3-hydroxy-1,4-benzodiazepine-2-ones

DECEMBER filed in support of a request

PATENT OF INVENTION

Luxembourg on behalf of: GEROT-PHARMAZEUTIKA GESELLSCHAFT mbH

for: Derivatives of 3-hydroxy-1,4-benzodiazepin-2-one_z their method of preparation and their therapeutic application.

The present invention relates to novel 3-hydroxy1,4-benzodiazepin-2-one of the following general formula

<img file="LU81990A1_D0001.tif" />

wherein R is methoxy or cyano, R is hydrogen, halogen, trifluoromethyl or nitro, and R is hydrogen or halogen, with the proviso that when R ^ ^es- ^a halogen atom in the ortho position, R is not a methoxy group.

The present invention also relates to a process for preparing these compounds.

This process is characterized in that one selectively substitutes the NH group of a 3-hydroxy-1,4-benzodiazepin-2-one of the following general formula 'i

<img file="LU81990A1_D0002.tif" />

(II) while the OH group in position 3 remains unchanged.

The new compounds of general formula I are pharmaceutically usable compounds which are characterized by low toxicity and strong sedative, sleep-prolonging or potentiating activity of hexobarbital and which can also be used as intermediates for obtaining new drugs.

The compounds of general formula (I) in which R is an OCH „or CN group, are not yet described. Such derivatives of formula I in which R represents another residue, are obtained in the usual way by means of the 4-oxide substituted in position 1, the Polonovsky transposition of which leads to the 3-acyloxy derivative and finally by saponification (see DE -OS 2,237,211, Arzneim.Forsch. 25, 720 (1975)),

The compounds of the formula ([£ have been known since 1962. However, the flexibility of a selective substitution on the Nil group has practically never been used up to now. single reaction step, from readily available compounds such as, for example, oxazepam, lorazepam, etc. ,,, (see AT-PS 309,436), new high activity sleep agents.

According to the process of the present invention, reacting 3-hydroxy-1,4-benzodiazepin-2-ones of general formula (II), or their alkali metal salts._zif desired, using basic agents and / or adding phase transfer catalysts such as phosphonium or quaternary ammonium salts or crown ethers and optionally with alkali iodides, with compounds of general formula:

CH - CH - R

I ² I (III).

Λ I in which R has the meaning mentioned above, X is a reactive residue such as, for example, a halogen atom or a sulfonyloxy group, and Y is a hydrogen atom, or when R is a CN group, X and Y together form a second bond.

As the reactive component of general formula (III), it is possible in particular to use 2-methoxy-ethyl chloride, 2-methoxy-ethyl or Γacrylonitrile bromide, as well as chlorc-3-propionitrile or bromo-3-propionitrile. .

The alkaline derivatives of the starting products of general formula (III), not yet also described to date, are for example easy to obtain by reaction of these compounds with one equivalent of potassium tert-butoxide in an absolute solvent such as dimethylformamide or dioxane. The starting material first dissolves and finally the potassium derivative precipitates or it can be obtained by precipitation with ether.

When attempting to react the alkaline derivatives of formula (II) thus obtained with a compound XCH CH -O-CH, in ZZ where X has the meaning above, we obtain, in the case where R ^ is a halogen atom in ortho, two isomers which do not however correspond to the structure of the compound of formula (I) (in which R = OCH). The same isomers are also obtained "5

e.

jsique of Polonovsky by N-oxide, by hydrolysis of the 1 - (2-methoxyethyl) -3-acetoxy-5- (o-halogenophenyl) derivative.

It is therefore surprising that it is possible to obtain easily and with good yields the new compounds of formula (I) in which R = OCH by carrying out the process according to

O present invention, from alkaline derivatives of formula (II) in which R_ is not a halogen atom in ortho, by means of a Z reaction with a compound of formula XCH CH_o-O-CH „.

In addition, the possibility of the selective cyanoethylation of the compounds of formula (II) on the nitrogen atom of the amide (position 1) is also surprising, since, for example, the acetanilide which corresponds to the present structure, In practice only reacts at 90-100 ° C with acrylonitrile, while the reaction with secondary alcohols already takes place at or even below room temperature (Org. Reactions 5, 88, 89 ( 1949)). According to the process of the present invention, the reaction on the nitrogen atom of the amide of the compound of formula (II) starts already at room temperature, without simultaneously a substitution taking place on the OH group, although 1 acrylonitrile is used in large excess as the reaction medium.

The substitution of the residue -CH ^ -CH ^ -R on the nitrogen atom of the amide can be proved by the coupling signal ^ CH-OH 5 in the NMR spectrum of the derivatives obtained and by the esterification of the OH group remained free.

The following nonlimiting examples are given by way of illustration of the invention.

Temperatures are given in degrees Celsius, unless otherwise specified.

EXAMPLE 1

Is added to a suspension of 10 g of 7-chloro-3-hydroxy5- (2'-fluoro-phenyl) -l, 3-dihydro-2H-l, 4-benzodiazepin-2-one in 50 ml of acrylonitrile, 1 g of triethyl-benzyl-ammo15 niu'm chloride (^{, Ir}f eba), then 8 drops of a 40% methanolic solution of benzyl-trimer thylammonium hydroxide (Triton B) are then added with stirring. After stirring for 8 hours at room temperature, the reaction mixture is left to stand at 4 ° C overnight, the precipitate is filtered off, washed with acetone and crystallized from ethanol, La 1- ( 2-cyanoethyl]) - 7-chloro-3hydroxy-5- (2'-fluoro-phenyl) -l, 3-dihydro-2H-l, 4-benzodiazepin-2one thus obtained melts at 190-193 °.

