NO140860B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF PHYSIOLOGICALLY ACTIVE TRIAZOLO-1,5-BENZODIAZEPINES - Google Patents

ANALOGICAL PROCEDURE FOR THE PREPARATION OF PHYSIOLOGICALLY ACTIVE TRIAZOLO-1,5-BENZODIAZEPINES Download PDF

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NO140860B
NO140860B NO741351A NO741351A NO140860B NO 140860 B NO140860 B NO 140860B NO 741351 A NO741351 A NO 741351A NO 741351 A NO741351 A NO 741351A NO 140860 B NO140860 B NO 140860B
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general formula
triazolo
benzodiazepines
hydrogen
trifluoromethyl
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NO140860C (en
NO741351L (en
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Adolf Bauer
Karl-Heinz Weber
Peter Danneberg
Franz-Josef Kuhn
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Boehringer Sohn Ingelheim
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

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Abstract

Analogifremgangsmåte for fremstilling av fysiologisk aktive triazolo-1,5-benzodiazepiner.Analogous process for the preparation of physiologically active triazolo-1,5-benzodiazepines.

Description

Denne oppfinnelse angår en fremgangsmåte for fremstilling av nye substituerte s-triazolo-1,5-benzodiazepiner med den generelle formel This invention relates to a process for the production of new substituted s-triazolo-1,5-benzodiazepines with the general formula

og syreaddisjonssalter derav. and acid addition salts thereof.

I formelen betyr: In the formula means:

hydrogen, en lineær eller forarenet alkylrest med 1-4 karbon atomer, en hydroksyalkylrest med 1-2 karbonatomer, en cyklo-.heksylrest eller en fenylrest, hydrogen, a linear or prepurified alkyl radical of 1-4 carbons atoms, a hydroxyalkyl radical with 1-2 carbon atoms, a cyclohexyl radical or a phenyl radical,

R2 et hydrogen-, fluor- eller kloratom eller en trifluormetyl- eller R 2 a hydrogen, fluorine or chlorine atom or a trifluoromethyl or

nitrogruppe, og nitro group, and

R3 et klor- eller bromatom eller en trifluormetyl- eller nitrogruppe. R 3 a chlorine or bromine atom or a trifluoromethyl or nitro group.

I henhold til oppfinnelsen fremstilles de nye forbindelser med den generelle formel I ved at forbindelser med den generelle formel According to the invention, the new compounds of the general formula I are prepared by making compounds of the general formula

hvor R_ og R, har den ovenfor angitte betydning og X betyr et halogenatom eller en lavere alkoksygruppe, omsettes med et monoacylhydrazid med den generelle formel hvor R-^ har den ovenfor angitte betydning. Herunder dannes først mellomproduktet where R_ and R, have the meaning given above and X means a halogen atom or a lower alkoxy group, is reacted with a monoacyl hydrazide of the general formula where R-^ has the meaning given above. Here, the intermediate product is first formed

(R^, R2 og R^ har den ovenfor angitte betydning), som uten forut-gående isolering kan ringsluttes til sluttproduktet. Dette overføres eventuelt ved vanlige metoder til et fysiologisk tålbart syreaddisjonssalt. (R^, R2 and R^ have the meaning given above), which can be ring-closed to the final product without prior isolation. This is optionally transferred by usual methods to a physiologically tolerable acid addition salt.

Ved fremgangsmåten omsettes en forbindelse med formel II fortrinnsvis med 2-7 gangers overskudd av syrehydrazidet. In the method, a compound of formula II is preferably reacted with a 2-7 times excess of the acid hydrazide.

Anvendelse av et inert organisk oppløsningsmiddel, f.eks. dioksan, toluen, benzen, xylen, acetonitril, dimetylformamid eller blandinger av disse oppløsningsmidler er avhengig av det anvendte benzodiazepin med formel II, og under visse omstendigheter kan man også arbeide uten oppløsningsmiddel. Use of an inert organic solvent, e.g. dioxane, toluene, benzene, xylene, acetonitrile, dimethylformamide or mixtures of these solvents depends on the benzodiazepine of formula II used, and under certain circumstances one can also work without a solvent.

