DE2157112C3 - Benzodiazepine derivative - Google Patents

Description

O CLIiCH.,

IICI

for the production of protein tablets and capsules.

The compound 7-chloro-1- (2-diethy! Amiiioäthyl) -5- (2-fhiorpheiiyl) -l, 3-dihydro-2H-1,4-benzodiazepin-2-one (hereinafter referred to as flurazepam) is from the DF-PS 14 45 874 and from). Med. Chcin. 8, 815-821 (1965). Due to its excellent therapeutic properties, Si ο has achieved leading slelking in the treatment of all sleep disorders, especially in those cases characterized by poor sleep, frequent nocturnal waking up or premature waking up in the morning. In addition, it has proven itself to regulate the disturbed sleep-wake Ithyihiniis and to remedy sleep disorders that occur as a result of a chronic illness. The compound has hitherto been used in practice as a dihydrochloride, although this dihydrochloride causes great difficulties in processing / \) perfect and stable medicinal formula). For example, the dihydrochloride is very sensitive to moisture and provides strongly acidic solutions. Fs is therefore only suitable for the production of capsules, and even with this pharmaceutical form of application, sufficient stability can only be achieved with strict observation of certain technical working restrictions, such as anhydrous granulation in rooms with less than 20% relative humidity, use of water-free ones that are difficult to obtain Lactose, L, ige tion of the capsules over Silicagcl and the like., Can be achieved.

Despite this N,:. Iiteile will - like a mentioned earlier - exclusively the dihydrochloride used. Accordingly, it was apparently believed that this dihydrochloride was practically the only usable salt of the mentioned lieii / odi.i / epine represents.

Surprisingly, it has now been found in the context of the present invention that the corresponding Monohydrochloride is easy to manufacture and that the therapeutic properties of Monohydrochloricis agree with those of the dihydrochloride. It was also found that this Surprisingly, monohydrochloride does not have the disadvantages of dihydrochloride mentioned above. In this way, the monohydrochloride can be processed galenically without any special precautionary measures.

To show this, capsule filling compound and tablets were produced which contain flurazepam mono- or Contain dihydrochloride. These products were made together with flurazepam mono- or dihydrochloride active ingredient stored under different conditions. The results of these experiments can be summarized as follows will:

a) capsule filler

The capsule filler contains 25% flurazepam mono- or dihydrochloride and 75% mannitol. Already at the beginning there is a difference between the capsule filler containing the monohydrochloride of flurazepam and the capsule filler containing the dihydrochloride of flurazepam, in that the capsule filler containing the dihydrochloride is yellowish, whereas the capsule filler containing the monohydrochloride is white.

In the case of the capsule filler containing the dihydrochloride, discoloration is rapid. So z. U. is the capsule filler containing the dihydrochloride after 6 days of storage at a relative humidity of 86 and 75.5% extremely yellow and wet and therefore technically unsuitable for further processing. In contrast, the capsule filler containing the monohydrochloride presents itself under the same conditions as practically white and dry.

b) tablets

E ^: .s are produced in a conventional manner! 'Derive; the composition of the tablets is as follows:

H) mg 52.58 mg Flurazepam monohydro 109.42 mg chloride 125 mg Flurazepam dihydrochloride 112 mg 2 mg Mannitol 125 mg Cornstarch 2 mg 11 mg Hydroxypropyl methyl 8.1 mg cellulose (HPMZ) 11 mg 0.9 mg microcrystalline cellulose 8.1 mg SOO mg Talk (), ¹ ) mg Magnesium stearate 500 mg total weight

Even after manufacture, there can be a gaping difference of these two types of tablets can be observed by adding the tablets containing the dihydrochloride are yellowish, whereas the derivatives containing the monohydrochloride are white.

To ! Days storage at! » and 45'C and 85 "/ iiiger relative humidity are the mono tablets containing hydrochloride are still practically white, whereas those containing dihydrodiloride Tablets begin to turn a strong yellow. After (i days at 75 and Hb% relative air purity the tablets containing the dihydrochloride are markedly yellow with a strong yellow lick, whereas the tablets containing the monohydrochloride are still practically white.

c) active ingredient

The originally yellowish flurazepam dihydrochloride active ingredient liquefies after 7 days 86% relative humidity and also after 7 days at 76.5% relative humidity. To 4 days at 86% relative humidity, partial liquefaction occurs. Apart from This liquefaction a strong yellow discoloration is observed, whereas the flurazepam monohydrochloride active ingredient remains white and dry under the same conditions.

