DE2311714A1 - NEW 1,4-BENZODIAZEPINE - Google Patents

Description

R.

a halogen atom or a nitro group.

a lower alkyl radical optionally substituted by halogen atoms or a dialkylaminoalkyl group, a hydrogen or halogen atom and

a hydrogen atom, an aliphatic acyl radical optionally substituted by a carboxy or carbalkoxy group or an aromatic acyl radical optionally substituted by halogen atoms are their physiologically acceptable acid addition salts with inorganic or organic acids or their physiologically acceptable salts with inorganic or organic bases, if R ₁ . represents an aliphatic acyl group substituted by a carboxy group, and a process for their preparation.

The compounds of the above general formula I have valuable pharmacological properties, especially sedative, tranquili-

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2341714

emptying, muscle relaxing, anxiolytic and anticonvulsant effects and can be manufactured using the following processes:

a.) For the preparation of compounds of the general formula I in which R _{J (represents} a hydrogen atom:

Implementation of a compound of the general formula II,

II

in the

R ₁ , Rp and R-, as defined at the outset, with formaldehyde in the presence of a base.

The reaction is carried out with formaldehyde in the presence of a base such as sodium hydroxide or potassium hydroxide, expediently in a suitable solvent such as ethanol or isopropanol at elevated temperatures, for example at temperatures between ² JO ⁰ and 100 ⁰ C, but preferably at the boiling point of the solvent used. -

b.) For the preparation of compounds of the general formula I in which R ₁ . a hydrogen atom represents:

Reduction of a compound of the general formula III,

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23Ή7Η

III

in the

R, R "and R_ are as defined at the outset and R "represents a hydrogen or alkali atom.

The reduction is preferably carried out with a complex metal hydride such as sodium borohydride and in a suitable solvent such as water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, chloroform or in a mixture thereof, expediently in a weakly acidic or weakly alkaline range and at temperatures between -10 and 50 ⁰ C, but preferably at temperatures between 0 and 10 C.

c.) For the preparation of compounds of the general formula I in which R _{1 represents} a hydrogen atom:

Implementation of a compound of the general formula IV,

in the

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23T17U

R ^ and R ^ are as defined at the outset, with a compound of general formula V,

R ₂ - Hal (V)

in the

Rp is as defined at the outset and
Hai represents a chlorine, bromine or iodine atom.

The reaction is preferably carried out in the presence of a base such as sodium hydride, sodium methylate or potassium tert-butoxide expediently in a solvent such as dimethylformamide or dimethyl sulfoxide and preferably carried out at temperatures between 0 and 25 ° C.

According to the methods a, b and c, a compound of the general is obtained Formula I, in which Rh represents a hydrogen atom, so can this with the corresponding carboxylic acid in the presence of a dehydrating agent such as N, N'-dicyclohexylcarbodiimide or with a corresponding reactive carboxylic acid derivative, e.g. the corresponding carboxylic acid halide or anhydride, expediently in the presence of a base such as sodium carbonate, triethylamine or pyridine into the corresponding acyl derivative of the general formula I will be convicted. This reaction is expediently carried out in an inert solvent such as benzene, chloroform, dimethylformamide, in an excess of the reactive acid derivative used or in an excess of the tertiary organic used Base expediently at temperatures between -10 and 80 ° C., but preferably at room temperature.

The compounds of general formula I obtained can be converted into their physiologically acceptable salts with the anhydrous solutions of inorganic or organic acids, for example in tetrahydrofuran, ether, dioxane or ethanol. Examples of acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, tartaric acid or maleic acid. However, if R ^ is an acyl radical substituted by a carboxy group, they can be converted into their carboxylic acid salt with an organic or inorganic base. All inorganic or organic bases are, for example, sodium hydroxide, cyclohexylamine, morpholine, dimethylaminoethanol

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or triethylamine into consideration.

A compound of the general formula II used as a starting material is obtained, for example, by reacting a corresponding 2-aminobenzophenone with a haloacetic acid halide and subsequent cyclization with ammonia. ^{A compound of the general formula II obtained in this way, in which R 1} represents a hydrogen atom, can then be converted into the corresponding compound of the general formula II with a corresponding alkyl halide (see Chera. Reviews 86, T 11? - 785 (1968) and J. Pharm. Sci. 53, 577-590 (1966)).

