NO156941B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE IMIDAZOLE HYDRAZONE AND HYDRAZINE DERIVATIVES. - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE IMIDAZOLE HYDRAZONE AND HYDRAZINE DERIVATIVES. Download PDF

Info

Publication number
NO156941B
NO156941B NO820311A NO820311A NO156941B NO 156941 B NO156941 B NO 156941B NO 820311 A NO820311 A NO 820311A NO 820311 A NO820311 A NO 820311A NO 156941 B NO156941 B NO 156941B
Authority
NO
Norway
Prior art keywords
imidazol
tetrahydro
production
starting materials
hydrochloride
Prior art date
Application number
NO820311A
Other languages
Norwegian (no)
Other versions
NO820311L (en
NO156941C (en
Inventor
Peter John Fellner
Christopher David Floyd
George Ellames
Paul William Manley
Original Assignee
Searle & Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Searle & Co filed Critical Searle & Co
Publication of NO820311L publication Critical patent/NO820311L/en
Publication of NO156941B publication Critical patent/NO156941B/en
Publication of NO156941C publication Critical patent/NO156941C/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Abstract

Forbindelser med de generelle formler:. der Ar og'Ar''", som kan være like eller forskjellige, er aromatiske radikaler eventuelt substituert én eller flere ganger av substituenter valgt fra halogen, lavere alkyl og lavere alkoksy, og Alk er en alkylengruppe inneholdende fra 1-4 karbonatomer som kan inneholde et heteroatom, samt syreaddisjonssalter derav.Disse forbindelser har virkning mot anaerobe bakterier og også mot sopper, og er ikke-mutagene.Fremstillingen av forbindelsene er beskrevet .Compounds of the general formulas:. where Ar and "Ar", which may be the same or different, are aromatic radicals optionally substituted one or more times by substituents selected from halogen, lower alkyl and lower alkoxy, and Alk is an alkylene group containing from 1-4 carbon atoms which may contain a heteroatom, as well as acid addition salts thereof.These compounds have action against anaerobic bacteria and also against fungi, and are non-mutagenic.The preparation of the compounds is described.

Description

Foreliggende oppfinnelse vedrører fremstilling av nye imidazolhydrazon- og -hydrazinderivater med terapeutisk virkning. The present invention relates to the production of new imidazole hydrazone and hydrazine derivatives with therapeutic effect.

Det er kjent at visse forbindelser slik som metronidazol som har formelen: It is known that certain compounds such as metronidazole which have the formula:

er virksomme mot anaerobe bakterier. Publiserte undersøkelser indikerer at virkningen skyldes tilstedeværelsen av nitro-gruppen. Denne forbindelsen er angitt å være mutagen og tera-togen. Man har funnet at visse imidazolhydrazon- og -hydrazinderivater med formel I som angitt nedenfor har anti-anaerob virkning spesielt mot bakterier som trives i fravær av luft. Virkningen av disse forbindlsene med anti-anaerobe midler er på høyde med eller bedre enn metronidazol, mens de ikke synes å være mutagene. Deres overlegne virkning demon-streres spesielt overfor P. acnes, en bakterie med tilknytning til akne. are effective against anaerobic bacteria. Published research indicates that the effect is due to the presence of the nitro group. This compound is reported to be mutagenic and teratogenic. It has been found that certain imidazole hydrazone and hydrazine derivatives of formula I as set forth below have anti-anaerobic activity particularly against bacteria which thrive in the absence of air. The activity of these compounds with anti-anaerobic agents is equal to or better than that of metronidazole, while they do not appear to be mutagenic. Their superior effect is demonstrated especially against P. acnes, a bacterium associated with acne.

De nye imidazolhydrazon- og -hydrazinderivatene som fremstilles ifølge oppfinnelsen, har den generelle formel: hvor A er hvor Ar er en fenyl- eller tienylgruppe som eventuelt er substituert med en eller flere halogen-, laverealkyl- eller laverealkoksygrupper; Ar er en fenylgruppe som eventuelt kan være substituert med en eller flere halogengrupper; og Alk er en alkylengruppe med 1-4 karbonatomer hvor alkylen-gruppen kan inneholde et oksygen- eller svovelatom; samt The new imidazole hydrazone and hydrazine derivatives produced according to the invention have the general formula: where A is where Ar is a phenyl or thienyl group which is optionally substituted with one or more halogen, lower alkyl or lower alkoxy groups; Ar is a phenyl group which may optionally be substituted with one or more halogen groups; and Alk is an alkylene group with 1-4 carbon atoms where the alkylene group may contain an oxygen or sulfur atom; as well

syreaddisjonssalter derav. acid addition salts thereof.

Den bølgede linje mellom C=N og NHAr^" gruppene i den ene av betydningene for A ovenfor indikerer muligheten for isomerisme. Forbindelsene kan isoleres i form av en blanding av isomerer eller som selve isomerene, særlig E- The wavy line between the C=N and NHAr^" groups in one of the meanings of A above indicates the possibility of isomerism. The compounds can be isolated in the form of a mixture of isomers or as the isomers themselves, especially E-

og Z-isomerene, og oppfinnelsen omfatter slike blandinger og slike isomerer. Videre inneholder forbindelser med formel I to asymmetriske sentrer, og det vil forstås at oppfinnelsen omfatrer fremstilling av de individuelle isomerene og isomerblandinger. and the Z isomers, and the invention encompasses such mixtures and such isomers. Furthermore, compounds of formula I contain two asymmetric centers, and it will be understood that the invention encompasses the preparation of the individual isomers and isomer mixtures.

I en foretrukken klasse av forbindelser med formel In a preferred class of compounds of formula

I er gruppen Ar fortrinnsvis en fenyl- eller tienylgruppe substituert med ett halogenatom, spesielt et kloratom. In, the group Ar is preferably a phenyl or thienyl group substituted with one halogen atom, especially a chlorine atom.

Gruppen Ar er fortrinnsvis en fenylgruppe substituert med halogenatomer, spesielt kloratomer, og blant slike grupper er 2,4-diklor, 2,6-diklor og 2,4,6-triklor spesielt foretrukket. Alk inneholder fortrinnsvis 3-4 karbonatomer. Foretrukne syreaddisjonssalter er hydrokloridene. The group Ar is preferably a phenyl group substituted with halogen atoms, especially chlorine atoms, and among such groups 2,4-dichloro, 2,6-dichloro and 2,4,6-trichloro are particularly preferred. Alk preferably contains 3-4 carbon atoms. Preferred acid addition salts are the hydrochlorides.