Hvis X betyr en lavere alkoksygruppe, settes det til reaksjonsblandingen hensiktsmessig en Lewis syre, f.eks. aluminium-klorid, sinkklorid, bortrifluorid eller trifluoreddiksyre, eventuelt også gassformig hydrogenklorid, og man arbeider fortrinnsvis ved høyere temperaturer, som ligger omtrentlig mellom 100°C If X means a lower alkoxy group, a Lewis acid is conveniently added to the reaction mixture, e.g. aluminum chloride, zinc chloride, boron trifluoride or trifluoroacetic acid, possibly also gaseous hydrogen chloride, and preferably work at higher temperatures, which lie approximately between 100°C

og reaksjonsblandingens tilbakeløpstemperatur. and the reflux temperature of the reaction mixture.

Hvis X betyr et halogenatom, bortfaller tilsetningen av If X represents a halogen atom, the addition of is omitted

de nevnte sure katalysatorer, og man omsetter forbindelsen med formel II (X = halogen) fortrinnsvis in situ og ved lavere temperaturer, omtrentlig mellom -10 og +50°C, med acylhydrazidet med formel III. the aforementioned acid catalysts, and the compound of formula II (X = halogen) is preferably reacted in situ and at lower temperatures, approximately between -10 and +50°C, with the acyl hydrazide of formula III.

Sluttproduktene med den generelle formel I kan eventuelt på vanlig måte overføres til de fysiologisk tålbare syreaddisjonssalter. Syrer som er egnet for saltdannelse, er f.eks. halogen-hydrogensyrer, svovelsyre, fosforsyre, cykloheksylsulfaminsyre eller metan- eller toluensulfonsyre. The end products of the general formula I can optionally be transferred in the usual way to the physiologically tolerable acid addition salts. Acids that are suitable for salt formation are e.g. halogen-hydrogen acids, sulfuric acid, phosphoric acid, cyclohexylsulfamic acid or methane or toluenesulfonic acid.

Utgangsstoffene med den generelle formel II kan f.eks. erholdes The starting substances with the general formula II can e.g. is obtained

a) når X er halogen, ved omsetning av en forbindelse med den generelle formel a) when X is halogen, by reacting a compound with the general formula

hvor IL, og har den ovenfor angitte betydning, med et uorganisk syrehalogenid, fortrinnsvis et fosforpentahalogenid, i et vannfritt inert organisk oppløsningsmiddel så som dioksan ved lave temperaturer (omtrentlig mellom -50 og +50°C); wherein IL, and has the above meaning, with an inorganic acid halide, preferably a phosphorus pentahalide, in an anhydrous inert organic solvent such as dioxane at low temperatures (approximately between -50 and +50°C);

b) når X er alkoksy, ved omsetning av en forbindelse med den generelle formel V med et trialkyloksoniumfluorborat i henhold b) when X is alkoxy, by reacting a compound of the general formula V with a trialkyloxonium fluoroborate according to

til belgisk patentskrift 774 873. to Belgian patent document 774 873.

Som det er kjent fra tallrike publikasjoner, vil tilknytning As is known from numerous publications, attachment will

av triazolo-ringen til 1,4-benzodiazepiner føre til en forsterkning av den beroligende virkning av denne klasse forbindelser. Det har nu overraskende vist seg at en tilsvarende tilknytning til ringsystemet i 1,5-benzodiazepiner bevirker en sterk differensiering av virkningsprofilen. of the triazolo ring to 1,4-benzodiazepines lead to an enhancement of the sedative effect of this class of compounds. It has now surprisingly been shown that a corresponding connection to the ring system in 1,5-benzodiazepines causes a strong differentiation of the action profile.

Således kan de nye triazolo-benzodiazepiner anvendes som Thus, the new triazolo-benzodiazepines can be used as

sterkt virksomme antikrampemidler, mens den minor-beroligende virkning trer helt i bakgrunnen. Antikrampevirkningen er bestemt ved hjelp av pentetrazolantagonisme, og den ligger for de nye forbindelser i samme størrelsesorden som antikrampevirkningen for diazepam og overgår langt virkningen for fenobarbital. highly effective anticonvulsants, while the minor sedative effect recedes completely into the background. The anticonvulsant effect has been determined using pentetrazole antagonism, and for the new compounds it is in the same order of magnitude as the anticonvulsant effect of diazepam and far exceeds the effect of phenobarbital.

Bivirkningene for de nye forbindelser er derimot langt The side effects for the new compounds, on the other hand, are far-reaching

mindre enn for begge de ovennevnte sammenligningsforbindelser. less than for both of the above comparison compounds.

