DE2062927A1 - Benzodiazepine derivatives - Google Patents

Description

Dr. Ing. A. van der Werft ■ Dr. Franz Leather "

PATENT ADVOCATE!

2 ΐ. Dec 1970

MN 4008/178 k

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

Benzodiazepine derivatives

The present invention relates to iodine-substituted Benzocüazepine derivatives. In particular it concerns connections the general formula

Bt / 10.12.70

109851/1930

where R. is hydrogen or methyl, and acid addition salts thereof.

The compounds of the above formula I and their acid addition salts can be prepared according to the invention by
a) a compound of the general formula

N-CO-CH ₂ -NH ₂

II

wherein R, has the above meaning, cyclizes or
b) a compound of the general formula

III

wherein R, has the above meaning, 109851/1930

treated with glycine or an ester thereof or c) a compound of the general formula

[COOR ₂

IV

where R, has the above meaning and R _{2 is} lower alkyl,

subjected to ring expansion and acid hydrolysis under aqueous conditions or
d) a compound of the general formula

where R, has the above meaning,
deoxidized or

r * <i 8 y 1/1 9 3 η

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

N C,

VI

wherein R _{1 has the} above meaning,

subjecting it to an exchange reaction of the Sandmeyer type or f) a compound of the general formula

VII

wherein R has the above meaning, oxidized or dehydrogenated or at the 4,5 bond

109851/1930

g) a compound of the general formula

VIII

wherein R, has the above meaning and R, halogen or Acyl means

converted into the corresponding 4,5-dehydro compound of the formula I by treatment with a strong base or h) a compound of the general formula

IX

wherein R _{1 has the} above meaning,

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

109851/1930

"■ '" Γ "' S B irSIIIi!

i) a compound of the general formula

wherein R, has the above meaning and R ₁ , acyl, is converted into the corresponding 4,5-dehydro compound of the formula I by treatment with a base, or j) a compound of the general formula

XI

where R, has the above meaning,

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

1098b

k) a compound of the general formula

O

XII

wherein R, and R _{2 have the} above meaning, saponified and decarboxylated or

1) the compound of the formula I in which R _{1 is} hydrogen, to the compound of the formula I in which R _{1 is} methyl, methylated and

m) if desired, a compound of the formula I obtained in transferred to an acid addition salt.

According to a first aspect of the method within the scope of the present invention, one thus arrives at the compounds of above formula I by cyclization of a compound of the above formula II, which in turn starting from a compound of general formula

R «

NCOCH ₂ X

XIII

wherein PL has the above meaning and X is a leaving group

10 9851/1930

20 ^ 2 "

927

means, for example halogen, such as chlorine, bromine or iodine, preferably bromine, alkyl «or arylsulfonyloxy groups, e.g., mesyloxy and tosyloxy, a carbobenzoxyamino group or a phthalimido group.

The amino compound of the formula II formed as an intermediate is preferably not isolated, but can instead be among those used Reaction conditions are cyclized in situ and thus go directly into the desired compound of formula I. On the other hand, the open-chain compound of the formula II isolated and then subsequently subjected to a ring closure to give the desired compound of the formula I. the Cyclization to the compound of the formula I is conveniently and easily carried out by gently heating the compound of the Formula II, which is preferably dispersed in an inert organic solvent.

If a compound of the above formula XIII, in which X is halogen, alkylsulfonyloxy or arylsulfonyloxy, is used as a preliminary product, the cyclization takes place in the presence of ammonia. For this cyclisation is conveniently effected using a temperature in the range of about -35 ° to 100 ⁰ C, preferably in the range of about -35 ° to 35 ° C. The reaction can be carried out in the presence of an inert solvent, conveniently in an inert organic solvent such as lower alkanols such as methanol, ethanol and the like, ethers such as ethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether and the like, chlorinated hydrocarbons such as methylene chloride and the like, and pyridine.

If a compound of the above formula XIII, in which X is a carbobenzoxyamino group, is used as a preliminary product, thus cyclization is carried out by first removing the amino protecting group, e.g., by treating the compound

109851/1930

of the formula XIII with hydrogen bromide in glacial acetic acid, a salt of the compound of the above formula II being obtained. This salt is then cyclized to the compound of formula I by making the reaction mixture alkaline. This reaction takes place Conveniently in the presence of an inert solvent, for which the above in connection with the cyclization of Compounds of the formula XIII in the presence of ammonia solvents mentioned are suitable.

If a compound of the formula XIIIj ₁ in which X is a phthalimido group is used as a preliminary product, the P cyclization is carried out by treating this compound with hydrazine hydrates. This reaction is again preferably carried out in the presence of an inert organic solvent.

According to another process aspect of the present invention, the compounds of the above formula I can thereby can be prepared by using a compound of the above formula III under weakly acidic conditions with glycine or an ester converts it (preferably the methyl or ethyl ester).

In a preferred embodiment of this method aspect is a compound of formula III under weakly acidic w conditions with a glycine ester of the formula

NHgCHgCOO-lower alkyl XVI

brought to reaction one obtains a compound of the formula

109851/1930

'"''" V- ¹ *! «!!""; ¹ - "1" 1 ¹ II !! ¹ ! ! "! iF» '^ lgll' · - «-" -JIf- >: ν »« -T IP «, r ■ ■,,

- 10 -

^R l

NH

Ν — CH ₂ -C00-lower alkyl XVII P

where R, has the above meaning,

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

When carrying out the above-described reaction between a compound of the formula III and a glyoin ester, the ester is preferably used in the form of its hydrochloride. This reaction is conveniently carried out in the presence of an inert solvent, such as alcohols with a chain of at least 3 carbon atoms, such as propanol, butanol, etc., or aromatic hydrocarbons, such as benzene, toluene, xylene, etc. Of the acids with which the Reaction device is conveniently made slightly acidic, pivalic acid and p-toluenesulfonic acid may be mentioned. The reaction takes place preferably at elevated temperatures, in particular at the reflux temperature of the reaction mixture.

According to a further process aspect within the scope of the present invention, the compounds of the above formula I can be prepared by subjecting a compound of the above formula IV to ring expansion and acid hydrolysis under aqueous conditions.

109851/1930

Compounds of the formula IV can partly in the form of the corresponding isomeric open compounds of the general formula

R,

N CO CH COOR,

NH.

IVa

wherein R ₁
to be available.

and R _{2 have the} above meaning,

Compounds of the formula IV can also be converted into the corresponding compounds of the formula I without that they are isolated from the reaction mixture.

This reaction is conveniently carried out in the presence an inert organic solvent. Suitable inert organic solvents for this purpose include aromatic ones 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 to the successful operation of this process, and the reaction can therefore be carried out at temperatures between about room temperature and about the reflux temperature of the reaction mixture but preferably one works with the application of heat, in particular at about the reflux temperature of the reaction mixture. Suitable acids for the purposes of this method aspect of the present invention include organic and inorganic acids., for example alkanecarboxylic acids such as

109851/1930

2Q62927

Formic acid, acetic acid, propionic acid and the like, aromatic acids such as benzoic acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acid, etc. The amount of acid is not critical, but complete protonation of the amine nitrogen in the starting material should be avoided. If acetic acid is used, it can also be used as a solvent to serve.

According to a further process aspect within the scope of the present invention, the compounds of the above formula I prepared by deoxidizing a compound of formula V above will.

The deoxidation of a compound of the formula V can be achieved by treatment with a phosphorus trihalide, such as phosphorus trichloride, be performed. This reaction is conveniently carried out in the presence of an organic solvent such as aromatic Hydrocarbons such as benzene, toluene and the like; chlorinated hydrocarbons e.g. B. carbon tetrachloride and the like., And at Room temperature, although temperatures above and below room temperature can also be used.

According to another embodiment, this / oxidation

a compound of formula V by hydrogenation in the presence of a hydrogenation catalyst such as Raney-Nlckel carried out will. This reaction is conveniently carried out in the presence of an inert organic solvent such as dioxane, dimethoxyethane, Ethyl acetate and the like, and at room temperature, although temperatures above and below room temperature as well can be used. In addition, the reaction can also be carried out under pressure.

According to a further embodiment, the deoxidation can be carried out in such a way that a compound of the formula V treated with zinc in a small amount of acetic acid. the

109851/193 0

- .1 / 5 -

The reaction is expediently carried out at room temperature in the presence an inert organic solvent such as methylene chloride.

According to a further process aspect within the scope of the present invention, the compounds of the above formula I starting from the corresponding 7-amino-1,4-benzodiazepin-2-ones be produced by an exchange reaction of the Sandmeyer type. When performing this aspect of the procedure becomes first the diazonium salt of the compound of the above formula

VI manufactured.

