride is obtained in form of yellow prisms with m.p. 226 - 229 etc.

A mixture of 5 g of this hydrochloride, 200 ml of 10% sodium carbonate solution and 200 ml of ether is shaken. The ether phase is separated, dried over sodium sulphate and evaporated in vacuo. The residue is crystallized in ether/petroleum ether and gives the free base with m.p. 107 - 115°. The ion recrystallized in ether/petroleum ether gives colorless prisms, m.p. 107 - 110°.

EXAMPLE 4

A mixture of 0.9 g of 2'-fluoro-5-iodo-2-methylamino-benzophenone,

0.9 g of glycine ethyl ester hydrochloride, 3 g of pivalic acid and 300 ml of toluene are boiled for 48 hours under reflux, whereby part of the solvent is distilled off. To begin with, 15 ml of distilled toluene is replaced, and after 24 hours the cooled reaction mixture is distributed between toluene and 10% aqueous sodium carbonate solution. The organic phase is washed with sodium carbonate solution and water, dried over sodium sulfate and evaporated. The residue is chromatographed using 20 g of silica gel and first methylene chloride and then 20% acetate in methylene chloride are used as eluent. Crystallization of the pure fraction gives 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one with amp. 106 - 109°.

EXAMPLE 5

0.5 g of 3-amino-3-carbomethoxy-4-(2-fluorophenyl)-1,2,3,4-tetrahydro-4-hydroxy-6-iodo-1-methylquinolin-2-one is boiled for 24 hours in 10 ml 80% acetic acid. The residue obtained by evaporation in vacuum is distributed between methylene chloride and 10% aqueous sodium carbonate solution. The methylene chloride phase is dried over sodium sulphate and evaporated. The residue is chromatographed using 8 g of silica gel and 20% ethyl acetate in methylene chloride. The pure fractions are combined and evaporated. Crystallization of the residue in ether/hexane gives 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one with m.p. 105 - 109°.

The starting material is produced as follows:

A mixture of 8 g of N-(benzyloxycarbonyl)-2-carbomethoxyglycine, 6.3 g of phosphorus pentachloride and 100 ml of methylene chloride is stirred for 45 minutes. at -20 to -15°. 5 g of 2'-fluoro-5-iodo-2-methyl]aminobenzophenone are then added and stirred while cooling for a further hour. Then add 50 ml of water and heat the 2-phase system for 1 hour under reflux. The methylene chloride layer is separated, washed with 10% aqueous sodium carbonate, dried over sodium sulfate and evaporated. The residue is dissolved in 50 ml of methanol containing 2 ml of triethylamine. After heating to the boiling point, the solution is cooled, after which the product crystallizes. The crystals are collected and recrystallized in methylene chloride/hexane, whereby 3-(benzyloxycarbonylamino)-3-carbomethoxy-4-(2-fluorophenyl)-1,2,3,4-tetrahydro-4-hydroxy-6-iodo-1 is obtained -methyl-quinolin-2-one with m.p. 210-220° (decomposition).

To a warm solution of 5 g of the above-mentioned product in 100 ml of methylene chloride, 20 ml of acetic acid, which contains 30% hydrogen bromide, is added. The reaction mixture is allowed to stand for 4 hours at room temperature and is then evaporated under reduced pressure. The residue crystallizes in methylene chloride/ether and gives a hydrobromide with m.p. 170 - 180° (cleavage). 4 g of this hydrobromide are distributed between methylene chloride and 10% aqueous sodium carbonate solution. The methylene chloride layer is dried and evaporated. The crystallization of the residue in ether gives 3-amino-3-carbomethoxy-4-(2-fluorophenyl)-1,2,3,4-tetrahydro-4-hydroxy-6-iodo-1-methylquinolin-2-one, which after recrystallization in methylene chloride/hexane melts at 170 - 172°.