Således inntrer også ved høye doser ingen vesentlig reduksjon av muskelkoordinasjonen, og bedøvende, psykofarmakologiske virkninger kan heller nesten ikke påvises for de nye forbindelser. Således hemmes ikke bevegelsen hos mus ved den såkalte "Open-Field-Test", Thus, even at high doses, no significant reduction of muscle coordination occurs, and anesthetic, psychopharmacological effects can hardly be detected for the new compounds. Thus, the movement of mice is not inhibited in the so-called "Open-Field-Test",

og ved et kondisjoneringsforsøk for beroligende midler som benyttes på rotter (Passive Avoidance) kan det praktisk talt ikke påvises noen virkning. En ytterligere fordel med de nye forbindelser er deres meget lave giftighet, som gjør det mulig å anvende for-bindelsene uten fare over et bredt doseområde. and in a conditioning experiment for sedatives used on rats (Passive Avoidance) practically no effect can be demonstrated. A further advantage of the new compounds is their very low toxicity, which makes it possible to use the compounds without danger over a wide dose range.

De nye triazolo-benzodiazepiner med den generelle formel I The new triazolo-benzodiazepines of the general formula I

og deres fysiologisk forlikelige syreaddisjonssalter representerer således verdifulle antikrampemidler med meget lav giftighet. Særlig skal fremheves slike forbindelser hvor and their physiologically compatible acid addition salts thus represent valuable anticonvulsants with very low toxicity. Special emphasis should be placed on such connections where

betyr et hydrogenatom, means a hydrogen atom,

R^ et kloratom eller en trifluormetylgruppe, og R^ a chlorine atom or a trifluoromethyl group, and

R^ et kloratom eller en nitro- eller trifluormetylrest. R^ a chlorine atom or a nitro or trifluoromethyl residue.

Som dose for anvendelse av de nye forbindelser med den generelle formel I foreslås 0,5 til 50, fortrinnsvis 1 til 25 mg som enkeltdose og 5 til 150 mg som daglig dose. As a dose for use of the new compounds of the general formula I, 0.5 to 50, preferably 1 to 25 mg as a single dose and 5 to 150 mg as a daily dose is suggested.

De nye forbindelser kan anvendes alene eller i kombinasjon The new compounds can be used alone or in combination

med andre aktive stoffer fremstilt ifølge oppfinnelsen, eventuelt også i kombinasjon med andre farmakologisk aktive stoffer så som spasmolytika eller psykofarmaka. with other active substances produced according to the invention, possibly also in combination with other pharmacologically active substances such as spasmolytics or psychopharmaceuticals.

De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere. The following examples shall serve to further illustrate the invention.

Eksempel 1 Example 1

6- fenyl- 8- trifluormetyl- 4, 6- dihydro- 5H- s- triazolo-( 4, 3- a)( 1, 5)-benzodiazepin- 5- on 3 g 2-etoksy-5-fenyl-7-trifluormetyl-4H-3,5-dihydro-l,5-benzodiazepin-4-on oppvarmes i 60 minutter med 1,8 g maursyrehydrazid i oljebad til 200°C. Derefter lar man det hele avkjøles til romtemperatur og utrører den stivnede smelte med 100 ml halv-konsentrert saltsyre. Man ryster suspensjonen med etylacetat, fra-skiller den vandige fase, nøytraliserer med konsentrert ammoniakk og ekstraherer flere ganger med metylenklorid. Man tørrer den organiske fase med magnesiumsulfat og inndamper i vakuum. Residuet krystalliserer ved tilsetning av isopropyleter og omkrystalliseres fra aceton. 6- phenyl- 8- trifluoromethyl- 4, 6- dihydro- 5H- s- triazolo-( 4, 3- a)( 1, 5)-benzodiazepine- 5- one 3 g 2-ethoxy-5-phenyl-7- Trifluoromethyl-4H-3,5-dihydro-1,5-benzodiazepine-4-one is heated for 60 minutes with 1.8 g of formic hydrazide in an oil bath to 200°C. The whole is then allowed to cool to room temperature and the solidified melt is stirred with 100 ml of semi-concentrated hydrochloric acid. The suspension is shaken with ethyl acetate, the aqueous phase is separated, neutralized with concentrated ammonia and extracted several times with methylene chloride. The organic phase is dried with magnesium sulphate and evaporated in a vacuum. The residue crystallizes by adding isopropyl ether and recrystallizes from acetone.

Utbytte: 2,7 g (= 91% av det teoretiske), sm.p. 261-263°C. Yield: 2.7 g (= 91% of the theoretical), m.p. 261-263°C.