The amino group of the compound of the formula VI can be diazotized by customary methods, for example by treatment with any combination of reagents that generate nitrous acid in situ, such as sodium nitrite in mineral acid, e.g. hydrochloric acid or sulfuric acid. The diazonium salt of the compound of formula VI is then treated with an iodide salt, preferably an alkali metal iodide such as Sodium iodide or potassium iodide, or with copper (I) iodide, viobei the compound of formula 1 is obtained.

As mentioned above, the diazotization of the compound of the formula VI carried out according to commonly used methods. For example, the amine is dissolved in an aqueous solution of mineral acid and the mixture is cooled to a temperature between 0 and -10 °. A watery one is then slowly added Sodium nitrite solution, whereupon the diazonium salt forms. To avoid decomposition, the salt is then added immediately the iodide salt reacted, with the exchange reaction and the formation of the iodine compound occurs.

According to a further procedural aspect within the scope of the present In accordance with the invention, the compounds of the formula I can be prepared by dehydrogenating or oxidizing a compound of the above formula

VII are produced.

109851/1930

The dehydrogenation or oxidation of the compound of the formula VII is carried out, for example, by means of oxygen, manganese dioxide, bromine, chlorine, azodicarboxylic acid esters (for example diethyl ester) and the like. This reaction is conveniently carried out in the presence of an inert organic solvent such as aromatic hydrocarbons such as benzene, toluene and the like, halogenated hydrocarbons such as carbon tetrachloride, alcohols such as methanol, ethanol and the like, ethers such as dioxane, tetrahydrofuran and the like ., and advantageously at a temperature between -4o ° C and the reflux temperature of the solvent. i

If halogen, such as bromine or chlorine, is used as the oxidizing agent, a compound can be used as an intermediate of the above formula VIII, wherein R is halogen, such as chlorine or bromine. Such an intermediate can be obtained by treatment with a strong base into the corresponding 4,5-dehydro compound of formula I are converted.

According to another method aspect of the present invention is a compound of general formula VIII wherein R, halogen, or acyl, such as, for example, tosyl alkylsulfonyl such as mesyl, or arylsulfonyl, by treatment with (a strong base into the corresponding 4,5 -Dehydrocompound of the formula I converted.

The splitting off of the substituent R- from a compound of formula VIII can be accomplished with a strong base, e.g. with alkali hydrides such as sodium hydride, alkali alkoxides, such as sodium methoxide and potassium t-butoxide, triethylamine and alkali amides such as sodium amide, which base is to be used in an anhydrous medium. This reaction is conveniently carried out in the presence of an inert organic solvent. As a suitable solvent for

109851/1930

for this purpose ethers, alcohols, for example ethanol, hydrocarbons, for example benzene and toluene, and dimethylformamide may be mentioned. The reaction is preferably carried out at temperatures between about 0 and about 120 ^° C. In this process aspect, a compound of the above formula XI can be formed as an intermediate product, which rearranges to the corresponding 4-, 5-dehydro compound of the formula I by treatment with a base can be.

According to a further aspect of the method within the scope of the present invention, a compound of the above formula IX converted into a compound of the formula I by elimination of water.

The elimination of water from the compound of formula IX can be achieved by treating this compound with any reagent suitable for dehydrating this alcohol, for example with thionyl chloride, phosphorus oxychloride and carbodiimides such as dicyclohexylcarbodiimide. This reaction is conveniently carried out at room temperature and in the presence an inert organic solvent such as hydrocarbons, alcohols, etc. In this process aspect, as an intermediate a compound of the above formula XI is formed which, by treatment with a base, gives the corresponding 4,5-dehydro compound of formula I can be rearranged.

In a further process aspect of the present invention, a compound of formula X above is treated by treatment with a base in the corresponding 4.5 dehydro compound of Formula I transferred '.

The acid cleavage of the compound of formula X can be accomplished with a strong base, conveniently with alkali hydrides, such as sodium hydride, triethylamine, alkali amides, such as sodium amide, alkali alkoxides such as sodium methoxide and potassium t-butoxide, these bases in an anhydrous medium

109851/1930

The reaction is expediently carried out in the presence an inert organic solvent, such as ether, alcohols, e.g. ethanol, hydrocarbons, e.g. benzene and toluene, Dimethylformamide and the like, and at temperatures between about -40 ° and about 120 ° C. The acyl group fU can be 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 the formula X, a compound of the above formula XI are formed, which rearranged to the corresponding 4,5-dehydrocompound of the formula I by treatment with a base can be.

In a further process aspect of the present invention, a compound of the formula XI can be rearranged to the corresponding 4,5-dehydro compound by treatment with a base, such as alkali alkoxides, for example sodium methoxide, alkali hydrides, for example sodium hydride, triethylamine and the like. The reaction is conveniently effected in an inert organic solvent such as hydrocarbons, ethers, alcohols and the like., And at temperatures between about ⁰ ° and 120 -4o C.

In a further process aspect of the present invention, the compounds of the formula I can be saponified and decarboxylation of a compound of the general formula XII.

The compounds of the above formula XII can by customary methods with formation of the corresponding compounds, wherein the substituent in the 3-position is the group -COOA is (where A is the cation of a base) are hydrolyzed. For example, a compound is hydrolyzed Formula XII by treating this compound with a bare such as alkali hydroxides e.g. sodium hydroxide, potassium hydroxide

109851/1930

and the like, alkaline earth hydroxides such as calcium hydroxide and the like, tertiary organic bases such as triethylamine and the like., or ethanolamine. The hydrolysis of the compound of the formula XII can also be carried out by Treatment done with an acid. If the hydrolysis is carried out using an acid, hydrolysis and decarboxylation can take place take place simultaneously, a compound of the above formula I being formed.

Subsequent to the hydrolysis, the compound obtained is converted into the desired compound by conventional methods Formula I decarboxylated. The decarboxylation can be carried out simply by leaving a solution of the hydrolyzed compound take place, or by heating or acidifying this compound in solution. This decarboxylation of the hydrolyzed compound occurs slowly when left to stand, faster when heated and spontaneously when acidified.

According to a further process aspect of the present invention, the compound of the formula I in which R 1 is methyl can be prepared starting from the corresponding desmethyl compound by methods known per se. The 1-position can be methylated by customary methods, for example by converting the compound of the formula I, in which R _{1 is} hydrogen, with an alkali metal hydride, such as sodium hydride, with potassium t-butoxide and the like, into the 1-alkali metal salt of the compound of the formula I and this is then converted into the 1-methyl compound by treatment with a methylening agent, such as methyl halides, for example methylodide, or methyl sulfates.

The methylation reaction is preferably carried out in the presence an inert organic solvent such as tetrahydrofuran. Temperature and pressure are not relevant for this procedure critical, so that the reaction is preferably carried out at room temperature and atmospheric pressure for the sake of simplicity.

109851/1930

The compounds of the above formula I can be converted into acid addition salts be converted, in particular into pharmaceutically acceptable acid addition salts, with organic and inorganic Acids such as hydrochloric acid, hydrobromic acid, nitric acid, Sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid The preparation of the pharmaceutically acceptable acid addition salts is carried out by generally customary methods.

The starting products of the process according to the invention can be produced by various processes.

One of these methods involves treating a compound of the formula

R-

NR ₁

XV

wherein R, has the above meaning and R, - is hydrogen, acetyl or -COCH ₂ X, where X is as defined above,

with Icdmonochlorid in the presence of an inert organic Solvent, the desired iodine-substituted Benzophenone of the formula

109851/1930

XIV

wherein R, and R ₁ . have the above meaning, 1 5

receives.

The treatment of the compound of the above formula XV with iodine monochloride is preferably carried out in the presence of an inert one organic solvent. Suitable solvents for this purpose are alcohols such as methanol, ethanol, etc., hydrocarbons, such as benzene, toluene and the like, halogenated hydrocarbons such as chloroform, carbon tetrachloride and the like, acetic acid and glacial acetic acid. In a preferred embodiment, Chloroform, acetic acid or glacial acetic acid are used as solvents .

When treating the compound of the formula XV with iodine monochloride, the reaction conditions can vary, since temperature, pressure and reaction time are not critical for the process. Thus, temperatures are within a range of about 10 ° to about 100 ⁰ C, the choice of the preferred temperature depends primarily on the used solvent system. For example, when chloroform is used as the solvent, the reaction is conveniently carried out at room temperature, whereas when using either acetic acid or glacial acetic acid, it is conveniently carried out at elevated temperatures, preferably between about 60 °

109851/1930

and 10O ⁰ C, in particular at about 80 ° C. Likewise, for convenience, the reaction is preferably carried out at atmospheric pressure.

The molar ratios in the iodination of ketones of the formula XV with iodine monochloride used reactants will depend on their selection, especially after the selection the solvent, and vary depending on the reaction conditions. If chloroform is used as the solvent in this monoiodination, it is preferably used in the reaction 2 moles of iodine monochloride, as this molar ratio gives the best yields. On the other hand, if one uses under the same 'f Acetic acid is preferably used as the solvent 1 mole of iodine monochloride.

