CA1181077A - Imidazole hydrazone derivatives production thereof and use in medicine - Google Patents

Imidazole hydrazone derivatives production thereof and use in medicine

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Publication number
CA1181077A
CA1181077A CA000395423A CA395423A CA1181077A CA 1181077 A CA1181077 A CA 1181077A CA 000395423 A CA000395423 A CA 000395423A CA 395423 A CA395423 A CA 395423A CA 1181077 A CA1181077 A CA 1181077A
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Prior art keywords
imidazol
prepared
compound
tetrahydro
hydrochloride
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French (fr)
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Peter J. Fellner
George Ellames
Christopher D. Floyd
Paul W. Manley
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GD Searle LLC
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GD Searle LLC
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic 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
    • C07D231/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic 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
    • C07D233/56Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Abstract Compounds of the general formulae: I II in which Ar and Ar1 which may be the same or different represent aromatic radicals optionally substituted once or more than by substituents selected from halogen, lower alkyl and lower alkoxy and Alk represents an alkylene group containing from 1 to 4 carbon atoms which alkylene group may be interrupted with a heteroatom; and acid addition salts thereof. These compounds have anti-anaerobe and also anti-fungal activity and are non-mutagenic.

Description

'7 This invention relates to novel imidazole hydrazone and hydrazine derivatives, to a process for their preparation and to compositions contain-ing them and to their use inter alia in medicine.
S It is known that certain compounds such as metronidazole which has the formula:-~ ~ - CH3 N2 CH CH 0~
are active ayainst anaerobic bacteria. Published work indicates that the activity is due to the presence of the nitro group. This compound has been reported as-being mutagenic and teratogenieO
- 15 We have found that certain imidazole hydrazone deri~atives of formula I s~t out below and related hydrazine derivatives of formula II below have anti-anaerobic activity par~icularly against bacteria which thrive in the absence of air. The activity of these compounds as anti-anaerobes is comparable or -superior to metronidazole, whilst they do not appear to be mutagenic. Their superior activlty is particularly demonstrated against'P.~ac*es, a bacteria whlch is associated with acn¢.
According to the present invent~on therefore ~ i there are provided compounds of the general formulae (I) and (II): NH NHAr N ~~NHArl CH
C \ _ N / \ ~=~ N

Ar/ ~CH N ~ Ar ~ ~ CH-N
. (Al ) (I) (II) . in which Ar and Arl represent aromatic radicals which may be substituted one or more times by substituents selected from the fo1lowing, that is:-halogen, - lower alky~ and - lower alkoxy;
. and . Alk represents an alkylene group containing 15 1-4 carbon atoms which may be interrupted with a heteroatom such as oxygen or sulphur; and acid-. addition salts thereof. Suitable salts include . hydrochloride, oxalate, sulphate, nitrate, acetate maleate, citrate and any other pharmaceutlcally-acceptable salt. It is understood that the term aromatic.in relation to the groups Ar and Ar includes heteroaromatic.
The wavy-line ~etween the C=N and NHArl groups in Formula I indicates the possibility of isomerism.
2S The compounds may be isolated in the form of a !