Bestemte foretrukne forbindelser er: Certain preferred compounds are:

(1) 2-klor-6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocykloheptanon, 2,4-diklorfenylhydrazon-hydroklorid, (2) 6-(IH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzo-cykloheptanon, 2,4-diklorfenylhydrazon-hydrogenoksalat, (3) 2-klor-8-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocykloheptanon, 2,4,6-triklorfenylhydrazon-hydroklorid, (4) 6-(lH-imidazol-l-yl)-7-8-9-10-tetrahydro-5(6H)-benzocyklooktanon, 2,4-diklorfenylhydrazon-hydroklorid, (5) 8-(IH-imidazol-l-yl)-4,5,6,7-tetrahydro-8H-cyklo-hepta[b]-tiofen-8-on, 2,4-diklorfenylhudrazon-hydrogenoksalat, (6) 6-(IH-imidazol-l-yl)-7.8.9.10-tetrahydro-5(6H)-benzocyklooktanon, 2,4,6-triklorfenylhydrazon-hydroklorid. (1) 2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone, 2,4-dichlorophenylhydrazone hydrochloride, (2) 6-(1H-imidazole -1-yl)-6,7,8,9-tetrahydro-5-benzo-cycloheptanone, 2,4-dichlorophenylhydrazone hydrogen oxalate, (3) 2-chloro-8-(1H-imidazol-1-yl)-6 ,7,8,9-tetrahydro-5-benzocycloheptanone, 2,4,6-trichlorophenylhydrazone hydrochloride, (4) 6-(1H-imidazol-1-yl)-7-8-9-10-tetrahydro-5( 6H)-benzocyclooctanone, 2,4-dichlorophenylhydrazone hydrochloride, (5) 8-(1H-imidazol-1-yl)-4,5,6,7-tetrahydro-8H-cyclo-hepta[b]-thiophene-8 -one, 2,4-dichlorophenylhudrazone hydrogenoxalate, (6) 6-(1H-imidazol-1-yl)-7.8.9.10-tetrahydro-5(6H)-benzocyclooctanone, 2,4,6-trichlorophenylhydrazone hydrochloride.

Andre bestemte, foretrukne forbindelser er de ytterligere som det i eksemplene er beskrevet fremstillingen av. Other specific, preferred compounds are those further the preparation of which is described in the examples.

Som angitt ovenfor, er forbindelsene med formel I As indicated above, the compounds of formula I

funnet å ha en virkning mot patogene anaerobe found to have an effect against pathogenic anaerobes

bakterier slik som Clostridium-arter, Bacterioides-arter og Propionibacterium acnes som har tilknytning til akne. bacteria such as Clostridium species, Bacterioides species and Propionibacterium acnes which are associated with acne.

Når det gjelder de to førstnevnte artene, er denne virk- In the case of the two first-mentioned species, this effect is

ningen på høyde med virkningen av metronidazol, mens mot P. acnes er virkningen signifikant større enn virkningen av metronidazol. Resultatene av in vitro-prøver av en rekke forbindelser fremstilt i henhold til oppfinnelsen er gjen- ning on par with the effect of metronidazole, while against P. acnes the effect is significantly greater than the effect of metronidazole. The results of in vitro tests of a number of compounds prepared according to the invention are re-

gitt tabell 1, som etterfølger eksemplene. given Table 1, which follows the examples.

Disse prøver ble utført ved å blande en serie av These tests were performed by mixing a series of

økende mengder med forbindelsen som skulle undersøkes, med et flytende næringsmedium som var blitt inokulert med én av prøveorganismene. Disse preparatene ble inkubert i 24 increasing amounts of the compound to be investigated with a liquid nutrient medium that had been inoculated with one of the test organisms. These preparations were incubated for 24

timer ved 3 7°C under anaerobe forhold og ble deretter under- hours at 37°C under anaerobic conditions and were then sub-

søkt med hensyn til vekst indikert ved turbiditet i det flytende medium. Resultater ble registrert i form av de laveste konsentrasjonene, i mg/l, av prøveforbindelser som forhindret vekst av prøveorganismene (minimale inhiberings-konsentrasjoner). Hver prøve ble gjennomført tre ganger og omfanget av resultater er angitt. sought for growth as indicated by turbidity in the liquid medium. Results were recorded in terms of the lowest concentrations, in mg/l, of test compounds that prevented the growth of the test organisms (minimum inhibition concentrations). Each test was carried out three times and the range of results is indicated.

Dertil kommer at forbindelsene med formel I har In addition, the compounds of formula I have

det fortrinnet fremfor metronidazol at de synes å være ikke-mutagene i både bakterielle Ames-prøver og forsøk med trans-formering av pattedyrceller (Ames et al., Mutation Res., (1973), 31, 347 og McCann et al., Proe. Nat. Acad. Sei. U.S.A., (1975), 75 (5135) mens metronidazol er angitt å våre både mutagene og teratogene. Dette er en svært viktig fordel når man betrakter bruken av en forbindelse som kan anvendes i stor målestokk innen repeterende terapi. preferred over metronidazole in that they appear to be non-mutagenic in both bacterial Ames tests and mammalian cell transformation experiments (Ames et al., Mutation Res., (1973), 31, 347 and McCann et al., Proe . Nat. Acad. Sei. U.S.A., (1975), 75 (5135) while metronidazole is indicated to be both mutagenic and teratogenic. This is a very important advantage when considering the use of a compound that can be used on a large scale in repetitive therapy .

Forbindelsene fremstilt ifølge oppfinnelsen er The compounds produced according to the invention are

også virksomme mot sopp, og denne virkning er på høyde med virkningen til miconazol som har formelen: also effective against fungi, and this effect is on par with the effect of miconazole, which has the formula:

Resultatene av in vitro-antisoppforsøk for en rekke forbindelser fremstilt ifølge oppfinnelsen mot patogene sopper slik som de ;som tilhører Trichophyton-artene, Candida-artene og Epidermo-phyton floccosum og Microsporum canis er ført opp i tabell 3 The results of in vitro antifungal tests for a number of compounds produced according to the invention against pathogenic fungi such as those belonging to the Trichophyton species, Candida species and Epidermophyton floccosum and Microsporum canis are listed in Table 3

som etterfølger eksemplene. which follow the examples.

Prøvene ble utført som beskrevet for de anaerobe bakteriene med unntak av at organismene ble inkubert aerobt og holdt ved 30°C, bortsett fra C. albicans som ble holdt ved The tests were carried out as described for the anaerobic bacteria with the exception that the organisms were incubated aerobically and kept at 30°C, except for C. albicans which was kept at

■7°C. Hver prøve ble utført to ganger. ■7°C. Each test was performed twice.

Forbindelsene med formel I fremstilles ifølge oppfinnelsen ved å omsette et keton med formelen: The compounds of formula I are prepared according to the invention by reacting a ketone with the formula:

hvor Ar og Alk har de ovenfor angitte betydninger, med et hydrazin med formelen: hvor Ar"*" har den ovenfor angitte betydning, hvorved det opp-nås forbindelser med formel I hvor A er lik where Ar and Alk have the meanings given above, with a hydrazine of the formula: where Ar"*" has the meaning given above, whereby compounds of formula I are obtained where A is equal to

om ønsket i form av et syreaddisjonssalt og, eventuelt, if desired in the form of an acid addition salt and, optionally,

reduserer dette produkt til en forbindelse med formel I hvor reduces this product to a compound of formula I where

Nevnte omsetning utføres fortrinnsvis i nærvær av Said turnover is preferably carried out in the presence of

et oppløsningsmiddel og en sur katalysator. Ett av eller begge utgangsmaterialene kan anvendes i form av et syre-addis jonssalt . Hydrazinet kan isoleres i form av et syre-addis jonssalt eller som den frie base som deretter eventuelt kan omdannes til et syreaddisjonssalt. a solvent and an acid catalyst. One or both of the starting materials can be used in the form of an acid addition salt. The hydrazine can be isolated in the form of an acid addition salt or as the free base which can then optionally be converted into an acid addition salt.

