Note: Descriptions are shown in the official language in which they were submitted.
~3~ `J
The present invention relates to novel imidazole deri-
vatives and more parti.cularly to l~[~-(R-thio)phenethyl]
imidazoles, l-~-(R-sulfinyl)phenethyl]imidazoles an~ 1-[~-
(R-sulfonyl~phenethyl]imidazoles having the formula
.~ 5 .
.~ . .
[ ~ ~ - C~l- C~l2- N
;(I)
and the addition salts thereof, wherein:
: R is alkyll alkenyl, aralkenyl, substituted aralkenyl,
alkynyl, cycloalkyl, cycloalkyl alkyl, aralkyl, substituted
aralkyl, aryl and substituted aryl, said substituted aralkenyl
and substituted aralkyl containing at least one substituent
on the aryl moiety selected from the group consisting of halo,
lower alkyl, lower alkoxy, trifluoromethyl, nitro and cyano
. .and sa.i~ substituted aryl containing at least one ~ubstituent
selected from the group consisting of halo~ lower alkyl, lower
. .
: ~o alkoxy, trifluoromethyl, nitro, amlno, acylamino and cyano;
l is hydrogen, halo, lower alkyl~ lower alkoxy, tri-
~1 1uoromethyl, nitro, cyano, thiocyanato and ~he group
.
(O)n
. ... . ~2
S
.. . .
`;~ in which R~ is alkyl; cycloalkyl, aralkyl, substi~uted aralkyl,
aryl and substituted aryl, said substi~uted aralkyl and said
subs~ituted aryl containing at least one substituen~ on the
. .
~: ~` aryl moiety selected rom the group consis~ing o halo,
~- 3~ iower aikyiJ lower al~oxy~ trifluoromethyl, nitxo and cyano,
2-
- 1 m, n and p are independently selected from the integers
zero, 1 and 2;
provided that:
the value of m cannot be greater than the value of n
except when R is the group
;
-S~O)n
and R is aryl or substituted aryl.
The term "alkyl" as ùsed in the speci:Eication and
appended claims refers to a saturated, unbranched or branched
acylic hydrocarbon group containing 1 to 20 carbon atoms in- ~
clusivel such as methyl, ethyl, n-propyl, isopropyl, n-butyl, ~-
i-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,
n-dodecyl, n-octadecyl and the like. The term "lower alkyl"
: ~ .
refers to an alkyl group as previously defined containing 1
` to 6 carbon atoms, inclusive. The term "lower alkoxy" refers
to groups of the formula
;
.''!,~ lower alkyl-0-
: ~i``;
wherein the lower alkyl substituent is as previously defined.
` 20 The term "cycloalkyl" as used herein refers to a saturated,
monocyclic hydrocarbon group having ~5 to 8 ring carbon atoms,
such as cyclopentyl, cyclohexyl, cyclopheptyl and the like.
e term "cycloalkyl alkyl" refers to a cycloalkyl group as
. previously defined attached to an unbranched acyclic hydrocarbon
-~; Z5 group containing 1 to 3 carbon atoms, such as cyclopentyl-
-~i propyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl
,,:
~i and the like. The term "alkenyl" refers to an unbranched or
;~ branched acyclic hydrocarbon group having carbon-carbon double
~ bo,l~ un~aturation and containing 2 to 12 carbon atoms such as
~ 30 allyl, 2-hexenyl, 3-octenyl, 2-octenyl, 2-decenyl and the like.
.... : ~ . . ~ . . . . . .
~ gt~
The term "aralkenyl" refers to a hydrocarbon moiety in which
the alkenyl portion containing ~ to 4 carbon atoms is attached
to a hydrocarbon group consisting of one or more aromatic
rings and containing 6 to 10 ring carbon atoms such as 3-
phenyl-2-propenyl, 4-phenyl-3-butenyl, styryl, 3-naphthyl 2-
propenyl and the like. The term "alkynyl" refers to an un-
branched or branched acyclic hydrocarbon group having carbon-
carbon triple bond unsaturation and containing 2 to 12 carbon
atoms, such as 2-propynyl, 3-hexynyl, 2--octynyl and the like.
The term "aryl" refers to a hydrocarbon group consisting of
one ~r more aromatic rings and containing 6 to 10 ring
. carbon atoms, such as phenyl and naphthyl. The tPrm "aralkyl"
refers to a hydrocàrbon moiety in which the alkyl portion
contains 1 to 4 carbon atoms and the aryl portion is defined
as above. Representative examp~es of aralkyl groups inclùde
.
: benzyl, 3-phenylpropyl and the like. The term acylamino,
i.e., R-C(O)-NH-, refers to substituents containing up to
~ 12 carbon atoms, wherein R in such substituents is methyl,
.~ . ethyl, i-propyl, n-butyl, pentyl, octyl and the like. The
te~m "halo" as used herein refers to chloro, fluoro and bromo.
The texm "acid addition salts" refers to salts of the subject
. . com~ounds formed with inorganic acids such as hydrochloric
; acid, hydrobromic acid, sulfuric acid, nitric acid and
: phosphoric acid and the liket or organic acids such as acetic
~ . .
acid~ propionic acid, glycolic acid, pyruvic acid/ oxalic acid,
malic acid, malonic acid, succinic acid, maleic acid, ~umaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
. .
mand~lic acid, methanesulfonic acid~ ethanesul~onic acid, p~
toluenesulfonic acid, salicylic acid and the like.
~3~
~ 4
;
.. . .
:
.
All compounds of Formula (I) process at least one
chiral center, i.e., the carbon atom to which are attached the
(Rl)p ~ , RS()m, H and CH2-N ~ moieties. Accordingly,
the compo-mds of the present invention may be prepared in
either optically active form, or as a racemic mixture.
Unless otherwise specified, the compounds described herein
are all in the racemic form. Howaver, the scope of the
subject inven~ion herein is not to be cons:idered limited to
the racemic form, but to encompass the individual optical
isomers of the subject compoun~s.
If desired, racemic intermediates or final products
prepared herein may be resolved into their optical antipodes
by conventional resolution means known per se, for example, as
described in`U.S. Patents 3,717,655 and 3,839,574 or by the
separation (e.g., fractional crystallization) of the diastereo-
meric salts formed by reaction of, e.g., racemic compounds of
.
Formula (I) wit~ an optically active acid, or the diastereomeric
esters formed by reaction of ~he racemic alcohol precursors of
compounds of Formula (II) with an optically active acid.
Exemplary of such optically active acids are the optically
active forms of camphor-10-sulfonic acid, a-bromo-camphor-~-
sulfonic acid, camphoric acid, menthoxy-acetic acid, tartaric
acid, malic acid, diacetyltartaric acid, pyrrolidone-5-carboxylic
acid, and the like. The separated pure diastereomeric salts or
esters may then be cleaved by standard means to afford the res-
pective optical isomers of the compounds of Formula (I~ or the
precursor alcohols.
. ~ ,
,
, .
,
, .
-4a-
;
~: . - - . .
^: . : :. . ' . ,, ~ .
A preferred subclass of compounds w.ithin the class
defined by Formula tI) are those compounds having the
formula
lR J ~ CH- CH2- N
R
and the acid addition salts thereof, wherein R, Rl and
p are as defined above.
A preferred group of compounds within the above defined
subclass are those wherein Rl is halo and R is alkyl,
alkenyl, aralkenyl, halo substituted aralkenyl, aralkyl,
. halo substituted aralkyl, aryl and halo substituted aryl.
- Particularly prefexred compounds within the group des-
cribed in the previous paragraph are those wherein [Rl]p
~: 15 is mono.halo or dihalo and R is alkyl con~aining 1 ~o 12
carbon atoms, 2-alkenyl, phenyl-2-alkenyl, chloro substituted
phenyl-2-alkenyl, benzyl, chloro or ~luoro substituted benzyl,
- . phenyl and chloro substituted phenylO Most particularly
preferred compounds are those wherein [Rl~p represents 2,4-
.~ 2~ ~ dichloro, 2,4 dibromo or 2,4-difluoroO . - .
.: The subject compounds o~ Formula (I) exhibit anti-fun~
; gal and anti-bacterial activity. For example, compounds
o~ the present invention exhibit anti-fungal activity
:~ ` against human and animal pathogens such as
Microsporum audouini,
;. ~icrosporum gypseum,
~icrosporum gypseum - canis,
Epidexmophykon ~loccosum,
... .
Txichophyton mentagrophytes,
: 30 Trichophyton rubrum,
Trichophyton tonsuransy
~`, .
, ~ .
:, ~ . , . ~ . . . . . .
. .
Candida albicans, and
Cryptococcus neo~ormans.
The compounds of the present invention also exhibit
anti-~ungal activity ayainst fungi of primaril~ agricultura
importance such as
Aspergillus flavus,
- Cladosporium herbarum,
Fusarium graminearum' ~ ~ -
Penicillium notatum,
- Aspergillus niger,
Penicillium oxalicum,
Penicillium spinulosum, and G¦
Pithomyces chartarum.
In addition, the compounds of the present invention
`I
exhibit anti-bacterial activity against human and animal
pathogens, such as
Staphylococcus aureus,
Streptocoacus faecalis,
- Corynebacterium acnes,
Erysipelothrix insidiosa,
~scherichia coli~ ~,
.
Proteus ~ulgaris,
-~ - Salmonella choleraesuis, ;
Pasteurella multocida, and
Pseudomonas aeruginosa. }
,
2S ;
,:
3Q ^ - -
.
' ' "'" ' ' -~;-
`.
:
' ' .' ' ~ ' '; , , '
A~ ¢~ s,~
In view of the aforementioned activities, the subject
compounds are found to be useful antimicrobials, having not
only pharmaceutical but also agricultural and industrial
application.
Accordingly, a further aspect of the present invention
relates to compositions for pharmaceutical, agricultural, and
industrial use, which compositions comprise the subject com-
po~ds of Formula (I) in combination with a suitable carrier.
A still further aspect of the present invention relates to
methodsof inhibiting the growth of fungi and bacteria by ap-
plying to a host object containing, or subject to attack by,
fungi or bacteria, a fungicidally or bacteriocidally effective
amount of a compound of the present invention or a suitable
composition containing same.
In pharmaceutical applications, compositions may be solid,
semi-solid or li~uid in form such as tablets, capsules, powders,
suppositories, liquid solutions, suspensions, creams, lotions,
ointments and the like. Phaxmaceutically acceptable non-toxic
carriexs, or excipients normally employed for solid formulations
include tricalcium phosphate, calcium car~onate, kaolin, bento-
nite, talcum, gelatin, lactose, starch and the like; or semi-
~; solid formulations there may be mentioned/ for example, poly-
alkylene glycols, vaseline and other cream bases; for liquid
~ormulations there may be mentioned, for example, watex, oils
2S o~ vegetahle origin and low boiling solvents such as isopropanol,
hydrogenated naphthalenes and the like. The pharmaceutical com-
positions containing the compounds of the present invention may
be subjected to conventional pharmaceutical expedients such as
sterilization and can contain conventlonal pharmaceutical excipi-
-~ 30 ents such as preservatives, stabilizing agents, emulsifying agents,
8alts fox the adiustment of osmotic pressure and buffers. The
^ -7-
:
~ , ,, .. ; . . ~;, ~
compositions may also contain other therapeutically active
materials. In pharmaceutical applications, the subject com-
pounds and compositions may be administered to humans and
animals by conventional methods, e.g.~ topically, orally,
parenterally and the like. When given orally the compounds,
alone or in admixture with a suitab]e carrier, may be adminis-
tered at a dosage of from about 12.5 mg to about 1000 mg. per
dose (assuming a 70 kg. host subject), one or more times daily,
extending over a period of several days to many weeks. Supposi-
tories may contain from about 1 mg. ~o 500 mg. of active com-
pounds.