0~7 mixture of isomers or as the isomers themselves in particular the E- and Z- isomers and the invention extends to such mixtures and such isomers. In addition compounds of formula II
S contain two asymmetric centres and it is-understood that the invention encompasses the individual isomers_and isomer mixtures.
In a preferred class of compounds according to the invention, the group Ar is preferably a phenyl or thienyl group, or alternatively a phenyl or thienyl group substituted by one halogen atom, particuQarly a chlorine atom.
The group Arl is preferably a phenyl group substituted with halogen atoms, in particular chlorine atoms; of such groups 2,4-dichloro,
2,6-dichloro and 2,4,6-trichloro are particularly preferred. Alk is preferably 3-4 carbon atoms.
Preferred acid addition salts are the hydrochlor;des Specific preferred compounds according to the inventio~ are:-(1) 2-Chloro-6-~lH-imidazol-l-yl)-6,7,8,9-tetra-hydro-5-benzocycloheptanone, 2,~-dichlorophenyl-hydrazone hydrochloride;
.
(2) 6-(lH-Imidazol-l-yl)-6,7/8,9-te~rahydro-5-benzocycloheptanone, 2,4-dichlorophenylhydrazone.
hydrogen oxalate;
(3) 2-Chloro-6-~lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone; 2,4,6-trichlorophenylhydrazone hydrochloride;
(4) 6-(lH-Imidazol-l-yl)-7,8,9,10-tetrahydro-5(6H3~
benzocyclooctanone, 2,4-dichlorophenylhydrazone hydro-chloride;
(5) 7-(lH-Imidazol-l-yl)-4,5,6,7-tetrahydro-8H-cyclohepta[b]-thiophen-8-one, 2,4-dichlorophenylhydrazone hydrogen oxalate.
(6) 6-(lH-Imidazol-l-yl)-7,8,9,10-tetrahydro-5(6H)-benzocyclooctanone, 2,4,6-trichlorophenylhydrazone hydrochloride.
Other specific preferred compounds are those o~hers, the preparation of which is described in the Examples.
As tndicated abovet the compounds according to the invention have been found to have an action against pathogenic anaerobic bacteria such-as Clostridium .. . .
species, Bacterioides species, and ~3gEL~ b_c~eri~m acnes which is associates~iathe. In the case of the two former species this activity is comparable with that of metronidazole whilst against P.acnes their activity is significantly greater than that of metronid a201é. The results ojf in v ro assays for a number bf compounds according to the t~7 invention are given in Table 1, which follows the Examples.
These tests were conducted by mixing a series o~
decreasing amounts oE the compound under test with a li~uid nutrient medium that had been inoculated with one of the test organisms. These preparations were incubated for 24 hours at 37C under anaerobic conditions and were then examined for the presence of growth as indicated by the turbidity in the liquid medium. Results were recorded as the lowest concentrations, in mg/l, of 10 test compound that prevented growth of the test organisms (minimal inhibitory concentrations). Each test was run three times and the range of results are indicated.
Additionally the compounds according to the invention have the advantagP over metronidazole that they 15 appear to be non-mutagenic in both bacterial Ames tests and mammalian cell transformation assays, (Ames et al., Mutation Res., (1975), 31, 3~7 and McCann et al., Proc.
Nat. Acad. Sci. U.S.A., (1975), 75, 5135) whereas metronidazole is reported to be both mutagenic and 20 teratogenic. This is a very impor-tant advantage when one is considering the use of a compound which could be used on a large scale in repetitive therapy.

.'~!

~:~L8~

In addition to the above, the compounds according to the invention have also been found to have an action against non-pathogenic anaerobic bacteria such as Desulfovibrio desulfuricans which S is an anaerobe present in oil wells. The use of the compounds of the invention to kill or effectively control such anaerobes is part of the present invention.
The results of the in vitro assays for'a number of compounds according to the invention against D, desulfuricans are given in Table 2 which follows .
the Examples.
`- The tests were conducted as described for the pathogenic organisms discussed above.
The compounds according to the m vention have also been found to have an action against fungi which is comparable with that of miconazole which has the formula ', ,' 20' ' ' ' ~ 1 ' ~ ~Cl f .', ~ I ,.
'Cl - !

The results of in vitro anti-fungal assay for a number of compounds according to the invention against pathogenic fungi such as those of the richophyton species, the Candida species, and Epidermophyton floccosum and Microsporum canis are tabulated in Table 3 which ollows the Examples.
The tests were conducted as described for the anaerobic bacteria with the exception that the organisms were incubated aerobically and kept at 30C, apart from C.albicans which was kept at 37C. Each test was run in duplicate.
The compounds according to the invention may be prepared by reacting the appropriate ketone of the formula III, (in which ar, alk O
C
/ \ f===N
~r / H-N
(Alk) (III) have the above-stated meanings) with the appropriate hydrazine of the formula IV
Arl-NH-NH2 IV
(in which Arl has the ahove-stated meaning).
The process is preferably carried out in the presence of a solvent and an acidic catalyst.
Either or both oE the starting materials may be ! ~