Foretrukne temperaturer for reaksjonen er 20-100°C, helst 78-80°C. Oppløsningsmiddelets art er ikke kritisk. Et foretrukket oppløsningsmiddel er en lavere alifatisk alkohol, slik som metanol og etanol. Som syrekatalysator kan det anvendes svovel- eller saltsyre. Preferred temperatures for the reaction are 20-100°C, preferably 78-80°C. The nature of the solvent is not critical. A preferred solvent is a lower aliphatic alcohol, such as methanol and ethanol. Sulfuric or hydrochloric acid can be used as an acid catalyst.

Etter omsetningen kan blandingen nøytraliseres med alkali, slik som natriumbikarbonat, og produktet gjenvinnes ved ekstraksjon med et organisk oppløsningsmiddel og isoleres ved gjerning av oppløsningsmiddelet. Syreaddisjonssalter kan fremstilles ved å oppløse produktet i et ikke-vandig opp-løsningsmiddel, f.eks. dietyleter, og omsette med en ikke-vandig oppløsning av den ønskede syre. After the reaction, the mixture can be neutralized with alkali, such as sodium bicarbonate, and the product recovered by extraction with an organic solvent and isolated by distillation of the solvent. Acid addition salts can be prepared by dissolving the product in a non-aqueous solvent, e.g. diethyl ether, and react with a non-aqueous solution of the desired acid.

Når det gjelder forbindelsen med formel I hvor A In the case of the compound of formula I wherein A

er is

så kan disse som nevnt ovenfor fremstilles fra de ovenfor beskrevne hydrazoner ved omsetning av hydrazonet med reduserende midler som reduserer hydrazonbindingen. Egnede reduserende midler omfatter organoboranene, f.eks. borantetrahydrofuran-komplekset (BH^•THF), i et oppløsningsmiddel slik som tetrahydrofuran ved en temperatur i området 0 - 50°C i 1 - 3 dager. Etter omsetning kan oppløsningsmidlet fjernes under redusert trykk hvorved det blir igjen en rest som behandles med natrium-hydrogenkarbonat, og råproduktet utvinnes ved ekstraksjon med et organisk oppløsningsmiddel og fjerning av oppløsnings-midlet. Det rensede produkt kan isoleres etter kromatografe-ring på silisiumdioksydgel med økende mengder av kloroform i then, as mentioned above, these can be prepared from the hydrazones described above by reacting the hydrazone with reducing agents that reduce the hydrazone bond. Suitable reducing agents include the organoboranes, e.g. the boranetetrahydrofuran complex (BH^•THF), in a solvent such as tetrahydrofuran at a temperature in the range 0 - 50°C for 1 - 3 days. After reaction, the solvent can be removed under reduced pressure, leaving a residue that is treated with sodium bicarbonate, and the crude product is recovered by extraction with an organic solvent and removal of the solvent. The purified product can be isolated after chromatography on silicon dioxide gel with increasing amounts of chloroform

heksan. Syreaddisjonssalter kan fremstilles som beskrevet for hydrazonet. hexane. Acid addition salts can be prepared as described for the hydrazone.

Ketonene med formel III er kjente forbindelser, eller de kan fremstilles ved konvensjonelle metoder, f.eks. ved metoden beskrevet i P.A.J. Janssen et al., J. Med. Chem., 1969, 12, 781 for 1-(4-klorfenyl)-2-(lH-imidazol-l-yl)-etanon. Hydrazinene med formel IV er også kjente forbindelser, eller de kan fremstilles ved konvensjonelle metoder, dvs. i henhold til Vogel's Textbook of Practical Organic Chemistry, Longman, London, 1978, side 72 7. The ketones of formula III are known compounds, or they can be prepared by conventional methods, e.g. by the method described in P.A.J. Janssen et al., J. Med. Chem., 1969, 12, 781 for 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-ethanone. The hydrazines of formula IV are also known compounds or they can be prepared by conventional methods, i.e. according to Vogel's Textbook of Practical Organic Chemistry, Longman, London, 1978, page 72 7.

For administrering som et farmasøytisk middel er det foretrukket å fremstille et preparat av én eller flere forbindelser fremstilt ifølge oppfinnelsen sammen med en eller flere ikke-toksiske, farmasøytiske akseptable bærere og/eller fortynningsmidler og/eller hjelpestoffer. Om ønsket, kan også ytterligere medisinske midler være til stede i slike prepara-ter. Preparatene kan gis lokalt, oralt eller ved injeksjon. For administration as a pharmaceutical agent, it is preferred to prepare a preparation of one or more compounds prepared according to the invention together with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or auxiliaries. If desired, further medical agents can also be present in such preparations. The preparations can be given locally, orally or by injection.

For lokal administrering kan preparatet være i For local administration, the preparation can be in

form av f.eks. en krem, gel eller salve. Et slikt preparat kan f.eks. anvendes lokalt to ganger om dagen i en passende periode slik som 2 eller 3 uker. En passende konsentrasjon av aktiv bestanddel i preparatet kan være 1-5%. For vaginal anvendelse kan den aktive bestanddelen være inkorporert i et pessar, eller det kan brukes en krem med et innførings-middel, eller det kan anvendes en impregnert tampong. form of e.g. a cream, gel or ointment. Such a preparation can e.g. applied topically twice a day for a suitable period such as 2 or 3 weeks. A suitable concentration of active ingredient in the preparation can be 1-5%. For vaginal use, the active ingredient may be incorporated into a pessary, or a cream with an introducer may be used, or an impregnated tampon may be used.

For oral administrering kan det farmasøytiske preparatet være i form av f.eks. en tablett, kapsel, suspensjon eller væske. En typisk oral mengde kan være 5-10 mg/kg kroppsvekt én gang pr. dag, f.eks. i 2 - 3 uker. For oral administration, the pharmaceutical preparation can be in the form of e.g. a tablet, capsule, suspension or liquid. A typical oral amount can be 5-10 mg/kg body weight once a day. day, e.g. for 2 - 3 weeks.

Den aktive bestanddelen kan også administreres The active ingredient can also be administered

ved injeksjon i form av et preparat der f.eks. saltvann, dek-strose eller vann kan brukes som en egnet bærer. En passende mengde kan være 5-10 mg/kg kroppsvekt, gitt én gang pr. dag i f.eks. 2-3 uker. by injection in the form of a preparation where e.g. saline, dextrose or water can be used as a suitable carrier. A suitable amount may be 5-10 mg/kg body weight, given once a day. day in e.g. 2-3 weeks.