The compounds of general formula III used as starting materials are. Subject of the German patent application P 23 O ¹ I 095.1 of January 27, 1973 and can be obtained by hydrolysis of a compound of the general formula VI,

VI

in the

^R 1 * ^R 2 ^{and 1} H ^w ^ " ^ee ^ ⁿ sangs are defined, and R ^ and R" denote any alkyl radicals , which in turn are the subject of German patent application P 22 34 150.0 of July 12, 1972 represent.

A compound of the general formula IV used as starting material is obtained by reacting a compound of the general formula II in which R _{2 represents} a hydrogen atom with formaldehyde in the presence of a base.

As already mentioned at the beginning, the new compounds have the general formula I valuable pharmacology properties especially sedative, tranquilizing, muscle relaxing,

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-6-anxiolytic and anticonvulsant effects. '' '

For example, the following substances were examined for their biological effects:

A = 7-chloro-5- (2-chloro-phenyl) -l, 3 ~ dihydro ~ 3-hydroxymethyl-l-

methyl-2H-1,4-benzodiazepin-2-one ₃
B = 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3 ~ hydroxymethyl-1-

methyl-2H-l, ⁱ l-benzodiazepin-2-one,
C = 7-bromo-5- ^ -chlor-phenyD-l ^ -dihydro - ^ - hydroxyrnethyl-l-

methyl-2H-1,4-benzodiazepin-2-one,
D = 3- (acetoxy-methyl) -7-broni ~ 5- (2-chloi-phenyl) -l, 3-dihydro-1-

methyl-2H-1,4-benzodiazepin-2-one and
E = 7-bromo-1,3-dihydro-5 ~ (2-fluorophenyl) -3-hydroxymethyl-imethy 1-2H-1,4-benzodiazepine-one.

1.) Muscle relaxing and sedating effects in mice:

This was carried out according to the method of Young and Lewis (Science 105 > 368 (19 ^ 7)) on female NMRI mice of our own breeding with a body weight between 20 and 26 g by means of slowly rotating wire cylinders inclined by 30 to the vertical (length: k ~ 5 cm; diameter: 22 cm; mesh size of the wire mesh: 0.6 cm). After peroral application of the substance to be tested in 1% Tylose suspension to groups of 10 mice / dose, their retention ability in the slowly rotating cylinders (2 rotations / minute) was tested against a control group. The dose (ED ^ ₀ ) was determined graphically at which 50 % of the animals had fallen out after the various times:

ED ₅₀ mg / kg po

Substance 30-60 90-120 210-240 270-300 min.

A 2.6 2.9 2.1 6.0

B 2.0 3, ¹ J 20.0

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C. 0.6 0.6 1.1 0.7 D. 1.8 2.6 2.6 3.5 E. 0.7 0.3 1.2 0.9

2.) Anticonvulsant effects. in mice:

The anticonvulsant effect; the maximum electric shock spasm in internal NMRI lice with a body weight between 20 and 26 g was poked as a protective effect based on the method of Swxnyard, Brown and Goodman (J. Pharmacol, exp. Therap. 106 , 319 (1952)). Here, the animals were exposed to a creature current of 50 Hz and 50 mA for a stimulus duration of 0.2 seconds, the occurrence of tonic stretching spasms being assessed as positive. After peroral application of the substances to be tested in liquid Tylose suspension, the dose (ED ₁ -Q) was determined graphically at which, after various times, 50 % of the animals were protected against the tonic extensor component of the rear extremities during convulsions:

30th ^ED 50 mg / kg p.o. substance 15th 150 300 minutes A. 6.2 16 32 B. 12.8 11 23 C. 3.0 9.8 33 D. 1.3 7.5 16.5 E. 9.1 10

In addition, it should be mentioned here that the substances are practical are non-toxic; for example, with a dosage of

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■ 231.1 7 U-

200 mg / kg ρ.ο. no toxic side effects were observed in the mouse and with a dosage of the substance Λ of 6400mg / kg p.o. Only one of 10 mice died.