~ 7 used in the form of an acid addition salt. The hydrazine may additionally be in the form of a hydrate. The product may be isolated in the form of an acid addition salt or as the free base which may optionally be converted to an acid addition salt.
Preferred temperatures for the reaction are from 20 to 100C, advantageously from 78 to 80C.
The nature of the solvent is not critical. A
preferred solvent is a lower aliphatic alcohol, such as methanol and ethanol. As an acid catalyst, sulphuric or hydrochloric acid may be used.
After reaction, the mixture may be neutralised with alkali; such as sodium bicarbonate and the product recovered by extraction into an organic solvent and isolated by removal of the solvent.
Acid addition salts may be made by dissolving the - product in a non-aqueous solvent, e.g. diethyl ether, and reacting with a non-aqueous solution of the desired acid.
In the case of the compounds of formula II, these can be prepared from the above described hydrazones by reaction of the hydra~one with reducing agentswhich reduce the hydr~zone linkage.
Suitable reducing a~ents include the organoboranes, .

~L~8~

for example, the borane. ~etrahydrofuran complex (BH3.THF), in a solvent such as tetrahydrofuran at a temperature in the range O-SO~ for 1-3 days~
After reaction the solvent may be removed under reduced pressure to leave a residue which is treated with sodium.hydrogencarbon-ate, and the crudP product recovered by extraction into an organic solvent and removal of the solvent.
The purified produc~ may be isolated follo~ina chromatography on silica gel in increasing quantities o~ chloroform in hexane. Acid addition salts may -be made as descxibed for the hydrazone.
The ketones of formula III are known compounds or can be prepared by ~nventional methods, for:
example by the method described in P.A.J. Janssen et al., J;Med.Chem_, 1969j 12, 781 for 1(4-chlorophenyl)-2-(lH-imida~ol-l-yl~ ethanone. The hydrazines of formula IV are also kn~wn compounds, or can be - prepared by conventional methods i.e. Vogel's Text-~0 book of Practical Organic Chemistry, Longman, London, 1978, p 727.
For administration as a pharmaceutical, one or more compounds according to the present invention are preferably formulated as a composi~ion, that is in association wi~h one or more non-toxic, pharm-.. ! .

~81~)~7 aceutically acceptahle carriers and/or diluentsand/or adjuvants. Accordingly, the present invention further provides such a composition and the preparation thereof. Additional medicinal agents may also be present in such compositions if desired. The compositions may be applied topically, orally or by injection.
For topical administration, the composition may be formulated as, for example, a cream,gel or ointment. Such a composition could, for example, be applied topically twice daily for a suitable - -period, such as two or three weeks. A suitable concentration of active ingredient in the composition could be from 1 to 5% w/w. For vaginal use, the activ~ ingredient may be incorporated in a pessary, or a cream may be ~ used with an applicator, or an impregnated tampon may be util'ized.
' For oral administration, the pharmaceutical c'omposition may take the form of, for example, a tablet, capsule, suspension or liquid. A typical oral dose may be from 5 to lO mg/ks body weiaht once daily, for say,'from 2 to 3 weeks.
The active ingredient'may also ~e administered by injection as a cdmposition wherein, for example, saline, dextrose or water for injection may be used as a suitable carrier. An appropriate dose may be from 5 to 10 mg/kg body weight, given once a day fox say, from 2 to 3 weeks.
The dose administered and the treatment regimeIl will be dependent, for example, on the infection, the severity thereof, on the patient being treated and his response to treatment and therefore may be widely varied.
The pharmaceutical compositions may be prepared by techniques well known in the art and described inter aliat in Remington's Pharmaceutical Science, Mach Publishing Co., Easton, Pa. 1965.
The following Examples (in which all temper-atures are in degrees Centigrade) illustrate the invention.-(a~ 6-(lH-Imidazol-l-yl)-6,7,8,9-tetrah~dro-S-benzocycloheptanone 2,4-dichlorophenylhydrazone 6-(lH-Imidazol-l-yl)-6,7,8,9-tetrahydro-S-benzocycloheptanone (1.46 g~ and 2,4-dichlorophenyl-hydrazine hydrochloride hydrate (1.52 g) were heated together in ethanol (150 ml) under reflux for 7 days at a temperature of 78C. ¦The solution was evaporated to d~yness 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 sulphate and the solvent was evaporated to leave an oil which was chromatographed on silica~ Elution with 1~ methanol in chloroform gave the hydrazone free base as an oil. A
portion of the oil was dissolved in ethyl acetate, the solution warmed to 60~C, and acidified wi~h one equivalent of oxalic acid. On cooling, the solution afforded white platelets of 6-(lH-'imidazol-l-yl) 6,7,8,9-tetrahydro-5 benzocyclo-. heptanone, 2,4-dichlorophenylhydrazone, hydrogen oxala~e, m.p. 185-187o .(b) 6~ imidazol 1-ylj-6,7,8,9-tetrahydro-5-benzocycloheptanone, 2,4-dichlorophenylhydrazone hydrochloride , ' A second portion of the oil.obtained in (a) 'above was dissolved in dichloromethane~ The solution was acidified with ethereal hydrogen chloride until t~rbid, and cooled to.give, as a white so].id, 6-(lH-imidazol-l-yl~-6,7,8,9-tetrahydro-5-benzo-cycloheptanone, 2,4-dichlorophenylhydrazone, hydrochloride, m.p. 199-20~