Topical application is preferred. For such treatment, an
area having an Pxisting fungal or bacterial growth, or to be
protected against attack by fungi or bacteria, may be treated
with the subject compounds or compositions by, for example,
dusting, sprinkling, spraying, rinsingl brushing, dipping,
smearing, coating, impregnating and the like. Pharmaceu-tical
compositions containing the compounds of the present invention
exhibit anti-fungal and anti-bacterial activity over a wide
range of concentration, for example, from about 0.1 to 10.0%
by weight of the composition. In any event, the composition
to be administered will contain a quantity of the subject com-
pound in an amount effective for relief or prevention of the
specific condition being treated. The exact regimen for pharma-
ceutical administration of the compounds and compositions dis-
closed herein will necessarily be dependent upon the needs of
the individual subject being treated, the typa o~ treatment
e.g., whether preventative or curative, the type of organism
involved and, o~ course, the judgment of the attending practi-
tlonexO
` .X/
~ ~ -8-
~,
:~ , . . . ~ . . .
~7~
In agricul~ural applications, the subject compounds may
be applied directly to plants (e.g., seeds, foliage) or to soil.
For example, compounds of the present invention may be applied
to seeds alone or in admixture with a powdered solid carrier.
Typical powdered carriers are the v~rious mineral silicates, e~g~
mica, talc, pyrophyllite, and clays. Th~e subject compounds
may also be applied to the seeds
, /
~; 10
/
:: .' /
,. / .
/ i
., /
: /
'' /
,..,
: . . /
/
~,
/ .
~ / ' .
.
' '
~ -8a-
-,~
in admixture with a con~entional surface-active wettiny agent
with or without additional solid carrier. Surface-active
wetting agents that can be used are any of the conventional
anionic, non-anionic or cationic types. As a soil treabment
for fungi and the like, the subject co~mpounds can he applied
as a dust in admixture with sand, soil or a powdered solid
carrier such as a mineral silicate with or without additional
surfa~e-active agent or the subject compounds can be applied
as an aqueous spray optionally containing a surface-active dis-
persing agent anda powdered solid carrier. As a foliage
treatment, the subject compounds may be applied to growing
plants as an aqueous spray which contains a surface-active
dispersing agent with or without a powdered solid carrier
and hydrocarbon solvents.
- 15 In industrial applications, the subject compounds may
be used to control bacteria and fungi by contacting the patho-
. gens with the compounds in any known matter. Materials capable
- of supporti~g bacteria and fungi may De protected by contacting,
. mixing or impregnating these materials with th subject com-
pounds. In order to increase their effect, the subject com-
~ pounds may be combined with other pesticidal control agents
; ~uch as fungicides, bactericides, insecticides, miticide~
and the like. A particularly important industrial/agricultural
use for the subiect compounds of the present invention is as a
~- 25 food preser~ative against bacteria and fungi which cause de-
~ terioration and spoilage of foods.
.,,.- .
~ 3~
: . ,
"`~' ' . .
: ,., , _g_ .
Deta.iled Description
:
The present lnvention, in a still further aspect,
is directed to methods for the preparation of the subject
compounds of Formula (I) according to the ollowing reaction
se~uence: .
1,
. , .
. . , , ,
. - ,
.
: . ;
.
~ . ~
., . ' i
~; 15 . I
.. ~. . . . - ~- .
~ ` ~
':
; 20
: ,.. - , . .
. ~ .. .. . - -
.~: . . . .
. ~5
.,:~ . . . , , ~
~ . . ~ . . . ... . .
:. . ,. :.. - .
, . . I
.. .. ..
. . , . .:: . . .. ... ,. .. ~ .. ..... ,.. ,., . . ~
LR3~ 11~ C~12--N~ SH
(II)
' '', ', ' ' ' '
[~IHCH N~=~
( C-A)
[3~lHCHZN~7~ [R~CHCH2N~
R
. . . .
~ . . . .
,
,".~
.~; 20 wherein R, Rl and p are as previously described and X represents
;.. ~ a conventional lea~ing`group such as chloro, bromo or a reactive
:~ ester group such as CH3-S(O)2-O~ or p-CH3-C6H4-S(O)2-O-.
i The l-[~-(R-thio)phenethyl]imidazoles o Formula I-A are
:: ~ prepared by condensing a compound of Formula II with a thiol of
.~ 25 Formula III.
.:~ In said condensation, the startin~ materials and reagents may`: :
be contacted in any convenient manner and maintained at a tempera-
ure and for a period of time su~ficient to complete the reaction.
~, ~
~ . Furthermore, the reaction products may be isolated and recovered
~j.
~- 30 from the reaction using,~asin the case of the reaction conditions
.. . .
~'':, :
~'~
`~ `''
~ 3L~
themselves, procedures conventional or known in the art for
conducting such reactions or analogous reactions. The nature of
the leaving group (X) is not critical, its selection being predi-
cated on relative reactivity rates known for reactions of this type.
S Chloro, bromo, and the two ester groups noted above are given by
way of typical examples only.
Generally, the reaction of compounds of Formula II with
compounds of Formula III wherein R in Formula III is alkyl, alkenyl,
aralkenyl, substituted aralkenyl, alkynyl, cycloalkyl, cycloalkyl
alkyl, aralkyl and substituted aralkyl is carried out in the
presence of an inert organic solvent, e.g. tetrahydrofuran, ether,
menthanol and the like in the presence of sodium hydride or other
suitable base at a temperature of 20 to 66C for a period of 30
minutes to 24 hours.
'!~ 15 The reaction of compounds of Formula II with compounds ofFormula III wherein R in Formula III is aryl or substituted aryl
is carried out in the presence of an inert organic solvent, e.g.
acetone, methanol, and the like and in the presence of potassium
carbonate or o~her suitable base under reflux conditions for a
period of 30 minutes to 12 hours.
The thus obtained l~ (R-thio~phenethyl]imidazole compounds
of Formula I~A are ~hen optionally oxidized to obtain the 1-[~-
~R-sulfinyl)phenethyl]-and the l-[~-(R-sulfonyl)phenethyl]imidazole
` compounds of Formulas I-B and I-C, respectively. Oxidation is
- 25 conducted by methods well-known in the art using hydrogen peroxide,
an organic peracid such as peracetic acid, p-nitroperbenzoic acid
,.i
~ and m-chloroperbenzoic or an inorganic peracid such as periodic
: .,;
~` acid. The oxiaation reaction ls prefexably conducted using m-
chloroperbenzoic in a liquid reaction medium, such as a chlor-
inated hydxocarbon.
~ -12-
.
.
In said oxidation, the startlny materials and reagents may
be contacted in any convenient manner and maintained at a
temperature and for a period of time sufficient to complete
the reaction. Furthermore, the reaction products may be isolated
and recovered from the reaction using, as in the case of the
reaction conditions themselves, procedures conventional or known
in the art for conducting such reactions or analogous reactions.
~n general, when the compounds o.f Formula I-A are contacted
with about one or more equivalents of oxidizing agent, such as
m-chloroperbenzoic acid, at a temperature of ~rom about ~30C
to about 30C, perferably in an organic medium, such as chloroform,
and for a period of about 30 minutes to about 6 hours, the
corresponding sulfinyl products of Formula I-B are obtained.
Similarly, when the compounds of Formula I-A are contacted
with about two or more equivalents of oxidizing agent, such
as m-chloroperhenzoic acid, at a temperature of from about
0C to about 60C, preferably in a~ organic medium, such as
chloroform, and for a period of about 1 to about 24 hours,
the corresponding sulfonyl products of Formula I-C are obtained.
.:
:
.
' , . '
. ;~ ,
'
~: 30
-''
12a-
~ .
:
~ he subject compounds of the instant invention can
be isolated as ~ree bases, however, since many o~ the com-
pounds in base form are oils or ~ums, it is more convenient
to isolate and characteriæe the compounds as acid addition
salts. These salts are prepared in the usual manner, i.e.,
by reaction of the base compound with suitable inorganic or
organic acid. If desired, the salts can be readily converted
to the compounds in base form by treatment with alkali, such
as potassium carbonate, sodium carbonate or sodium or potas-
sium hydroxide.
The starting compounds of Formula II, wherein Rl is
hydrogen, meth~l, methoxy, halo, nitro or lower alkyl sulfonyl
a~e disclosed together with a met~od for their preparation in
U.S. Patent 3,679,697. Compounds o~ Formula II wherein Rl is
other khan those groups disclosed in the above-identified pa-
tent, with the exception of R2S(O) -, can be analo~ously pre-
pared, i.e., by bromina~ion of the appropriate acetophenone,
reaction of the resultant 2-bromo acetophenone compound with
imiaazole, reduction o the resultant 2~ imidazolyl)aceto-
phenone compound with sodium tetrahydroborate, and inally,
reaction of the resultant l~imidaæoleethanol compound with a
~ .
`~ thionyl halide to yield the l-(~-halophenethyl)imidazole com-
pounds of Formula II. Compounds of Formula II wherein Rl is
- ~ ~he group R2S(O) - are prepared by oxidation of corresponding
~5 compounds o~ Formula II where Rlis the group R~S- using con-
`~ ventional methods known in ~he art as described earlier in
~ this invention.
i ,: .
. ~
.. : .... :.~ . , .
- 3
. :
~ ~13
;~ ~
'
:
; , ,
. , . . . : . ,
~ f~
When acetophenones containing the group
-I()n
.,
wherein R~ is as previously defined, are required as reactants
for the preparation of starting compounds o~ Forrnula II, i.e.,
L 'o'~f 2 ~ 1
wherein R2 and X are as previously defined, these acetophenones
.~ may be prepared by the following processes:
: (A~ Friedel-Crafts Acylation of a known alkyl-, cyclo-
. alkyl-, aral~yl- or aryl phenyl sulfide with acety].
~, 15 . chloride or with acetic anhydride ln the presence of. AlCl~ to yield the corresponding alkylthio-, cyclo-
'~ alkylthio-, aralkylthio or arylthioacetophenone.which
.;~ ~ . , .
. ~an be ,converted ~o the corresponding sulfonyl
, . derivatives by oxidation with hydrogen peroxide
. ~i . . .
'- 20 ~ in acetic acLd. These methods are described in
the Journal of American Chemical Socie~y 74, 5475-
31, (195~) and U.S. 2,763,~92.