Den administrerte mengde og behandlingsforløpet vil være avhengig f.eks. av infeksjonen, dens alvorlighet, av pasienten som behandles og hans reaksjon på behandlingen, og vil derfor være svært varierende. The amount administered and the course of treatment will depend e.g. of the infection, its severity, of the patient being treated and his response to the treatment, and will therefore be highly variable.

De farmasøytiske preparatene kan fremstilles ved teknikker som er velkjente og beskrevet bl.a. i Remington's Pharmaceutical Science, Mach Publishing Co., Easton, The pharmaceutical preparations can be prepared by techniques that are well known and described, e.g. in Remington's Pharmaceutical Science, Mach Publishing Co., Easton,

Pa. 1965. On. 1965.

Følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.

Eksempel 1 Example 1

(a) 6-(lH-imidazol-l-yl)-6.7.8.9-tetrahydro-5-benzocyklo-heptanon- 2, 4- diklorfenylhydrazon (a) 6-(1H-imidazol-1-yl)-6.7.8.9-tetrahydro-5-benzocycloheptanone-2,4-dichlorophenylhydrazone

6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzo-cykloheptanon (1,46 g) og 2,4-diklorfenylhydrazin-hydroklorid-hydrat (1,52 g) ble oppvarmet sammen i etanol (150 ml) under tilbakeløpskoking i 7 dager ved en temperatur på 78°C. Opp-løsningen ble fordampet til tørrhet under redusert trykk og resten ble deretter behandlet med mettet vandig natriumhydro-genkarbonatoppløsning og ekstrahert med diklormetan (3 x 80 ml). De kombinerte ekstraktene ble tørket over vannfri magnesiumsulfat og oppløsningen ble fordampet hvoretter det ble igjen en olje som ble kromatografert på silisiumdioksyd. Eluering med 1% metanol i kloroform ga den frie base av hydrazonet i form av en olje. En del av oljen ble oppløst i etylacetat, oppløsningen oppvarmet til 60°C og surgjort med en ekvivalent mengde oksalsyre. Etter avkjøling frembragte opp-løsningen hvite, små plater av 6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocykloheptanon,"2,4-diklorfenylhydrazon-hydrogenoksalat, smeltepunkt 185 - 187°C. 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzo-cycloheptanone (1.46 g) and 2,4-dichlorophenylhydrazine hydrochloride hydrate (1.52 g) were heated together in ethanol (150 ml) under reflux for 7 days at a temperature of 78°C. The solution was evaporated to dryness under reduced pressure and the residue was then treated with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (3 x 80 mL). The combined extracts were dried over anhydrous magnesium sulfate and the solution was evaporated leaving an oil which was chromatographed on silica. Elution with 1% methanol in chloroform gave the free base of the hydrazone as an oil. Part of the oil was dissolved in ethyl acetate, the solution heated to 60°C and acidified with an equivalent amount of oxalic acid. After cooling, the solution gave white, small plates of 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone,"2,4-dichlorophenylhydrazone hydrogen oxalate, mp 185-187 °C.

(b) 6-(IH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocyklo-heptanon, 2, 4- diklorfenylhydrazon- hydroklorid (b) 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone, 2,4-dichlorophenylhydrazone hydrochloride

En annen del av oljen erholdt i (a) ovenfor ble oppløst i diklormetan. Oppløsningen ble surgjort med eter-isk saltsyre inntil turbiditet inntrådte og avkjølt hvorved man fikk, i form av et hvitt fast stoff, 6-(lH-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocykloheptanon, 2,4-diklorfenylhydrazon-hydroklorid, smeltepunkt 199 - 201°C. Another portion of the oil obtained in (a) above was dissolved in dichloromethane. The solution was acidified with ethereal hydrochloric acid until turbidity occurred and cooled to give 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone as a white solid , 2,4-dichlorophenylhydrazone hydrochloride, melting point 199 - 201°C.

De følgende forbindelser ble fremstilt på en analog måte: (c) 2-klor-6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocykloheptanon, 2,4-diklorfenylhydrazon-hydroklorid, smeltepunkt 214-215°C, (d) 6-(lH-imidazol-l-yl)-7,8,9,10-tetrahydro-5(6H)-benzocyklooktanon, 2,4-diklorfenylhydrazon-hydroklorid, smeltepunkt 122 - 125°C, (e) 3,4-dihydro-2-(lH-imidazol-l-yl)-1-naftalenon, 2,4-diklorfenylhydrazon-hydrogenoksalat, smeltepunkt 121 - 123°c, (f) 3,5-dihydro-4-(lH-imidazol-l-yl)-l-benztiapin-5-2H)-on, 2,4-diklorfenylhydrazon-hydroklorid, smeltepunkt 181 - 184°C, (g) 3,4-dihydro-4-(lH-imidazol-l-yl)-l-benzoksepin-5-(2H)-on, 2,4-diklorfenylhydrazon-hydroklorid, smeltepunkt 180 - 182°C, (h) 6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzo-cykloheptanon, 2,6-diklorfenylhydrazon-hydrogenoksalat, smeltepunkt 142 - 144°C, The following compounds were prepared in an analogous manner: (c) 2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone, 2,4-dichlorophenylhydrazone hydrochloride , melting point 214-215°C, (d) 6-(1H-imidazol-1-yl)-7,8,9,10-tetrahydro-5(6H)-benzocyclooctanone, 2,4-dichlorophenylhydrazone hydrochloride, melting point 122 - 125°C, (e) 3,4-dihydro-2-(1H-imidazol-1-yl)-1-naphthalenone, 2,4-dichlorophenylhydrazone hydrogen oxalate, melting point 121 - 123°c, (f) 3, 5-dihydro-4-(1H-imidazol-1-yl)-1-benzthiapin-5-2H)-one, 2,4-dichlorophenylhydrazone hydrochloride, m.p. 181 - 184°C, (g) 3,4-dihydro -4-(1H-imidazol-1-yl)-1-benzoxepin-5-(2H)-one, 2,4-dichlorophenylhydrazone hydrochloride, melting point 180 - 182°C, (h) 6-(1H-imidazol- 1-yl)-6,7,8,9-tetrahydro-5-benzo-cycloheptanone, 2,6-dichlorophenylhydrazone hydrogen oxalate, melting point 142 - 144°C,

1(i) 3,4-dihydro-4-(lH-imidazol-l-yl)-l-benzoksepin-5-(2H)-on, 2,6-diklorfenylhydrazon-hydroklorid, smeltepunkt 181 - 185°C. 1(i) 3,4-dihydro-4-(1H-imidazol-1-yl)-1-benzoxepin-5-(2H)-one, 2,6-dichlorophenylhydrazone hydrochloride, melting point 181 - 185°C.