EXAMPLE 6

To a solution of 0.41 g of 5-(2-fluorophenyl)-1,3-dihydro-7-j6d-1-methyl-2H-1,4-benzodiazepine-2-one-4-oxide in 10 ml of methylene chloride add man 1 ml phosphorus trichloride. This is left at 30

minutes at room temperature and distribute the mixture between 10% aqueous sodium carbonate and benzene. The organic phase is dried over sodium sulphate and evaporated. Crystallization of the residue in ether/hexane gives 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one with m.p. 104 - 108°.

The starting material can be produced as follows:

A mixture of. 102.3 g of 2-amino-2'-fluoro-5-iodo-benzophenone, 24 g of hydroxyl amine sulfate, 45 g of dichloroacetaldehyde and 1 liter of ethanol are, to prepare a solution, heated with stirring and then stirred overnight at room temperature. The mixture is neutralized by adding saturated sodium bicarbonate solution and diluted with plenty of water. The precipitated solid is collected, washed with water and dried. Yellow 2-dichloromethyl-4-(2-fluorophenyl)-1,2-dihydro-6-iodoquinazoline-3-oxide is obtained with m.p. 184 — 187°.

To a suspension of 45.1 g of 2-dichloromethyl-4-(2-fluorophenyl)-1,2-dihydro-6-iodoquinazoline-3-oxide in 750 ml of ethanol, 100 ml of 3-n aqueous sodium hydroxide is added. The mixture is stirred for 2 1/2 hours at room temperature and then evaporated under reduced pressure. The remainder is distributed between methylene chloride and 1-n hydrochloric acid. The organic phase is washed with water, dried over sodium sulphate, filtered and evaporated. The residue is crystallized and recrystallized in ethanol, whereby 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepine-2-one-4-oxide with m.p.

192 - 196°.

To a cooled to 0° solution of 19.8 g of 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepine-2-one-4-oxide in 250 ml of tetrahydrofuran add man under, nitrogen atmosphere and with stirring 6.2 g of potassium t-butoxide. After stirring for 1 hour at 0°, add 7.8 g of methyl iodide, after which the mixture is stirred while cooling for a further 2 hours. It is then filtered and evaporated to dryness. The remainder is distributed between methylene chloride and water. The methylene chloride layer is dried, filtered and evaporated. After crystallization in ethanol, 5-(2-fluoro-phenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one-4-oxide is obtained, which, recrystallized -in ethanol . and then melts at 178 - 181°..

EXAMPLE 7

To a solution cooled to 0° of 1.2 g of 7-amino-5-(2-fluoro-phenyl)-1,3-dihydro-1-methyl.-2H-1,,4-benzodiazepine-2-one a solution of 0.33 g of sodium nitrite is added to 3.5 ml of 6-n hydrochloric acid. in 5 ml of water. The yellow solution is stirred for 10 minutes at 0 to +5°. A solution of 1.2 g of potassium iodide in 5 ml of water is then added and stirred for 30 minutes at room temperature. Filter, make the filtrate alkaline with ammonia and extract it with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and evaporated to give an orange-colored oil, which crystallizes in methylene chloride/ether/petroleum ether to give 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-l -methyl-2H-1,4-benzodiazepine-2-one with m.p. 102 - 107°.

The starting material can be produced as follows:

To a solution of 12.5 g of 5-(2-fluorophenylj-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepine-2-one in 80 ml of 6-n hydrochloric acid is added a dissolving 30 g of tin(II) chloride dihydrate in 80 ml of 6-n hydrochloric acid. The mixture is stirred overnight and the suspension obtained is made alkaline by the addition of 50% aqueous potassium hydroxide. The precipitated yellow solid is collected, washed with water, dried and recrystallized in tetrahydrofuran/hexane, whereby 7-amino-5-(2-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2-one with mp 206 - 208°

available (split.