~: (B) Coupling a diazotized aminoacetophenone with an
~ . . ary~ thiol or a substituted aryl thiol, said sub-
.~ 25 . s~itutèd thiol containing at least one substituent
selected from the gxoup consisting o halol lower
. alkyl, lower alkoxy, trifluoromethyl, nitro and
.. .
c~anot to obtain the substituted arylthio aceto-
~: phenone. Alternatively, a d~azotized aryl amino
~ 30 . compound, substituted with at least one of th&
:,,; above substituents can be coupled with a mercapto-
""' -14- .
... .
. .~
.
t ~ C
acetophenone to obtain the substituted arylthio-
acetophenone. These proceduxes are described in
Boll. sci. fac. chim. ind. Bolo~na 17, 33-43 ~1959).
(C) Alkylation of an o-, m- or p- mercaptoacetophenone
with a known alkyl, cycloalkyl, aralkyl or substi-
tuted aralkyl halide, said substituted aralkyl halide
substituted on the aryl moiety with at least one
substituent selected from the group consisting of
halo, lower alkyl, lower alkoxy, trifluoromethyl
lQ nitro and cyano to obtain the corresponding alkyl~
cycloalkyl-, aralkyl- or substituted aralkylthio-
acetophenone. This procedure is described in the
- Journal o American Chemical Society 78, 4792-7
i ~1956).
, . .
Oxidation of the products of processes ~B) and (C) in the
manner described in process (A) produced the corresponding R2-
sulfonylacetophenones wherein R2 is as previously defined.
.
:
ao
.
: . . , ~ .
. .
:. .
. .~ .
. ~ .
,.
~ ~ : .
3~
-15-
:
.
.
DESCRIPTION OF SPECIFIC EMBODIMENTS
-
; The following specific description is given to enable
those skilled in the art to more clearly understand ancl
practice the present invention. It should not be considered
as a limitation upon the scope of the invention but merely
as being illustrative and representative thereof.
.
' :
.
. . .
~';:,:'
'.:
, '
, ~
... . .
.,.~.,
'. 20
,' '
`'
: ;.;
';
::` 25
"
. -16-
. ~,~, .
: : .
; ,~
:,
, ,~ , . . . .. . . .. . . . .. . . .. ... . . . . .
-., - - ; ., .. .. , . . . -- . - ,.,, . . , . .. ::
PREPA~ATI~N A
A mixture of 1.52 ~, of 4-r~excaptoacetophenone, 1.7~ g.
~f 4~methoxybenzyl chloride and 1.5 g. o~ anhydrous potassium
carbonate in 50 ml. o~ acetone is stirred and refluxed under
5 nitxogen. After 4 hours the solvent and exces5 4-methox~benz~l
chloride are evaporated under vacuum and ~ater is ad~ed to the
residue. The resultant aqueous mixture is extracted with ethcr
and the ekher extract washed with water, dried over magnesium
sulfate and evaporated to dryness. Tlle resulting residue is
~ . , .
recrystallized from cyclohexzne to yield ~-(4'-methoxy~enzyl-
; thio)-acetophenone.
Similarly, replacing 4-methoxy benzyl chloride ~ith other
aralkyl halides or substituted aralkyl halide~ containin~ at
. least one substituent on th~ aryl moiety selected from the
~roup consisting of halo, lower al~yl, lo~Jer alkoxy, ~ri-
, ~luororneth~l, nitro and cyano is productive o the corxesponding
~ubstituted aralkylthioacetophenones.
;~ The staxting compounds of Formula II axe pxepared from
the above substituted aral~ylthioacetophenones according ~o
; 20 the procedure in U~S. 3,679,697.
,
PREPAR~TI0~ B
A mixture of 2 g. of 4-methylthioacetophenone, 5 g. o
ac~tic acid, and approximately 3.8 gO o 30~O hydrogen peroxide
` ~5 heated ak 85 ~ 95C. until an exo~hermic reaction is ini-
,?.`i 25 tiated. When the reaction su~sides, .002 g. of palladium-on-
carbon is introduced and the reaction mLxture is ~iltered
through diatomaceous earth. The filtrate is chi:Lled to pre-
.
~ipi~a~e the product which is isolated by filtxation and air
dried to yield 4-methylsulfonyl ~c~tophenone,
.. ~ ,
~ ,
-17-
~ .
, . :. ~ , . . : . -
. .
Similarly, replacing 4-methylthioacetophenone with
other thioacetophenones, ~or example~
4-t-butylthioacetophenone,
4-benzylthioacetophenone,
4-(4'-chlorobenzylthio)acetophenone,
- 4~(4'-methoxybenzylthio)acetophenone,
4~phenylthioacetophenone, and
4-(4'-chlorophenylthio)acetophenone
is productive of the following sulfonyl substituted aceto-
10 phenones: . 5 ' ;'
4-t-butylsulfonylacetophenone,
4-benzylsulfonylacetophenone,
4-(4'-chlorobenzylsulfony1)acetophenone,
.. 4-(4'.-methoxybenzylsulfonyl)acetophenone,
. 4-phenylsulfonylacetophenone, and
4-~4'-chlorophenylsulfonyl)acetophenone.
: . .. The starting compounds of Formula II are prepared from
the above sulfonyl substituted acetophenones according to the
.~ .
` .procedure.in ~.S. 3,679j697.
.
.. .
. .
~ 25
: .
~ , ' .
'' ' : '
: 30
... . .
; -18-
. .
: .
. :- . .. , . - : :' ' . . , ' . ~ ': : :
X~MP~E
A mix~ure of 1 g. o 1-(2,4,~-trichloropheneth~l)
.
imida~ole. 1.8~g. of 3,4-dichlorothiophenol and 1.5 g. of po-
tassium carbonate in 50 ml. of acetone is stirred and refluxed
~or 4 hours. The solvent is evaporated under vacuum and 20 ml.
o~ water is added to the residue. The resultant aqueous mix-
ture is ex~racted ~ith e~her and the ether extract washed with
50 ml. of a saturated sodium chloride solution. The organic
phase is dried over magnesium sulfate and evaporated to
yield 1-~2,4-dichloro-~-(3',4'-dichlorophenylthio)phenethyl]
imidazole. - , ,, , ~ ~
- . .
The'oxalate sal't of ~he '~ree base is pxepared by the
dropwise addition of ethereal oxalic acid to the free base
; in ether until precipitation is complete. The product
i~ collected by ~iltration and recrystallized from a
',, mixture of acetone and ethyl acetate to yield 1-[2,4-dichloro-
3',4'-dichlorophenylt~io)phenethyl]imidazole oxalate,
', m~p. 161.5-163.5C.
. .
,~ 20
'. ~ ', , :
~`'' ' '
,~ . .
~ 25
~......................... .
~ ,:`~,' , .
.,~
. .
~`'. : ' .
,~,, 30
1 9
`'` ~ ' .
' ' ' ~
L'~ ~ `s ~r
B; Similarly, substituting o~her starting materials
of Formula II Eor 1-(2,4,~-trichlorophenethyl)imidazole,
.for example,
~ chlorophenethyl~imidazole;
1-~ chloro-4-ethylphenethyl)imidazole;
-chloro-4-t-butylphenethyl)imidazole;
l~(~-chloro-4-ethoxyphenethyl)imidazole;
-chloro-4-n-butoxyphenethyl)i~idazole;
chloro-4 ~-butoxyphenethyl)imidazole;
. 1-(4l~-dichlorophenethyl)imidazole;
1-(3,4,~-trichlorophenethyl)imidazole;
1-(4-bromo-~-chlorophenethyl)imidazole;
1-(2,4-dibromo-~-chlorophenethyl)imidazole;
~-chloro-4-fluorophenethyl)imidazole;
15 1-~-chloro-2,4-difluorophenethyl)imidazole;
chloro-2-trifluoromethylphenethyl~imidazole;
-chloro-4-trifluoromethylphenethyl)imida~ole;
-chloro~4-cyanophenethyl)imidazole,
.~, ,, . - . ~ .
.
:. ~0 ' ' '. ~
., , , ~ i
" ., , .
~ 25 ..
. . .
`
-20-
.:
, . . .
chloro-9-nitrophenethyl)i~idazole, and
chloro-2-thiocyanatophenethyl)imidazole
.is productive of the ~ollowing 1-[~-(3',4'-dichlorophenyl-
thio)phenethyl]imidazoles which, where indicated, are further
characteriæed as the acid addition salts by treatment in
the conven~ional manner wi~h the appropriate acid:
1-[~-(3',4' dichlorophenylthLo~p~enethyl]imidazole;
1-[4-ethyl-~-(3',4'-dichlorophenylthio)phenethyl~im-
. idazole;
1-~4-t-butyl~ 3',4'-dichlorophenylthio)phenethyl]im-
idazole, nitrate salt,decomp. 142.5-146.5C.
1-[4-ethoxy-~-(3',4'-dichlorophenylthio)phenethyl]im-
. idazole;
1-[4-n~butoxy-~-(3'~4'-dichlorophenylthio)phenethyl]im-
. idazole;
~: ` . 1-[4-t-butoxy-~-(3',4'-dichlorophenylthio)phenethyl]im-
~-. .
:~ idazole;
[4-chloro-~-(3l~4~-dichlorophenylthio)phenethyl]im
:,'
. idazole;
1-13,4-dichloro-~-(3',4'-dichlorophenylthio)phen-
. ~ ethyl]imidazole, nitrate sal~ decomp. 133-137C.;
: 1-[4-bromo-~-(3',4'-dichlorophenylthio)phenethyl]im-
~ . . idazole;
[2,4-dibromo-~-(3',4'-dichlorophenylthio)phen-
~thyl]imidazole, nitrate sal~ decomp. 132.5-134.5C.;
.
1-[4-~luoro-~-(3' t 4'-dichlorophenylthio)phenethyl~im-
idazole,
.~;
12,4~di~1uoro ~-(3li4l-ai chlorophenyl~hio)phen-
~thyl]imidazole, oxalate salt, decomp. 172.5-175C.;
3~ 2-trifluoromethyl-~-(3',4'-dichlorophenylthio)phen-
.
: ethyl]imidazole;
-21
~' ~
. .
J
l-[4-trifluoromethyl-~-(3',4'-dichlorphenyltllio)phen-
ethyl]imidazole;
l-[4-cyano-~-(3',4'-dichlorphenylthio)phenethyl.]im-
idazole;
l-[4-nitro-~-(3',4'-dichlorphenylthio)phenethyl]im-
idazole, and
[2-thiocyanato-~-(3',4'-dichlorophenylthio)phen-
ethyl]imidazole.
~ C) In like manner, substituting other starting
::~ 10 materials of Formula III for 3,4-dichloro~hiophenol, for
example, 4-chlorothiophenol and 2,4-dichlorothiophenol and
: using the above recited starting compounds of Formula II
. is productive of the following l-[~-(R-thio)phenethyl~im-
idazoles which~where indicate~ are further characterized as
~ 15 the acid addition salts by treatment in the conventional
~ manner with the appropriate acid:
.' '
l-[~-t4'-chlorophenylthio)phenethyl]imidazole, oxalate
salt,decomp. l47.5~14gC.;
[~-(2',4'-dichlorophenylthio)phenethyllimidazole;
,j .