The new compounds of the general formula I can be used in the customary pharmaceutical preparation forms for pharmaceutical use such as tablets, coated tablets, capsules and suppositories, if necessary in combination with other active ingredients. The single dose is 2 to 20 mg, preferably 5 to 10 mg, and the daily dose is 5 to 80 mg, preferably 10 to 40 mg.

The following examples are intended to explain the invention in more detail:

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example 1

7-chloro-5 ~ (2-chloro-phenyI) -I, 3-dihydro-3-hydroxymethyl-1-methy1-2H -1, ^f t-ben zo (3.ia-zep in ~ 2-one

l | ₃ 8 g of 7-chloro-5- (2-chloro-phenyl) -l, 3-dihydro-l-methyl-2H-i, J4-bettzodiazepin-2-one, 270 mg paraformaldehyde and 30 mg sodium hydroxide are dissolved in 80 ml 95 ^ strength ethanol suspended and refluxed for 12 hours. This creates a clear solution. After cooling down and standing over power, a small amount of colorless crystals will separate out, which will be sucked off and discarded. The PiI - entered is concentrated to dryness in vacuo and the residue is ^{purified on a silica gel column with benzene / acetone - 1} IOZl as the eluent. The fractions with the desired substance are combined and freed from solvent in vacuo. The residue is crystallized from ether-petroleum ether.
Melting point: 182 - 18 * J ° C.
Melting point of the hydrochloride: 1-6 ° C (decomposition).

Example 2

7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-hydroxyethyl-1-methyl- 2H-1 »4-benzodiazepine - » 2-o n

130 g of 7-chloro-5- (2-fluoro-phenyl) -l, 3-dihydro-3-hydroxymethylene-imethyl-2H-1,4-benzodiazepin-2-one sodium salt are dissolved in 1.5 l of chloroform with stirring and 1.5 l of water suspended. At an internal temperature of 15 ° C., 10 g of sodium borohydride are added with continued stirring
and stirred for 6 hours at this temperature, a further 2 g of sodium borohydride being added every 2 hours. The suspension is then filtered off with suction and the red residue is reduced again in a suspension of 1 l of chloroform and 1 l of water under the above conditions with a total of a further 10 g of sodium borohydride, a clear two-phase system being obtained after 6 hours. The chloroform phases of the first and second reduction are combined, dried over sodium sulfate and concentrated to dryness on a rotary evaporator. The residue, a pale yellow resin,
is crystallized from 100 ml of toluene, suction filtered and with a little

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Washed toluene.

Melting point: Uli - 143 ° C

Melting point of the hydrochloride: 202-2O4 ° C (decomposition).

Example 5

_7-Chloro-l> 3-dihydro ~ 3-hydroxymethyl-l-methyl-5-phenyl-2H-l, 4-benzodiazepin-2-one

6.7 g of 7-chloro-1,3-dihydro-3 "hydroxymethylene-1-methyl-15-phenyl-2H-1,4-benzodiazepin-2-one sodium salt are dissolved in 200 ml of water and 20 ml of isopropanol. While stirring, 1 g of sodium borohydride is added in portions over a period of 2 hours at room temperature. A viscous brown oil separates from which is decanted off and washed well with water. The oil is dissolved in ether, the ether solution is dried over sodium sulfate . and evaporated to dryness in vacuo the remaining foam is dissolved in 40 ml of isopropanol and weakly acidified with ethereal hydrochloric acid, with addition of et, separate \ ^r as ether, crystals _of}, the suction filtered and recrystallized from absolute ethanol melting point of the hydrochloride:. 21 ¹ I - 217 ° C (decomposition).

Example 4

5- (2-chloro-phenyl) -1, 3-dihydro-3-hydroxymethyl-1-methyl-7-nitro- 2H-1,4-benzodiazepin-2-one

3.5 g of 5- (2-chloro-phenyl) -1, 3-ciihydro-3-hydroxymethyl-7-nitro-2H-. 1,4-Benzodiazepin-2-one dissolved in 35 ml of absolute dimethylformamide and treated with 2.5 g of a 30% solution of sodium methylate in methanol. It is cooled to about 10 ⁰ C, admits 4.2 g of methyl iodide and stirred for 3 hours at room temperature. Water is added, the mixture is etherified, the ether solution is dried over sodium sulfate, filtered over charcoal, evaporated to dryness in vacuo and the residue is recrystallized from acetone.
Melting point: 229-231 ° C.

