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

For the preparation of 3-hydroxy-1,4-benzodiazepin-2-one

The invention relates to a process for the preparation of novel sedative and sleep-prolonging 3-hydroxy-1,4-benzodiazepin-2-ones having the general formula. CH₂ -CH₂--- R

<img file="FI67375C_D0001.tif" />

wherein R represents a methoxy or nitrile residue, R 1 is halogen or nitro, and R 1₂ may be hydrogen or halogen, provided that R does not represent a methoxy residue when R₂ = ortho-halogen.

The method according to the invention is characterized in that it is administered

3-hydroxy-1,4-benzodiazepin-2-ones of the general formula

<img file="FI67375C_D0002.tif" />

<img file="FI67375C_D0003.tif" />

N-CO

CH - OH

<img file="FI67375C_D0004.tif" />

N (II)

<img file="FI67375C_D0005.tif" />

wherein R 1 and R 2₂ the same as defined above, or these alkali compounds, if desired using basic additives and / or adding phase change catalysts such as quaternary ammonium or phosphonium salts or crown ethers and optionally alkali iodides, react with compounds of the general formula

CH

CH - R (III) wherein R is as defined above, X is a reactive residue such as, for example, a halogen atom or a sulfonyloxy group, Y is hydrogen or, in the case where R = CN, X may form together with Y another atomic bond, the compounds of formula III also act as a reaction medium or can be diluted with an inert solvent.

The novel compounds of the general formula I are pharmaceutically useful compounds which have a low toxicity and a strong sedative and sleep-prolonging effect, i.e. hexobarbital potentiating effect, and which can also be used as intermediates for the preparation of new pharmaceutical substances.

Compounds of general formula I in which R = OCH 2 or CN are not yet described. Such I-derivatives, in which R denotes other residues, are usually obtained by rotation from the 4-oxide substituted in position 1, which is converted to the 3-acyloxy derivative by the Polonovsky reaction and then saponified / DE-OS 2 237 211, Arzneim.-Forsch. 25, 720 (1975 //.

Compounds of general formula II have been known since 1962. Nevertheless, the possibility of selective substitution at the NH group has hardly been used so far. Thanks to the method according to the invention, new, very potent sleeping pills can now be obtained from readily available compounds such as oxazepam, lorazepam and others (cf. AT-PS 309 436) through a single-step reaction.

Suitable reaction components of the general formula III are, for example, 2-methoxyethyl halide or acrylonitrile.

Alkali compounds of the starting materials of the general formula II, which have also not been described so far, can be easily obtained, for example, by reacting these compounds with an equivalent of potassium tert-butylate in absolute solvents such as dimethylformamide or dioxane. In this case, the starting material first dissolves and then the potassium compound precipitates or can be obtained by precipitation with ethers.

In an attempt to react the alkali compounds of compounds II thus obtained with X · CH₂CH₂-O-CH₃ with where X is as defined above is obtained in the case that R_q - ortho-halogen, two isomers which, however, do not correspond to formula I (where R = OCH 2). The same isomers are also obtained using the commonly used Polonovsky method via N-oxide by hydrolysis of 1- (2-methoxyethyl) -3-acetoxy-5- (o-halophenyl) derivatives.

It is therefore surprising that of the alkali compounds of formula II in which R₂ does not represent an ortho-halogen, X · Cl-CH2-O-CH2-m is obtained by reacting easily and in good yield by the process according to the invention new compounds of the formula I in which R = OCH4.

Furthermore, it is also surprising the possibility of selectively cyanethylating compounds of the formula II at the amide-nitrogen site, i.e. at position 1, since, for example, acetanilide corresponding to the structure here has only been reacted with acrylonitrile at 90100 ° C, while reacting with secondary alcohols. already at room temperature and even below / org. Reactions 5, 88 (1949) _ /. By means of the process according to the invention, the reaction at the amide nitrogen of the compounds of the formula II begins at room temperature without the simultaneous substitution in the OH group, even if there is a large excess of acrylonitrile as reaction medium.

Amide-nitrogen-related residues -CH₉CH₂The -R substitution can be demonstrated in the NMR spectra of the derivatives obtained as 7CH-OH coupling signals and by esterification of the free OH group.

Because the compounds of the invention have an asymmetric carbon atom, they are obtained as a racemic mixture. The optical antipodes of the racemic mixture can be separated by methods known per se.