; 1 20 l~[4-ethyl-~-(4'-chlorophenylthio)phenethyl]imidazole;
[4-ethyl-~-(2',4'-dichlorophenylthio)phenethyl3im-
id~zole;
l-[4-t-butyl-~-(4' chlorophenyl-thio)phenethyl]im-
~: : . ` idazole;
`:~J
:~ 25 1-14-t-butyl-~-(2',4'-dichlorophenylthio)phenethyl]im-
i.dazole;
14-ethoxy-~-(4'-chlorophenylthio~phenethyl]im-
idazole;
. .:
4-ethoxy-13-(2',4'-dichlorophenylthio3phenethyl]im-
: .!
'.1 30 idazole
: -22-
.~,
~'' . '
; , . - , . - . . .
1-[4-n-butoxy-~-(4'-chlorop}lenylthio)phenethyl]im-
idazole;
1-[4-n-butoxy-~-(2',4'-dichlorophenylthio~phenethyl]im-
idaæole;
1-[4-t-butoxy-~-(4'-chlorphenylt}lio)phenethyl]imidazole;
1-[4-t-butoxy-~ (~',4'-dichlorop}lenylthio)phenethyI]im-
idazole;
1-[4-chloro-~-(4'-chlorophenylthio)phenethyl]imidazole/
. oxalate sal~ decomp. 190-191C.J
1-[4-chloro-~-~2',4'-~dichlorophenylthio)phenethyl]im-
; . . idazole;
1-[2,4-dichloro-~-(4'-chlorophenylthio)phenethyl]im-
. idazole, nitrate salt~.P. 169.5-170C ;
1-12,4-dichloro-~-~2',4'-dichlorophenylthio)phen- -:
ethyl~imidazole, nitrate salt, M.P. 150-151C ;
[3~4-dichloro-~-(4!-chlorophenylthio)phenethyl]im-
. ~ . idazole, nitrate sal~ decomp. 123-125.5~C.;
- 1-[3,4-dichloro-~-~2',4'-dichlorophenylthio)phen-
ethyl]imidazole, oxalate salt, decomp. l~9-I71~5C.;
: 20 . 1-[4 bromo-~-(4'-chlorophenylthio)phenethyl~imidazole;
; . 1-[4-bromo-g-(2',4'-dichlorophenylthio)phenethyl]im-
~- . .idazole;
... 1-[2,4-dlbromo-g-~4'-chlorophenylthio)phenethyl]im-
idazole;
:. .1-~2,4-dibromo-~-(2',4'-dichlorophenylthio~phenethyl]im-
. :. ..idazole;
. .
~ 4-fluoro-~-(4'-chlorophenylthiojphenet~yl~imidazole;
.~, .
1~[4-fluoro~ ',4'-dichlorophenylthio)phene~hyl~im-
:. . .. idazole;
3~ 1~12,4-difluoro~ (4'-chlorophenylthio)phenethyl]im-
.
id~zole;
i : -23
"
. . .
1-~2,4-difluoro-~-(2',4'-dichlorophenylthio)phenethyl]im~
. idazolei -
1-~2-trifluoromethyl-~ ' chlorophenylthio)phen-
ethyl]imidazole;
S 1-[2-tri~luoromethyl-~-(2',4l-dichlorophenylthio)phen-
'ethyl]imidazole;
[4-trifluoromethyl-~-(4'-chlorophenylthio)phen-
ethyl]imidazole;
1 [4-trifluoromethyl-~-(2',4'-dichlorophenylthio)phen-
. 10 . ethyl]imidazole;
4-cyano-~ chlorophenylthio)phenethyl]imidazole;
1-[4-cyano-~-(2',4'-dichlorophenylthio)phenethyl]im-
' idazole;
14-nitro-~-(4'-chlorophenylthio)phenethyl]imidazole;
, . and
~ 4 nitro-~-(2',4l-dichlorophenylthio)phenethyl]im-
'' . idazole.
~ . EX~MPLE 2
'` . . ~A? A solution of 1 g. of 1-(2,4~-trichlorophenethyl)im-
. idazole in 10 ml. of tetrahydrofuran is added to a mixture
.~ ~ of 1 g. of 2,4-dichlorobenylmercaptan and 220 mg. of 56
odium ,hydride dispersion in 40 ml. of tetrahydrofuran.
. . After stirring for 12 hours at room temperature, the solvent
, i~ evaporated under vacuum and 10 ml. of water is added to
`t~ ~ ~5 the residue. The resultant aqueous mixture is extracted
.~. , with ether and the ether extract washed with 50 ml. of a
~aturated sodiula chloride solution. The organic phase is
; , dried over magnesium sulfate and evaporated to yield 1-
-, 12,4-dichloro-~-(2',4'-dichlorobenzylthio)phenethyl~imidazole.
~he nitrate salt of ~he free base is prepared by the
dropwise addi~ion of nitric acid to the free base in ether
. -2~-
. " , .. .: . . .
.
~ 3~
until precipitation is complete. The product is collected by
filtration and recrys~allized from ethyl acetate to yield 1
[2,~-dichloro-~ (2',4'-dichlorobenzylthio)phenethyl]imidazole
nitrate, decomp. 133.5-134.5C.
(B) Similarly, substitutin~ other starting materials
of Formula II, i.e,, those recited in paragraph B of Ex~mple
1~ is productive of the following 1-[~-(2',4'-dichlorobenzyl-
thio)phenethyl]imidazoles whic~ where indicate~ are further
characterized as the acid addition salts by treatment in
the conventional manner with the appropriate acid:
~ -(2',4'-dichlorobenzylthio)phenethyl]imidazole;
1-[4-ethyl-~-(2',4'-dichlorobenzylthio)phenethyl]im-
idazole;
1-[4-t-butyl-~-(2',4l-dichloroben~ylthio)phenethyl]im-
idazole;
1-[4-ethox~ (2',4'-dichlorobenzylthio)phene~hyl]im-
idazole;
1-[4-n-butoxy-~-(2',4' dichlorobenzylthio)phenethyl]im-
- idazole;
1-[4-t-butoxy-~-(2',4'-dichloroben~ylthio)phenethyl3im-
idazole;
1 ~4-chloro-~-~2',4'-dichlorobenzylthio)phenethyl3im-
. ' . . '' idazole; '
-~-[3,4-dichloro-~-(2',4'-dichlorobenzylthio)phenethyl]im-
idazole, nitrate salt,decomp. 107-110C.;
[4-bromo-~-(2',4i-dichlorobenzylthio)phenethyl]im-
~dazole;
1-[2,4-dibromo-~-~2',4'-dichloxobenzylthio)phenethyl]im-
i~ zole;
3~ fluoro-~-(Z',4'-dichlorobenzylthio)pllenethyl]im-
.
ida201e;
5-
.~ , ' .
!
'~ ' . . ' '
. ' '
- l-[2,4-difluoro-~-(2',~'~dichlorobenzylthio)phen-
ethyl]imidazole;
l-[2-trifluoromethyl-~-(2',4'~dichlorobenzylthio)phen- i
ethyl]imidazole;
l-l4-trifluorom~thyl-~-(2',~'-diohlorobenz~lthio)phen-
: ethyl]imidazole;
. l [4-cyano-~ (2',4'-dichlorobenzylthio)phenethyl]im- j
. idazole;
[4-nitro-~-(2',4'-dichlorobenzylthio)phenethyl]im-
~ . lO. idazole; and
: l-[2-thiocyanato ~-(2',4' dichlorobenzylthio)phen- .
- ethyl]imidazoleO
(C) In like manner, substituting other starting
materials of Formula III for 2,4-dichlorobenzylmercaptan,
. 15 for example, 4-chloro~enzylmeraptan, 3~4-d.ichlorobenzyl- ~;
. mercap~an or heptylmercaptan and using the starting materials.. , 1
: . o~ Formula II ~ecited in paragraph B of Example l .is productive
of the following l-[~-(R-thio)phenethyl~imidazoles which,
.
. . where indicated, are further characterized as the acid
addition salts by treatment in the conventional manner -
. " .
with the appropriate acid. ~ .
(4'-chloxobenzylthio)phenethyl]imidazole;
(3',4'-dichlorobenzylthio)phenethylJimidazole;
,~ .
1-[~ (n heptylthio)phenethyl]imida20le; .
:.25 . 1-14~ethyl-~-(41-chlorobenzylthio)phenethyl~imidazole;
l-[4-ethyl-~-(3',4'-dichlorobenzylthio)phenethyl]im- .
.~dazvle; .
,. . . .
~ [4-ethyl-~-(n-heptylthio)phenethyl]imidazole;
.,~ .
. l-14-t-buty1~ 4'-chlorobenzyithio)phenethyl3imida~ole,
- oxalate sal~ decomp. 156-158.5C.,
~` ' ' ' ' ,
.~ .
1-[4-t~butyl-~-(3',4'-dichlorobenzylthio)phenethyl]im-
idazole;
1-[4-t-butyl-~-(n-hept~lthio)phenethyl]imidazole;
1-[4-ethoxy-~-(4'-chlorobenzylthio~phenet}lyl]imidazole,
1-~4-ethoxy-~-(3',4'-dichlorobenzylthio)phenethyl]im-
idazole;
1-[4-ethoxy-~-(n-heptylthiolphenethyl]imidazole;
1-[4-n-butoxy-~4'-chlorobenzylthio)phenethyl]imidazole,
nitrate salt, decomp. 113-114C.;
~- 10 - 1-[4-n-butoxy-~-(3',4'-dichlorobenzylthio)phenethyl3im- idazole;
1-[4-n-butoxy-~-(n-heptylthio)phenethyl]imidazole,
oxalate sal~ decomp. 124.5-130C.;
1-[4-t-butoxy-~-(4'-chlorobenzylthio)phenethyl]imidazole;
.
1-[4-t-butoxy-~-(3',4'-dichlorobenzylthio)phenethyl]im-
azole;
.,.. ~ , . ....................... .
1-[4-t-butoxy~ n-heptylthio)phenethyl]imidazole;
1-~4-chloro-~-(4'-chlorobenzylthio)phenethyl]imidazole,
oxalate salt, decomp. 148-149.5C., nitrate salt,
m~p . 103~5-105.5C.;
. . .
1-[4 chloro-~-(3',4'-dichlorobenzylthio)phenethyl~im-
; `idazole;
[4-chloro~ n-heptylthio)phenethyl~imidazole;
1-[2,4-dichloro-~-(4'-chlorobenzylthio)phenethyl~im-
.
`~ ~5 idazole, nitrate salt, ~.P. 130.5-132C.;
~ [2,4-dichloro~ 3',4'-dichlorobenzylthio)phen-
. .,: .
et~yl]imidazole, nitrate salt, decomp. 95-96.5C.;
[2,4-dichloro~ n-heptylthio)phenethyl]imi~azole,
alate salt~ M~P. 106-lO9~C.;
1-[3,4-dichloro-~-(4'-chlorobenzylthio1phenethyl]im-
"r
`~ idazole, oxalate salt, decomp. 174-175C.;
1 -27-
,
~,. : .
., .
. ~ . , . . , .. . . . . . . .. . . - .
~ .