Eksempel 2 Example 2

l- metyl- 8- nitro- 6- fenyl- 4, 6- dihydro- 5H- s- triazolo-( 4, 3- a)( 1, 5)-benzodiazepin- 5- on l- methyl- 8- nitro- 6- phenyl- 4, 6- dihydro- 5H- s- triazolo-( 4, 3- a)( 1, 5)- benzodiazepine- 5- one

Til en oppløsning av 39,4 g fosforpentaklorid i 2 50 ml absolutt toluen tilsettes dråpevis 8,3 g 7-nitro-5-fenyl-lH-1,5-benzodiazepin-2/4-[ 3H, 5H]-dion, oppløst i 90 ml absolutt dioksan og 15 ml acetonitril. Man lar det hele reagere i 30 minutter ved 0°C under omrøring. Den dannede suspensjon tilsettes langsomt i en oppløsning av 70 g acetylhydrazid i 200 ml dimetylformamid, slik at temperaturen ikke overstiger +3°C. Efter 15 minutter inndampes i vakuum, residuet utrøres med vann, utrystes med metylenklorid, og derefter ekstraheres metylenkloridfasen flere ganger med halv-konsentrert saltsyre. Den videre opparbeidelse skjer som beskrevet i eksempel 1. Det erholdte sluttprodukt omkrystalliseres fra metylenklorid/isopropyleter. To a solution of 39.4 g of phosphorus pentachloride in 250 ml of absolute toluene, 8.3 g of 7-nitro-5-phenyl-1H-1,5-benzodiazepine-2/4-[3H,5H]-dione, dissolved in 90 ml of absolute dioxane and 15 ml of acetonitrile. The whole is allowed to react for 30 minutes at 0°C with stirring. The resulting suspension is slowly added to a solution of 70 g of acetylhydrazide in 200 ml of dimethylformamide, so that the temperature does not exceed +3°C. After 15 minutes, it is evaporated in vacuo, the residue is stirred with water, shaken out with methylene chloride, and then the methylene chloride phase is extracted several times with semi-concentrated hydrochloric acid. The further processing takes place as described in example 1. The final product obtained is recrystallized from methylene chloride/isopropyl ether.

Utbytte: 5,7 g (= 63% av det teoretiske), sm.p. 302-305°C. Yield: 5.7 g (= 63% of the theoretical), m.p. 302-305°C.

Eksempel 3 Example 3

8- brom- 6- fenyl- 4, 6- dihydro- 5H- s- triazolo-( 4, 3- a)( 1, 5)- benzodiazepin- 5- on 6 g 2-etoksy-7-brom-5-fenyl-4H-3,5-dihydro-l,5-benzodiazepin-4-on og 4,8 g maursyrehydrazid oppløses i 150 ml absolutt dioksan under lett oppvarmning og oppvarmes under tilbakeløps-kjøling med 2 ml trifluoreddiksyre i 60 minutter. Derefter inndampes oppløsningen og opparbeides videre som beskrevet i eksempel 1. Sluttproduktet omkrystalliseres fra metylenklorid/isopropyleter. Utbytte: 5,9 g (=96% av det teoretiske), sm.p. 282-284°C. 8- bromo- 6- phenyl- 4, 6- dihydro- 5H- s- triazolo-( 4, 3- a)( 1, 5)- benzodiazepine- 5- one 6 g 2-ethoxy-7-bromo-5- phenyl-4H-3,5-dihydro-1,5-benzodiazepine-4-one and 4.8 g of formic hydrazide are dissolved in 150 ml of absolute dioxane under gentle heating and heated under reflux with 2 ml of trifluoroacetic acid for 60 minutes. The solution is then evaporated and processed further as described in example 1. The final product is recrystallized from methylene chloride/isopropyl ether. Yield: 5.9 g (=96% of the theoretical), m.p. 282-284°C.