If the substituent R ₁ - in a compound of the formula XV is haloacetyl, the treatment of this compound with iodine monochloride can also lead to a halogen exchange in the haloacetyl radical in addition to iodination of the benzophenone part, ie chlorine, bromine or fluorine present in the haloacetyl radical can be replaced by the more reactive iodine be replaced.

On the other hand, the compounds of the above formula XIV can also be prepared by a compound of the above formula XV treated with iodine in the presence of a suitable oxidizing agent.

Any suitable oxidizing agent can be used in performing this iodination of a compound of Formula XV with iodine. Representative of the oxidizing agents which can be used for this purpose are sodium persulfate, nitric acid, iodic acid, mercury oxide, lead oxide, silver oxide, etc. In a preferred embodiment, the oxidizing agent used is matrix persulfate .

10985 1/1930

The iodination of a compound of the above formula XV with Iodine under oxidative conditions may be the result of removal of the by-product formed in the reaction Iodide ion by oxidation. So there is some oxidizing agent which so formed hydriodic acid or iodide ions Iodine oxidized, suitable for the present purpose. The above-mentioned oxidizing agents represent preferred examples, however, it should be noted that any suitable oxidizing agent can be used; it is only necessary that the oxidizing agent brings about the formation of iodine under the reaction conditions used.

If the substituent R_ is in a compound of the formula

XV means haloacetyl so can treatment of this compound with iodine under oxidative conditions in addition to iodination of the benzophenone also a halogen exchange in the haloacetyl radical bring about, i.e. chlorine present in the haloacetyl radical. Bromine or fluorine can be replaced by the more reactive iodine.

The treatment of a compound of the formula XV with iodine under oxidative conditions is preferably carried out in the presence an inert organic solvent. Suitable solvents for this purpose include alcohols such as methanol, ethanol and the like, hydrocarbons such as benzene, toluene and the like are halogenated e hydrocarbons such as chloroform, carbon tetrachloride and the like, acetone, ether, petroleum ether, carbon disulfide and Glacial acetic acid. In a preferred embodiment, glacial acetic acid is used as the solvent.

The reaction conditions used in the iodination of a compound of formula XV with death in the presence of an oxidizing agent can vary since temperature, pressure and reaction time are not critical to the process. Thus, temperatures are suitable within a range of about 10 ° to about 100 ⁰ C. In order to achieve optimal yields, everybody should use them

10 9851/1930

preferably temperatures above room temperature are used. Reaction times that lead to a termination are used in the same way allow reaction, usually between 12 and 36 Hours. For convenience, the reaction will be at atmospheric pressure executed. The compounds of the above formula XIV and the processes for their preparation, which consist in that a compound of the above formula XV with either iodine monochloride or treated with iodine in the presence of an oxidizing agent are also encompassed by the present invention.

The compounds of the

Formula XV above are known compounds or can be prepared in analogy for the preparation of known compounds "are obtained".

If in the compounds ^ of the above formula XIV the substituent R ₁ . Is hydrogen, these compounds can be converted into compounds of the formula XIII by combining them with a compound of the formula

X'-CO-CH ₂ -X XVIII

wherein X ^{1 is} halogen and X has the above meaning, brings it to reaction.

If the substituent R _r in a compound of the formula XIV is an acetyl group, this compound can be converted into a compound of the formula XIII in such a way that this compound is hydrolyzed in order to remove the acetyl group and the compound obtained with a compound of the above formula XVIII implements.

2'-Fluoro-5-iodo-2-methylaminobenzophenone can be obtained from 2-Amino-2'-fluoro-5-iodobenzophenone by tosylation, methylation and

109851/1930

Cleavage of the tosyl group is produced by acid hydrolysis.

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

R.

wherein R, has the above meaning, with a compound of the general formula

XIX

• CO - CH-

COOR,

NHR ₆

XX

where R_ and X 'have the above meaning and R ^ a Carbobenzoxy group means

brings to reaction and either a compound obtained the general form]

109851/1930

R-,

N CO CH COOR,

NHR 5

XXI

wherein R ₁ , R ₂ and Rg have the above meanings, treated with a hydrohalic acid, such as hydrobromic acid, and glacial acetic acid, or this compound is treated with a base and the resulting compound of the general formula

CO COOR,

NHR ^

XXII

where R ,, R_ and R _{r have the} above meaning,

Ld O

treated with a hydrohalic acid.

Compounds of Formula IV are made except for learning v / ground that you can use a Bour-.oph & non of formula XIX a compound of all T ^ -CM new K'or'juel

X'-CO CH -COOR ₂ XXIII

109ü ¹ J 1/1930

BATH ORIGINAL

wherein R and X ^{1 have the} above meaning, treated, a compound of the general formula obtained

R ¹

N CO CH ₂ COOR

XXIV

where R, and Rp have the above meaning,

nitrated or nitrosated and a preserved compound of all ~ common formula

CO CH-COOR

or

CO C COOR ^

NOH

XXVct

XXVb

wherein R _{1 and R 2 have the} above meanings, reduced.

The compounds of the above formula V can be prepared by the processes shown in the reaction scheme below Ground Vf:

10985 1/1930

Reaction scheme A

Hydroxylamine sulfate dichloroacetaldehyde

C-O

CHCl,

Methylation

base

109851/1930

Process stage a is conveniently carried out in the presence of an inert organic solvent, for example in the presence of alcohols such as methanol, ethanol and the like.

The conversion of the quinazoline compound 2 into the 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 is preferably carried out in the presence of an inert organic Solvent such as ethanol.

The optional methylation of the benzodiazepines 3 to the Benzodiazepine 4 can be carried out according to the methods described above.

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

XXVI

where R- has the above meaning,

be prepared, for example by means of tin (II) chloride in aqueous hydrochloric acid.

The compounds of the above formula VII can be deoxidized and reduction of a compound of formula V by means of

109851/1930

ejncis excess zinc can be produced in acetic acid.

Compounds of the above formula VIII, in which R is acyl, can be prepared by treating a compound of the formula VII can be obtained with a suitable acylating agent.

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

Compounds of the above formula X can by treatment a compound of formula IX with a suitable acylating agent can be obtained.

Compounds of the above formula XII can be prepared according to the procedure outlined in the following reaction scheme the preparation of compounds of the formula XII in which Rp Methyl can be obtained:

109851/1930

Reaction scheme B

NH.

d)

= 0 I.

COOCIL

.NH-CO-CH-NH-COO-Ch ₀ -C ^ H-

2 ο 5

C = O

e)

COOCPL NH-CO-CH-NH ₀

N C

CH-COOCIL

G)

109851/1930

N-

VcOOOH ₃

τ /

Compound 1 is obtained by reaction with N-benzyloxycarbonyl-2-carbomethoxyglycine chloride Transferred in connection 5. Compound 5 is used to split off the benzyloxycarbonyl group treated with hydrobromic acid in acetic acid. Compound 6 is cycllsiert to the benzodiazepine derivative 7, which to the benzodiazepine derivative 8 can be methylated.

The compounds of formula I above and their pharmaceutically acceptable salts are useful as anticonvulsants, Muscle relaxants and sedatives. Thus, these compounds and their pharmaceutically acceptable salts can be used as medicaments will.

For example, they can be used in the form of pharmaceutical preparations containing them or their salts in a mixture with a pharmaceutical, organic or inorganic inert which is suitable for enteral or parenteral administration Carrier material, such as water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, gum arabic, Contain polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form (e.g. as tablets, coated tablets, Suppositories, capsules) or in liquid form (e.g. all solutions, suspensions or emulsions). If necessary are they sterilized and / or contain additives such as preservatives, stabilizers, wetting agents or emulsifiers, Salts to change the osmotic pressure or buffers. she can also contain other therapeutically valuable substances.

When administering the compounds of the formula I or their pharmaceutically acceptable salts, the dosage is adapted to the individual requirements and the pharmaceutical needs of the situation. Conveniently, the dosage is in the range from about O ₄ 05 mg to about 1 mg per day.

109851/1930

2082927

As mentioned above, the compounds of formula I and their pharmaceutically acceptable salts are useful as sedatives, Muscle relaxants and anticonvulsants. The utility of the invention Compounds can be observed in numerous experiments. Used in the experiments described below the compounds of the above formula I, i.e. 5- (2-fluorophenyl) -7-iodo-1,3-dihydro-imethyl-2H ~ 1,4-benzodiazepin-2-one, are used as test substances (Compound A) and 5- (2-fluorophenyl) -7-iodo-1,3-dihydro-2H-1,4-benzodiazepin ~ 2-one (Compound B).