1~[3,~-dichloro-~-(3',4'-dichlorobenzylthio)phenethyl]im-
idazole, oxalate salt, decomp. 176-177~5C~;
1-[3,~-dichloro-~-(n-heptylthio)phenethyl]imidazole;
4-bromo-~-(4l-chlorobenzylthio)phenethyl]imidazole;
1-[4-bromo-~-(3',4'-dichlor~benzylthio)phenethyl]im-
idazole;
1-~4-bromo-~-(n-heptylthio)phenet~yl]imidazole;
1-12,4-dibromo~-(4l-chlorobenzy:Lthio)phenethyl]im-
; idazole, nitrate salt, decomp. 126~5-128Co;
- 1-[2,4-dibromo-~-t3',4'-dichlorobenzylthio)phenethyl~im-
idazole;
2,4-dibromo-~-~n-heptylthio~phenethyl]imidazole;
1-[4-fluoro-~-(4'-chlorobenzylthio)phenethyl]imidazole;
1-[4-fluoro-~ (3',4'-dichlorobenzylthio)phenethyl~im-
idazole;
[4-fluoro-~-(n-heptylthio)phenethyl]imidazole;
1-[2,4-difluoro-~-(4'-chlorobenzylthio)phenethyl]im- -
:: `
idazole;
~ .
[2,4-difluoro-~ ~3',4'-dichlorobenzylthio)phen-
2~ eth~l]imidazole, oxalate salt, d~comp. 89~5-93.5C.;
1-12,4-difluoro~ n-heptylthio)phenethyl]imidazole;
~ ~ 1-12-trifiuoromethyl ~-~4'-chlorobenzylthio)phenethyl]im-
,;~ . .
. idazole; ~ ~
1~[2-trifluoromethyl~-(3',4'-dichlorobenzylthio~phen
~25 ~ -:ethyl~imidazole, nitra~e salt, decompO 134.5-137C.;
[2-tri1uoromethyl-~-(n heptylthio)phenethyl~imidazole;
~ 4-trifluoromethyl-~-(4'-chlorobenzylthio)phenethyl]im-
: ~ idazole;
.
1-~4-trifluoromethyl-~-(3' J 4~-dichlorobenzylthio)phen-
ethyl]i~ida~ole;
... .
~ - ~28-
r!;~
., ` .
. . . . . ... . .. .
:i ~
1-[4-trifluoromethyl~-(n-heptylthio)phenethyl]im-
idazole;
1-[4-cyano-~-(4'-chlorobenzylthio)phenethyl]imi~azole;
~'. 1-14-cyano-~-(3',4'-dichlorobenzylthio)phenethyl]im~-
idazole;
~: . 1-[4-ryano-~-(n-heptylthio)phenethyl]imidazole;
: 1-[4 nitro-~-(4'-chlorobenzylthio)phenethyl]imidazole;
1-[4-nitro-~-(3'.,4'-dichlorobenzylthio)phenethyl]im-
. idazole;
~ 10 1~[4-nitro~ ~heptylthio)phenethyl]imidazole;
[2-thiocyanato~ 4'-chlorobenzylthio)phenethyl]im-
idazole;
1-12-thiocyanato~ 3',4'-dichlorobenzylthio)phen-
ethyl]imidazole; and
... .
.1-[2-thiocyanat.o-~n-heptylthio)phenethyl]imidazole.
~ . . .......... EX~MPLE 3
.. ; Repeating the procedure recited in paragraph A of
. . Example 1 using 1-(2,4,~-trichlorophenethyl)imidazole and
~ ,4,~-trlchlorophenethyl)imidazole as starting materlals
.~ 20 of Formula II and using 4-trifluoromethylthiophenol, 4-chloro-
..3-trifluoromethylthiophenol, 3,4,5-trichlorothiophenol and
... . .
pentachlorothiophenol as starting materials of Formula III
` .i9 produ~tive of the following 1-[~ thio)phenethyl3imidazoles
which, where indicated, ara urther characterized as the
~i,. . .
,~ 25 acid addition salts by.treatment in the conventional
~, ~ manner with the appropriate acid: i
.. : ~ :
. , ~
~1~ 30
:
: ~ ~29- .
.. .. .
,.. . .
~,
' .
1-~2,4-dichloro-~-(4'-trifluoromethylphenylthio)phen-
ethyl]imidazole, oxalate salt, decomp. 178-178.5C.;
2,4-dichloro-~-(4'-chloro-3'-trifluoromethylphen~lthio)-
phenethyl]imidazole, oxalate ~alt, decomp. 186-187.5C.;
1 [2,4-dichloro-,B-(3't4',5'-trichlorophenylthio)phen-
ethyl]imidazole, nitrate salt, decomp. 178-185.5C.;
1-~2/4-dichloro-~-(pentachlorophl~nylthio~phenethyl]im-
idazole, nitrate salt, decomp. 201-202.5C.;
1-13,4-dichloro-~-(4'-trifluoromethylphenylthio)phen-
ethyl]imidazole, oxalate salt, decompO 170-171C.;
3,4-dichloro-~-(4'-chloro-3'-trifluoromethylphenyl-
thio~phenethyl]imidazole, oxalate salt, decomp.
165-166C.;
1-[3,4-dichloro-~-(3',4',5'-trichlorophenylthio)phen-
lS ethyl]imidazole; and
1-[3,4-dichloro-~-(pentachlorophenylthio)phenethyl]im-
idazole. ~ ~
, . . .
" . .
~ ~ 20
,,~:, ' '
:
.
:. ~
... . .
' ~ :
. . .
, : , : . .
; 30
-3
: ~
... . .
EXAMPLE ~ .
Repeating the procedure recited in paragraph ~ of Example
2.but substitu~ing other starting materials of Formula III for
2 t ~-dïchlorobenzyl mercaptan, for example
ethyl mercaptan,
pentyl mercaptan,
octyl mercaptan,
~onyl mercap~an,
dodecyl mercaptan
. octadecyl mercaptan,
:.; 3-phenylpropyl mercaptan,
cyclopentylpropyl mercaptan,
cyclohexyl mercaptan,
- cyclohexylmethyl mercaptan,
cyclohexylethyl mercaptan,
~ cycloheptylmethyl mercaptan,
. . .
~ allyl mercaptan,
.,,,: , .
~ - . 2`-oc~enyl mercaptan,
: . .
3-phenyl-2-propenyl mercaptan,
- 3-(4-chlorophenyl~-2-propenyl mercaptan,
3 hexynyl mercaptan
2-octynyl mercaptan,
` . benzyl mexcaptan,
-~ 4-methylbenzyl mercaptan,
` ~ 2S 4 t~b~tylbenzyl mercaptan,
;, . .
~-trifluoromethylbenzyl mercaptan,
. 4-methoxybenæyl mercaptan,
: 3,4,5-trime~hoxybenæyl mercaptan,
n-butoxybenzyl mercap~an,
` 2,4,5 trichlorobenæyl mercaptan,
.~ . .
. .
.~ .
~ -31-
~ .
, : . , , : .. , . - ,. .. . . . . .
, , ,
6~
A-bxomobenzyl mercaptan,
. 4-1uorobenz~.~1 mercapt~n,
4~ni~robenzyl mercaptan, and .
. 4-cyanobenzyl me.rcaptan,
is productive of the following 1 [2,9-clichloro-~-(R-thio)phen~
:~ ethyl]imidazoles which, where indicatecl, are further char-
act~rized as the acid addition salts b~ treatment in the
conventional manner wi~h the appropriat:e acid:
. 1-[2,4-dichloro-~-(ethylthio)phenethyl]imidazole;
[2,4-dichloro-~-(n-pentylthio)phenethyl~imidazole,
oxalate salt, coalesces 99C.;
- . .1~[2,4-dichloro-~-(n-octylthio)phenethyl]imidazole,
oxalate salt, M.P. 101.5-103.5C.;
12 t 4-dichloro-g-(n-nonylthio)phenethyl]imidazole,
. oxalate salt, gels 82.5C.;
... . . 1-l2,4-dichloro~-(n-dodecylthio)phenethyl]imidazole,
oxalate salt, M.P. 124~5C.;
12,4-dichloro-~-(octadecylthio)phenethyl]imidazole,
. . . . oxalate salt, gels 91~5-150C.;
. 20 1 ~2,4-dichloro-~-(3~phenylpropylthio)phenethyl~im-
, ~ .
: idazole, oxalate salt, M.P. 87.5-90C.;
:.; .
12,4-dichloro-~-(cyclopentylpropylthio)phenethyl]im- -
~- idazole;
.. . . . . .
,4-dichloro-~-(cyclohexylthio)phenethyl3imidazole
~ 5 . nitrate salt, M.P. 114.5 117.5C.;
.- : : 1-[2~4-dichloro-~-(cyclohexylmethylthio)phenethyl]im-
~: idazole, oxalate salt, decomp. 122.5-140C.;
. : 1-[2,4-dichloro-~-(cyc.lohexylethylthio)phenethyl~im-
....
:` : . idazole,.oxalate salt/ decomp. 104-108.5C;
~ 30. : 1-12,4-dichloro-~-~cycloheptylmethylthio)phenethyl]im-
.~ ... ..
daæole;
-32-
. !, , .
.~
1-l2~q-dichloro-~-(allylthio)pheneth~l]imidazole
oxalate salt, M.P. 84.5-123C.;
; 1-[2,4-di~hloro-~-(2-octenylthio)ph~nethyl~imidazole,
oxalate salt, M.P. 112.5-116.5C.;
1-[2,4-dichloro-~-(3-phenyl-2-prc)penylthio)phenethyl]im~
idazole, oxalate salt, decomp. 151-160.5C.;
1-[2,4-dichloro- ~-(4'-ch].orophenyl)-2-propenylthio)-
phenethyl]imidazole, nitrate salt, decomp. 123 126C.;
1-[2,4-dichloro-~-(3-hexynylthio)phenethyl]imidazole,
oxalate salt, M~P. ~0.5-9S~C.i
[2,4-dichloro-~-(2-octynylthio)phenethyl]imidazole,
oxalate salt, decomp. 118-119.5C.;
2~4-dichloro-~-(benzylthio)phenethyl]imidazole;
~ . , .. ... -
:. ni~rate salt, m.p. 110-112C.; .
~ 2,.4-dichloro-~-(4.' methylbenzylthio)phenethyl]im-
. idazole, nitrate salt, M.P. 110.5-112C.;
1-~2,~-dichloro-~-(4r-t-butylbenzylthio)phenethyl~im-
.: idazole, nitrate salt, decomp. 162.5 163C.;
1-[2,4-dichloro-~-(4'-trifluoromethylbenzylthio)phen-
20 : .. . ethyl]imidazole, nitrate salt, decomp~ 112-114C.;
: . 1-[2,4-dichloro-~-(4'-methoxyb2nzylthio~phenethyl]im-
idazole, nitrate salt, decomp. 118-119.5C.;
,. 1-[2,~-dichloro-~-t3',4',5'-trimethoxybenzylthio)phen-
e~hyl]imidazole, ~xal~te salt, ~els 147C.;
. 1-12,9-dichloro-~-(4'-n-butoxybenzylthio)phenethyllim-
: ~ , :.. .... .