Analogt med eksemplene 1-3 fremstilles følgende forbindelser: Analogous to examples 1-3, the following compounds are prepared:

Eksempel Example

Claims (2)

1. Analogifremgangsmåte for fremstilling av fysiologisk aktive forbindelser med den generelle formel hvor betyr hydrogen, en lineær eller forgrenet alkylrest med 1-4 karbonatomer, en hydroksyalkylrest med 1-2 karbonatomer, en cykloheksylrest eller en fenylrest, R2 betyr et hydrogen-, fluor- eller kloratom eller en trifluormetyl- eller nitrogruppe, og R3 betyr et klor- eller bromatom eller en trifluormetyl- eller nitrogruppe, og syreaddisjonssalter derav, karakterisert ved at en forbindelse med den generelle formel hvor R2 og R^ har den ovenfor angitte betydning og X betyr et halogenatom eller en lavere alkoksygruppe, kondenseres med et monoacylhydrazid med den generelle formel hvor har den ovenfor angitte betydning, og eventuelt overføres det således erholdte sluttprodukt med den generelle formel I på vanlig måte til et fysiologisk godtagbart syreaddisjonssalt.1. Analogy method for the production of physiological active compounds of the general formula where means hydrogen, a linear or branched alkyl radical of 1-4 carbon atoms, a hydroxyalkyl radical of 1-2 carbon atoms, a cyclohexyl residue or a phenyl residue, R2 means a hydrogen, fluorine or chlorine atom or a trifluoromethyl or nitro group, and R3 means a chlorine or bromine atom or a trifluoromethyl- or nitro group, and acid addition salts thereof, characterized in that a connection with it general formula where R 2 and R 3 have the meaning given above and X means a halogen atom or a lower alkoxy group, is condensed with a monoacyl hydrazide of the general formula where has the above meaning, and optionally the thus obtained final product with the general formula I is transferred in the usual way to a physiologically acceptable acid addition salt. 2. Fremgangsmåte som angitt i krav 1, for fremstilling av 8-klor-6-(o-klorfenyl)-4,6-dihydro-5H-s-triazolo-[4,3-a]-[1,5]-benzodiazepin-5-on, karakterisert ved at det anvendes utgangsmaterialer hvor R^ betyr hydrogen og R2 og R^ hver betyr klor.2. Process as stated in claim 1, for the production of 8-chloro-6-(o-chlorophenyl)-4,6-dihydro-5H-s-triazolo-[4,3-a]-[1,5]- benzodiazepine-5-one, characterized in that starting materials are used where R^ means hydrogen and R2 and R^ each mean chlorine.
NO741351A 1973-04-13 1974-04-10 ANALOGICAL PROCEDURE FOR THE PREPARATION OF PHYSIOLOGICALLY ACTIVE TRIAZOLO-1,5-BENZODIAZEPINES NO140860C (en)

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Publication number Priority date Publication date Assignee Title
US4080323A (en) * 1977-03-07 1978-03-21 Hoffmann-La Roche Inc. Imidazo [1,5-a][1,5] benzodiazepines
US4118386A (en) * 1977-04-04 1978-10-03 Hoffmann-La Roche Inc. Synthesis of imidazo[1,5-a]diazepine-3-carboxylates
DE3435972A1 (en) * 1984-10-01 1986-04-10 Boehringer Ingelheim KG, 6507 Ingelheim PHARMACEUTICAL COMPOSITIONS CONTAINING DIAZEPINE WITH PAF-ANTAGONISTIC EFFECT
KR100840852B1 (en) * 2004-05-25 2008-06-23 화이자 프로덕츠 인크. Tetraazabenzo[e]azulene derivatives and analogs thereof
JP4069159B2 (en) 2004-05-25 2008-04-02 ファイザー・プロダクツ・インク Tetraazabenzo [e] azulene derivatives and analogs thereof
DE102005061840A1 (en) 2005-12-23 2007-06-28 Merck Patent Gmbh New polyaza-benzo-azulene compounds are transforming growth factor-beta receptor kinase inhibitors used for treating e.g. cancer, HIV infection and Alzheimer's disease
DE102006051796A1 (en) * 2006-11-03 2008-05-08 Merck Patent Gmbh Triaza-benzo [e] azulene derivatives

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FR2225164B1 (en) 1977-05-06
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JPS5052093A (en) 1975-05-09
SU730307A3 (en) 1980-04-25
SE419989B (en) 1981-09-07
DK136821C (en) 1978-05-08
FI56837B (en) 1979-12-31
DE2318673A1 (en) 1974-11-07
BE813677A (en) 1974-10-14
ES425216A1 (en) 1976-05-16
CH591486A5 (en) 1977-09-30
NO741351L (en) 1974-10-15
JPS5753797B2 (en) 1982-11-15
AT336025B (en) 1977-04-12
ATA248274A (en) 1976-08-15
FR2225164A1 (en) 1974-11-08
DK136821B (en) 1977-11-28

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