The sedative and muscle relaxing activity of the invention Connections can be observed in the following experimental set-ups:

Test on the inclined plane : the test substance is administered to male mice in doses of up to a maximum of 500 mg / kg po, the animals are placed on an inclined plane and observed for at least 4 hours whether they slide off the plane due to symptoms of paralysis. The PD, - _{0 is} ^{determined using} the Behrens method [Arch.Exp.Pathol.Pharmakol.14o, 237 (1929)] on the basis of 6 mice per dose and at least 2 points between 100 and 0%. In this experiment compound A shows a PD ^ ₀ of 1 mg / kg and compound B a PDp- ,. of 3.5 mg / kg.

Try on the awake cat ; Treat normal cats orally and see if there are any significant changes in their behavior. The minimum effective dose (MED) is the lowest dose at which symptoms are observed. In this experiment, compound A shows a MED of 0.05 mg / kg and compound B a MED of 0.1 mg / kg.

Combat test : Two mice are placed under an inverted 1-liter beaker on a grid, through which they are hit on the feet. You choose pairs of mice, which one

109851/1930

BATH ORIGINAL

xyou have fought at least five times during a 2-minute test period under these circumstances, administered the test substance to them by the oral route and repeated the test after one hour. Here one uses logarithmically increasing doses up to a maximum of 100 mg / kg. The 100% inhibitory dose (PD, ₀₀ ) is defined as the dose which prevents any fight in 3 of 3 pairs of mice for one hour. In this experiment, compound A shows a PD ₁₀₀ of 1.0 mg / kg and compound a PD ₁₀₀ of 2 mg / kg.

The anticonvulsant activity of the compounds of the invention can be demonstrated in the following experiment: f

Maximum electrical shock : This test is carried out according to the method of Swinyard, Goodman and Brown [J.Pharmacol.Exp.Ther. lOjS, 319 (1952)], but with the following modifications. Male mice are used and shocked in the same manner and duration as in the method described above; however, the current surge is not 50 nA, but 30 mA. One hour after administration of the test substance, the animals receive the electric shock mentioned. The criterion for the effectiveness of the test substance is the absence of stretching cramps in the hind paw. In this test, compound A shows an ED ^ ₀ of 1.6 mg / kg and compound B an EDp. ^ Of 1.3 mg / kg. '

7-HaIo-1,4-bensodiazepin-2-ones belong to a well-known group of compounds. The particularly pronounced sedative, muscle-relaxing and aritic-convulsive properties of 5- (2-fluorophenyl) -7-iodo-1 _, 4-benzodlazepin-2-ones of the formula Ϊ, which make these compounds extremely useful as tranquillizers, are, however, still so far not recognized. The discovery of these hitherto not described compounds within the well-known class of compounds and their unusual ability to serve as particularly effective sedatives make up the main part of the present invention.

109851/1930

BATH ORIGINAL

The following examples illustrate the invention without being intended to restrict it. All temperatures are given in degrees Celsius.

109851/1930

example 1

A mixture of 27 g (58.5 mmol) of 2-bromo-2 '- (2-fluorobenzoyl) ~ V ~ iodoacetanilide and 750 ml of liquid ammonia becomes stirred for 5 hours under a condenser charged with dry ice, after which the ammonia is evaporated off overnight leaves. The residue is refluxed with 1.2 liters of pyridine while stirring for 2 hours. Then distilled the pyridine is removed in vacuo and the residue is partitioned between methyl chloride and water. The backlog of over Sodium sulfate-dried organic phase is crystallized from ether and gives 5- (2-fluorophenyl) -l, 3-dihydro-7 ~ iodo-2H-1,4-benzodiazepin-2-one from melting point 221-223 °. Recrystallization from ethanol gives colorless ones Needles with a melting point of 222-224 °. During the reaction described above, 2-amino-2 '- (2-fluorobenzoyl) -4'-iodoacetanilide is formed, awake is not isolated.

The starting product can be produced as follows:

65 g (0.4 mol) of iodine monochloride in 50 ml of chloroform are added at room temperature to a stirred solution of 4.5 g (0.2 mol) of 2-amino-2'-fluorobenzophenone in 1 liter of chloroform. This mixture is stirred for 1 hour at room temperature and the excess iodine ionochloride is then destroyed by adding 1 liter of saturated sodium bisulfite solution. Then neutralize with concentrated ammonium hydroxide. The chloroform layer is separated, dried over sodium sulfate and concentrated in vacuo. When the residue is crystallized with hexane, 2-amino-2 ^f -fluoro-5-iodobenzophynone with a melting point of 93-96 ° is obtained. Recrystallization from ethanol / water gives orange-colored needles with a melting point of 102-105 °.

109851/1930

BATH ORIGINAL

A mixture of 32.1 g (94.3 mmol) of 2-amino-2'-fluoro-5-iodobenzophenone, 40.2 g (0.2 mol) of bromoacetyl bromide and 500 ml of benzene is refluxed for 2 hours, then cooled and neutralized with dilute ammonium hydroxide. Methylene chloride is then added and the organic phase is separated off. The organic phase is washed with water, dried over sodium sulfate and concentrated in vacuo to a volume of 200-300 ml. Addition of petroleum ether affords 2-bromo-2 ^t - (2-fluoi-benzoyl) -4 ^t -iodacetanilid of melting point 148-151 ° · Recrystallization from ethanol P is obtained off-white needles of melting point I5O-I5I ⁰ ·

2-Amino-2 ^f -fluoro ~ 5-iod.benzophenone can also be prepared as follows:

A mixture of 12 g (55 mmol) of 2-amino-2'-fluorobenzophenone, 125 ml of glacial acetic acid, 12.7 g (50 mmol) of iodine and 47.6 g (200 mmol) of sodium persulfate for 3 days at 20-25 ° stirred, then diluted with 500 ml of water and extracted with 3 × 100 ml of methylene chloride. The combined organic phases are shaken with 200 ml of 10 ^ sodium bisulfite solution. The aqueous phase is made alkaline with concentrated w Ammoniumhydrcxyd and again shaken with the organic phase. The organic phase is separated off, dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from hexane to give crude 2-aniino-2 ^: -fluoro-5-iodobesophenone. When recrystallizing from mixtures of ethanol and water, n-an receives a pure product with a melting point of 102-105 °.

Example 2

A mixture of 1 g of 2-bromo-2 '- (2-fluorobenzoyl) -4 ^l iodo-N-ynethylacetanilide, 10 ml of dimethylformamide and 2 ml of concentrated ammonia is refluxed for 3 minutes

109851/1930

heated. After cooling, the solution is diluted with water and extracted with ether. The combined ether extracts are washed with water, dried over sodium sulfate and evaporated. Chromatography of the residue on * 8 g Silica gel with ethyl acetate / methylene chloride 1: 1 gives 5- (2-fluorophenyl) -l >> - dihydro-7-iodo-l-methyl-2H-l, 4 ~ benzodiazepin-2-one, which after crystallization from ether / hexane at 106-109 ° melts. During the reaction described above, 2-amino-2 '- (2-fluorobenzoyl) -4'-iodo-N-methylacetanilide is produced 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 of dry pyridine is on for 1 hour Heated to reflux and 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 using concentrated ammonium hydroxide. The methylene chloride phase is separated off, dried over sodium sulfate and filtered through 300 g of aluminum oxide, 1 liter of methylene chloride being used for the elution. Evaporate the eluate in vacuo, the residue is crystallized from ether and g is obtained 2 '- (2-fluorobenzoyl) -4'-iodo-p-toluenesulfonanilide a melting point of l46-l49 °. For further purification, 1 g is dissolved in methylene chloride and the solution is filtered through 20 g of aluminum oxide. The eluate on evaporation residue is crystallized from ether dee and then recrystallized ^ by distilling off from a solution of this material in methanol and methylene chloride, the methylene chloride; whitish prisms with a melting point of 151-153 ° are obtained.

To a solution of 9.9 g (0.02 mol) 2 ^f - (2-fluorine-109851 /1930

benzoyl) -4 ^t -iodo-p-toluenesulfonanilide in 125 ml of dry dimethylformamide is added to 0.6 g (0.0125 mol) of sodium hydride ($ 50 in mineral oil). The mixture is stirred for 10 minutes and then 1.87 ml (0.03 mol) of methyl iodide are added. The mixture is stirred for 18 hours at room temperature and then poured into 300 ml of water and 75 nl of ether. The crude 2 '- (2-fluorobenzoyl) -4'-iodo-N-methylp-toluenesulfonanilide obtained as a solid is collected and melts at 162-164 °. When recrystallizing from chloroform / petroleum ether, colorless prisms with a melting point of 146-148 ° are obtained.