The aforementioned discoloration of the dihydrochloride active ingredient and the galenic forms with the dihydrochloride active ingredient are an indication of rapid chemical decomposition. A galenic processing of the Dihydrochloikls is only possible under careful working conditions (very low relative humidity) possible.

With all these benefits the flurazepam mono-hydrochloride shows, its production was by no means obvious, what from the following Remarks stating.

In J. Med. Chem. 8, 815-821 (1% 5), several Basically substituted in the 1-position benzodiazepinones described, either as free bases or identified in the form of addition salts with hydrochloric acid or maleic acid.

In the case of the addition salts with hydrochloric acid disclosed there, with the exception of number 32, all are always present Nitrogen atoms of the side chain protonated, with number 32 probably therefore an exceptional position occupies, since in the l'iperazino side chain a secondary and tertiary nitrogen atom are in competition. Most of these addition salts with hydrochloric acid however, if the Schiff base is also protonated, it is noticeable that the Schiff base then if in the 5-position of the benzodiazepine there is an o-fluorophenyl residue is present, is always protonated, while in the corresponding l'henyl radical unsubstituted in the stationary Compounds the Schiff base is not always protonated. The o-phenyl compounds therefore occupy a special position within this liaison group, a fact that is still due to this it is confirmed that even with a weak acid, namely with maleic acid, the Schiff base is a o-fhior phenyl compound (No.! 8) was protonated, which does not occur with other substituted compounds.

From these experimental results one must conclude that in the case of the benzodiazepines under discussion with an o-fluorophenyl radical, the Schiff base is very easily obtained by strong acids such as hydrochloric acid is protonated, but that rotation can also occur with weak acids.

Given this situation, it was not an obvious choice to manufacture the monohydiol chloride of flurazepam. In particular, in.in had to assume that one would get through Reaction of the base with an equimolar amount of hydrochloric acid is not a uniform product that can be used as a medicament Product, d. left no selective at the basic nitrogen atom the .Seilenkelle prolonieries product would be obtained. Given this starting point, a person skilled in the art does not cover an addition salt. selected with a strong acid, rather an addition salt, with an ι as weak as possible Acid, /. B. with fumaric acid to iimarat. a salt, which is common in the animal pharmaceutical industry. to manufacture.

The present invention thus relates to the use of the monohydrochloride salt of 7-chloro (2-diethylaminoethyl) -5- (2-fluorophenyl) -1, 3-dihydro-2H-1,4-benzodiazepin-2-one the formula

CU, CH,

/ CH ₅ -CH ₁ -N

O CH ₂ CII,

HCl

for the production of medicinal tablets or capsules.

The aforementioned monohydrochloride salt of flurazepam can be prepared by using flurazepain with no more than the equimolar amount Hydrochloric acid reacts, oiler that the corresponding dihydrochloride with the equimolar Reacts amount of base or with water and that the flurazepam monohydrochloride formed is isolated.

The reaction of flurazepam with no more than the equimolar amount of hydrochloric acid takes place expediently in an organic solvent such as methanol, ethanol, isopropanol, acetone and the like. Preferably the reaction is carried out with alcoholic hydrochloric acid, e.g. B. ethanolic hydrochloric acid, the Monohydrochloride can be precipitated by adding ether. In the case of large batches, the monohydrochloride can also be prepared by adding an equimolar amount of hydrogen chloride gas to a solution of flurazepam initiates.

The reaction of flurazepani dihydrochloride with the equimolar amount of base is also expedient in an organic solvent such as methanol, ethanol, acetone, chloroform and the like. Or mixtures of which, carried out. Alkali hydroxides such as sodium hydroxide, potassium hydroxide, Alkaline earth hydroxides such as barium hydroxide. Amines such as triethylamine and the like can be considered. Preferably a base is used which, with hydrochloric acid, forms a salt which in the solvent used or solvent mixture, is soluble. In another, particularly preferred embodiment Flurazepam is used as the base. In a further preferred embodiment, the dihydrochloride is dissolved in water and the formed flurazepam monohydrochloride with a suitable solvent, preferably methylene chloride, extracted.