(j) 7-(lH-imidazol-l-yl)-4,5,6,7-tetrahydro-8H-cyklo-hepta[b]-tiofen-8-on, 2,4-diklorfenylhydrazon-hydrogenoksalat, smeltepunkt 104 - 106°C, (j) 7-(1H-imidazol-1-yl)-4,5,6,7-tetrahydro-8H-cyclo-hepta[b]-thiophen-8-one, 2,4-dichlorophenylhydrazone hydrogen oxalate, melting point 104 - 106°C,

(k) 6-(IH-imidazol-l-yl)-3-metyl-6,7,8,9-tetrahydro-5-i enzocykloheptanon, 2,4-diklorfenylhydrazon-hydroklorid, smeltepunkt 193 - 197°C. (k) 6-(1H-imidazol-1-yl)-3-methyl-6,7,8,9-tetrahydro-5-i enzocycloheptanone, 2,4-dichlorophenylhydrazone hydrochloride, mp 193-197°C.

Eksempel 2 Example 2

(a) 2-( lH- imidazol- l- yl)- 1- indanon, 2, 4- diklorfenylhydrazon 2-(lH-imidazol-l-yl)-1-indanon (6,7 g) og 2,4-di-klorf enylhydrazin-hydroklorid (7,0 g) ble oppvarmet sammen under tilbakeløpskoking i to;luen-etanol (3:1), 250 ml i 18 timer. Deretter ble oppløsningen fordampet til tørrhet under redusert trykk, behandlet med natriumhydrogenkarbonatoppløs-ning og ekstrahert med diklormetan (3 x 200 ml). De kombinerte ekstraktene ble tørket over vannfri magnesiumsulfat og oppløsningene fordampet hvorved man fikk en gummiaktig masse som ble kromatografert på silisiumdioksyd. Eluering med kloroform ga to faste produkter som ble rekrystallisert fra toluen og identifisert som E- og Z-isomerene av 2-(lH-imidazol-l-yl)-1-indanon, 2/4-diklorfenylhydrazon. En av (a) 2-(1H-imidazol-1-yl)-1-indanone, 2,4-dichlorophenylhydrazone 2-(1H-imidazol-1-yl)-1-indanone (6.7 g) and 2,4- dichlorophenylhydrazine hydrochloride (7.0 g) was heated together under reflux in toluene-ethanol (3:1), 250 ml for 18 hours. The solution was then evaporated to dryness under reduced pressure, treated with sodium bicarbonate solution and extracted with dichloromethane (3 x 200 ml). The combined extracts were dried over anhydrous magnesium sulfate and the solutions evaporated to give a gummy mass which was chromatographed on silica. Elution with chloroform gave two solid products which were recrystallized from toluene and identified as the E and Z isomers of 2-(1H-imidazol-1-yl)-1-indanone, 2/4-dichlorophenylhydrazone. One of

isomerene hadde smeltepunkt 115 - 117°C.N.M.R. (CDC13> 2,95 (1H, dobbel dublett, J 7 og 36 Hz), 3,70 (1H, dd, J 14 og 36 Hz), 5,55 (1H, dd, J 7 og 14 Hz) og 6,9 - 7,8 (11H, multiplett) (Funnet: C 60,57 H 4,01 N 15,57. ci8Hi4N4C12 krever C 60,52 H 3,95 N 15,68%). Den annen isomer hadde smeltepunkt 181 - 184°C. N.M.R. (CDC13) 3,17 (1H, dd, J 8 the isomers had a melting point of 115 - 117°C.N.M.R. (CDC13 > 2.95 (1H, double doublet, J 7 and 36 Hz), 3.70 (1H, dd, J 14 and 36 Hz), 5.55 (1H, dd, J 7 and 14 Hz) and 6 .9 - 7.8 (11H, multiplet) (Found: C 60.57 H 4.01 N 15.57. ci8Hi4N4C12 requires C 60.52 H 3.95 N 15.68%). The other isomer had m.p. 181 - 184° C. N.M.R. (CDCl 3 ) 3.17 (1H, dd, J 8

og 33Hz), 3,71 (1H, dd, J 15 og 33Hz), 5,33 (1H, dd, J 8 og 15Hz), 6,7 - 7,7 (10H, multiplett) og 8,6 (1H, singlett). and 33Hz), 3.71 (1H, dd, J 15 and 33Hz), 5.33 (1H, dd, J 8 and 15Hz), 6.7 - 7.7 (10H, multiplet) and 8.6 (1H , singlet).

De følgende forbindelser ble fremstilt på en analog måte fra det samme ketonet og 2,6-diklorfenylhydrazin: (b) 2-( lH- imidazol- l- yl)- 1- indanon, 2, 6- diklorfenylhydrazon The following compounds were prepared in an analogous manner from the same ketone and 2,6-dichlorophenylhydrazine: (b) 2-(1H-imidazol-1-yl)-1-indanone, 2,6-dichlorophenylhydrazone

En isomer hadde smeltepunkt 96 - 9 7°C. N.M.R. One isomer had a melting point of 96 - 97°C. N.M.R.

(CDC13) 2,92 (1H, dd, J 6 og 34Hz), 3,71 (1H, dd, J 9 og 34Hz), 5,55 (1H, dd, J 6 og 9Hz), 6,60 - 7,65 (11H, multiplett), (Funnet: C 60,67 H 3,99 N 15,54. ci8Hl4N4C12 krever C 60,52 H 3,95 N 15,68%). Den annen isomer hadde smeltepunkt 103 - 105°C. N.M.R. (CDC13), 2,73 (1H, dd, J 6 (CDC13) 2.92 (1H, dd, J 6 and 34Hz), 3.71 (1H, dd, J 9 and 34Hz), 5.55 (1H, dd, J 6 and 9Hz), 6.60 - 7 .65 (11H, multiplet), (Found: C 60.67 H 3.99 N 15.54. ci8Hl4N4C12 requires C 60.52 H 3.95 N 15.68%). The other isomer had a melting point of 103 - 105°C. N.M.R. (CDCl 3 ), 2.73 (1H, dd, J 6

og 32Hz), 3,17 (1H, dd, J 15 og 32Hz), 5,35 (1H, dd, J 6 og 15Hz), 7,3 - 8,1 )11H, multiplett), (Funnet: C 60,43 H 4,03 N 15,4<4.> C18H14N4C12 krever c 60,52 H 3,95 N 15,68%). and 32Hz), 3.17 (1H, dd, J 15 and 32Hz), 5.35 (1H, dd, J 6 and 15Hz), 7.3 - 8.1 )11H, multiplet), (Found: C 60 .43 H 4.03 N 15.4<4.> C18H14N4C12 requires c 60.52 H 3.95 N 15.68%).