Without the addition of Teba, l- (2-cyanoethyl) -7-chloro-3- (2-cyanoethoxy) -5- (2'-fluorophenyl) -l, 3-dihydro25 2H-1, 4- is also formed. disubstituted benzodiazepin-2-one which, by recrystallization from acetonitrile, melts at 204-207 °.

For the separation of the mono and di-substituted products from the starting product, a thin layer chromatography of silica gel 60 F 254 is used and as an eluting mixture of benzene:

dioxane: glacial acetic acid (90: 25: 4 by volume). EXAMPLE 2

Is added to a suspension of 10 g of 7-chloro-3-hydroxy5- (2'-chlorophenyl) -l, 3-dihydro-2H-l, 4-benzodiazepin-2-one (Lorazepam) in 50 ml of acrylonitrile , 1 g of Teba and 8 drops of a 40% methanolic solution of Triton B and the mixture is stirred for 24 hours at room temperature. The reaction mixture is then cooled to 4 °, the precipitate is filtered off and crystallized from ethyl acetate. This gives 1- (2-cyanoethyl) -7-chloro-3-hydrcxy-5- (2'-chloro-phenyl) -l, 3-dihydro-2H-l, 4-benzodiazepin-2-one, of which the melting point is 198-202 ',

Without addition of Teba also forms 1- (2-cyanoethyl) -7-chloro-3- (2-cyanoethoxy) -5- (2'-chloro-phenyl) -l, 3-dihy10 dro-2H- 1,4-benzodiazepin-2-one, the melting point of which is 210.213 ° (after recrystallization from acetonitrile).

EXAMPLE 3 g of potassium derivative of 7-chloro-3-hydroxy-5-phenyl1,3-dihydro-2H-1,4-benzodiazepin-2-one (Oxazepam) are suspended in 340 ml of 2-methoxy chloride -ethyl and, after addition of each time 6 g of Teba, aliquat and sodium iodide, the mixture is heated for 20 hours with stirring at 50 ° and then for 15 hours at 40 °. The reaction mixture is evaporated in vacuo, the oily residue is dissolved in CHCl 3 and extracted several times with water while shaking. The chloroform solution is dried over Na₂SO ^, filtered, evaporated, and the residue is taken up in CC1₄, which allows the crystallization of the substance. After recrystallization from isopropanol or ethyl acetate, 1 - (2-methoxy-ethyl) -7-chloro-3-hydroxy-5-phenyl-l, 3-dihydro25 2H-1, is obtained, 4-Benzodiazepin-2-one as a colorless powder having a melting point of 160-161 '.

The potassium derivative used as starting product is obtained by heating for one hour a mixture of 60 g of oxazepam and 24.9 g of potassium tert-butoxide in 600 ml of absolute dioxane, with stirring at 75^e. First a dissolution occurs, then a thick precipitate. The latter is filtered off with the cooled mixture left to stand overnight, then washed with isopropyl ether and dried under vacuum. Melting point 192-197 ° / Λ (with decomposition).

EXAMPLE 4

To a suspension of 20 g of oxazepam in 240 ml of acrylonitrile is added, with stirring, and dropwise, 3 ml of a 40% methanolic solution of Triton B and, then, heated for one hour at 50 °, which leads to the formation of an orange colored solution. After standing overnight, the reaction is terminated. The solution is concentrated in vacuo and on cooling the concentrate a precipitate is obtained which is recrystallized from CHClO 10 The latter melts at 192-194 ° and consists of 1- (2-cyanoethyl) -7chloro-3-hydroxy-5- phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2one.

If the reaction mixture is heated for 2 hours at 50 °, then 1 - (2-cyanoethyl) -7-chloro-3- (2-cyano15 ethoxy) -5-phenyl-1,3-dihydro is formed. Disubstituted -2H-1,4-benzodiazepin-2-one, which is practically insoluble in CHCl1 Recrystallization from acetonitrile affords a product melting at 215-218 °. EXAMPLE 5

A suspension of 2 g of Lorazepam in 20 ml of acryloni20 trile is heated to 50 ° after addition of 0.1 g of Teba and 1 ml of triethylamine, with stirring. A yellowish solution is then formed in which a precipitate gradually appears. After 3 hours, the mixture is concentrated in vacuo and the concentrate is allowed to crystallize overnight at 4 °. The precipitate is filtered off, recrystallized from ethyl acetate and is identical to the mono-substituted product obtained according to Example 2 (melting point: 198-202).

From the methods described, the following compounds are also obtained:

- (2-cyanoethyl) -7-nitro-3-hydroxy-5-phenyl-1,3-dihydro-2H-1,430 benzodiazepin-2-one, p. F. 185-188 °,

- (2-cyanoethyl) -7 -nitro-3-hydroxy-5- (2 '-chloro-phenyl) -l, 3-dihydro-2H-1,4, benzodiazepin-2-one, p. Mp 191-194 °.

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1- (2-cyanoethyl) -7-nitro-3-hydroxy-5- (2 '-fluoro-phenyl) -l, 3dihydro-2H-l, 4-ύοηζοάί &amp; ζέρΐη-2-ΰηβ, p. Mp 183-186 °.