EXAMPLE 8

A solution of 0.4 g of 5-(2-fluorophenyl)-1,3,4,5-tetrahydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one in 10 ml of chloroform is cooled to -20°. 3.6 ml of a 0.5 molar solution of bromine in chloroform is added and stirred for 15 minutes at -10°. The reaction mixture is distributed between 1-1 sodium hydroxide solution and chloroform. The organic phase is dried and evaporated. The residue is dissolved in 10 ml of ethanol and, after adding 10 mg of sodium methylate, it is stirred for 10 minutes. The mixture is diluted with water and extracted with benzene. The benzene layer is separated, dried over sodium sulphate and evaporated. The residue is chromatographed using 6 g of silica gel and 20% ethyl acetate/methylene chloride. The crystallization of the pure fraction in ether/hexane gives 1,3-dihydro-5-(2-fluorophenyl)-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one with m.p. 106 - 109°:

The starting product can be produced as follows:

A mixture of 2.05 g of 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one-4-oxide, 20 ml methylene chloride, 2 g zinc dust and 5 ml acetic acid are stirred for 30 minutes at room temperature. The mixture is filtered and distributed between methylene chloride and 10% aqueous sodium carbonate. The methylene chloride layer is washed with water. dried over sodium sulfate and evaporated. The rest of the crystals Lii are seen in methylene chloride/ether. thereby obtaining crude c>-(2-fluorophenyl)-1,3,4,5-tetrahydro-7-iodo-1-methyl-2H, 1,4-benzodiazepine-2-one.

On recrystallization in methyl encl ori d/hexar, m?.n et is obtained

pure product with m.p. 171 - 173°.'

EXAMPLE 9

A mixture of 10 ml of ethanol. 0.2 ml of azodicarboxylic acid diethyl ester and 0.4 g of 5-(2-fluorophenyl)-1,3,4,5-tetrahydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one are refluxed for 2 hours . After evaporation, the residue is chromatographed using 8 g of silica gel.

and methylene chloride/acetic ester 1:1. Crystallization of the pure fraction gives 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methy1-2H-1,4-benzodiazepine-2-one with m.p. 106 - 109°.

EXAMPLE 10

A mixture of 0.55 g of 5-(2-fluorophenyl)-1,3,4,5-tetrahydro-7-iodo-1-methyl-4-(p-toluenesulfonyl)-2H-1,4 -benzcdiazeptn-2-one. 20 ml of benzene, 2 ml of t-butanol and 0.16 g of potassium t-butoxide are boiled under a nitrogen atmosphere and refluxed. 20 minutes. The reaction mixture is cooled and distributed between water and ether. The organic phase is dried and evaporated. Residues, NOK oma Lograf is washed using 6 g of silica gel and vinegar/methylene chloride 1:1

(v/v). Crystallization of the pure fraction in ether/hexane gives 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-.1,4-benzoaiazepin-2-one with m.p. 106 - I10°-

The starting product can be produced as follows:

A mixture of 1 g of 5-(2-fluorophenyl)-1,3,4,5-tetrahydro-7-iodo-1-methyl-2K,1,4-benzodiazepmin-2-one, 0.6 g of p-toluene -sulfonyl chloride and 10 ml of pyridine are allowed to stand at room temperature overnight. The residue is then evaporated and partitioned between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase is washed with 1-1 hydrochloric acid and water, dried over sodium sulphate and evaporated. The residue is crystallized in methylene chloride/ether and recrystallized in methylene chloride/ethanol, whereby 5-(2-fluorophenyl)-1,3,4,5-tetrahydro-7-iodo-1-methyl-4-(p-toluenesulfonyl)- 2H-1,4-benzodiazepine-2-one with m.p. 255 - 258 .

EXAMPLE 11

0.17 g of 5-(2-fluorophenyl)-1,5-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one is dissolved in a solution of 50 mg of sodium in 5 ml of water free ethanol. It is then stirred for 30 minutes at room temperature under a nitrogen atmosphere. Acid is made by adding acetic acid. The remainder is distributed between methylene chloride and 10% aqueous sodium carbonate solution. The methylene chloride layer is dried over sodium sulfate and evaporated. Crystallization of the residue in ether/hexane gives 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one with m.p. 106 - 109 .