The following compound~ were prepared in an analogous manner.
(c) 2-Chloro-6-(lH-imidazol-l~yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone, 2,4-dichlorophenyihydra~ ne hydrochloride, m.p. 214-5~.
(d) 6-(lH-Imidazol-l-yl)-7,8,9,10-tetrahydro-5(6H)-benzocyclooctanone, 2,4-dichlorophenylhydrazone hydrochloride, m.p. 122-5~. .
(e) 3,4-Dihydro-2-(lH-imidazol-l-yl)-l-napthalenone, 10 2,4-dichlorophenylhydrazone hydrogen oxalate, m.p.
121-3.
(f) 3,5-Dihydro-4-(lH-imidazol-l-yl)-l-benzthiapin-5-(2H)-one, 2,4-dichlorophenylhydrazone hydrochloride, m.p. 181-4.
lS (g) 3,4-Dihydro-4-(lH-imidazol-l-yl)-l-benzoxepin-S-t2H~-one , 2l4-dichlorophenylhydrazone hydrochloride, m.p. 180-2-.
(h) 6-~lH-Imidazol-l-yl)-6,7,8,9-tetrahydro-5-ben20-cycioheptanone, 2;6-dichlorophenylhydrazone hydrogen oxalate, m.p. 142-4.
(i) 3.,4-Dihydro-4-(lH-imidazol-l-yl)-l-benzoxepin-5(2H)-one, 2,6-dichlorophenylhydrazone hydrochloride, m.p.
181-5.
(j) 7 (lH-Imida201-l-yl)-4/5,6,7-tetr~hydro-8H-cyclo-hepta[b]-thiophen-8~one, 2,4-dichlorophenylhydra~one hydrogen oxalate, m.p. 104-6.

(k) ~-(lH-Imidazol-l-yl)-3-methyl-6,7,~,9-~etrahydro-5-benzocycloheptamone, 2, 4-dich~lorophenylhydrazone hydrochloride, m.p. 193-7 (a) 2-(1H-Imidazol-l-yl)-l-indanone, 2,4-dichloro~henyl hydrazone 2-(lH-Imidazol-l-yl)-1-indanone (6.7-g) and 2,4-dichlorophenylhydrazine hydrochloride (7.0 g3 were heated together under reflux in toluene-ethanol '(3:1~2~0 ml) for 18 hours. The solution was then evaporated to dryness under reduced pressure, treated with sodium'hydrogen carbonate solution and extracted ' with dichloromethane (3 x 200 ml). The combined extracts were dried over anhydrous magne~um sulphate and the solvents evaporated to leave a gum which was chromatographed on silica. Elution with chloroform ' gave two solid products which were recrystallised from toluene and indentified as the E- and Z-isomers o~
'2-(lH imidazol-l-yl)-l-indan,one, 2,4 dichlorophenyl-hydrazone'. One isomer had m.p. 115-117, n.m.r.
(CDC13)2.95(1H, double doublet, J 7 and 36~), 3.70 (lH, dd, J 14 and 36Hz), 5.55(1H, dd, ~ 7 and 14Hz) 2S and 6.9-7.8 (llH, multiplet), (Found: C,60.57; H,4.01;