100 ml of 70% sulfuric acid are heated to 105 ° and 5 g of 2 '- (2-fluorobenzoyl) - ⁱ i- ^! -iod-N-meth3i-p-toluenesulfonanilide to. The temperature is increased to 145 ° within about 10 minutes. At 125 °, purple vapors begin to evolve, indicating loss of iodine. The solution is poured onto 1 kg of crushed ice. The mixture is extracted with 3 × 250 ml of methylene chloride. The extracts are dried over sodium sulfate and evaporated to dryness in vacuo. When the residue is recrystallized from 100 ml of boiling hexane, crude 2 -'-fluoro-5-iodo-2-methylaminobenzophenone with a melting point of 93-96 ° is obtained. Recrystallization from hexane gives yellow needles with a melting point of 97-100 °.

A mixture of 3.6 g of 2'-fluorine-5-iQd-2-methylamino-benzophenone, 30 ml of methylene chloride and 3 g of bromoacetyl bromide is stirred at room temperature for 1 hour, washed with water and with saturated sodium bicarbonate solution, over sodium sulfate dried and evaporated. The residue is crystallized from methanol and recrystallized from methylene chloride / hexane, 2-bromo-2 '- (2-fluorobenzoylJ- ¹ J-' -iodo-N-methylacetanilide having a melting point of 90 ° -93 °).

109851/1930

Example 3

A solution of 16.2 g (40 mmol) 5- (2-fluorophenyl) -1, 3> -dihydro-7-iodo-2H-1,4-benzodiazepin-2 ~ one in 500 ml dry tetrahydrofuran is mixed with 6, 72 g (60 mmoles) of potassium t-butoxide and then treated with 11.4 g (80 mmoles) of methyl iodide. The mixture is stirred overnight at room temperature, the mixture is filtered through diatomaceous earth and the filtrate is evaporated in vacuo. 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 ablated from methanol / ether umkristalli- i to give 5- (2-fluorophenyl) -l, 3-dihydro-7-iodo-l-methyl-2H-l, 4-benzodiazepin-2-one hydroehlorid in the form of yellow prisms with a melting point of 226-229 °.

A mixture of 5 g of this hydrochloride, 200 ml of 10 ^ -iger sodium carbonate solution and 200 ml of ether is shaken. The ether phase is separated off, dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from ether / petroleum ether and gives the free base with a melting point of 107-13.5 °. Recrystallization from ether / petroleum ether gives colorless prisms with a melting point of 107-110 °. i

Example 4

A mixture of 0.9 g of 2 ¹ -fluoro-5-iodo-2-methylaminobenzophenone, 0.9 g of glycine ethyl ester hydrochloride, 3 g of pivalic acid and 100 ml of toluene is refluxed for 48 hours, some of the solvent being distilled off . At the beginning, 15 ml of toluene are distilled off and replaced, and after 24 hours the cooled reaction mixture is partitioned between toluene and 10 ^ aqueous sodium carbonate solution. The organic phase is washed with sodium carbonate solution and water, dried over sodium sulfate and

109851/1930

steamed. The residue is chromatographed on 20 g of silica gel and uses methylene chloride first and then ethyl acetate in methylene chloride for the elution. Crystallization of the pure fractions yields 5- (2-fluorophenyl) -l, 3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepin-2-one from, melting point 10β ~ 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 in 10 ml of 80 # acetic acid for 24 hours. The one during evaporation residue obtained in vacuo is between methylene chloride and 10 ^ -iger aqueous sodium carbonate solution distributed. The methylene chloride phase is dried over sodium sulfate and evaporated. The residue is on 8 g of silica gel with 20 $ Chromatographed ethyl acetate in methylene chloride. The pure fractions are combined and evaporated. Crystallization the residue from ether / kexane yields 5- (2-fluorophenyl) -l, 3-dihydro-7-iodo-l-methyl-2iI-1,4-benzodiazepin-2-one with a melting point of 105-109 °.

The raw material is produced as follows:

A mixture of 8 g of N- (Benzyloxy carbonyl) -2-carbo.-methoxyglycine, 6.3 g of phosphorus pentachloride and 100 ml of methylene chloride are stirred for 45 minutes at -20 to -15 °. On that 5 g of 2'-fluoro-5-iodo-2-methylaminobenzophenone are added and the mixture is stirred for a further hour without cooling. Subsequent brew 50 ml v / ater are added and the 2-phase system is refluxed for 1 hour. The methylene chloride layer is separated off with 10 ^ aqueous sodium carbonate washed, dried over sodium sulfate and evaporated. The residue is dissolved in 50 ml of methanol containing 2 ml of triethylamine, dissolved «After heating to the boiling point, the solution a.b-

109851/1930 ORIGINAL BATHROOM

cooled, whereupon the product crystallizes out. The crystals are collected and recrystallized from methylene chloride / llexane, using 3- (benzyloxycarbonylamino) -3-carbomethoxy-4- (2 - fluorophenyl) -l, 2.5> ¹ l - tetrahydro- ⁱ l - hydroxy- 6-iodo-1-methylquinolin-2 ~ one with a melting point of 210-220 ° (2ers.) Is obtained.

To a warm solution of 5 6 of the above product 20 ml of acetic acid containing 30% of hydrogen bromide are added to 100 ml of methylene chloride. The reaction mixture v.'ird during Left to stand for 4 hours at room temperature and then concentrated under reduced pressure. The residue is made from methylene chloride / ether crystallizes and yields a hydrobromide I.

with a melting point of 17O-18O ⁰ (decomp.)

4 g of this hydrobromide are distributed between methylene chloride and 10% aqueous sodium carbonate solution. The methylene chloride mixture is dried and evaporated. Crystallization of the residue from ether gives 5-amino-3 "carbomethoxy-4- (2-fluoropheriyl) -l, 2,3 _i 4-tetrahydro- ⁱ i -hydroxy-6-iodo-1-methylquinoline-2-o: i, which melts ^{at 170-172 0} after recrystallization from methylene chloride / hexane.

Example 6

To a solution of 0.4 l g of 5- (2-fluorophenyl) -1, j5-dihydro-7-iodine-1-methyl-2H-1,4-benzodiazepin-2-one- ¹ } oxide in 10 ml of methylene chloride is added to 1 ml of phosphorus trichloride. The mixture is left to stand for> 0 minutes at room temperature and the mixture is partitioned between 10% aqueous sodium carbonate and benzene. The organic phase is dried over sodium sulfate and evaporated. Crystallization of the residue from Aefcher / kexan gives 5- (2-fluorophenyl) -l, 3-dlhydro-7-iodo-1-methyl-2H-1,4-benzodiazopi.n-2-one with a melting point of 104-108 .

The starting material can be produced as follows:

109851/1930 BAD original

A mixture of 102.3 S 2-amino-2'-fluoro-5-iodobenzophenone, 24 g hydroxylamine sulfate, 45 g dichloroacetaldehyde and 1 liter of asthanol is used to generate a solution under Stirring warmed up and then further stirred overnight at room temperature. The mixture becomes saturated by adding Sodium bicarbonate solution neutralized and diluted with plenty of water. The failed body is collected with Washed with water, dried and yields yellow 2-dichloromethyl ~ 4 ~ (2-fluorophenyl) - 1,2-dihydro-6-iodoquinazoline-3-oxide from melting point 184-187 °.

To a suspension of 45.1 g of 2-dichloromethyl-4- (2-fluorophenyl) -l, 2-dihydro-6-iodoquinazoline-3-oxide 100 ml of j5N aqueous sodium hydroxide are added to 750 ml of ethanol. That The mixture is stirred for 21/2 hours at room temperature and then concentrated under reduced pressure. The residue Zivi will see methylene chloride and distributed in hydrochloric acid. the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. The residue will crystallized from ethane oil and recrystallized, whereby one 5- (2-fluorophenyl) -1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one-4-oxide obtained from melting point 192-196 °.

To a solution, cooled to 0 °, of 19 * 8 g of 5 ~ (2-fluoropheny I) -I ^ -CU hydro-7 ~ ioä-2H-i, 4 ~ berizodiazepin-2-one-4-oxide in 250 ml Tetrahydrofuran is added 6.2 g of potassium t-butoxide under a nitrogen atmosphere and with stirring. After stirring for 1 hour at 0 ° , 7.8 g of mefchyiiodide are added, whereupon the mixture continues for a long time? Stirred for 2 hours without cooling, then filtered and evaporated to dryness. The residue is partitioned between methylene chloride and water. The methylene chloride layer is dried, filtered and evaporated. By crystallization from ethanol, 5- (2 ~ fluorophenyl) ~ l _J 5-dihydro-7-iodo-li; iethyl-2H-l, 4-benzodlazepin-2-one · 4-oxide, which is recrystallized from ethanol and then

... . 109851/1930 bad original

- Κ2 -

melts at 178-18I ^0.