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-11- Example 5

3-Ace toxymethy 1-7-chloro-1,3-dihydro-5- (2-fluorophenyl) -l-methyl- 2H- 1,4-b enzodiazepin-2-one .

4 g of 7-chloro-1,3-dihydro-5- (2-fluoro-pheinyl) -3-hydroxymethyl-l-methyl-2H-l _s ⁱ l-benzodiazepin-2-one are dissolved in 15 ml of pyridine and 7 ml
Acetic anhydride is dissolved and left to stand at room temperature for 2 hours. Then it is diluted with 200 ml of ether and washed successively with water , 1% acetic acid, water, 10% sodium hydrogen carbonate solution and again with water After standing overnight at +5 ° C., the precipitated crystals are filtered off with suction and washed with Xther.
Melting point: 168-170 ⁰ C.

Example 6

7-chloro-5- (2-chloro-phenyl) -l, 3-dihydro-3-hydroxymethyl-1-methyl- 2H-1, ⁱ -benzodi- azepin-2-one

Prepared from 7-chloro-5 ~ (2-chlorophenyl) -1, 3-dihydro-3-hydroxymethyl-2H-1, ² 4-benzodiazepin-2-one and methyl iodide analogously to Example H. Melting point: ^{182-184 0} C.

Example 7

7-chloro-1,3-dihydro-5- (2-fluoro-phenyl 5 -3-hydroxyinethy 1-1-methyl- 2H-l ₅ *} - benzodiazepin-2-one

Made from 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -l-methyl-2H-l _I ¹ l-benzodiazepin-2 ~ one, paraformaldehyde and sodium hydroxide
analogous to example 1.
Melting point: 1 * »1 - °

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Example 8

7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-hydroxymethyl-1-niethyl- 2H-1, ^ "benzodiazepin-2-one ;

Manufactured from 7-chloro-1,3-dihydro-5- (2-fluoro-phenyl) -3-hydroxymethyl-2H-l, ¹ <-benzodiazepin-2-one and methyl iodide analogously to Example ⁱ Melting point: 14l - 1 ^ 3 ° C.

Example 9 ,

7-chloro-5 ~ (2-chloro-phenyl) -l _} 3-dihydro-3-hydroxymethy1-1-methy1-2H -1, ^j 4-benzodiazepin-2-one '

Made from 7-chloro-5- (2-chloro-phenyl) -l, 3-dihydro-3-hydroxymethylene-l-methyl ~ 2H-l, l (-benzodiazepine ~ sodium salt and sodium borohydride analogous to Examples 2 and 3 · Melting point: 182-184 ° C.

Example 10

3-acetoxy-methyl-7-chloro-5- (2-chloro-phenyl) -1, 3-dihydro -1-methyl-2H-1 _J ^j {-benzodiazepin-2-one .

Prepared from 7 ~ chloro-5 ~ (2-chloro-phenyI) -I ₅ 3-dihydro-3 "hydroxymethyl-1-methyl-2H-1,4-benzodiazepin-2-one, acetic anhydride and pyridine analogously to Example 5 color less Foam. C ₁₉ H ₁₆ Cl ₂ N ₂ O ₃ (391.267)

Calc .: C 58.36 H 4.12 Cl 18.12 N 7.16 Found: 58, * JO 4.1618, O4 7.12

Example 11

3 "-Benzoxymethyl-7" -chlor-1 "-3 ^< " dihydro-5- (2-fluoro-phenyl) -l-methyl- ' 2H-1,4-benzodiazepin-2-one

Made from 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-hydroxy-

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~ ¹³ ~ 23117U

methyl-l-methyl- ^ H-lj ^ -benzodiazepin - ^ - one, benzoyl chloride and pyridine analogous to Example 5
Melting point: 120 - 123 ° C.