8~7 N, 15.57.C18H14N4~1~ requires Ct60~52; H,3.95; N,15-68~).
` The othPr isomer had m.p. 181-184~, n.m.r. (CDC13) 3.17 (lH, dd, J 8 and 33Hz), 3.71 (lH, dd, J 15 and 33Hz), 5.33(lH, dd, J 8 and 15Hz) 6~7-7.7 (lOH, multiplet) and 8.6(1H,singlet).
The following compound was prepared in an analogous manner from the same ketone and 2~6-dichloro-phenylhydrazine:
(b) 2-(lH-Imidazol -l-yl)-l-indanone, 2,6-dichlorophenyl-hydrazone One isomer had m.p. 96-97, n.~.r. (CDC133 -2.92(1H, dd, 3 6 and 34Hz), 3.71(1H, dd J 9 and 34Hz), 5.55~1~, dd, J 6and 9Hz), 6.60-7.65(11H, multiplet~, ( d C ~ 67; H,3.99; N,15.54. C18H14N4C12 q C,60.52; H,3.95; N,15.68~). The other isomer had m~p.
- 103-105~, n.m.r. (CDC13~ 2.73(lH, dd. J 6 and 32Hz), 3.17 (lH, 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,15.44.
C18H14N4Ci2 requires C,60.52; H,3.95; N,15.68~)~

(a~ 3,4-Dihydro-2-(lH-imidazol-l-yl)-l-na~thalenone, 2,4,6-trichiorophenylhydrazone 3,4-Dihydro-2-(lH-imidazol-l-yl)-l-naFthalenone (1.27g) and 2,4,6-trichlorophenylhydra~zine (1.09g) in ethanol (150ml) and'a saturated solution of hydrogen ~ 17-chloride in ether (lOml) were heated together under reflux for 48 hour~. The solution was then evaporated to dryness under reduced pressure, treated with sodium hydrogen carbonate solution and extracted with dichloromethane (4 x l~Oml).
-The combined extracts were dried over anhydrous magnesium sulphate and the solvent evaporated to leave a gum which was chromatographed on silica.
Elution with chlorform gave the hydrazone free base as an oil. The oil was dissolved in ethyl acetate, the solution warmed to 60~ and acidified .with one equivalent of oxalic acid. On cooling, the solution afforded 3,4-dihydro-2-(lH-imidazol-l-yl)-l-naptHalenon~,.2,4,6 trichlorophenylhy~razone, .. 15 hydrogen oxalate as a white solid, m.p. 173-175.
. The following compounds were prepared in an analogous manner ~om the appropriate ketone and the approprïate hydraæine (b):2-Chloro 6-(lH-imidazol~l-yl)-6,7,8,9-tetrahydro-20 . 5-benzocycloheptanone, 2,4,6-trichlorophenylhydrazone hydrochloride, m.p. 166-8.
(c) 6-(lH-Imidaæol~l-yl)-7,8,9,10-tetrahydro-5(6H)-benzocyclooctanone, 2,4,6-trichlorophenylhydrazone . hydrochloride, m.p. 178-182.
(d) 6-(lH-Imidazol-l~yl)-6,7,8,9-tetrahydro-5-benzo-..

cycloheptanone, 2,4,6-trichlorophenylhydrazone hydrogen oxalate~ m.p. 87-91-.
(e) 6,7-Dihydro-5-~1H-imidazol-l-yl)-benzo[b~thio-phen-4(5H)-one, 2,4,6-trichlorophenylhydrazone hydrochloride, m.p. 141-3.
(f) 2-(lEI-Imidazol-l-yl)-l-indanone, 2,4,6-trichloro-phenylhydrazone hydrochloride, m.p. 151-3.
(g) 3,4-Dihydro-4-(lH-imidazol-l-yl)-l-benzthiapin-5(2H)-one, 2,4,6-trichlorophenylhydrazone hydro-chloride, m.p. 94-6 D.
(h) 3-(lH-Imidazol-l-yl)-chroman-4-one, 2,4,6-trichloro-.phenylhydrazone hydrochloride m.p. 166-7.
(i) 3,4-Dihydro-4-(lH-imidazol~1-yl)-1-benzoxepin-5 (2H)-one, Z,4,6-trichlorophenylhydrazone hydroc~loride, m.p. 198-200.
~j) 3,4-Di-hydro-4-(1H-imidazol-l~yl)-l-benzoxepin-5(2H~-one, 2,3,4,5,6-pentafluoroph2nylhydrazone hydrochloride, m~p~ 169-72g.
, (k) 6-(lH-Imidazol-l-yl)-6,7,8,9-tetrahydro-S-benzo-cycloheptanone, 2,3,4,5,6-pentafluorophenylhydrazone hydrochloride, m.p. 124-6.
(1) 5-(lH-Imidazol-l-yl)-5,6,7,8-tetrahydro-4H-cyclo-hepta[b]thiophen-4-one, 2,4,6-trichlorophenylhydrazone hydrogen oxalate, m.p; 113-6.