Example 7

To a solution, cooled to 0 °, of 1.2 g of 7-amino-5- (2-fluoropheny1) -1,3-dihydro-1-methy1-2H-1,4-benzodiazepin-2-one a solution of 0.35 g is added to 3 × 5 ml of 6N hydrochloric acid Sodium nitrite in 5 nil water. The yellow solution is stirred for 10 minutes at 0 to + 5 °. A solution is given to this of 1.2 g of potassium iodide in 5 RiI of water and stirred during another 30 minutes at room temperature. It is filtered, sets alkaline the piltrate with ammonia and extract it with |

Methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and evaporated, an orange-colored oil remaining. Crystallization from methylene chloride / ether / petroleum ether gives 5- (2-fluorophenyl) -l, 3-dihydro-7 "iodo-1-methyl-2H-l, ⁱ J-benzodia2epin-2-one with a melting point of 102-107 °.

The starting material can be prepared as follows:

A solution is added to a solution of 12.5 g of 5- (2-fluorophenyl) -l, 3-dihydric-l-methyl-7-nitro-2H-1,4-benzodite-zppin-2-one in 80 ml of 6N hydrochloric acid of 30 g of tin (II) chloride dihydrate in 80 ml of 6N hydrochloric acid. The mixture is stirred overnight and the suspension obtained is made alkaline by adding 50% aqueous potassium hydroxide. The precipitated yellow solid is collected, washed with water, dried and recrystallized from tetrahydrofuran / hexane, 7-amino-5- (2-fluorophenyl) -l, 3-dihydro-1-methyl-2H-l, ¹ f- benzodiasepin-; 2-'On with a melting point of 206-208 ° (Zors.).

109851/1930 bad original

Example 8

A solution of 0.4 g of 5- (2-fluorophenyl) -l, j5,4,5-tetrahydro-7-iodo-1-methyl-2H-1,4-benzodiazepin-2-one. in 10 ml of chloroform is cooled to -20 °. J> _S 6 ml of a 0.5 molar solution of bromine in chloroform are added and the mixture is stirred for a further 15 minutes at -10 °. The reaction mixture is partitioned between sodium hydroxide solution and chloroform. The organic phase is dried and evaporated. The residue is dissolved in 10 ml of ethanol and, after the addition of 10 mg of sodium methylate, stirred for 10 minutes. The mixture is diluted with water and extracted with benzene. The benzene layer is separated, dried over sodium sulfate and evaporated. The residue is chromatographed on 6 g of silica gel with 20% ethyl acetate / methylene chloride. Crystallization of the pure fractions from ether / hexane yields 1 _J .3-Dihydro-5- (2-fluorophenyl) -7-iodo-1-methyl-2H'-1,4-benzodiazepin-2-one with a melting point of 106-109 ° «

The starting product can be produced as follows:

A mixture of 2.05 g of 5- (2-fluorophenyl) -1,> - dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepin-2-one-4-oxide, 20 ml of methylene chloride, 2 g zinc dust and 5 ml acetic acid are stirred for 30 minutes at room temperature. The mixture is filtered and partitioned between methylene chloride and 10% aqueous sodium carbonate. The Kethylene chloride layer is washed with water, dried over sodium sulfate and evaporated. DeT residue is crystallized from methylene chloride / ether, crude 5- (2-fluorophenyl) -l, ^, 4,5-tetraliydro-7'-iodyl-methyl-2Ii-1,4-benzo ^ iazepine 2-one receives. By recrystallization from methylene chloride / Flexan obtained a pure product of melting point 171-I75 ^0th

BAD 109851/1930

Example 9

A mixture of 10 ml of ethane oil, 0.2 ml of azodicarboxylic acid diethyl ester and 0.4 g of 5- (2-fluorophenyl) -l, 3>, 4,5-tetrahydro-7-iodo-1-methyl-2H-1,4-benzodiazepin-2-one is refluxed for 2 hours. Chromatographed after evaporation the residue on 8 g of silica gel with methylene chloride / ethyl acetate 1: 1. Crystallization of the pure fractions provides 5- (2-fluorophenyl) -1,3-dihydro-7-iodo-l-nie thy 1-2H-1,4-benzodiazepin-2-one with a melting point of 106-109 °

Example 10

A mixture of 0.55 g of 5- (2 ~ fluorophenyl) ~ l,; 5, '! , 5-tetrahydro-7-iodo-l-methyl-4- (p-toluenesulfonyl) -2H-l, ^Jl r-benzodiazepin-2-one, 20 ml benzene, 2 ml t-butanol and 0.16 g potassium t- buto>: yd is refluxed under a nitrogen atmosphere for 20 minutes. The reaction mixture is cooled and partitioned between water and ether. The organic phase is dried and evaporated. The residue is chromatographed on 6 g of silica gel with ethyl acetate / methylene chloride 1: 1 (v / v). Crystallization of the pure fractions from ether / hexane delivers 5 ~ (2-fluorophenyl) -1,> dihydro-7 ~ iodo-1-methyl-2H-1,4-benzodiazepin-2-one with a melting point of 106-110 °.

The starting product can be produced as follows:

A mixture of 1 g of 5- (2-fluorophenyl) -i, 3, ⁱ f, 5-tetrahydro-7-iodo-1-niethyl-2H-1,4-benzodiazepin-2 ~ one, 0.6 g of p- Toluene sulfonyl chloride and 10 ml of pyridine are left to stand at room temperature overnight. The mixture is then evaporated and the residue is partitioned between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase is washed with 1N hydrochloric acid and water, dried over sodium sulfate and evaporated The residue is made from methylene chloride / ether

^109851/1930 BADOR.Q .. *:

crystallized and recrystallized from methylene chloride / ethanol 5- (2-Fluoro ^ henyl) -1,; 5,4,5-tetrahydro-7-iodo-1-methyl ~ 4- (p-toluenesulfonyl) -2H-1,4-benzodiazepin-2-one of melting point 255-258 °.

Example 11

0.17 g of 5- (2-fluorophenyl) -l, 5-ciihydro-7-iodo-l-ynethyl-2H-1,4-benzodiazepin-2-one is In a solution of 50 mg of sodium in 5 ml of anhydrous ethanol dissolved. Then the mixture is stirred JO minutes at room temperature under atmosphere stickst off, acidified at gut by adding acetic acid and evaporated. The residue is partitioned between methylene chloride and 10% aqueous sodium carbonate solution. The methylene chloride layer is dried over sodium sulfate and evaporated. Crystallization of the residue from ether / hexane gives 5- (2-fluorophonyI) -I, jj-dihydro-iodine-1-methyl-2H-1,4-benzodiazepin-2-one with a melting point of 106-109 °.

The starting material can be produced as follows:

To a solution of 4.1 g of 5- (2-fluorophenyl) -l, 3-dihydro-7-iodo-1-methyl-2H-1,4-benzodiazepine-2 -on-4-oxide in 100 ml of ethanol and 50 ml of tetrahydrofuran are added 0.6 g of sodium borohydride. The mixture is stirred for 1 1/2 hours at 40-5O °, concentrated in vacuo and treated with water, whereupon Crystallization occurs. The solid is collected, dried and recrystallized from methylene chloride / hexane, whereupon 5 ~ (S-B'luorophenyl) -1,3,4,5 ~ tetrahydro-4-hydroxy-7-ioä-imethyl-2H-1,4-benzodiazepin-2-one .from the Melting point 216-220 °.

2 g of the above compound are taken over power at room temperature left to stand in 20 ml of pyridine and 2 ml of acetic anhydride. The reaction mixture is evaporated and crystallized

109851/1930

BAD oRIGINAL

the residue from methanol, whereupon 4-acetoxy-5- (2-fluorophenyI) -I, 3,4,5-tetrahydro-7-iodo-1-methyl-2H-1,4-benzodiazepln-2 ~ one obtained from melting point 172-174 °.

A mixture of 1 g of the above material, 15 ml of Aethano3 and 5 ml of diethylamine is refluxed for 1 hour cooked. The residue obtained on evaporation becomes on 20 g silica gel chromatograph, used for the elution 10 $ ethyl acetate used in methylene chloride. The pure ones Fractions are combined and evaporated. When recrystallizing of the solid obtained from methyl chloride / etexan 5- (2-Fluoropheiiyl) -1, 5-dihydro-7-iodo-1-methyl-2H- | is obtained 1,4-benzodiazepin-2-one with a melting point of 191-195 °

Example 12

0.5 g of 4-acetoxy ~ 5- (2-fluorophenyl) -1,5,4,5-tetraliydro-7-iodo-1-methyl-2H-1,4-benzodiazepin-2-one is dissolved in 10 ml of ethanol. 0.15 g of potassium-t-buto :: yd are then added and the mixture is boiled reflux the mixture for 15 minutes. After evaporation, the residue is partitioned between benzene and water. The benzene layer is dried and evaporated. Chromatography of the residue on 10 g of silica gel with ether / benzene (2: 1) gives 5- (2-fluorophenyl) -l, 3- I

dihydro-7-iodo-1 ~ methyl-2H-1,4-betzcäiacepin ^ -one of melting point 106-110 °.