The following examples illustrate the goodwill. All temperatures are given in degrees Celsius. The ether used is diethyl ether.

example 1

38.8 g (0.1 mol) 7-chloro-1- (2-diethylaminoyl) - ■ "> (. ' fluorophenyl) -l, 3-dihydro-2H-1,4-benz () diazepine-2- (in u ν. ι the finely powdered, suspended in 115 ml of ethanol and while stirring drop by drop with 16.8 ml 6 N aiha-

Nolischer hydrochloric acid is added, the suspension gradually changing into a clear solution. When the addition is complete, the reaction solution is evaporated under reduced pressure and the remaining pale yellow oil is dissolved in 28 ml of ethanol, 250 ml of ether are added and the solution is left to stand overnight at 0 °, 7-chloro-1 - (2-diethylaminoethyl) -5 - (2-fluorophenyl) -1, 3-dihydro-2H-1,4-benzodiazepin-2-one monohydrochloride is obtained.
Snip. 202-203 °.

C ₂ IH ^ iNiOClF - HCl (424.34):

Calculated: C 59.44, H 5.70, N 9.90. Cl! 6.71%:
Found: C 59.56. H 5.84, N 9.80, Cl 16.98%.

Example! 2

In a stirred kettle, a mixture of 56.20 kg of water, 10.60 kg of 28% sodium hydroxide solution and 60.50 kg of toluene at 25 ° with thorough stirring, 15.54 kg (33.72 mol) of 7-chloro-1- (2-diethylaminoethyI) -5- (2-fluorophenyl) -1, 3-dihydro-2H-1 , 4-benzodiazepin-2-one dihydrochloride added in portions. After the addition has ended, the reaction mixture is stirred for a further 30 minutes and then transferred to a pointed kettle. The stirred kettle is washed with 36.5 kg of toluene. This toluene solution is combined with the reaction mixture. The aqueous phase is then separated off, transferred to a second pointed kettle and extracted with 48.5 kg of toluene. After that the two Toluene extracts washed with twice 40 kg and once 25 kg of water, combined and placed in a distillation kettle transferred. The solvent is then distilled off under reduced pressure at 35 ° -45 °. After the oily residue has been dissolved in 31.0 kg of abs. Ethanol is left for 30 minutes 5.620 liters of a 6.0 N ethanolic hydrochloric acid flow in, the temperature between 25 ° by cooling and held at 30 °. After the addition has ended, stirring is continued for 5 minutes. After that it will The solvent is distilled off under reduced pressure at 30 ° -35 °, the residue in 7.5 kg abs. Ethanol Dissolved at 25 °, mixed with 31.5 kg of ether and inoculated. After the suction filter, the crystalline product is with Washed twice 5.5 liters each of an ether / alcohol mixture (5.3: 1) pre-cooled to 0 ° and then washed dried at 60 ° and under reduced pressure, with 7-chloro-1- (2-diethylaminoethyl) -5- (2-fluorophenyl) -1,3-dihydro-2H-l ^ -benzodiazepine ^ -one monohydrochloride is obtained, Snip. 203.5 °.

Example 3

2.3g (5.0 mmol) 7-chloro-1- (2-diethylaminoethyl) -

5- (2-fluorpheny I) -1,3-dihydro-2 H-1,4-benzodiazepin-2-one dihydrochloride and 2.1 g (5.4 mmol) 7-chloro-i-

(2-diethylaminoethyl) -5- (2-fluorophenyl) -i, 3-dihydro-2H-1,4-benzodiazepin-2-one are dissolved together in 5 ml of ethanol and mixed with 15 ml of ether. After inoculation and leaving it to stand overnight becomes 7-chlorine-l-

(2-diethylaminoethyl) -5- (2-fluorophenyl) -l, 3-dihydro-2H-1,4-benzodiazepin-2-one monohydrochyl oride is obtained, m.p. 203 °.

