NO133714B

NO133714B -

Info

Publication number: NO133714B
Application number: NO4214/71A
Authority: NO
Inventors: J Hellerbach
Original assignee: Hoffmann La Roche
Priority date: 1971-06-08
Filing date: 1971-11-15
Publication date: 1976-03-08
Also published as: BE777897A; CY868A; NO133714C; PH13530A; FR2140371B1; DE2157112B2; DK127506B; BG19173A3; SE388856B; MX149567A; CS155105B2; SU444369A3; IE35846B1; IL38252A0; PL81437B1; DD98679A5; ZA717880B; DE2157112C3; CS155106B2; ES397552A1

Description

Forbindelsen 7-klor-l-(2-dietylaminoetyl)-5- (2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on har ifolge sine fremragende terapeutiske egenskaper oppnådd en ledende posisjon ved be-handling av alle slags søvnforstyrrelser, og da spesielt slike som innebærer forstyrrelser ved innsovning, hyppig oppvåkning om natten eller for tidlig oppvåkning om morgenen. Dessuten egner forbindelsen seg for regulering av den forstyrrede sove-oppvåknings-rytmen, og for fjerning av sovn-forstyrrelser, hvilke oppkommer som folge av kroniske sykdommer. The compound 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one has achieved a leading position in be - action of all kinds of sleep disorders, and especially those that involve disturbances when falling asleep, frequent awakenings at night or waking too early in the morning. Furthermore, the compound is suitable for regulating the disturbed sleep-wake rhythm, and for removing sleep disturbances, which arise as a result of chronic diseases.

Forbindelsen ble tidligere anvendt som dihydroklorid til tross The compound was previously used as the dihydrochloride despite

for at dette dihydroklorid ved bearbeidelse til tilfredsstillende. so that this dihydrochloride by processing to satisfactory.

og stabile legemidler har bydd på store vanskeligheter. Således er dihydrokloridet f.eks. meget sterkt fuktighetsomtålig og gir sterke sure losninger. Det er derfor bare egnet for fremstilling av kapsler, og selv i denne farmasøytiske anven-delsesform kan en tilfredsstillende stabilitet bare oppnås under iakttagelse av visse arbeidstekniske grenser, såsom vannfri granulering i lokaler med mindre enn 20% relativ luft-fuktighet, anvendelse av bare meget vanskelig tilgjengelig, vannfri laktose, lagring av kapsler over silikagel o.l. and stable drugs have presented great difficulties. Thus, the dihydrochloride is e.g. very highly resistant to moisture and produces strong acidic solutions. It is therefore only suitable for the production of capsules, and even in this pharmaceutical form of use, a satisfactory stability can only be achieved by observing certain work-technical limits, such as anhydrous granulation in premises with less than 20% relative humidity, the use of only very difficult to access, anhydrous lactose, storage of capsules over silica gel, etc.

Til tross for de her beskrevne ulemper blir, som innledningsvis nevnt, utelukkende dihydrokloridet anvendt. Man var tidligere åpenbart av den oppfatning at dette dihydrokloridet var det eneste praktisk brukbare saltet av det nevnte benzodiazepinet. Despite the disadvantages described here, as mentioned at the outset, only the dihydrochloride is used. It was previously evidently of the opinion that this dihydrochloride was the only practically usable salt of the aforementioned benzodiazepine.

Innen rammen av nærværende oppfinnelse ble det nå overraskende funnet at det tilsvarende monohydrokloridet lett lar seg fremstille, og at de terapeutiske egenskapene til monohydrokloridet overensstemmer med egenskapene til dihydrokloridet. Det ble videre overraskende fastslått at monohydrokloridet ikke oppviser de ovennevnte ulempene til dihydrokloridet. Således kan monohydrokloridet bearbeides uten at man må ta spesielle forholdsregler, og det er uinnskrenket stabilt også Within the scope of the present invention, it was now surprisingly found that the corresponding monohydrochloride can be easily prepared, and that the therapeutic properties of the monohydrochloride correspond to the properties of the dihydrochloride. It was further surprisingly established that the monohydrochloride does not exhibit the above-mentioned disadvantages of the dihydrochloride. Thus, the monohydrochloride can be processed without having to take special precautions, and it is also infinitely stable

i tablettform og i torre ampuller. Monohydrokloridet har dessuten i tillegg den fordel at det gir betydelig mindre sure losninger enn det tilsvarende dihydrokloridet. in tablet form and in dry ampoules. The monohydrochloride also has the additional advantage that it produces significantly less acidic solutions than the corresponding dihydrochloride.

Nærværende oppfinnelse vedrorer således monohydrokloridet av 7-klor-l-(2-dietylaminoetyl)-5- (2-fluorfenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-on, dvs. en forbindelse med formel, såvel som en fremgangsmåte for dets fremstilling. The present invention thus relates to the monohydrochloride of 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, i.e. a compound of formula , as well as a method for its production.