Example .13

A solution of 0.45 g of 5 - ('- ·: · Fluorophunyl) -1, J-dihydro-7-iodo-1-methyl-2H-1,4-benzodia2: opin-2-one-3-carboxylic acid methyl ester in 10 ml of methanol is degassed with nitrogen and after addition of 2 nl in sodium hydroxide solution for J5 hours at room temperature touched. The reaction mixture is made by adding Acidified in hydrochloric acid, made alkaline with ammonia

109851/1930

BATH ORIGINAL

and extracted with ether. The ether extracts are dried over sodium sulfate and evaporated. Chromatography of the residue on 6 g of silica gel with methylene chloride / vinegar. Ester (1: 1) gives 5 - (2-fluoropbenyl) -l, 3-dihydro-7-iodo-methyl-2K-l, ¹ f-benzodiazepine-2-Gn with a melting point of ^{106-110 c} .

The starting product can be manufactured as follows:

To a suspension of 8 g cooled to -20 ° H- (Benzylo> cycarbonyl) 2-carboniethoxyglyc3n in 100 ml methylene--. chloride is given to 6, jg of phosphorus pentachloride. The G-amish will ' v.'for JO minutes at -20 to -15 °. HereftuT there one at 0 to 5 ° 6.7 ß 2-Amino-5-iodbenJr.ophenDn and then 100 ml 1.0 / j - aqueous sodium carbonate to. The ethylene chloride layer is separated off, twice with sodium arbophate - solution washed, dried and evaporated. Crystallization of the residue from ethylene chloride / llezane yields c .'- [- (DGnzylo>: y cr..rbonyl) anjino] -2-carboroiethxy ~ 2 '- (2-fluorobenzoyl} -4' »iodoacetanide from Schir.elzounkt 100-10 ^ °

To a solution of 5 E of the above product in 50 ml of methylene chloride gjbt adding 20 rnl of acetic acid containing 30p Bronv; asserstoffsäure. The mixture is left to stand for k hours at room temperature and then evaporated. The residue is slurried with ether and the crystalline solid is isolated, giving an Ilydrobrowid with a melting point of 188-.V92 ^C (Zei-ε.).

3 g of this hydrobromide are distributed between methylene chloride and 10% aqueous sodium carbonate solution. The MsthyJonchioridschicht is dried over sodium sulfate, filtered and evaporated. Crystallization of the residue from methyl enchl or id / Rexan gives 2-amino-2-carbomethoxy-2 ^f (2 ~ flDorbenEoyl) ~ 4'-iodoacetanilide with a melting point of 120-123 °.

10 9 8 51/19 3 0 ^Β ^ ό OR) GiMAL

■ '!! «" f- if' ¹ : ¹ ". ¹ '! Il ■; '■ ■ ": ■ ΊΓ»

1 * 5 S of the above amine are in 50 ml. "L of toluene, containing 5 ml of acetic acid, refluxed. The residue obtained on evaporation of the reaction mixture is crystallized from methylene chloride / ether and gives 5- (2-I «auorphenyl) -l, 5 - '(Unydro-7-iocl-2H-l, ^ - benzo» diazepin-2-one ~ 3-carboxylic acid ethyl yter with a melting point of 230- (dec.)

0.88 g of the above compound is dissolved in 20 ml of dimethylformamide and cools the solution to -20 °. Then 0 * 3 S potassium t-butoxide is added and, after stirring for 5 hours, 0.2 ml Dimethyl sulfate too. Let the temperature rise to 0 °. f

The reaction mixture is acidified with acetic acid and poured into ice water. The precipitated product is collected and dissolved in methylene chloride. The solution is dried over sodium sulfate, filtered and evaporated. Crystallization (Ige residue from ether / hexane gives 5- (2-puuophenyl) ~ lo-dihjuro-Y ^ io-dl-methyl -2: 11-1 _i ^J l -ber \ Küdiaxepin-2-one ~ 3 "carbcnsUureruethyXester, v; more according to Uinkrir.tcilliyieren from Methyleni melts at 135-139 °.

A mixture of 0, h 5- (2-Flu H'phenyl) ~ l, 3> ^J ^ 5-hydrc tstra ·· ^"i-1 hyciroxy-7-ioü-l-'R ₁ g c! ^I. thyl-2H-1 _J ^ -byriy, odia7epin-2-an _J , 5 n: 1 pyridiii and O ₄ 2 uil phosphorus oyyohl or id. is refluxed for 5 minutes and reduced in the intestine evaporated under pressure. The residue is mixed with benzene and 10% vüicxi'iijer sod.iunicarbonablö: distributed young. The organic ο üchichi; is left over; r Ndtriui.i.si · Ifal gotrooknet iw.d daiuped. Chromatography on β g Ki ^ ο υ hedgehog üit 10 · 'ί EiJfvi _t; ster provides in methylene chloride ^ - (S-Pluoi-phenylJ-li ^ -dihydiro-Y-iodo-l-iiiethyl-2H ~ l, ^ - bcn5'.ocUa. .iOpin-2-one, v.'el.oh - '>; -, according to KrU: dilution from hexane / riothylene chloride melts at 188-1%. From the fractions eluted later, rr.an da :; isomers '.> (2-PIuOi ¹ J) IItUIy!) ■ ·

10S851 / 193Q

BATH ORIGINAL

- ilQ ..

1 , 3-dihydro -T-iodo-1-methyl- ^ Hl, 4-benzodiazepin-2 - one, which after crystallization from ether / lfexane melts at 102-106 °.

Manufacture of capsules

Per capsule

5- (2-fluorophenyl) -l, 5-dihyclro ~ 7-iodo-

-SH l, ²⁾ 10 -ben-zodiaze-p.iri.-2-one ng

Milk sugar 165 nig

Corn starch 30 ir.g

Talc ' 5 mg

Total weight 210 mg

Benzodiazepine - 2- \ cn, lactose and corn starch are mixed in a suitable mixer. The mixture is passed through a grinder for further use. The mixed powder is returned to the mixer, the TaIK "is added and the mixture is mixed thoroughly. The mixture is mechanically filled into hard gelatine capsules,

Beispi el. B.
Solution for injection

Per cc

5- (S-pluorophenyl) -1,5-dihydro-7-iodo-K3thyl-2H "1.4-ben20qiazepin-2-one 5 * 1 mg.

Benzyl alcohol 0.015 ml

Propylene glycol 0.5 ml

Ethyl alcohol (anhydrous) 0.1 π 1

Sodium acetate tx'ihydr-at 1.4 mg

Icy 0.6 mg '

109851/1930

BAD ÖPAGmfi

After 10 $ solution q.s. ad pH 6.0

Water for injections q.s. ad 1.0 ml

To prepare 5000 cc of solution, add 5 ~ (2-Fluorphe.ayl) -1, j5-dihydro-7-iod-1 - i;: ethyl ~ £ H-1, ^{} <} -beni.odia. z »; pin-2-one to propylene glycol and benzyl alcohol and heated, while stirring, to - ¹ IO"ur; to bring about reading. The l. duun-s wjn. l; ü.}: ohol, D5-Natriur.i-Edetat, Urtriumaoetat und Ei .-; o3sig turn in et :: a ijOO ir.l V / ater for injection purposes gelür'o urd zu ύον obi ^ eu Lö ^r - u; · ^; given. The solution is adjusted to a pH of 6.0 with 10 / '· -ϋ fjfi "sodium hydroxide solution and t. _; it V.'aüKcr f'ii · Tnjnk'ri c \: r: zv? eek « ^: 8.brrc.oht to the desired volume. The solution is filtered through a candle filter under nitrogen heat: filled into 2 cc ampoules, which melt to - :; and v; ähreii:>;; 0 younger at 0.7 atinosphereis sterilized in AuLoklavi-n , v.xrd * Di-lTatriur.sulr: from Aethylcncij awialetT ti ^ ssj gcävire.

Example C

TaW etten

Per tablet

5- (2-fluorophenyl) -l,
^{l-üietliyl-2H-l;} ! -benz 3-dJ.hydro-7 "iodine
; odiaxepin-2-one 100 rrg Lactose 202 kg Cornstarch 80 ras vorhyf.rolysierl - '= I! ai ^srt;? rkc 20 mg Kai ζ i ü: r. ste ar at 8 mg G £ s fc_ \ nt _L : c >: ic; 11 '{10 mc

5- (2-Plucrphenyl) -1, i-cahy dro-7-i od-lr, ethy 1-2ΙΪ-1 , ^h - benzodiazepin-2-one, milk sugar, l'.Hi e.s'. äri: c and vorhyarclyr; "rT, e cornstarch cords in a gooigucten iiisci-er restricted. The mixture is granulated with water to a hard paste, then the moist mass through a. ·; v? i3: l'3irierur; ^ t'i;iasehii; e given and then dried ^{over power at 'V-? 0 .vrirc 7.} The dried granulate v.'ird durc]: eire Zerkleinerun / fs: rc, ru! Sue

10 9 8 51/19 3 0

BATH

25th ing 175 mg P.h mg 1 mg

given and then placed in a suitable mixer. Calcium stearate is added, mixed thoroughly and the mixture is compressed into tablets each weighing ¹ HQ mg.