Example 12

7-chloro-3- (iJ-chlorobenzoxyinethyl) -l, 3-dihydro ~ 5- (2-fluoro-phenyl) -1-methyl-2H-1 _> ⁱ -benzodiazepin-2-one

Made from 7-chloro-1,3-dihydro-5 ~ (2-fluorophenyl) - 3 ~ hydroxymethyl-l-methyl-2H-l, ^ - benzodiazepin-2-one, 4-chloro-benzoyl chloride and pyridine analogous to example 5
Melting point; 160 - 163 ° C

Example 13

7-Bromo-5- (2-chloi-phenyl) -1, 3-dihydro-3-hydroxymethyl-1-ynethyl- 2H-1, ^j {-benzodiazepin-2-one

Prepared from 7-bromo-5- (2-chloro-phenyi) -l, 3-dihydro-l-methyl-2H-1,4-benzodiazepin-2-one, paraformaldehyde and sodium hydroxide analogously to Example 1.
Melting point: 198-201 ° C.

Example lfl

7-Bromo-5- (2-chloro-phenyl) -1 _J 3-dihydro-3-hydroxymethyl-1-methyl- 2H-1,4-benzodiazepin-2-one

Made from 7-bromo-5- (2-chloro-phenyl) -l, 3-dihydro-3-hydroxymethylene-l-methyl-2H-l _J ⁱ f-benzodiazepin-2-one or from its sodium salt and sodium borohydride in Methanol analogous to Example 3 · • Melting point: 198 - 201 ⁰ C.

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Example 15

7-Bromo-5- (2-ehlor-phenyI) -I ₃ 3-dihydro ~ 3-hydroxymethyl-1-methyl-2ΓΙ- 1, ^ i-benzodiazepin ^ -one

Prepared from 7-bromo-5 ~ (2-chloro-phenyl) -l, 3-dihydro ~ 3-hydroxy ~ methyl-2H-l, ^ - benzodiazepin-2-one and methyl iodide analogously to Example Melting point: 198-201 ⁰ C. .

Example 16

7-bromo-1,3-dihydFa-5- (2-fluorophenyl) -3-hydroxymethyl-1-methyl-.2 H-1 _? fy-benzodiazepin-2-one

Made from the matrix salt of 7 ~ bromo-1,3-dihydro-5- (2-fluorophenyl) -3-hydroxymethylene-1-m & thyl ~ 2H-l , il - benzodiazepin-2-one and Sodium borohydride in methanol analogous to Example 3 · Melting point: 152-155 ° C.

Example 17

7-Bromo-1,3-dihydro-5- (2-fluoro-phenyl) -3 "hydroxymethyl-1-methyl- 2H-1, fr-benzodiazepin-2-one

Prepared from 7-bromo-l, 3-dihydro-5- (2-fluoro-pbenyl) -3-hydroxy ~ methyl-2H-l, ⁱ i-benzodiazepin-2-one and methyl iodide analogously to Example k Melting point: 152-155 ° C.

Example 18

7-Bromo-5- (2-chloro-phenyl) -1- (diethylamino-ethy1) -1,3-dihydro-3- hydroxymethyl-2H-1,4-benzodiazepine-2-one

Made from the sodium salt of 7-bromo-5- (2-chloro-phenyl) -l- (diethylamino-ethy1) -1,3-dihydro-3-hydroxymethylene-2H-l, 4-benzodiazepin-2-one and sodium borohydride in methanol analogous to the example Amorphous substance.

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? 311 71 Λ

C ₂₂ H ₂₅ BrClU ₃ O ₂ (478.8)

Calc .: C 55.20 H 5.26 Br 16.69 Cl 7.4l N 8.78 Found: 55.10 5/39 16.85 7.5 * 8.81

Ex iel 19

7-Bromo-5- (2-chloro-phenyl) ~ 1,3 ~ dihydro-3-hydroxyiriethyl-1- (2,2,2- trifluoro-§thyl ) -2H-l, ^

Made from 7 ~ Brow ~ 5 ~ (2-chloro-phenyl) -l ₃ 3-dihydro ~ 3-hydroxymethylene-1- (2,2,2 "trif." Iuor-ethyl) -2K ~ l , 4-ben »odiaj5epin-2-one-hydi ⁱ ochlorrld and sodium boron hydride in methanol analogous to Example 3
Amorphous substance.
C ₁₈ H ₁₃ BrClP ₃ M ₂ O ₂ (461.7)