E ksempel 3 Example 3

(a) 3,4-dihydro-2-(lH-imidazol-l-yl)-1-naftalenon, 2,4,6-triklorfenylhydrazon (a) 3,4-dihydro-2-(1H-imidazol-1-yl)-1-naphthalenone, 2,4,6-trichlorophenylhydrazone

3,4-dihydro-2-(lH-imidazol-l-yl)-1-naftalenon (1,27 g) og 2,4,6-triklorfenylhydrazin (1,09 g) i etanol (150 ml) og en mettet oppløsning av hydrogenklorid i eter (10 ml) ble sammen oppvarmet og tilbakeløpskokt i 48 timer. Oppløsningen ble deretter fordampet til tørrhet under redusert trykk, behandlet med natriumhydrogenkarbonatoppløs-ning og ekstrahert med diklormetan (4 x 100 ml). De kombinerte ekstraktene ble tørket over vannfri magnesiumsulfat og oppløsningen fordampet hvorved det ble oppnådd en gummiaktig masse som ble kromatografert på silisiumdioksyd. Eluering med kloroform ga hydrazonet i fri baseform som en olje. Oljen ble oppløst i etylacetat, oppløsningen oppvarmet til 60°C og surgjort med en ekvivalent mengde oksalsyre. Etter avkjøling ga oppløsningen 3,4-dihydro-2-(lH-imidazol- 3,4-dihydro-2-(1H-imidazol-1-yl)-1-naphthalenone (1.27 g) and 2,4,6-trichlorophenylhydrazine (1.09 g) in ethanol (150 ml) and a saturated solution of hydrogen chloride in ether (10 ml) was heated together and refluxed for 48 hours. The solution was then evaporated to dryness under reduced pressure, treated with sodium bicarbonate solution and extracted with dichloromethane (4 x 100 mL). The combined extracts were dried over anhydrous magnesium sulfate and the solution evaporated to give a gummy mass which was chromatographed on silica. Elution with chloroform gave the hydrazone in free base form as an oil. The oil was dissolved in ethyl acetate, the solution heated to 60°C and acidified with an equivalent amount of oxalic acid. After cooling, the solution gave 3,4-dihydro-2-(1H-imidazole-

1-yl)-1-naftalenon, 2,4,6-triklorfenylhydrazon-hydrogenoksa- 1-yl)-1-naphthalenone, 2,4,6-trichlorophenylhydrazone-hydrogenoxa-

lat i form av et hvitt fast stoff, smeltepunkt 173 - 175°C. lat in the form of a white solid, melting point 173 - 175°C.

De følgende forbindelser ble fremstilt på en analog måte fra det passende ketonet og det passende hydrazinet: (b) 2-klor-6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocykloheptanon, 2,4,6-triklorfenylhydrazon-hydroklorid, smeltepunkt 166 - 168°C (c) 6-(lH-imidazol-l-yl)-7.8.9.10-tetrahydro-5(6H)-ben-zocyklooktanon, 2,4,6-triklorfenylhydrazon-hydroklorid, smeltepunkt 178 - 182°C. (d) 6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzo-cykloheptanon, 2,4,6-triklorfenylhydrazon-hydrogenoksalat, smeltepunkt 87 - 91°C. (e) 6,7-dihydro-5-(lH-imidazol-l-yl)-benzo[b] tiofen-4(5H)-on, 2,4,6-triklorfenylhydrazon-hydroklorid, smeltepunkt 141 - 143°C, (f) 2-(lH-imidazol-l-yl)-1-indanon, 2,4,6-triklorfenylhydrazon-hydroklorid, smeltepunkt 151 - 153°C. The following compounds were prepared in an analogous manner from the appropriate ketone and the appropriate hydrazine: (b) 2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone , 2,4,6-trichlorophenylhydrazone hydrochloride, melting point 166 - 168°C (c) 6-(1H-imidazol-1-yl)-7.8.9.10-tetrahydro-5(6H)-benzocyclooctanone, 2,4 ,6-trichlorophenylhydrazone hydrochloride, melting point 178 - 182°C. (d) 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzo-cycloheptanone, 2,4,6-trichlorophenylhydrazone hydrogen oxalate, mp 87-91°C. (e) 6,7-dihydro-5-(1H-imidazol-1-yl)-benzo[b]thiophen-4(5H)-one, 2,4,6-trichlorophenylhydrazone hydrochloride, mp 141 - 143°C , (f) 2-(1H-imidazol-1-yl)-1-indanone, 2,4,6-trichlorophenylhydrazone hydrochloride, mp 151-153°C.

(g) 3,4-dihydro-4-(lH-imidazol-l-yl)-l-benztiapin-5(1H)- (g) 3,4-dihydro-4-(1H-imidazol-1-yl)-1-benzthiapine-5(1H)-

on, 2,4,6-triklorfenylhydrazon-hydroklorid, smeltepunkt 94 - 96°C. (h) 3-(lH-imidazol-l-yl)-kroman-4-on, 2,4,6-triklorfenylhydrazon-hydroklorid, smeltepunkt 166 - 167°C. on, 2,4,6-trichlorophenylhydrazone hydrochloride, melting point 94 - 96°C. (h) 3-(1H-imidazol-1-yl)-chroman-4-one, 2,4,6-trichlorophenylhydrazone hydrochloride, mp 166-167°C.

(i) 3,4-dihydro-4-(lH-imidazol-l-yl)-l-benzoksepin-5- (i) 3,4-dihydro-4-(1H-imidazol-1-yl)-1-benzoxepin-5-

(2H)-on, 2,4,6-triklorfenylhydrazon-hydroklorid, smelte- (2H)-one, 2,4,6-trichlorophenylhydrazone hydrochloride, melt-

punkt 198 - 200° C. point 198 - 200° C.

(j) 3,4-dihydro-4-(lH-imidazol-l-yl)-1-benzoksepin- (j) 3,4-dihydro-4-(1H-imidazol-1-yl)-1-benzoxepin-

5(2H)-on, 2,3,4,5,6-pentafluorfenylhydrazon-hydroklorid, 5(2H)-one, 2,3,4,5,6-pentafluorophenylhydrazone hydrochloride,

smeltepunkt 169 - 172°C. melting point 169 - 172°C.

(k) 6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzo-cykloheptanon, 2,3,4,5,6-pentafluorfenylhydrazon-hydro- (k) 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzo-cycloheptanone, 2,3,4,5,6-pentafluorophenylhydrazone-hydro-

klorid, smeltepunkt 124 - 126°C. chloride, melting point 124 - 126°C.

(1) 5-(lH-imidazol-l-yl-5,6,7,8-tetrahydro-4H-cyklo-hepta[b]tiofen-4-on, 2,4,6-triklorfenylhydrazon-hydrogen- (1) 5-(1H-imidazol-1-yl-5,6,7,8-tetrahydro-4H-cyclo-hepta[b]thiophen-4-one, 2,4,6-trichlorophenylhydrazone-hydrogen-

oksalat, smeltepunkt 113 - 116° C. oxalate, melting point 113 - 116° C.