Fremgangsmåten ifolge oppfinnelsen er karakterisert ved at man bringer 7-klor-l-(2-dietylaminoetyl)-5- (2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on til reaksjon med ikke mer enn den ekvimolare mengden klorhydrogensyre, eller at man omsetter det tilsvarende dihydrokloridet med den ekvimolare mengde base eller vann, og at man isolerer det dannede 7-klor-l-(2-dietylaminoetyl)-5- (2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiaze-pi n - 2 - on-monohy dr oki or i d. The method according to the invention is characterized by bringing 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one into reaction with more than the equimolar amount of hydrochloric acid, or that one reacts the corresponding dihydrochloride with the equimolar amount of base or water, and that one isolates the formed 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1, 3-dihydro-2H-l,4-benzodiaze-pi n - 2 - on-monohy dr oki or i d.

Omsetningen av 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on med ikke mer enn den ekvimolare mengde klorhydrogensyre, foretas hensiktsmessig i et organisk losningsmiddel, såsom metanol, etanol, isopropanol, aceton o.l. Fortrinnsvis foretas omsetningen med alkoholholdig saltsyre, f.eks. etanolholdig saltsyre, hvorved monohydrokloridet kan utfelles ved tilsetning av eter. Ved fremstilling av storre mengder kan monohydrokloridet også fremstilles ved at man i en losning av 7-klor-l-(2-dietylaminoetyl)-5-(2-fluor-fenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-on innleder en ekvi-molar mengde klorhydrogengass. The reaction of 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one with no more than the equimolar amount of hydrochloric acid is conveniently carried out in an organic solvent, such as methanol, ethanol, isopropanol, acetone, etc. Preferably, the reaction is carried out with alcoholic hydrochloric acid, e.g. ethanolic hydrochloric acid, whereby the monohydrochloride can be precipitated by the addition of ether. When producing large quantities, the monohydrochloride can also be prepared by adding, in a solution of 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluoro-phenyl)-1,3-dihydro-2H-1,4- benzodiazepine-2-one introduces an equimolar amount of hydrogen chloride gas.

EKSEMPEL 2 EXAMPLE 2

I et rorekar tilsettes til en blanding av 56,20 kg vann, 10,60 In a stirring vessel, add to a mixture of 56.20 kg of water, 10.60

kg 28%'ig natronlut og 60,50 kg toluen ved 25° under god omror-ing 15,54 kg (33,72 mol) 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-dihydroklorid i små porsjoner. Etter endt tilsetning rores reaksjonsblandingen ytterligere 30 minutter, hvorefter man overforer reaksjonsblandingen til en spiss kjele. Rorekjelen vaskes derefter med 36,5 kg toluen. Denne toluenlosningen forenes med reaksjonsblandingen. Derefter avskilles den vandige fasen, hvorefter den bringes over i den spiss-formede kjelen og hvor man ekstraherer med 48,5 kg toluen. Derefter blir begge toluen-ekstraktene vasket med to ganger 40 kg og en gang med 25 kg vann, hvorefter de forenes og overfores til en destillasjonskjele. Til slutt blir losningsmidlet avdestillert under redusert trykk ved 35 - 45°. Efter opplosning av den oljeaktige resten i 31,0 kg abs. etanol, lar man i lopet av 30 minutter 5,620 liter av en 6,O-n etanolholdig saltsyre stromme til, hvorved tem-peraturen holdes mellom 25 og 30° ved kjoling. Efter endt tilsetning omrores ytterligere 5 minutter. Derefter blir losningsmidlet avdestillert under redusert trykk ved 30 - 35°. Resten opploses ved 25° i 7,5 kg abs. etanol, tilsettes 31,5 kg eter og tilsatt krystallisasjonskimer. Efter sugefiltrering blir det krystallinske produktet vasket to ganger med hver gang 5,5 liter av en til 0° forkjolt eter/alkohol-blanding (5,3:1), kg 28% caustic soda and 60.50 kg toluene at 25° under good stirring 15.54 kg (33.72 mol) 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)- 1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride in small portions. After the addition is complete, the reaction mixture is stirred for a further 30 minutes, after which the reaction mixture is transferred to a pointed kettle. The stirrer is then washed with 36.5 kg of toluene. This toluene solution is combined with the reaction mixture. The aqueous phase is then separated, after which it is transferred to the tip-shaped boiler and extracted with 48.5 kg of toluene. Both toluene extracts are then washed twice with 40 kg and once with 25 kg of water, after which they are combined and transferred to a still. Finally, the solvent is distilled off under reduced pressure at 35 - 45°. After dissolving the oily residue in 31.0 kg abs. ethanol, 5.620 liters of a 6.0-n ethanol-containing hydrochloric acid is allowed to flow over the course of 30 minutes, whereby the temperature is kept between 25 and 30° during cooling. After the addition is complete, stir for a further 5 minutes. The solvent is then distilled off under reduced pressure at 30 - 35°. The residue is dissolved at 25° in 7.5 kg abs. ethanol, 31.5 kg of ether are added and added crystallization chemical. After suction filtration, the crystalline product is washed twice with each time 5.5 liters of an ether/alcohol mixture precooled to 0° (5.3:1),