The starting material can be produced as follows:

To a solution of 4.1 g of 5-(2-fluorophenyl)-1,S-dihydro^-iodo-1-methyl^H-1,4-benzodiazepine-2-one-4-oxide in 100 ml of ethanol and 50 ml of tetrahydrofuran, 0.6 g of sodium borohydride is added. The mixture is stirred for 1 1/2 hours at 40 - 50°, evaporated in a vacuum and water is added, after which crystallization occurs. The solid is collected, washed and recrystallized from 1 methylene chloride/hexane, after which 5-(2-fluorophenyl)-1,3,4,5-tetrahydro-4-hydroxy-7-iod-1-methyl-2H- 1,4-benzodi azepi n-2-one with m.p. 216 - 220°. 2 g of the above-mentioned compound are allowed to stand at room temperature overnight in 20 ml of pyridine and 2 ml of acetic anhydride. The reaction mixture is evaporated and the residue crystallized in methanol, whereby 4-acetoxy-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-7-iodo-1-methyl-2H-1,4-benzodiazepine- 2-on with m.p. 172 - 174 .

A mixture of 1 g of the above material, 15 ml of ethanol and

5 ml diethylamine is boiled for 1 hour under reflux. The residue obtained by evaporation is chromatographed using 20 g of silica gel, whereby 10% ethyl acetate in methylene chloride is used for elution. The pure fraction is purified and evaporated.

After recrystallization of the obtained solid in methylene chloride/hexane, 5-(2-fluorophenyl)-1,5-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one is obtained with m.p. 191 - 195°.

EXAMPLE 12

0.5 g of 4-acetoxy-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one is dissolved in 10 ml of ethanol .

0.15 g of potassium t-butoxide is then added and the mixture is refluxed for 15 minutes. After evaporation, the residue is distributed between benzene and water. The benzene layer is dried and evaporated. By chromatographing the residue using IO

g of silica gel and ether/benzene (2:1) gives 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one with m.p.

106 - 110°.

EXAMPLE 13

A solution of 0.45 g of 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H,1,4-benzodiazepine-2-one-3-carboxylic acid methyl ester in 10 ml of methanol is degassed with nitrogen, and after adding 2 ml of sodium hydroxide solution, stir for 3 hours at room temperature. The unreacted mixture is made acidic by the addition of 1-n hydrochloric acid, made alkaline with ammonia and extracted with ether. The ether extracts are dried over sodium sulphate and evaporated. Chromatography of the residue using 6 g of silica gel and methylene chloride/acetic ester (1:1) gives 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4- benzodiazepine-2-one with m.p. 106 - 110°.

The starting product can be produced as follows:

To a suspension cooled to -20° of 8 g of N-(benzyloxycarbonyl)-2-carbomethoxyglycine in 100 ml of methylene chloride, 6.3 g of phosphorus pentachloride is added. The mixture is stirred for 30 minutes at -20 to

-15°. Then, at 0 to 5°, 6.7 g of 2-amino-5-iodobenzophenone is added and then 100 ml of 10% aqueous sodium carbonate is added. The methylene chloride layer is separated, washed 2

times with sodium carbonate solution, dried and evaporated.

Crystallization of the residue in methylene chloride/hexane gives 2-[(benzyloxycarbonyl)amino]-2-carbomethoxy-2'-(2-fluorobenzoyl)-41-iodoacetanilide with m.p. 100 - 103°.