:~ idazole;
. ~ 1-[2,4-dichloro~ 2.',4',5'-trichloroben~ylthio)phen-
:: : ethyl]imidazole, nitrate salt, decomp. 172.5-173.5~C.;
. ., . . : . .
~ 1 [2,4-dichloro-~:-(4'-bromobenæylthio)phenethyl~im-
:., : ..
. ~ 30 idazole, nitrate salt, ~ecomp. 137~138~C.;
.,,; ~
: 1~[2,4-dichloro-~-(4'-fluorobenzylthio3phenethyl].im-
idazole, nitrate salt, decomp. 104.5-107.5C.;
33-
: ,
1-[2,4-dichloro-~-(4'-nitrobenzylthlo)phenethyl]im-
ida201e, nitrate salt, decomp. 129.5-132C.;
1-[2,4~dichloro-~-(4'-cyanobenzylthio)phenethyl]im-
idazole, nitrate salt, decomp. 119.5-123C.;
S . EXAMPLE 5
Repeating the procedure recited in paragraph A of
Example 1 using 1-(4,~-dichlorophenylethyl)imida201e and
1-[2,4/~-trichlorophenethyl)imidazole as starting materials
. of Formula II and using other s~arting materials of Formula
III for 3,4-dichlorothiophenol for example,
thiophenol,
. ~-thionaphthol,
. 4-methylthiophenol,
~, 4-metho~ythiophenol,
.. . . .
. 3-methoxythiophenol,
.2-chlorothiophenol,
- 3-chlorothiophe~ol~
., .
~ . . 2,~-dichlorothiophenol,-
.
bromothiophenol,
`~ ~0 - . 4-fluorothiophenol,
. ~ . .
~ 4-nitrothiophenol,
i: , . . .
. 4-aminothiophenol,
4-acetamidothiophenol, and
cyanothiophenol,
~ .
2~i~ productive of the ~ollowing 1-~4-chloro-~-(R-thio)phen-
ethyl~imidazoles and 1-[2,4-dichloro~ thio)phenethyl]im-
,,:
~ . idazoles which, where indicated, axe further chaxacterized
, . . . . .
~,. : .
.: ~ as t~e acid addition salts by treatment in the conventional
.~ manner with the appropriate acid:
30~1~[4-chloro-~-(phenylthio)phenethyl]imidazole, oxalate
salt! decomp 166-167C.,
~ .
. ~3~-
.,- :
.,, . :
,
~:,.,
1-[4-chloro-~-(2-naphthylthio)phenethyl]imid~zole,
oxalate salt, M.P. 193~5-194Co;
1-[4-chloro-~-(4'-methylphenylthio)phenethyl]imidazole,
oxalate salt, decomp. 199O5-200C.;
51-[4-chl~ro-~-(4'-methoxyphen~lthio)phenethyl]imidazole,
oxalate salt, decomp. 177-178t'.;
1-[4-chloro-~-(3'-methoxyphenylt~?io)phenethyl]imidazole,
oxalate salt, M.P. 164.5-165.5~C.;
1-[4-chlcro-~-(2'-chlorophenylthio)phenethyllimidazole,
10oxalate salt, M.P. 177-178C.;
1-[4-chloro-~-(3'-chlorophenylthio)phenethyl]imidazole,
oxalate salt, M~P. 169.5-171.5C~;
1-14-chloro-~-(2',5'-dichlorophenylthio)phenethyl]im-
dazole, oxalate salt, M.P. 1~1.5-183.5C.;
151-14-chloro-~-(4'-hromophenylthio)phenethyl]imidazole,
oxalate salt, decomp. 185-186.5C ;
1-[4-chloro-~-(4'-fluorophenylthio~phenethyl~imidazole,
oxalate salt, M.P~ 182.5 183C.;
4-chloro-,B-(4'-nitrophenylthio)phenethyl]imidazole,
;20oxalate salt, M.P. 203-204.5C.;
1-~4-chloro-~-(4'-aminophenylthio)phenethyl]imidazole;
1-~4-chloro-~-(4'-acetamidophenylthio)phenethyl]im-
idazole, oxalate salt, M.P. 149.5-152C.;
9-chloro-~-(4'-cyanophenylthio)phenethyl~imidazole;
251-t2,4-dichloro~ phenylthio)phenethyl]imidazole;
1~l2~4-dichloro-~(2-naphthylthio~phenethyl~imidazole;
2~4-dichloro-~-(4'-methylpllenyl~hio)phenethyl~im-
idazole: ~
1-[2,4-dichloro-~-(4'-methoxyphenylthio)phenethyl]im-
.; .
idazole;
-35-
,.
.~.
.. . . . . . . . . . .
1-12,4-dichloro-~-(3'-methoxyphenylthio)phenethyl]im-
idazole;
1-[2,4-dichloro-~-(2'-chlorophenylthio)phenethyl]im-
idazole;
. 1-[2/4-dichloro-~-(3'-chlorophenylthio)phenethyl]im-
idazolei
2,4-dichloro-~-(2',5'-dichlorophenylthio)phenethyl]im-
idazole;
1-[2,4-dichloro-~-(4'-bromophenylthi.o)phenethyl]im-
. 10 iaazole;
. 1-(2,4-dich~oro-~-(4'-fluorophenylthio)phenethyl]im-
idazolei
[2,4-dichloro-~-(4'-nitrophenylthio)phenethyl]im-
idazole;
1-12,4-dichloro-~-(4'-aminophenylthio)phenethyl]im-
idazole;
,4-dichloro-~-(4'-acetamidophenylthio)phenethyl~im-
: idazole; and
. 1-[2,4~dichloro~-(4'-cyanophenylthio)phenethyl]im-
.. 20 . idazole.
: ,~
': - - - . '
., .
~ 5
... .
~,,.
.~s
:.
.
... . .
. .
:~ 30 ~ . .
~36~
','
i.
3~D ~
EXi~t'lPL~: 6
To a ~olution o~ 400 mg. of 1-[4-chloro-~-(4'-amino-
phenylthio)phenethyl]imidazole oxalate in 20 ml. o tetrahy-
drofuran containing 1 ml. o triethylamine is added 0.5 ml.
of hexanoyl chloride. Afte~ stirrin~ for 30 minutes at room
~emperature, the solvent is evaporated under vacuum and
a~ueous potassium carbonate is added to the residue. The re-
~ult~nt a~ueous mixture is extracted with dichloromethane and
the organic phase is acidified with oxalic acid. The product
which pr~cipitates is filtered off and recrystallized from a
mixture of acetone and ethyl acetate to yield l-~I4-chloro-
~-(4' hexanoylaminophenylthio)phenethyl]imidazole oxalate,
M.P. 9~5-102~o
Similarly, su~stituting other acid chlorides ~or he~{-
ano~l chloride, for example propionyl chloride, n-valeryl
chloride~ decanoyl chloride and the like is productive of
the oorresponding
.
~ 1~[4-~hl~ro-~-(4~-propionyl~minophenylthio)phenethyl]im-
. . .
~-~ idazole oxalate,
~. .~ . .. . ... .
1-[4-chloro-?3-(4'-valeroylami~ophenylthio)phenethyl]im-
` ~ - idazole oxalate; ?
., .
~ 4-chloro-~-(4'-decanoylaminophenylthio)phenethyl]im-
~: .
~ ~~ idazole oxalate, and so forth.
. : . . .
. . .
.`. 25
.
:.
. . ....
~-37--
.
.. ~ . . ~ ,. .... . . . .
,, . . . ` . . .. .. :: : -
- EX~MP~E 7
1-[4-chloro-~-(4'~chlorophellyl~hio)phenethyl]imidazole
nitrate ( 1 g~) is treated with aqueous potassium carbonate
until a pH of approximately 11 is obtained, whereupon the
Xree base, i.e., 1-[4-chloro-P-(4'-chlorophenylthio)phenethyl~
imidazole, which separates is extract.ed with dichloromethane.
~he extract is dried with magnesium sulfate and evaporated.
To the resulting residue, in 50 ml. of chloroform at OC.
~s slowly added wikh stirring, a solution of 700 mg. of 85%
lQ m-ch~oroperbenzoic acid in 50 ml. of chloroform. When the
; addition is complete, s~irring at 0C. is continued for ap-
proximately 3 hours. Thereater, the reaction mixtur~ is
washed with aqueous potassium carbonate and aqueous sodium
chloride, dried over magnesium sulfate and evaporated. The
residue is crystallized rom benzene to yield 1-~4-chloro-~-
(4'-chlorophenylsulfinyl)phenethyl]imidazole, M.P. 13~-140C ,
which is further charactërized as the oxalate sa~t~ M.P.
1~7-16~5C.
, Similarly, repeating the above procedure on the 1-[~-
~-~hio?phenethyl]imidazole ~alts obtained in Examples 1 thru
~ 6 is productive of the corresponding l-[~-(R-sulfinyl)phen-
- ethyl~imidazoles which can be further characterized by
conversion in the usual manner to he indicated acid
-~ addition salts, e.g.,
1-12,4-dichloro-~-(n-dodecylsulfinyl~phenethyllim-
-~ idazole, oxalate salt,decomp. 134-138C.;
4-chloro~ 4'-chlorob~nzylsulfinyl~phenethyllim- -
idazole, nitrate salt, decomp 161~5-162C.; and so
forth.
3~
-38-
.~ :
.
.
:; ~ . : . .. .. .
EXAMPLE 8
1-[4-(chloro-~-(4'~chlorophenylthio)phenethyl]im-
idazole nitrate (1 g.) is treated with aqueous potassium
carbonate until a pH of approximately 11 is obtained where-
upon the free base, i.e. 1-[4-chloro-~-(4'-chlorophenylthio)-
phenethyl]imidazole, which separates is extracted with
dichloromethane. The extract is dried with magnesium
sulfate and evaporated. To the resulting residue in 50 ml.
of chloroform at room temperature is slowly added with
; ~o stirring a solution of 1.7 g. of 85~ m-chloroperben~oic
acid in 50 ml. of chloroform. When the addition is complete,
stirring at room temperature is continued for approximately
24 hours. Thereafter, the reaction mixture is washed with
- agueous potassium carbonate and aqueous sodium chloride,
dried over ma~nesium sulfate and evaporated. The residue
~is crystallized from benzene to yield 1-[4-chloro~ 4'-
'~ chlorophenylsulfonyl)phenethyl]imidazole, M.P. 176-178.5C.
Similarly, repeating the a~ove procedure on the 1-[~-
' ~R-thio~phenethyl~imidazoles or acid addition salts obtain~d
~' 20 in Examples 1 thru 6 is productive of the corresponding 1
~-R-sulfonyl) phenethyl]imidazoles which can be further
characterized b~ conver~ion in the usual manner to the
' indicated acid addltion salts, e.g.,
~ ,4-dichloro ~-~dodecylsulfonyl~phenethyi'~im-
idaæole, oxalate salt, decomp. 105.5-110C~; ;
1-[4-chloro-~-(4' chlorobenzylsulfonyl)phenethyl]im-
azole, nitrate salt, decomp. 181C.; and so forth.
,: .
.": . , .
.,. ' ' .
~ 30
~`' .