(m) 3,4 - Dihydro-2-(~H-imidazol-l-yl)-6-methoxy-1-napthalenone, 2,4,6- trichlorophenylhyprazone hydro-ch.oloride, m.p. 218-21 .

~19-E~PLE 4 N-[2-C loro-6-(lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocycloheptyl]-N'-(2,4-dichlorophenyl) hydrazine A solution of borane-tetrahydrofuran complex (BH3.THF) in dry tetrahydrofuran (30ml, I~ solution) was added dropwise to a solution of 2-chloro-6 (lH-imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone, 2t4-dichlorophenylhydrazone (4g) in tetrahydrofuran (250ml), under an atmosphere of nitrogen, cooled in an ice bath. The reaction mixture was allowed to reach room temperature over two days before treatment with an aqueous solution of sodium hydrogen carbonate and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulphate and the solvents evaporated to af~ord a solid. The solid was dissolved in ethyl acetate, the solution warmed to 60, and acidified with one equivalent of oxalic acid. On cooling, the solution afforded N[2-chloro-6~ imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocycloheptyl]-N'-(2,4-dichlorophenyl) hydrazine oxalate as a white solid, m.p. 95-97.
The following compounds were prepared in an analogous manner:
(b) N-[4-(lH-Imidazol-l-yl)-2,3,4,5-tetrahydro-5-benzoxepinyl]-N'-(2,4-dichlorophenyl)hydrazine dihydrochloride, m.p. 138-40.
(c) N'-[6-(lH-Imidazol-l-yl)-6,7,8,9-tetrahydro-5-benzocycloheptyl]-N-(2,6-dichlorophenyl)hydrazine dihydrochloride m.p. :L10-115.
,, The activities of representative .compounds accordin~ to the invention is giv~n below.

Minimum Inhibitor~____centrations (m~/l) Compound Clostridium Bacterioides Propionibacterium sporogenes fragilis_ acnes Example No.
(ATCC 19404) (ATCC 23745) (ATCC 6919) l(b) 0.5-1.0 0.5-1.0 2.5 l(a). 0.5 2.5 1.0-2.5 2.5 3(b) 0.75-1.0 0.75-1.0 5.0 l(d) 0.5-0.75 1.0-2.5 0.5-2.5 l(j) 1.0-2.5 0.75-1.0 5.0 3(c) 0.5-1.0 2.~ 2.5 Metronidazole 0.5 . 0.5 ~100 .
~ABLE 2 Minimum Inhibitory Concentrations (mg/l) - Compound . . Desulfovibrio desulfuricans D.desulfuricans D.desulfuricans Example No.
API-COR AIP-BREWER ~PI SW2 l(b) 0.5 0.5-0.75 0.5-1.0 l(a) 0.5 . 0.5 0.5 . 3(b)0.75-1.0 0.75 0.75~2.5 .l(d) 0.5-2.5 0.5-1.0 ; 0.5-0.75 .l~j). 0.75-1;0 0.5-0.75~ 0.75-1.0 3(c) 0.75-1.0 0.5-0.751 0.5-0.75 Metronidazole 0.5 0.5 0.5 Minimum In-hi~itory Concentrations (mg/l) Compound Trichophyton Trichophyton Epidermophyton mentagrophytes rubrum floccosom Example No.
3(b) 25 25-12.5 . 50-25 3(d)? 1~0 1.5 3(1) 25 12.5 6.~
3(i) 3.1 6.2 3.1 Miconazole1.5 3.1 6.2 Compound Microsporum Candida canis albicans A C.albicans B
Example No.
: - 3(b). 25 6.2 6.2 : 3~(d~- 6.2 6~2 6.2 - 3~1) 12.5 . 6.2 6.2 3(i) 3.1 12.5. 12.5 Miconazole6.2 6.2 6.2 :
Compound C.albicans . C.albicans . . . G~ _ _ 3153 . Example No.
3(b) 6.2 6.2 3(d~ - 12.5 12.5 3(1) NT 12.5 3(i) NT 12.5 . Miconazole12.5 12.5 .
I