Calc .: C 46.83 H 2.84 K 6.07
Found: 46.30 3.03 5.94

Beir.pj.el 20

2H-1, 4-ben rc- ri ΐ az, epl n- 2-on

Made from 7 ~ B "ora ~ 5- (2-chlorophenyl) -l ₅ 3 ~ dihydro-3 ~ hydroxyinethyl ~ 1-inet} iyl-2II-l, 4-benzodiaKepin-2-one, acetic anhydride and

Pyridine analogous to Example 5 · Schrielcpunk-i ι 121-123 ⁰ C

C ₁₉ K ₁₆ BrClM ₂ O ₃ (435.7).

Calcd .: C 52.37 H 3.71 Br 18.3 "Cl 8.14 N 6.43 Found: 52.50 3.80 18.10 8.03 6.48

Example 21

7 ~ Brorn-5- (2-chloro-pheny 1) -1,3-dihydro-3- (hemisuccinoy loxy-methy 1) ■ l-methy l-2H "i, 4-benzod5; - ?: epin- 2-on ■

Made from 7 ~ broin-5- (2-chloro-phenyl) -l, 3 ~ dihydro-3-hydroxy-

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001 171 Λ

methyl-l-methyl-2H-l, ^ - benzodiazepin-2-one, succinic anhydride and pyridine analogous to Example 5.
Melting point: 175 - 177 ° C (decomposition).

Example 22

5- (2-chloro-phenyl) -l, 3-dihydro-3 ~ hydroxymethyl-l-methyl-7-nitro- 2H-1, ^ - benzodiazepin-2-one _:

Prepared from ¹ J- (2-chloro-phenyl) -l, 3-dihydro-1-methyl-7-nitro-2H-1j4-benzodiazepin-2-one _J paraformaldehyde and sodium hydroxide analogously to Example 1.
Melting point: 229-231 ° C

Example 23

5- (2-chloro-phenyl) -l, 3-dihydro-7-fluoro-3 ~ hydrox ₍ ymethyl-1-methyl- 2H-1, ^j <-b en zodiazepin-2-one

Manufactured from 5- (2-chloro-phenyl) -l, 3-dihydro-7-fluoro-3-hydroxymethylene-1-methyl-2H-l, ⁱ -benzodiazepin-2-one sodium salt and sodium borohydride analogous to the example 3 ·
Melting point: 202 - 2O4 ^G C.

Example 24

5- (2-chloro-phenyl) -1, 3-dihydro-3-hydroxymethyl-7-iodo-i-methyl-2H- 1, ^ -benzodiazepin-2-one

Prepared from the sodium acid of 5 ~ (2-chloro-phenyl) -l, 3-dihydro-3-hydroxymethylene-7 ~ iodo-l-methyl-2H-lj * i-benzodiazepin ~ 2-one and I sodium borohydride analogous to Example 3
Melting point: 192 - 196 ° C (decomposition) »

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Example 25

7-bromo ~ 5- (2-chloro-pheny 1) -1,3-dihydro- 3 ~ (heinif umaroy loxy-methy 1) - l-methyl-2H-l , ^ -benzodiazepin-2-one

Prepared by rearrangement from 7-bromo-5 ~ (2-chloro-phenyI) -I, 3 ~
dihydro-l-methyl-2H ~ l, ^ - benzodiazepin-2-one _> maleic anhydride
and pyridine at 80 ° C analogous to Example 5
Melting point of the dimethylaminoethanol salt: 133 - 135 C.

Example 26

Tablets with 5 mg 7-chloro-1,3-dihydro-5- (2-frior-phenyl) -3- hydroxymethyl-1-ynethyl-2H-1,3-benzene, odiazepin- 2-one

Composition: 5 mg 1 tablet contains: 75 mg Active ingredient 37 mg Lactose 2 mg Cornstarch 1 mg gelatin 120 mg Magnesium stearate Manufacturing:

The mixture of the active ingredient with milk sugar and corn starch is passed through a sieve with an 8 # solution of gelatin in water

1.5 mm granulated, dried at M5 ° C and again through a sieve 1.0 mm given. The granules obtained in this way are mixed with magnesium stearate and compressed into tablets.