In order to determine the effect of the compounds prepared according to the invention in comparison with known compounds of similar structure, the following experiments were performed:

Sleep prolonging effect

Method: The substances were administered orally to mice of both sexes 30 'after it was of 100.0 mg / kg of hexobarbital ip.

Result: Substance Dose Sleep prolonging effect in mg / kg% of comparison

<td>Ox 373</td><td> 2,0</td><td> 236</td>

<td>(eg 1, 1 pc)</td><td></td><td></td>

<td>Fluratsepam</td><td> 2,0</td><td> 226</td>

<td>Ox 3 53 (eg 2, 1 pc)</td><td> 2,0</td><td> 214</td>

<td>Ox 310 (eg 3, 1 pc)</td><td> 2,0</td><td> 207</td>

The formula of the known flurazepam used as a reference compound is as follows:

<img file="FI67375C_D0006.tif" />

The results show that the sleep prolonging effect of the compounds according to the invention is of the same order of magnitude as or even better than that of flurazepam.

In the following experiments, the most potent compound, Ox 373, was used either alone or compared to flurazepam.

Anaesthetic effect

Method: Huntingdon twist test: After administration of 0.25 ml of 0.5% acetic acid, twists were counted during 20 ':

Result: Dose mg / kg Sensitivity (writhing)

Ox 373

5,0 - 25,1

10,0 - 40,1

Effect on spontaneous mobility

Method: Animex device - female mice

Result: Substance Dose Change in% from comparison mg / kg over 6 hours

Ox 373 10.0 - 73.12

Flurazepam 10.0 - 25.6

Impact on orientationMobility (Exploratory behavior)

Method: For both sexes, mice were dosed orally. They then entered the labyrinth cage and for 30 'into the Animex device.

Result:

Method:

Result:

The ED-50 was defined as the dose that halved mobility in this half hour.

Ox 373: DE-50 = 0.79 mg / kg

Flurazepam: DE-50 = 3.45 mg / kg

Toxicity

Acute oral toxicity in mice and rats

Ox 373: Mice DL-50&gt; 3500.0 mg / kg

Rat DL-50&gt; 3500.0 mg / kg

Fluracepam: Mice DL-50 = 740 mg / kg

Literature: Chem.Abstr. 76, 108184w (1972)

Rat DL-50 - 1300 mg / kg

Literature: The Benzodiazepines S. Garattini, E. Mussini, LO Randall; Raven Press,

New York, 1973, p. 35.

The following pharmacological comparative experiments compared the most potent compound Ox 373 with two compounds known from U.S. Patent 3,531,473.

Pharmacological comparative tests

Substance (internal label)

Acute toxicity LD-50 (mq / kg) mouse, oral

Sleep prolonging effect EU-50 (mg / kg) mouse, oral

Muscle relaxing effect (rotating rod) Dose (mg / kg) mouse, oral% after 4 h

<img file="FI67375C_D0007.tif" />

(Ox 161-CN) US-3531473

<img file="FI67375C_D0008.tif" />

(Ox 332) US-3531473 ch₂ch₂n (ch₃)₂

<img file="FI67375C_D0009.tif" />

50,0

50,0 25,0

50,0 12,5

Compared to both known compounds as Ox 373, Ox 373 has the essential advantage that there is no rubber knee effect after awakening, which manifests itself in the absence of a muscle relaxant effect. Both Ox 332 and also Ox 161-CN in particular show a clear muscle relaxant effect in the rotary bar test. Compared to Ox 161-CN, Ox 373 according to the invention is furthermore advantageous due to its substantially lower toxicity, and compared to Ox 332, Ox 373 11a has a substantially better sleep-prolonging effect, which is manifested as a lower ED-50.

The following examples further illustrate, but do not limit, the invention. Temperatures are currently expressed in degrees Celsius.

Example 1:

A suspension of 10 g of 7-chloro-3-hydroxy-5- (2'-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one in 50 ml of acrylonitrile is reacted with: with triethylbenzylammonium chloride (Teba), then Add with stirring 8 drops of 40% benzyltrimethylammonium hydroxide (Triton B) in methanol. After stirring for 8 h at room temperature, the reaction mixture is allowed to stand overnight at 4 °, the suction is filtered off with suction, washed with acetone and recrystallized from ethanol. The 1- (2-cyanoethyl) -7-chloro-3-hydroxy-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one thus obtained melts at 190-193 °.