Claims (37)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-
1. A process for the preparation of a compound of the formula (I) or (II):

wherein Ar and Ar1, which may be the same or different, re-present aromatic radicals optionally substituted by one or more substituents selected from halogen, lower alkyl and lower alkoxy and Alk represents an alkylene group containing from 1 to 4 carbon atoms which alkylene group may be inter-rupted with a heteroatom, or an acid addition salt thereof, which comprises either a) reacting a ketone of the formula with a hydrazine of the formula Ar1-NH-NH2 wherein Ar, Ar1 and Alk have the meanings stated above, to provide a compound of formula I; or b) reducing a compound of formula (I) to a compound of formula (II) wherein Ar, Ar1 and Alk have the meanings stated above; or c) converting a compound of formula (I) or (II) to a corresponding acid addition salt thereof.
2. The process as in claim 1 wherein the reaction of the ketone and the hydrazine is carried out in the presence of a solvent and an acidic catalyst.
3. The process as in claim 1 wherein the ketone and/or the hydrazine is used in the form of an acid addition salt thereof or the hydrazine is used in the form of a hydrate.
4. The process as in claim 1 wherein the reaction of the ketone and the hydrazine is carried out at a temperature of from about 20° to about 100°C.
5. The process as in claim 4 wherein the temperature is from about 78° to about 80°C.
6. The process as in claim 2 wherein the solvent is methanol or ethanol.
7. The process as in claim 2 wherein the acidic catalyst is sulphuric acid or hydrochloric acid.
8. The process as in claim 1 wherein the ketone and the hydrazine are reacted together in a solvent selected from methanol and ethanol in the presence of an acidic catalyst selected from sulphuric acid and hydrochloric acid and at a temperature of from about 78° to about 80°C.
9. The process as in claim 1 wherein the reduction is carried out with an organoborane.
10. The process as in claim 9 wherein the organoborane is the borane tetrahydrofuran complex BH3-THF.
11. The process as in claim 9 wherein the reduction is carried out in the presence of a solvent.
12. The process as in claim 11 wherein the solvent is tetrahydrofuran.
13. The process as in claim 9 wherein the reduction is carried out at a temperature of from about 0° to about 50°C.
14. The process as in claim 1 wherein Ar represents a phenyl or thienyl group optionally substituted by one halogen atom.
15. The process as in claim 14 where the halogen atom is chlorine.
16. The process as in claim 1 wherein Alk is an alky-lene group of 3 or 4 carbon atoms.
17. The process as in claim 1 wherein 2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone is re-acted with 2,4-dichlorophenylhydrazine, or the hydrochloride hydrate thereof, and the product is isolated in the form of the hydrochloride salt and the compound thus prepared is 2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocyclo-heptanone, 2,4-dichlorophenylhydrazone hydrochloride.
18. The process as in claim 1 wherein 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone is reacted with 2,4-dichlorophenylhydrazine, or the hydrochloride hydrate there-of, and the product is isolated in the form of the hydrogen ox-alate salt and the compound thus prepared is 6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone, 2,4-dichloro-phenylhydrazone hydrogen oxalate.
19. The process as in claim 1 wherein 2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone is re-acted with 2,4,6-trichlorophenylhydrazine, or the hydrochloride thereof, and the product is isolated in the form of the hydro-chloride salt and the compound thus prepared is 2-chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone, 2,4,6-trichlorophenylhydrazone hydrochloride.
20. The process as in claim 1 wherein 6-(1H-imidazol-1-yl)-7,8,9,10-tetrahydro-5(6H)-benzocyclooctanone is reacted with 2,4-dichlorophenylhydrazine, or the hydrochloride hydrate there-of, and the product is isolated in the form of the hydrochloride salt and the compound thus prepared is 6-(1H-imidazol-1-yl)-7, 8,9,10-tetrahydro-5(6H)-benzocyclooctanone, 2,4-dichlorophenyl-hydrazone hydrochloride.
21. The process as in claim 1 wherein 7-(1H-imidazol-11-yl)-4,5,6,7-tetrahydro-8H-cyclohepta[b]-thiophen-8-one is re-acted with 2,4-dichlorophenylhydrazine, or the hydrochloride hydrate thereof, and the product is isolated in the form of the hydrogen oxalate salt and the compound thus prepared is 7-(1H-imidazol-1-yl)-4,5,6,7-tetrahydro-8H-cyclohepta[b]-thiophen-8-one, 2,4-dichlorophenylhydrazone hydrogen oxalate.
22. The process as in claim 1 wherein 6-(1H-imidazol-1-yl)-7,8,9,10-tetrahydro-5(6H)-benzocyclooctanone is reacted with 2,4,6-trichlorophenylhydrazine, or the hydrochloride there-of, and the product is isolated in the form of the hydrochloride salt and the compound thus prepared is 6-(1H-imidazol-1-yl)-7, 8,9,10-tetrahydro-5(6H)-benzocyclooctanone, 2,4,6-trichloro-phenylhydrazone hydrochloride.
23. A compound of the formula (I) or (II):