Tablet weight: 120 mg

Stamp: 7 mm

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23117H.

Example 27

Tablets with 10 mg of 7-bromo-5- (2-chlorophenyl) -l, 3-dihydro-3- hydroxyme thy ll ~ me thy 1-2H-1 , ^ 1-- benzodiazepine-one

Composition:
1 tablet contains:

Active ingredient 10 mg

Lactose ■ 70 mg

Corn starch 37 mg

Gelatin 2 mg

Magnesium stearate 1 mg

120 mg

Manufacturing:

Analogous to example 26

Tablet weight: 120 mg

Stamp: 7 mm

Example 28

Dragees with 5 mg of 7-chloro- 1,3-dihydro-5- (2-fluorophenyl) -3-hydroxymethyl-1-methyl-2H-l _> ^ -benzodiazepin-2-one _;

Manufacturing:

The tablets produced in Example 26 are made according to known methods Process coated with a shell consisting essentially of sugar and talc. The finished coated tablets are made with the help polished by beeswax. Dragee weight: 170 mg

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2i 23117H

Coated tablets with 10 mg of 7-brorn-5 ~ (2-chloro-phenyl) -l, 3-dihydro-3-hydroxy methyl-l ~ methyl-2H-l, ^ - benzodiazep in-2-one .

Manufacturing :

Analogous to example 28
Dragee weight: 170 mg

Example 50

Suppositories with 30 mg of 7-chloro-1,3-dihydro ~ 5- (2-fluorophenyl) -3-hydroxymethyl-l-methyl-2H-l _t * 4-benzodiazepin ~ 2-one

Composition:
1 suppository contains:

Vfirksubstanz 30 mg

Suppositories (e.g. Witepsol V / 45) 1,670 mg

1,700 mg

Manufacturing: _

^{The ground active substance is stirred into the melted suppository mass, cooled to JJO 0} C, with the help of an immersion homogenizer and poured into the slightly pre-cooled molds at 3 ° C.
Suppository weight: 1.7 g

Example 31

Capsules with 5 mg 7-bron ~ 5- (2-chloro-phenyl) -l, 3-dihydro-3-hydroxyiue5hyl "l-methyl-2H-l, ^f J-ben zodia zepin -2-one

Composition:
1 capsule contains:

Wxrksubstanz 5 mg

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Dried corn starch 17 * ί mg

Magnesium stearate 1 mg

180 mg production:

The substances are intensively mixed and placed in gelatine capsules Bottled size iJ.

Example 32

Capsules with "10 mg 7 ~ chlorine-l ^ -di methyl-l-methyl-2H-l, ^ - benzodiazepin-2-one

Composition:
1 capsule contains:

Active ingredient 10 mg Dried corn starch 169 mg Magnesium stearate 1 mg

180 mg production:
Analogous to example 31

- $ 09838 / 106.0

Claims (12)