og derefter torket ved 60° under redusert trykk. Herved får man 7-klor-l-(2-dietylamirioétyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-on-monohydroklorid, smp. 203,5°. and then dried at 60° under reduced pressure. This gives 7-chloro-1-(2-diethylamirioethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one monohydrochloride, m.p. 203.5°.

EKSEMPEL 3 EXAMPLE 3

2,3 g (5,0 mol) 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-dihydroklorid og 2,1 g 2.3 g (5.0 mol) 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride and 2.1 g

(5,4 mmol) 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on opploses sammen i 5 ml etanol og tilsettes 15 ml eter; Efter tilsetning av krystallkimer og henstand over natten får man 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydrb-2H-l,4-benzodiazepin-2-on-mono-hydroklorid med smp. 203°. (5.4 mmol) 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one are dissolved together in 5 ml of ethanol and 15 ml of ether are added; After addition of crystal seeds and standing overnight, 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydrob-2H-1,4-benzodiazepine-2-one-mono- hydrochloride with m.p. 203°.

EKSEMPEL 4 EXAMPLE 4

2,3 g (5,0 mmol) 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-dihydroklorid suspenderes i 2,5 ml etanol, tilsatt en opplosning av 0,33 g (5 mmol) kaliumhydroksyd i 2,5 ml etanol, og omrystet 30 minutter på en rystemaskin, derefter avfiltreres det utfelte kaliumkloridet, 2.3 g (5.0 mmol) of 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride are suspended in 2.5 ml of ethanol, added a solution of 0.33 g (5 mmol) of potassium hydroxide in 2.5 ml of ethanol, and shaken for 30 minutes on a shaking machine, then the precipitated potassium chloride is filtered off,

og filtratet inndampes under redusert trykk til 3 ml. Efter tilsetning av 3 ml eter blir den svakt grumsete losningen fil- and the filtrate is evaporated under reduced pressure to 3 ml. After adding 3 ml of ether, the slightly cloudy solution is filtered

trert, tilsatt ytterligere 3 ml eter og derefter tilsatt krystallkimer. Man får 7-klor-l- (2-dietylaminoetyl)-5- (2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-monohydro- triturated, added another 3 ml of ether and then added crystal chyme. 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-monohydro-

klorid med smp. 202 - 203°. chloride with m.p. 202 - 203°.

EKSEMPEL 5 EXAMPLE 5

1 g (2,17 mmol) 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-dihydroklorid opploses i 20 ml vann og ekstraheres tre ganger med hver gang 25 ml metyl-enklorid. Metylenkloridekstraktene blir torket med natriumsul-fat og inndampet under redusert trykk til torrhet. Krystal- 1 g (2.17 mmol) of 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-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 under reduced pressure to dryness. crystal

lisasjon av resten i etanol/eter gir 7-klor-l-(2-dietylaminoetyl)-5- (2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-mono-hydroklorid med smp. 202 - 203°. lysis of the residue in ethanol/ether gives 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-mono-hydrochloride with m.p. 202 - 203°.

EKSEMPEL 6 EXAMPLE 6

Man fremstiller tabletter med folgende sammensetning: Tablets are produced with the following composition:

Pr. tablett 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-1,4-benzodi azepin-2-on-mono- Per tablet 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one-mono-

Aktivsubstansen, mannitten og en del av maisstivelsen blandes godt i et egnet blandingskar, hvorefter dette fuktes med en polyvinylpyrrolidon-losning i etanol eller et klorert hydrokarbon, granulert og torket. Derefter tilsettes talkum, magnesiumstearat og resten av maisstivelsen. Blandingen blandes og presses. The active substance, the mannitol and part of the maize starch are mixed well in a suitable mixing vessel, after which this is moistened with a polyvinylpyrrolidone solution in ethanol or a chlorinated hydrocarbon, granulated and dried. Talc, magnesium stearate and the rest of the cornstarch are then added. The mixture is mixed and pressed.

EKSEMPEL 7 EXAMPLE 7

Claims

Analogous process for the production of a therapeutically active and galenically well processable benzodiazepine derivative characterized by bringing 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4 -benzodiazepine-2-one to reaction with no more than the equimolar amount of hydrochloric acid, or that one reacts the corresponding dihydrochloride with the equimolar amount of base or with water and that one isolates the formed 7-chloro-1-(2-diethylaminoethyl)- 5-(2-Fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-monohydrochlori-