(m) 3,4-dihydro-2-(lH-imidazol-l-yl)-6-metoksy-l- (m) 3,4-dihydro-2-(1H-imidazol-1-yl)-6-methoxy-1-

naftalenon, 2,4,6-triklorfenylhydrazon-hydroklorid, smelte- naphthalenone, 2,4,6-trichlorophenylhydrazone hydrochloride, melting

punkt 218 - 221°C. point 218 - 221°C.

Eksempel 4 Example 4

N-[2-klor-6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzo-c ykloheptyl]- N'-( 2, 4- diklorfenyl) hydrazin N-[2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzo-cycloheptyl]- N'-(2,4-dichlorophenyl)hydrazine

En oppløsning av borantetrahydrofurankompleks (BHj.THF) i tørr tetrahydrofuran (30 ml, IM oppløsning) ble dråpevis tilsatt til en oppløsning av 2-klor-6-(lH-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocykloheptanon, 2,4-diklorfenylhydrazon (4 g) i tetrahydrofuran (250 ml) under nitro-genatmosfære og avkjølt i et isbad. Reaksjonsblandingen ble hensatt ved romtemperatur i 2 dager før behandling med en vandig oppløsning av natriumhikarbonat og ekstrahert med dietyleter. Den organiske fasen ble tørket over vannfri magnesiumsulfat og oppløsningsmidlene fordampet hvorved det ble oppnådd et fast stoff. Det faste stoffet ble oppløst i etylacetat, oppløsningen oppvarmet til 6 0°C og surgjort med en ekvivalent mengde oksalsyre. Etter avkjøling frembragte opp-løsningen N-[2-klor-6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocykloheptyl]-N-(2,4-diklorfenyl)-hydrazinoksalat i form av et hvitt fast stoff, smeltepunkt 95 - 97°c. A solution of boranetetrahydrofuran complex (BHj.THF) in dry tetrahydrofuran (30 ml, 1M solution) was added dropwise to a solution of 2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9- tetrahydro-5-benzocycloheptanone, 2,4-dichlorophenylhydrazone (4 g) in tetrahydrofuran (250 ml) under a nitrogen atmosphere and cooled in an ice bath. The reaction mixture was left at room temperature for 2 days before treatment with an aqueous solution of sodium bicarbonate and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate and the solvents evaporated to give a solid. The solid was dissolved in ethyl acetate, the solution heated to 60°C and acidified with an equivalent amount of oxalic acid. After cooling, the solution yielded N-[2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptyl]-N-(2,4-dichlorophenyl)- hydrazine oxalate in the form of a white solid, melting point 95 - 97°c.

De følgende forbindelsene ble fremstilt på en analog måte: (b) N-[4-(lH-imidazol-l-yl)-2,3,4,5-tetrahydro-5-benz-oksepinyl]-N1 -(2,4-diklorfenyl)hydrazin-dihydroklorid, smeltepunkt 138 - 140°. (c) N'-[6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocykloheptyl]-N-(2,6-diklorfenyl)hydrazin-dihydroklorid. The following compounds were prepared in an analogous manner: (b) N-[4-(1H-imidazol-1-yl)-2,3,4,5-tetrahydro-5-benz-oxepinyl]-N1 -(2, 4-dichlorophenyl)hydrazine dihydrochloride, melting point 138 - 140°. (c) N'-[6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptyl]-N-(2,6-dichlorophenyl)hydrazine dihydrochloride.

Virkningene av representative forbindelser fremstilt ifølge oppfinnelsen er angitt nedenfor. The effects of representative compounds prepared according to the invention are indicated below.

Claims (10)

1. Analogifremgangsmåte for fremstilling av terapeutisk virksomme imidazolhydrazon- og -hydrazinderivater med den generelle formel hvor Ar er en fenyl- eller tienylgruppe som eventuelt er substituert med en eller flere halogen-, laverealkyl- eller laverealkoksygrupper; Ar"*" er en fenylgruppe som eventuelt kan være substituert med en eller flere halogengrupper; og Alk er en alkylengruppe med 1-4 karbonatomer hvor alkylen-gruppen kan inneholde et oksygen- eller svovelatom; samt syreaddisjonssalter derav, karakterisert ved at man omsetter et keton med formelen: hvor Ar og Alk har den ovenfor angitte betydning, med et hydrazin med formelen: hvor Ar<1> har den ovenfor angitte betydning, hvorved det opp-nås forbindelser med formel 1 hvor A er lik om ønsket i form av et syreaddisjonssalt, og, eventuelt, reduserer dette produkt til en forbindelse med formel I hvor A er lik1. Analogy process for the production of therapeutically effective imidazole hydrazone and hydrazine derivatives with the general formula where Ar is a phenyl or thienyl group which is optionally substituted with one or more halogen, lower alkyl or lower alkoxy groups; Ar"*" is a phenyl group which may optionally be substituted with one or more halogen groups; and Alk is an alkylene group with 1-4 carbon atoms where the alkylene group may contain an oxygen or sulfur atom; as well as acid addition salts thereof, characterized by converting a ketone with the formula: where Ar and Alk have the meaning indicated above, with et hydrazine with the formula: where Ar<1> has the meaning stated above, whereby compounds of formula 1 are obtained where A is equal to if desired in the form of an acid addition salt, and, optionally, this product reduces to a compound of formula I where A is equal 2. Fremgangsmåte ifølge krav 1, for fremstilling av 6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocykloheptanon-2,4-diklorfenylhydrazon, hydrogenoksalat, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.2. Process according to claim 1, for the production of 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone-2,4-dichlorophenylhydrazone, hydrogen oxalate, characterized in that one uses corresponding substituted starting materials. 3. Analogifremgangsmåte ifølge krav 1, for fremstilling av 6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-benzocykloheptanon-2,4-diklorfenylhydrazon, hydroklorid, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.3. Analogous process according to claim 1, for the production of 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-benzocycloheptanone-2,4-dichlorophenylhydrazone, hydrochloride, characterized in that correspondingly substituted starting materials are used . 4. Analogifremgangsmåte ifølge krav 1, for fremstilling av 6-(lH-imidazol-l-yl)-7,8,9,10-tetrahydro-5(6H)-benzocyklo-heptanon-2,4-diklorfenylhydrazon, hydrazonhydroklorid, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.4. Analogous process according to claim 1, for the production of 6-(1H-imidazol-1-yl)-7,8,9,10-tetrahydro-5(6H)-benzocycloheptanone-2,4-dichlorophenylhydrazone, hydrazone hydrochloride, characterized by using correspondingly substituted starting materials. 5. Analogifremgangsmåte ifølge krav 1, for fremstilling av 7-(lH-imidazol-l-yl)-4,5,6,7-tetrahydro-8H-cyklohepta[b]-tiofen-8-on-2,4-diklorfenylhydrazon, hydrogenoksalat, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.5. Analogous method according to claim 1, for the preparation of 7-(1H-imidazol-1-yl)-4,5,6,7-tetrahydro-8H-cyclohepta[b]-thiophen-8-one-2,4-dichlorophenylhydrazone , hydrogen oxalate, characterized by using correspondingly substituted starting materials. 6. Analogifremgangsmåte ifølge krav 1, for fremstilling av 2-klor-6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzo-cykloheptanon, 2,4,6-triklorfenyl, hydroklorid, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.6. Analogous method according to claim 1, for the production of 2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzo-cycloheptanone, 2,4,6-trichlorophenyl, hydrochloride, characterized by using correspondingly substituted starting materials. 7. Analogifremgangsmåte ifølge krav 1, for fremstilling av 6-(lH-imidazol-l-yl)-7,8,9,10-tetrahydro-5-(6H)-benzo-cyklooktanon-2,4,6-triklorfenylhydrazon, hydroklorid, karakterisert ved at man anvender til svarende substituerte utgangsmaterialer.7. Analogous method according to claim 1, for the production of 6-(1H-imidazol-1-yl)-7,8,9,10-tetrahydro-5-(6H)-benzo-cyclooctanone-2,4,6-trichlorophenylhydrazone, hydrochloride, characterized by being used for correspondingly substituted starting materials. 8. Analogifremgangsmåte ifølge krav 1, for fremstilling av 6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydrobenzo-cykloheptanon-2,4,6-triklorfenylhydrazon, hydrogenoksalat, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.8. Analogous process according to claim 1, for the production of 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydrobenzo-cycloheptanone-2,4,6-trichlorophenylhydrazone, hydrogen oxalate, characterized in that one uses corresponding substituted starting materials. 9. Analogifremgangsmåte ifølge krav 1, for fremstilling av 3,4-dihydro-4-(lH-imidazol-l-yl)-l-benzoksepin-5-(2H)-on-2,4,6-triklorfenylhydrazol, hydroklorid, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.9. Analogous method according to claim 1, for the production of 3,4-dihydro-4-(1H-imidazol-1-yl)-1-benzoxepin-5-(2H)-one-2,4,6-trichlorophenylhydrazole, hydrochloride, characterized by using correspondingly substituted starting materials. 10. Analogifremgangsmåte ifølge krav 1, for fremstilling av 5-(lH-imidazol-l-yl)-5,6,7,8-tetrahydro-4H-cyklohepta[b]-tiofen-4-on-2,4,6-triklorfenylhydrazon, hydrogenoksalat, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.10. Analogous process according to claim 1, for the production of 5-(1H-imidazol-1-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]-thiophen-4-one-2,4,6 -trichlorophenylhydrazone, hydrogen oxalate, characterized by using correspondingly substituted starting materials.
NO820311A 1981-02-03 1982-02-02 ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE IMIDAZOLE HYDRAZONE AND HYDRAZINE DERIVATIVES. NO156941C (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB8103280 1981-02-03