Example 4

2.3 g (5.0 mmol) of 7-chloro-1- (2-diethylaminoethyl) -5- (2-fluorophenyl) -1.3-dihydro-2H-1,4-benzodiazepin-2-one dihydrochloride are suspended in 2.5 ml of ethanol with a solution of 0.33 g (5 mmol) of potassium hydroxide added in 2.5 ml of ethanol and gcschülelt on the peeling machine for 30 minutes. Thereafter the precipitated potassium chloride is filtered off and that The filtrate was concentrated to 3 ml under reduced pressure. After adding 3 ml of ether, it becomes slightly cloudy Solution filtered, add another 3 ml of ether! and inoculated, whereby 7-Ch! or-1- (2-diethylaminoethyl) -5- (2-

fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazcpin-2-one monohydrochloride is obtained. 202-203 °.

Example 5

Ig (2.17 mmol) 7-chloro-1- (2-diethylaminoethyl) -5- (2-fluorophenyl) -1, 3-dihydro-2H-1,4-benzodiazepin-2-one- dihydrochloride is dissolved in 20 ml of water and extracted three times with 25 ml of methylene chloride each time. The methylene chloride extracts are dried with sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ethanol / ether provides 7-chloro-1- (2-diethylaminoethyl) -5- (2-fluorophenyl) -l, 3-dihydro-2H-1,4-benzodiazepin-2-one- monohydrochloride, m.p. 202-203 °.

Example 6
Capsules are made with the following composition:

Per capsule 7-chloro-1- (2-diethylaminoethyl) -5- 16.4 mg (2-fluorophenyl) -l, 3-dihydro-2H-l, 4- benzodiazepin-2-one-monohydro- chloride Mannitol 105.0 mg Talk 8.1 mg Magnesium stearate 0.5 mg total weight 130.0 mg

The active ingredient, the magnesium stearate and the talc are gradually mixed together and then passed through a sieve. Then the mannitol is mixed in, the whole thing is passed through a sieve and then mixed again. The mixture is filled into hard gelatine capsules by machine.

Example 7
Capsules are made with the following composition:

Per capsule 7-chloro-l- (2-diethylaminoethyl) - 32.8 mg 5- (2-fluorophenyl) -l, 3-dihydro-2H- 1,4-benzodiazepin-2-one mono- hydrochloride Mannitol 88.1 mg Talk 8.1 mg Magnesium stearate 1.0 mg total weight 130.0 mg

The active ingredient, the magnesium stearate and the talc are gradually mixed together and then passed through a sieve. Then the mannitol is mixed in and the whole thing is passed through a sieve and then mixed again. The mixture is filled into hard gelatine capsules by machine.

Example 8

Tablets are made with the following composition:

Per tablet

7-chloro-1- (2-diethylaminoethyl) - 16.41 mg

5- (2-fluorophenyl) 3-dihydro-2H-1 ^ -benzodiazepin ^ -one-mono-

hydrochloride

Mannitol 74.59 mg

Corn starch 50.00 mg

Polyvinylpyrrolidone 6.00 mg

Talc 2.70 mg

Magnesium stearate 0.30 mg

Total weight 150.00 mg

The active ingredient, the mannitol and part of the corn starch are mixed well in a suitable mixer and then with a polyvinylpyrrolidone solution in ethanol or a chlorinated hydrocarbon moistened, granulated and dried. After that, the talc, the magnesium stearate and the remaining Corn starch added. The mixture is mixed and compressed.

Example 9

Tablets are made with the following composition:

Per tablet

7-chloro-1- (2-diethylaminoethyl) - 11.00 mg

5- (2-fluorophenyl) -l, 3-dihydro-2H-l, 4-benzodiazepin-2-one-mono-

hydrochloride

Mannitol 80.00 mg

Corn starch 50.00 mg

Polyvinylpyrrolidone 6.00 mg

Talc 2.70 mg

Magnesium stearate 0.30 mg

Total weight 150.00 mg

The active ingredient, the mannitol and some of the corn starch are mixed well in a suitable mixer.

2 «and then with a polyvinylpyrrolidone solution moistened in ethanol or a chlorinated hydrocarbon, granulated and dried. Thereafter the talc, the magnesium stearate and the remaining corn starch are added. The mix will

2Ί mixed and pressed.

Claims (1)

Claim: Use of the monohydrochloride salt of 7-chloro-1- (2-diethylaminoethyl) -5- (2-fluorophenyI) -1, 3-dihydro-2H-1,4-bep. '. Odiazepin-2-one the formula CH ₁ CH, CH, -CU, -N