_~9_
.- ,. .
EX~MPLE 9
A solution o 85% m-chloroperbenzoic acid in chloroform
(2 g/100 ml.) is added dropwise, over a period o~ one hour,
to a stirred solution of 2.53 g. of 1~ chloro-4-methylthio-
phenethyl]imidazole in ]50 ml. of chloro~orm at 0C... After
6 hours, the resultant solution is washed with aqueous potas-
sium car~onate and with water. The organic phase is separated
and dried over magnesium sulate. Evaporation of the solvent
l-[~-chloro-4-methylsul~inylphenethyl]imidazoleO
iO Similarly, replacing l-[~-chloro-4-methylthiophenethyl]
imidazole with other l-[~-chloro-thiophenethyl)imidazoles, for
example,
l-t~-chloro-4-t-butylthiophenethyl]imidazole;
' i
chloro-4--benzylthiophenethyl]imidazole;
lS l-l~-chloro-4-(4i-chlorobenzylthio)phenethyl]imidazole;
; ; ~ l-[~-chloro-4-(4'-methoxybenzylthio)phenethyl]imidazole;
;,~ .
. ,
.~ ..... , ~
. . .
.,~ ' .
.: . -
., .:,` . : '
. ' . ' '
~:
.
:;.
~ .
: .......... .
... .
.
i~ 30
~40-
.
... . . .
.,
.
- . . - , .. ~ ~ . :
l-[~~chloro-4-phcnylthiophenethyl]imidazole, and
~ -chloro-4~ chloroph~nylthio)phenc~hyl~imi~azole,
,
. is productive of:
; l-[~-chloro-4-t-butylsulfinylphenethyl]imidazole;
1~ chloro-4-benz~lsulfinylphenethyl]imidaæole;
chloro-4-(4'-chlorobenzylsulfinyl)phenethyl]imidazole;
l-[~-chloro-4-(4'-methoxybenzylsulfinyl)phenethyl]imidazole;
~ ' ' ' ' ' .
-chloro-4-phenylsulfinylphenethyl~imidazole, and
1-[~-chloro-4-(4'-chlorophenylsulfinyl)phenethyl~imldazole.
, . . . .
.E ~ ~PLE 10
Repeating the procedure reci~ed in paragraph A of Example
1 using 3,4-dichlorothiophenol as the star~iny material of For-
: mula III and using other starting material~ of Formula II for
. 1-(2,4,~-tri~hlorophenethyl)imidazole, for example,
chloro-4~methylthiophenethyl~imidaæole;
chloro-4-t-butylthiophenethyl)imidazole;
chloro-4-benzylthiophenethyl)imidazole;
.
,B-chloro-4-(41-chlorobenzylthio~phenethyl]imidazole;
0
l-[~-chloro-4-(4'-me~hoxybenzylthio)phenethyl~imidazole,
-chlorQ-4-phenylthiophenethyl)imidazc:le;
l-[~-chloro-4-(4'-chlorophenylthio)phenethyl]imidazole;
ch~oro-4-methylsulfinylphenethyl)imidazole;
-chloro-4-t-butylsulfinylphenethyl)imidazole; .
~-~ 25
chloro-4 benzylsulfinylphenethyl)imidazole;
t~-chloro-4-(4'-chlorobenzy3.sulinyl~ph~neth~rl~i~idazc:le,
lP-chloro 4-(4~-metho~yben~ylsulfinyl)phenethyl~imidazol~;
chloro-4-phenylsulinylphenethyl~imiclazole;
-chloro-4-(4'-chlorophenylsulfinyl)phenethyl]imidazole;
, ~0
... ~ .
: ~41-
,, . ' ,
,~ , .
~-~,...................................................................... .
.~3~ s'i '
l-t~-chloro-4-methylsulfollylphenethyl)imida~ole;
-chloro-4-t-butylsulfonylphenethyl)imidazole;
-chloro-4-benzylsulfonylphenethyl)imidazole;
~ chloro-4-(4'-chlorohenzylsulfonyl)phenethyl]im-
idazole;
: l-[~-chloro-4-(4'-methoxyben2ylsulfonyl)phenethyl]im- idazole;
l-[~-chloro-4-phenylsulfonylphenethyl)imidazole, and
l-[~-chloro-4-(4'-chlorophenylsulfonyl)phenethyl]im-
. idazole;
ls productive of the foll.owing 1-[~-(3',4~-dichlorophenylthio~-
phenethyl]imidazoles:
l-(4-methylthio-~-(3',4'-dichlorophenylthio)phenethyl]im
. . . idazole;
. 1- ~4-t-butylthio-~-(3',4'-dichlorophenyltbio)phenethyl~im-
idazole;
.. .
t4-benzylthio-~-(3',4'-dichlorophenylthio)phenethyl]im-
. i~azole;-
. I-t4-(4-chlorobenzylthio)-~-(3';4'-dichlorophenylthio~phen-
- ~ 20 . ethyl]imidazole;
. . I-l4-~4-methoxybenæylthio)-~-53',4'-dichlorophenyl-
s-~ ~. thiojphenethyl]imidazole,
4-phenylthio ~-(3',4'-dichlorophenylthio)phenethyl]im-
idazole;
; ~ 25 l-14 (4-chlorophenylthio)-~-(3',4l~dichlorDphenylthio)phen-
.~ -ethyl]imidazole;
, ~
~ -methylsulfiny~ 3~4~-dichlorophenylthio)phen
.: ethyllimidazole;
~, .
4-t~bu'tylsulfinyl-~-(31,4'-dichlorophenylthio)phen-
3~ e~hyl]imidazole;
~ ,
~ 42-
.~ , .
. :~ . ~ .
,,
' . :
: .
, ' ''' :
1-14-~enzylsulfinyl-~-(3',4'-dichlorophenylthio)phen-
ethyl]imidazole;
l-[4-~4-chlorobenzylsulfinyl)~ 3',~'-dichlorophenyl-
thio)phenethyl]imidazole;
l-[4-(4-methoxybenzylsulfinyl)-~-(3',4'-dichlorophenyl-
~hio)phenethyl~imidazole;
l-[4-phenylsulfinyl-~-(3',4'-di.chlorophenylthio)phen-
ethyl]imidazole;
l-[4-~4-chlorophenylsulfinyl)-~-(3',4'-dichlorophenyl-
thio~phenethyl]imidazole;
l-[4 methylsulfonyl-~3',4'-dichlorophen~lthio)phen-
; ethyl]imidazole;
. , .
~ 4-t-butylsulfonyl-~ (3',4' dichlorophenylthio~phen-
, .
. . e~hyl~imidazole,
~ 15 - l-[4-benzylsulfonyl ~-(3',4'-dichlorophenylthio)phen
. ethyl]imidazole;
. l t4-t4-chloro:benzylsulfonyl?-~-(3~4l dichlorophenyl-
. thio~phenethyl~imidazole;
.
14-(4-methoxybenzylsulfonyl)-~-(3',4'-dichloro-
~henylthio)phenethyl]imidazole;
[4-phen~lsulfonyl-~-~3',4'-dichlorophenylthio)phen-
. . . . ethyl]imidazole; and .
.~ . .l-[4-(4-chlorophenylsulfonyl)-~ (3',4'~dichlorophenyl-
, .............................. . . .
thio)phenethyl]imidazole.
.~ 25 . ~ : . EXAMPLE ll
.: ~ . Repeating the procedure recited in para~raph A o~
~ .
Example 2 using 4-chIorobenzyl mercaptan as the staxting
material of Formula III and using other starting materials
; o Formula II for 1 (2,4,~-trichlorophenethyl)imidazole, i.e.,
; ~ 30those starting materials of Formula II reci~ed in Example lO,
. _~3
,
. .~ . .
.,., . ' '
; .
.
, - . ~- .. .. ~ . . ~. , . . -
is pxoductive of the following 1-[~-(4'-chlorobenzylthio)phen-
ethyl]imldclzoles:
1-[4-methylthio-~-(4'-chlorobenzylthio)phenethyl]im-
idazole;
1-~4-t-butylthio-~~(4l-chlorobenzyl.thio)phenethyl]im-
ida~ole;
4-benzylthio~ 4'-chlorobenzylthio)phenethyl]im-
idazole;
:~ . l-t4-t4-chlorobenzylthio)-~-(4'-chlorobenzylthio)phen-
; 10 ethyl3imidazole;
. 1-[4-(4-methoxybenzylthio)-~-(4'-chlorobenzylthio)phen-
ethyl]imidazole;
4-phenylthio-~-(4'-~hlorobenzylthio)phenethyl~im-
. idazole;
1-[4-(4-chlorophenylthio)-~-(4'-chlorobenzylthio)phen-
. ethyl]imidazole;
1-[4-methylsulfinyl-~-(4'-chlorobenzylthio)phenethyllim-
idazole;
[4-t-butylsulfinyl-~-(4'-~hlorobenzylthio)phenethyl~im-
~. 20 idazole;
: 1~[4-benzylsul~inyl-~ (4'-chlorobenzylthio)phenethyllim-
idazole;
1-14-(4-chlorobenzylsulfinyl)-~-(4'-chlorobenzylthio)phen-
ethyl]imidazole;
1-~4-(4-methoxybenzylsulfinyl)-~-(4'-chlorobenzyl-.
thio)phenethyl]imidazole;
4-phenylsulfinyl-~-(4'-chlorobenzylthio)phenethyl]im- .
. - .
. idazole;
`; 1-[4-(4-chlorophenylsulfinyl)-~-(4'-chlprobenzyl- .
thio3phenethyl]imidazole;
. ~
' ' ' ' ' ' ' .
.
,. ,
1 [4-methylsulfonyl-~-(4'-chlorobenzylthio)phen-
ethyl]imidazole;
: 1-[4-t-butylsulfonyl-~-(4l-chlorobenzylthio)phen
- ethyl}imidazole;
1-[4-benzylsulfonyl-~-(4'-chlorobenzylthio)~henethyl]im-
idazole;
1-(4-(4~chlorobenæylsulfonyl)~-t4'-chlorobenzyl- .
~hio)phenethyl]imidazole;
1-[4-t4-methoxybenzylsulfonyl)-~-(4'-chlorobenzyl-
thio)phenethyl]imidazole;
1-[4-phenylsulfonyl-~-(4'-chloro~benzylthio)phenethyl]im-
idazole; and
4-(4-chlorophenylsulfonyl~ t4'-chlorobenzyl~
thio)phenethyl]imidazole.
:. , , - ,, , ' , .
: , . . .
~. . .
~0
- . .
. . ,- . . . .
1 . . . .. .
, . :
. 25
,, , . - . .
- .. . .:
i;:,. . .
. _ ....... _ _ . .
,: ~ , ~ .. . _ .... .
: : 45
.. . .
., .
.