Publications (3)

Publication Number Publication Date
NO820311L NO820311L (en) 1982-08-04
NO156941B true NO156941B (en) 1987-09-14
NO156941C NO156941C (en) 1987-12-23

Family

ID=10519420

Family Applications (1)

Application Number Title Priority Date Filing Date
NO820311A NO156941C (en) 1981-02-03 1982-02-02 ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE IMIDAZOLE HYDRAZONE AND HYDRAZINE DERIVATIVES.

Country Status (10)

Country Link
AU (1) AU547399B2 (en)
CA (1) CA1181077A (en)
DE (1) DE3266884D1 (en)
DK (2) DK160551C (en)
ES (1) ES509249A0 (en)
IE (1) IE820230L (en)
NO (1) NO156941C (en)
NZ (1) NZ199633A (en)
PT (1) PT74375B (en)
ZA (1) ZA82632B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK176742B1 (en) 2004-06-30 2009-06-02 Hans Jensen Lubricators As Method and apparatus for lubricating the cylinder surfaces of large diesel engines

Also Published As

Publication number Publication date
DK160551B (en) 1991-03-25
NO820311L (en) 1982-08-04
DK160551C (en) 1991-09-02
DE3266884D1 (en) 1985-11-21
NO156941C (en) 1987-12-23
ES8305732A1 (en) 1983-04-16
CA1181077A (en) 1985-01-15
DK160252B (en) 1991-02-18
DK45482A (en) 1982-08-04
PT74375B (en) 1984-05-08
PT74375A (en) 1982-03-01
IE820230L (en) 1982-08-03
NZ199633A (en) 1985-05-31
AU547399B2 (en) 1985-10-17
ZA82632B (en) 1983-03-30
DK160252C (en) 1991-07-22
ES509249A0 (en) 1983-04-16
AU8011382A (en) 1982-08-12
DK169589A (en) 1989-04-07
DK169589D0 (en) 1989-04-07

Similar Documents

Publication Publication Date Title
US5371100A (en) Optically active tetrazole compounds, and fungicidal compositions thereof
US5925769A (en) Acetylenic 1,5-diarylpyrazoles as antiinflammatory agents
US4402968A (en) Antifungal benzofuranyl imidazole compounds
NO980055L (en) Antifungal agent, compound thereof, and method of preparation thereof
US4710506A (en) Antihypertensive thienopyridines
US4661507A (en) Antifungal S-ethers of 2-aryl-3-mercapto-1-(1H-1,2,4-triazol-1-yl) propan-2-ols and corresponding sulfoxides and sulfones
EP0057461B1 (en) Imidazole hydrazone and hydrazine derivatives, production thereof and use in medicine
US5110831A (en) Vinylogous hydroxamic acids and derivatives thereof as 5-lipoxygenase inhibitors
DK162842B (en) METHOD OF ANALOGUE FOR THE PREPARATION OF 1-PERFLUORALKYL-2- (1,2,4-TRIAZOL-1-YL) ETHANOL COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS THEREOF
KR870000358B1 (en) Process for preparing triazole antifungal agents
IE56055B1 (en) Triazole antifungal agents
JPH0278670A (en) Triazole antifungal agent
CZ285385B6 (en) Derivatives of acylated aminoalkaneimidazoles and -triazoles, process of their preparation and pharmaceutical composition containing thereof
US4678789A (en) Triazole antifungal agents
US4831151A (en) Antimicrobial imidazolium derivatives
EP0151477B1 (en) 1h-imidazole derivatives, a process for preparing them and pharmaceutical compositions containing them
US5023258A (en) Triazole antifungal agents
NO156941B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE IMIDAZOLE HYDRAZONE AND HYDRAZINE DERIVATIVES.
US4351948A (en) Imidazole hydrazone derivatives
Castellano et al. Azole antifungal agents related to naftifine and butenafine
GB2067993A (en) Imidazole hydrazone derivatives
US5276030A (en) Triazolyl thioamide derivates
HU209302B (en) Method for producing dihydro-benzo-(b)-thiphenes and pharmaceutical preparatives containing these compounds
EP0111384B1 (en) Thioketal substituted n-alkyl imidazoles and pharmaceutical compositions containing them
FI74280B (en) FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA AZOLDERIVAT.