(I) (II) wherein Ar and Ar1, which may be the same or different, repre-sent aromatic radicals optionally substituted by one or more substituents selected from halogen, lower alkyl and lower al-koxy and Alk represents an alkylene group containing from 1 to 4 carbon atoms which alkylene group may be interrupted with a heteroatom, or an acid addition salt thereof, when prepared by the process of claim 1.
24. A compound as defined in claim 23, when prepared by the process of claim 2 or 3.
25. A compound as defined in claim 23, when prepared by the process of claim 4 or 5.
26. A compound as defined in claim 23, when prepared by the process of claim 6 or 7.
27. A compound as defined in claim 23, when prepared by the process of claim 9 or 10.
28. A compound as defined in claim 23, when prepared by the process of claim 11 or 12.
29. A compound as defined in claim 23, when prepared by the process of claim 15 or 16.
30. 2-Chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone, 2,4-dichlorophenylhydrazone hydrochloride, when prepared by the process of claim 17.
31. 6-(1H-Imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocyclo-heptanone, 2,4-dichlorophenylhydrazone hydrogen oxalate, when prepared by the process of claim 18.
32. 2-Chloro-6-(1H-imidazol-1-yl)-6,7,8,9-tetrahydro-5-benzocycloheptanone, 2,4,6-trichlorophenylhydrazone hydrochlor-ide, when prepared by the process of claim 19.
33. 6-(1H-Imidazol-1-yl)-7,8,9,10-tetrahydro-5(6H)-benzocyclooctanone, 2,4-dichlorophenylhydrazone hydrochloride, when prepared by the process of claim 20.
34. 7-(1H-Imidazol-1-yl)-4,5,6,7-tetrahydro-8H-cyclo-hepta[b]-thiophen-8-one, 2,4-dichlorophenylhydrazone hydrogen oxalate, when prepared by the process of claim 21.
35. 6-(1H-Imidazol-1-yl)-7,8,9,10-tetrahydro-5(6H)-benzocyclooctanone, 2,4,6-trichlorophenylhydrazone hydrochlor-ide, when prepared by the process of claim 22.
36. A compound as defined in claim 23, when prepared by the process of claim 8.
37. A compound as defined in claim 23, when prepared by the process of claim 13 or 14.
CA000395423A 1981-02-03 1982-02-02 Imidazole hydrazone derivatives production thereof and use in medicine Expired CA1181077A (en)

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DK160252B (en) 1991-02-18
AU547399B2 (en) 1985-10-17
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DK160551B (en) 1991-03-25
IE820230L (en) 1982-08-03
AU8011382A (en) 1982-08-12
PT74375A (en) 1982-03-01
NZ199633A (en) 1985-05-31
ES8305732A1 (en) 1983-04-16
NO156941B (en) 1987-09-14
DK45482A (en) 1982-08-04
DK160252C (en) 1991-07-22
DK160551C (en) 1991-09-02
ZA82632B (en) 1983-03-30
DK169589D0 (en) 1989-04-07
ES509249A0 (en) 1983-04-16
DK169589A (en) 1989-04-07
PT74375B (en) 1984-05-08

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