Without the addition of Teba, disubstituted 1- (2-cyanoethyl) -7-chloro-3- (2-cyanoethoxy) -5- (2'-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2 ion, which melts when recrystallized from acetonitrile at 204-207 °.

Silica gel 60 F 254 and a eluent mixture of benzene / dioxane / glacial acetic acid (90: 25: 4 by volume) are suitable for separating the mono- or disubstituted product from the starting material.

Example 2:

A suspension of 10 g of 7-chloro-3-hydroxy-5- (2'-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (Lorazepam) in 50 ml of acrylonitrile is reacted With 1 g of Teba containing 8 drops of a 40% methanol solution of Triton B and stirred for 24 h at room temperature. The reaction mixture is then cooled to 4 °, the precipitate is filtered off with suction and recrystallized from ethyl acetate. There is thus obtained 1- (2-cyanoethyl) -7-chloro-3-hydroxy-5- (2'-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one, melting 198-202 °.

Without the addition of Teba, disubstituted 1- (2-cyanoethyl) -7-chloro-3- (2-cyanoethoxy) -5- (2'-chlorophenyl) -1,3-dihydro-1,3-dihydro -2H-1,4-benzodiazepin-2-one, m.p. is 210-213 ° (from acetonitrile).

Example 3:

g of the potassium compound 7-chloro-3-hydroxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Oxazepam) is suspended in 340 inl of 2-methoxyethyl chloride and 6 g of Teba are added, aliquot, and sodium iodide with stirring at 50 ° C for 20 h and then at 40 ° C for 15 h. The reaction mixture is evaporated to dryness in vacuo, the oily residue is dissolved in CHCl 3 and shaken several times with water. The chloroform layer is dried over Na₉SO₄*. n, filtered, evaporated to dryness and the residue taken up in CCl₄to which crystallization occurs. Recrystallize from isopropanol or ethyl acetate to give 1- (2-methoxy-ethyl) -7-chloro-3-hydroxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one as a colorless powder, m.p. 160-161 °.

The potassium compound used as starting material is obtained by heating for 1 h a mixture of 60 g of oxazepam and 24.9 g of potassium tert-butylate in 600 ml of abs. dioxane with stirring at 75 °. Dissolution occurs first, after which a thick precipitate precipitates. This is filtered off with suction overnight from the cooled mixture, washed with isopropyl ether and dried in vacuo. M.p .: 192-197 ° (decomposed).

Example 4:

To a suspension of 20 g of oxazepam in 240 ml of acrylonitrile is added dropwise, with stirring, 3 ml of a 40% solution of Triton B in methanol and then heated at 50 ° for 1 h to form an orange solution. After standing overnight, the reaction is complete. The solution is evaporated in vacuo to a smaller volume and on cooling forms a concentrate. A precipitate which is recrystallized from CHCl 3.₃:from. This melts at 192-194 ° and is 1- (2-cyanoethyl) -7-chloro-3-hydroxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one.

If the reaction mixture is heated at 50 ° for 2 h, disubstituted 1- (2-cyanoethyl) -7-chloro-3- (2-cyanoethoxy) -5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine -2-one, which is practically insoluble in CHCl 3. Recrystallized from acetonitrile, it melts at 215-218 °.

Example 5:

A suspension of 2 g of lorazepam in 20 ml of acrylonitrile is heated with stirring at 50 ° after the addition of 0.1 g of Teba and 1 ml of triethylamine. This produces a yellowish solution which gradually forms a precipitate. After 3 h, the mixture is evaporated in vacuo to a smaller volume and the concentrate is allowed to crystallize overnight at 4 °. The precipitate is filtered off with suction, recrystallized from ethyl acetate and is identical to the roon substitution product obtained in Example 2 (m.p. 198-202 °).

According to the examples given, the following new compounds are also obtained:

1- (2-cyanoethyl) -7-nitro-3-hydroxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 185-188 °.

1- (2-cyanoethyl) -7-nitro-3-hydroxy-5- (2'-chlorophenyl) 1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 191-194 °.

1- (2-cyanoethyl) -7-nitro-hydroxy-5- (2'-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 183-186 °.