To a solution of 5 g of the above-mentioned product in 50 ml of methylene chloride, 20 ml of acetic acid, which contains 30% hydrobromic acid, is added. The mixture is allowed to stand for 4 hours at room temperature and then evaporated. The residue is slurried with ether and the crystalline solid is isolated, thereby obtaining the hydrobromide with m.p. 188 - 192° (decomposition). 3 g of this hydrobromide are distributed between methylene chloride and 10% aqueous sodium carbonate solution. The methylene chloride layer is dried over sodium sulphate, filtered and evaporated. Crystallization of the residue in methylene chloride/hexane gives 2-amino-2-carbomethoxy-2'-(2-fluorobenzoyl)-4'-iodoacetanilide with m.p. 120 - 123°.

1.5 g of the above-mentioned amine is refluxed for 1 1/2 hours with 50 ml of toluene, which contains 5 ml of acetic acid. The residue obtained by evaporation of the reaction mixture crystallizes in methylene chloride/ether, giving 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepine-2-one-3-carboxylic acid methyl ester with m.p. . 230 - 236° (decomposition).

0.88 g of the above-mentioned compounds are dissolved in 20 ml of dimethylformamide and the solution is cooled to -20°. 0.3 g of potassium t-butoxide is then added, and after 5 minutes of stirring, 0.2 ml of dimethylsulphate is added. The temperature is allowed to rise to 0°. The reaction mixture is made acidic with acetic acid and poured into ice water. The precipitated product is collected and dissolved in methylene chloride. The solution is dried over sodium sulphate, filtered and evaporated. Crystallization of the residue in ether/hexane gives 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one-3-carboxylic acid methyl ester, which after recrystallization in methylene chloride/hexane melts at 135-139°.

EXAMPLE 14

A mixture of 0.4 g of 5-(2-fluorophenyl)-1,3,4,5-tetrahydro-4-hydroxy-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one. 5 ml of pyridine and 0.2 ml of phosphorus oxychloride are boiled for 5 minutes under reflux,

and then the mixture is evaporated under reduced pressure. The remainder is distributed between benzene and 10% aqueous sodium carbonate solution. The organic layer is dried over sodium sulfate and evaporated. Chromatography using 6 g of silica gel and 10% ethyl acetate in methylene chloride gives 5-(2-fluorophenyl)-1,5-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one, which after crystallization in hexane/methylene chloride melts at 188 - 192°. From the later eluted fraction, the isomer 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2-one is obtained, which after crystallization in ether/hexane melts at 102 - 106°.

Claims (1)

Analogous process for the preparation of therapeutically active benzodiazapine derivatives of the general formula, where R^ means hydrogen or methyl, and their acid addition salts, characterized by a) cyclizing a compound with the general formula, where R has the above meaning, or b) treats a compound of the general formula, where R^ has the above meaning, with glycine or an ester thereof, or c) submits to a compound of the general formula, where R., has the meaning given above and R.sup. means lower alkyl, a ring expansion and an acid hydrolysis under aqueous conditions, or d) deoxidizes a compound of the general formula where R^ has the above meaning, or e) subjects the diazonium salt of a compound of the general formula, where R^ has the above meaning, an exchange reaction according to the Sandmeyer type, or f) oxidises or dehydrogenates a compound of the general formula, where R1 has the above-mentioned meaning, in the 4,5 bond, or g) transfers a compound of the general formula where has the above-mentioned meaning, R 1 means halogen or acyl. by treatment with a strong base in the corresponding 4,5-dehydro compound of formula I, or h) dehydrates a compound of the general formula, where has the above-mentioned betvdnina, to the corresponding 4,5-dehydro compound of formula I. or i) transfers a compound of the general formula, where R^ has the meaning indicated above and R4 means acyl, by treatment with a base to the corresponding 4,5-dehydro compound of formula 1, or j) rearranges a compound of the general formula, where R^ has the above meaning, to the corresponding 4,5-dehydro compound of formula I, or k) saponifies and decarboxylates a compound of the general formula, where and R^ have the above meaning, or 1) methylates the compound of formula I, wherein R is hydrogen, to the compound of formula I, wherein R^ is methyl, and transfers, if desired, a compound of formula I obtained in an acid addition salt.