Claims 1.) New 1, ^ - benzodiazepines of the general formula I, / I ² / / I ² / in the R. a halogen atom or a nitro group, Rp is an optionally substituted by halogen atoms lower alkyl radical or a dialkylaminoalkyl group,
R, a hydrogen or halogen atom and Rj, a hydrogen atom, an aliphatic which is optionally substituted by a carboxy or carbalkoxy group
Acyl radical or an aromatic acyl radical optionally substituted by halogen atoms, and their physiologically compatible acid addition salts with inorganic and organic acids or their physiologically compatible ones
Salts with inorganic and organic bases, if R ^ is an aliphatic acyl radical substituted by a carboxy radical. 2.) New 1,4-benzodiazepines of the above general formula I, in
the R. a chlorine or bromine atom,
Rp the methyl group,
R, a fluorine or chlorine atom and Rj. Mean a hydrogen atom or the acetyl radical, and their physiologically compatible acid addition salts with inorganic 409838/1060 -22-visual and organic acids * 23117H 3) 7-Chloro-5 '(2-chloro-phenyl) ~ i ^ -dihydrö ^ -hydroxy-l-methyl-2H-l, ⁱ i-benzodiazepin-2-one and its acid addition salts, 4.) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-hydroxymethyl-imethyl-2H ~ 1,4-benzodiazepin-2-one and its acid addition salts. 5) 7-bromo-5 "(2-chloro-phenyl) -1,3-dihydro-3-ethyl-l ^ hydroxyIϊ-methyl-2H-l, ⁱ i-benzodiazepin-2 ~ one and its acid addition salts, 6.) 3- (Acetoxymethyl) -7-bromo-5- (2-chloro-phenyl) -1, 3-dihydro-imethyl-2H-lj4-benzodiazepin-2-one and its acid addition salts. 7.) 7-Bromo-1,3-dihydro-5- (2-fluorophenyl) -3-hydroxymethyl-imethyl-2H-1,4 "benzodiazepin-2-one and its acid addition salts. 8.) Medicines containing at least one compound of the above general formula I in addition to optionally one or more inert carriers. 9.) Process for the preparation of new 1j ^ -Benzodiazepinen der general formula I, ■ I in the R. a halogen atom or a nitro group R ₂ a lower alkyl radical optionally substituted by halogen atoms or a dialkylaminoalkyl group, 4 09 8 3 8/10 6 0 R represents a hydrogen or halogen atom and 231 1714 Rj represents a hydrogen atom, an aliphatic acyl radical optionally substituted by a carboxy or carbalkoxy group or an aromatic acyl radical optionally substituted by halogenation, as well as their physiologically acceptable acid addition salts with inorganic and organic acids or of their physiologically compatible salts with inorganic and organic bases, if R ₁ . represents an aliphatic acyl radical substituted by a carboxy radical, characterized in that a.) for the preparation of compounds of general formula I, in which Rj, represents a hydrogen atom, a compound of general formula II, in the R ₁ , R- and R, as defined at the outset, is reacted with formaldehyde in the presence of a base or b «) for the preparation of compounds of the general formula I in which Rj represents a hydrogen atom, a compound of general formula III, 409838/1060 -2 * 1- 231T7U III in the ^R l * ^R 2 ^{and R} 3 ^W ^ " ^ee ^ - ⁿ S are defined ^at S ^{s and} R ₁ - represents a hydrogen or alkali atom, is reduced or c.) for the preparation of compounds of the general formula I in which R _{1 represents} a hydrogen atom, a compound of the general formula IV, .0 'tr IY \ _GH OH in the R ₁ and R, as defined at the outset, with a compound of the general formula V, - shark (V) in the R_ is defined as above and Hai represents a chlorine, bromine or iodine atom _{s is} implemented and a compound obtained according to methods a), b) and c) of the general formula I, in which R ^ represents a hydrogen atom, if desired, subsequently aylated and / or into a physiologically compatible acid addition salt with an inorganic or organic acid or into a physiologically compatible acid Salt with an inorganic or organic base «, -40983871080 if R ^ is an aliphatic substituted by a carboxy radical Represents acyl radical, is converted. 10.) The method according to claim 9, characterized in »that the Reaction is carried out in a solvent. 11.) Process according to claim 9a and 10, characterized in that the reaction is carried out in the presence of sodium hydroxide or potassium hydroxide and at temperatures between 40 and 100 ^° C. ·. 12.) Method according to claim 9b and 10, characterized in that that the reduction is carried out with a complex metal hydride and at temperatures between -10 and +80 C. 13 ·) Process according to claim 12, characterized in that sodium borohydride is used as the complex metal hydride. 14 ») Method according to claim 9c and 10, characterized in that that the reaction in the presence of a strong base and at temperatures between 0 and 25 ° C is carried out. 15 ·) Method according to claim 14, characterized in that as base sodium hydride, sodium methylate or potassium tert-butylate is used. l6.) The method according to claim 9 and 10, characterized in that the subsequent acylation with the appropriate Car bonsäure ^u in the presence of a dehydrating agent such as N, N'-dicyclohexylcarbodiimide or with a corresponding reactive carboxylic acid derivative such as the corresponding carboxylic acid halide or anhydride with Temperatures between -10 and 80 ° C is carried out. 409838/1080