Example i)
Tablets

5 ~ (2-P: 1 uor phenyl) -1, 3-dihydro ~ 7- iodo - ·
1 -me thy 1-2K-1, 4 -ben zodiazti pin- 2- on

Dikalziun: phospli * .t ~ tUhydrate (ungsmahlen)

Corn starch magnesium stearate

total weight

5- (2-fluorophenyl) -lo-dihydro-.7-iodine-1-methyl-2H-i _i 'I-berjzodiazepin-2-one and natural starch are mixed together and passed through a grinder. The mixture is then mixed with dicalcium phosphate and half of the magnesium stearate, passed through a grinding machine and granulated. The grains are given four through a grinding machine, before the rest of the magnesia is added, mixed and compressed.

Beis pie l E

Capsules

i! £ 2_Ji5ܧ2.1.

5- (2-Fluorophenyl) -1, '- dihydro-7-iodl-methyl ~ 2H-l, ^ - be)' jZod.i azepin ~ 2-one 50 mg

Milk sugar 125 mg

Corn starch 30 mg

Talk 5_m £

Total weight 210 mg

benzodiazepin-2-one is j η a suitable mixer with milk

109851/1930

BATH ORIGINAL

sugar and corn starch mixed together. The mixture is used for the purpose further confusion given by a? / 3rsmallerunr; n machine The mixed powder is returned to the mixer, whereupon the talc is added and mixed thoroughly. Dan mixture maischinoll is filled into hard gelatine capsules.

S {j>: Iel F

One divides pharmaceutical preparations in analogy zv. the method described in Examples A to E above, but uses 5 ~ (L-Pluorpbftnyl) -1,3-dihydro-7'-iodine, 4-bonzodiazepin-2-one as active ingredient.

109851/1930 bad original

Claims (1)

Patent claims UJL Process for the preparation of benzodiazepine derivatives of the general formula wherein R _{1 is} hydrogen or methyl, and their acid addition salts, characterized in that one a) a compound of the general formula N-CO-CH II wherein R, has the above meaning, cyclizes or
b) a compound of the general formula 109851/1930 BAD ORiGiNAL III where TL has the above meaning, with glycine or an ester thereof, b ^ hanuel X or c) a compound of the general formula R, IV where H, oMg-e meaning benit ^ t unH Rp lower Alkyl means a Ringerv.-3iterung and an external hydrolysis under aqueous conditions or
d) a connection of the general formula R, 109851/1930 BATH ORIGINAL wherein R, has the above meaning, is deoxidized or
e) the Diazoniunisalz of a compound of the general formula VI wherein R _{1 has the} above meaning, subject to an exchange reaction of the Sandmeyer type or f) a compound of the general formula VII where R-, has the above meaning, oxidized or doiydrogenated at the 4,5 bond or BAD ORiGiNAL 109851/1930 g) a compound of the general formula VIII wherein R, has the above meaning and R-, halogen or -acyl means, by treatment with a strong base into the corresponding ^, 5 ~ dehydrocompound of the formula I Ub ο rf o'clock t or h) a compound of the general formula IX where R, has the above meaning, dehydrated in the corresponding ^, 5-hydrochloride compound of the formula I or 109851/1930 BATH ORIGINAL i) a compound of the general formula wherein R has the above meaning and R _{2 is} acyl, converted into the corresponding h ^ -O compound of the formula I by treatment with a base, or j) a compound of the general formula XI where R, above- has meaning, rearranged to the corresponding 4,5-Dehydroverbindurig of the formula I. or BATH ORIGINAL 1098S1 / 1930 .- 58 - k) a compound of the general formula XII where R, and R "have the above definition, saponified and decarboxylated or l) the compound of the formula I in which R 1 is hydrogen, methylated to the compound of the formula I in which R 1 is methyl and rn) if desired, a compound of the formula I obtained in an acid addition salt transferred. 2. The method according to claim 1, characterized in that that the cyclization of the compound of formula II by gentle heating in the presence of an inert organic Solvent performs. 3. The method according to claim 1 or 2, characterized in that that the compound of the formula II from a compound of the general formula _N CO CH .. X XIII 109851/1930 wherein R has the meaning given in claim 1 and X is a leaving group, a carbobenzoxyamino group or a phthalimido group,
manufactures. 4. The method according to claim; 5, characterized in that . that the intermediate of formula II is not isolated, but is cyclized in situ under the reaction conditions used. ρ 5 «Method according to claim 3 or 4, characterized in that that a compound of the formula XIII, in which X is a leaving group, is treated with ammonia « 6. The method according to claim 5> characterized in that the leaving group is halogen, alkylsulfonyloxy or arylsulfonyloxy is. 7. The method according to claim 3 or h, characterized in that the carbobenzo ^ y group is removed from a compound of the formula XIII, v.'orin X is a carbobenzoxyandno group. P 8. Method according to claim Y, characterized in that that the carbobenzo>: y group by treatment with hydrogen bromide removed in acetic acid. 9. The method according to claim 3 or 4, characterized in that that a compound of the formula XIlI, for which X is a phthalimido group, is treated with hydrazine « 10. The method according to claim 1, characterized in that that treatment of the compound of formula III with glycine weak or a glycine ester under / acidic conditions. 109851/1930 BATH ORIGINAL 11. The method according to claim 1, characterized in that d, -v; s the deoxidation of the compound: of the formula V by means of a phosphorus tr \ Lh & .lo £ enLas, by hydrogenation in the presence a hydrogenation catalyst ?? or mediate zinc in acetic acid he follows. 12. The method according to claim 1, characterized in that because «ο the Dia? oniumaalζ the verbirdunc of the formula VI with treated with an alkali metal oxide or with copper (J) iodide. 15. The method according to claim 1> characterized in that Λ "the oxidation oclur Dehydrogenierun ;; the compound of the formula VII with oxygen, manganese dioxide, bromine, chlorine or azodicarboxylic acid esters. 14. The method according to claim 1, characterized in that that the compound of formula VIII or X in anhydrous Medium with an alkali metal hydride, an alkali alkoxide, an alkali amide or triethyiamine is treated. 15. The method according to claim 1, characterized in that the compound of formula IX with thionyl chloride, Phosphoroxychloride or a Carbodiimld treated. f 16. Verfaliren according to claim 1, characterized by f; ekemizeichnet, that the compound of the formula. JCI treated with a bar; e v / irdi 17. The method according to An; i-. Claim 16, characterized in that that the base is an alkali alkoxide, an A.lkalihydrid or Triethyiamine used. 18. The method of claim L, wherein _{v is} the "the hydrolysis of the Vei'bindung Foriiiel XII 109851/1930 BATH ORIGINAL alkaline conditions and the decarboxylation is thus stated, ciasc ιλρπ °: Lne solution dor hydrolyzed Connect loosely, heated or acidified. ^! 19. The method according to claim 1, characterized in; by treating the compound of the formula XII with an acid. 20. Proceed according to Ans] 1 after 1, dadurc.ng * »k ^ nnzeic] in» t that the compound of the formula I, in which Π, is hydrogen, is converted into a 1-alkali metal:; alz üi'i .; «? Leads κ \ ι: ϊ this is then dealt with with a methylation agent. 21. The method according to any one of claims 1-19 »thereby characterized that 5- (2-Plu «rpLfcnyl) -l, ^ - dihydro-7-iodo- SH-ii'l-benzodiazepln-S-one is produced. 22. The method according to any one of claims 1-20, characterized characterized, dans 5- (2-fluoropheriyl) -l, 5-dihydro-7-iodo-methyl-2H-1,4-benzodiazepin-2-one will be produced. ORIGINAL BATHROOM 1 0985 1/1930 UL 23 Process for the manufacture * »! Iuji ^ from pharmaceutical · Prüparateh ».it antj kcuvjl si ven, mu & kel relax Jen And sedative properties, marked by this» '! rhr.pt .. that ir, an i? in ftenzd diai'.epinderivat of the general formula I defined in claims 1 as an effective ingredient ir.it? .ur tl ^ i apeuti see 'Verabr'5icluing more suitable-, non-toxic :, inert, solid 'per se' common in such preparations! or fiü ^ sippen TräßGi'n 'and / or Excipi ent Ven threshed. 24. pharmaceutical preparations with a «ti convulsive s, muskeirelax.1erenck ;. and cedativen property s containing an air Bensodiazepinderivat defined in claim 1 f general forrr> l J and phnr.ra ^ euti & ch inzcXf *, Tr "df, <? r; f.at <? ri al Λ '· ■:; - ■. '<>' 10 9 8 5 1/19 3 0 ■ ^ P ' BAD original