IMIDAZOLE HYDRAZONE DERIVATIVES PRODUCTION THEREOF AND USE IN MEDICINE

DERIVES DE L'IMIDAZOLE HYDRAZONE, PROCEDE DE PRODUCTION ET APPLICATION EN MEDECINE

English Abstract

Abstract
Compounds of the general formulae:
<IMG> <IMG>
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.

Claims

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):
<IMG>
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
< IMG >
with a hydrazine of the formula
Ar1-NH-NH2
wherein Ar, Ar1 and Alk have the meanings stated above, to
22

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
23
23

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
24

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):
<IMG> <IMG>
(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
26

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)-
27

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.
28

Description

'7
--2--
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

--3--
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
--4--
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
--6--
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
--3--
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
--11--
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,

-12-
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.-
EXAMPLE 1-
(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
'
.

-13-
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~

-14-
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.

--15--
(k) ~-(lH-Imidazol-l-yl)-3-methyl-6,7,~,9-~etrahydro-5-
benzocycloheptamone, 2, 4-dich~lorophenylhydrazone hydrochloride,
m.p. 193-7
EXAMPLE 2
(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
-16-
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~)~
EXAMPLE 3
(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-
..

-18-
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.
,,

-20-
The activities of representative .compounds
accordin~ to the invention is giv~n below.
TABLE 1
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

-21-
TABLE 3
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