, ., , . , . , "
;,. ,, : i . ; ' ' ! . . ' . ` ' ~ ' ' '
EXAMPLE 12
Repeating the procedure recited in Example 7 (using the
appropriate quantity of m-chloroperbenzoic acid) on the pro-
ducts obtained in Examples 10 and 11 is p:roductive of the
followin~ l-[~-R-sulfinyl)phenethyl]imidazoles;
1-[4-phenylthio-~-(3',4'-dichlorophenylsulfinyl)phen-
ethyl]imidazole;
1-[4-(4-chlorophenylthio)-~-(3',4'-dichlorophenyl-
sulfinyl)phenethyl]imidazole;
1-[4-methyl.sulfinyl-~-(3',4'-dichlorophenylsulfinyl)phen-
ethyl]imidazole;
1-[4-t-butylsulfinyl-~-(3',4'-dichlorophenylsulfinyl)phen-
ethyl]imidazole;
1-[4-benzylsulfinyl-~-(3',4'-dichlorophenylsulfinyl)phen-
ethyl]imidazole;
[4-(4-chlorobenzylsulfinyl)-~-(3',4'-dichlorophenyl-
: sulfinyl)phenethyl]imidazole;
1-[4-(4-methoxybenzylsulfinyl)-~-(3',4'-dichlorophenyl-
sulfinyl)phenethyl]imidazole;
,1 20 1.-[4-phenylsulfinyl-~-(3',4'-dichlorophenylsulfinyl)phen-
`?::
ethyl]imidazole;
1-[4-(4-chlorophenylsulfinyl)-~-(3',4'-dichlorophenyl-
sulfinyl)phenethyl~imidazole;
1-[4-mthylsulfonyl-~-(3',4'-dichlorophenylsulEinyl)phen-
ethyl]imidazole;
1-[4-t-butylsulfonyl-~-(3',4'-dichlorophenylsulfinyl)phen-
ethyl]imidazole;
1-[4-benzylsulfonyl-~-(3',4'-dichlorophenylsulfinyl)phen-
ethyl]imidazGle;
1-[4-(4-chlGrobenzylsulfonyl)-~-(3',4'-dichlorophenyl-
sulfinyl)phenethyl]imidazole;
-4~-
~ ~ . . . - ,: : . . .
1 ~4-(4-methoxybenzylsulfonyl)-~-(3',4l-clichloro-
phenylsulfinyl)phenethyl]imidazole;
1 ~4-phenylsulfonyl-~-(3',~'-dichlorophenylsulfinyl)phen-
ethyl]imidazole;
1-[4-(4-chlorophenylsulfonyl-~-(3',4'-dichloropherlyl-
sulfinyl)phene~hyl~imidazole;
1-[4-phenylthio-~-(4.'-chlorohenzylsulfinyl)phenethylJim-
ldazole;
1-[4~(4-chlorophenylthio)~~ (4'-chlorobenzylsulfinyl~phen-
~thyl]imidazole;
1-[4-methylsulfinyl-~-(4'-chlorobenzylsulfinyl~phen-
ethyl]imidazole; - .
t-butylsulfinyl-~ (4'-chlorobenzylsulfinyl)phen-
ethyl]imidazole;
. 1-[4-benzylsulfinyl-~-(4'-chlorobenzylsulfinyl3phen-
ethyllimidazole;
: 1-[~-(4-chlorobenzylsulfinyl)-~-(4' chlorobenzyl-
~: s~lfinyl)phenethyl]imidazole;
1-[4-~4-methoxybenzylsulfinyl)-~-(4'-chloroben2yl
.. ..
. sulfinyl~phenethyl]imudazole;
1-[4-phenylsulfinyl-~-(4'-chlorobenzylsulfinyl)phen-
. ethyl]imidazole;
~-[4-(4-chlorophenylsulfinyl1-~-~4'-chlorobenzyl-
.~ sulfinyl)phenethylJimidazole;
~: 2S 1 [~methylsulfonyl-~-(4l-chlorobenzylsulfinyl~phen-
,:; - , .
:~ ethyl~imidazole;
1-[4-t~butylsulfonyl-~-(4'-chlorobenzylsulfinyl~phen-
` ethylJimidazole;
: 1-14~benzylsulfonyl-~-(4'-chloxobenzylsulfinyl)phen-
. : 30 ethyllimidazole;
_
;`~ . .
:
: .
1-[4-(4-chlorobenzylsulfonyl).~ chlorobc-~nzyl-
sulfinyl)phenethyl]imidazolei and
1-[4-(4-methoxybenzylsulEonyl)-~-(4'-chlbrobenzyl-
sulfinyl)phenethyl]imidazole.
EXAMPLE 13
Repeating the procedure recited in Example 8 on the
products obtained in Examples 10 and 11 is productive of the
:~ following l-[~(R-sulfonyl)phenethyl]imidazoles:
1-[4-phenylthio-~-(3',4'-dichlorophenylsulfonyl)phen-
. 10 .ethyl]imidazole;
. 1-~4-(4-chlorophenylthio)-~-(3',4'~dichlorophenyl-
. sulfonyl)phenethyl]imidazole;
4-phenylsulfi.nyl-~-~3',4' dichlorophenylsulfonyl)phen-
. ethyl]imidazole;
1-[4-(4-chlorophenylsulfinyl)~ 3',4'~dichlorophenyl-
. sulfonyl~phenethyl]imidazole;
. 1-[4-methylsulfonyl-~-(3',4'-dichlorophenylsulfunyl~phen-
ethyl]imidazole;
[4-t-butylsulfonyl-~-(3',4'-dichlorophenylsulfonyl)-
phenethyl]imidazole;
[4-benzylsulfonyl-~-(3',4'-dichlorophenylsulfonyl)-
phenethyl]imidazole;
4-~4-chlorobenzylsulfonyl)~ 3',4'-dichlorophenyl~
. sulfonyl)phenethyl]lmidazole; .
1-[4-(4-methoxybenzylsulfonyl)-~-(3',4'-dichlorophenyl-
sulfonyl)phenethyl]imidazole;
. 3~ .
' , , . ' ' .
~ -~8
`I .
- . ~ -
1-[4~phenylsulfonyl- ~ (3',4'-dichlorophenylsulfonyl~phen-
ethyl]imidazole;
1~[4-(4-chlorophenylsulfonyl)-~-(3',4'-dichlorophenyl-.
~ulfonyl~phenethyl]imidazole,
1-[4~phenylthio-~ '-chlorobenzylsulfonyl)phellethyl]lm-
idazole;
1~[4-(4-chlorophenylthio)-~-(4'-chl~robenzylsulfonyl)phen-
ethyl3imidazole;
1-[4-phenylsulfinyl-~-~4'-chlorobenzylsulfonyl)phen-
ethyl]imidazole;
1-[4-(4-chlorophenylsulfinyl)-~~(4'-chlorobenzylsul-
- fonyl)phenethyl]imidazole;
1-~4-methylsulfonyl-~-t4' chlorobenzylsulfonyl)phen-
. ethyl]imidazole;
.... .
1~ t-butylsulfon~ (4'-chlorobenzulsulfonyl)phen-
e~hyl]imidazole;
4-benzylsulfonyl-~-~4'-chlorobenzylsulfonyl)phen- ..
ethyl~imidazole;
[4-(4-chlorobenzylsulfonyl)-~-(4'-chlorobenzyl-
~o . . sulfonyl)phenethyl]imidazole;
1-[4~(4-methoxybenzylsulfonyl)-~-(4'-chlorobenzyl-
... . . .
sulfonyl) phenethyl]imidazole;
[4-phenylsulfonyl-~-(4'-chlorobenzylsulfonyl)phen-
: ethyl]imidazole; and
- 25 -1 [4-(4-chlorophenylsulfonyl)-~-(4'-chlorobenzyl-
sulfonyl)phenethyl~imidazole.
EX~MæLE 14
:~ Repeating the procedure recited in Example 1~ using
reactants as dictated by the particular l-[~-(R-thio)phen-
~` 30 ethyl~imidaæole de~ixed, is prodùctive of th~ following
.. . ..
. --49~ .
. . .
:.
` .
: .
~ 3 ~J~
compounds which, where indicated, are further chaxacterized
- as the acid addition salts by treatmen~ in the conventional
manner with the appropriate acid.
1-[2,4-dichloro-~-(4'-nltro-~trifluoromethylphenyl-
S thio)phenethyl]imidazole, nitrate salt, decomp.
127.5-130.5C.;
1-[4-trifluoromathyl-~-(4'-tert-butylphenylt~io)phen-
ethyl3imidazole, oxalate salt, MoP~ 161-162C.;
1-[2,4-dimethyl-~-(3',4'-dichlorophenylthio)phen-
e~hylJimidazole, nitrate salt, decomp. 165~5-166C.;
1-[4-methoxy-~-(3',4'-dichlorophenylthio)phen-
ethyl]imidazole, oxalate salt, M.P. 145.5C.;
1~[4~methoxy-~-(4'-tert-butylphenylthio)phen-
ethyl]imidazole, oxalate salt, M.P. 139.5-141.5~C.;
1-~2,4-dimethoxy-~-(3',4'-dichlorophenylthio)phen-
ethyl~imidazole, nitrate salt, decomp. 155.5-158C~;
1~[4-nitro-~-(pentachlorophenylthio)phenethyl]im-
idaæole, nitrate salt, decomp. 163.5-165.5C;
1-[2,4-dichloro-~-~n-butoxyphenylthio)phenethyl]im-
idazole, oxalate salt, m~p. 143-144C.;
; 1-[4-cyano-~-(pentachlorophenylthio)phenethyl]im-
idazole, nitrate salt, m.p~ 18205-183~5C. (foaming~;
1-[4-n-butylthio-~-(4'-chloxophenylthio)phenQthyl]im-
idazole; and
1-[4-methylthio~ 3',4'-dichlorophenylthio)phen-
- etbyllimidazole.
. .
., -- . .. ~ .. .. .
~; 30
.~ - . - .... .
.. . -50-
; . . ... - . ,
~ EX~MPLE 15
Repeating the procedure reci.ted in Example 2, using
.. reactants as dictated by the partlcula:r 1-[~-(R-thio)phen-
ethyl]imidazole desired, is productive of the following com-
pounds which; where indicated,are further characterized as
the acid addition salts by treatment in the conventional
manner with the appropriate acid:
1-[2,~-di~luoro-~-(n-nonylthio)phenethyl]imidazole,
. oxalate salt, M.P. 79.5-84C.;
: 10 . 1 [2,4-dimethyl~ 4'-chlorobenæylthio)phenethyl]im-
idazole, oxalate~salt, decomp. 80.5-83C.;
1-[4 methoxy-~-(3-phenylpropylthio)phenethyl]im-
idazole,.oxalate salt, M.P. 75-83C;
4-methoxy-~-(n-dodecylthio)phenet.hyl]imidazole;
.
~` 15 oxalate salt, m.p, 90-93C.;
1-[2,~-dichloro-~-(1'-naphthylmethylthio)phen--
!- ethyl]imidazole, oxalate salt, coalesces 86C.. ,
;~ . . .~oams 86-121~ 5Co;
.~ . 1-~4-chloro-~-.(ethylthio)phenethyl]imidazole, oxalate
saltl M.P.. 157-158C.;
~ . 1-[2,4-dichloro-~-(n-undec-10-enylthio)phenethyl]im-
idazole, oxalate salt, M.P. 82-107C.;
[2,4-dichloro~ 3-(4'-methylphenyl~prop-2-enylthio)-
phenethyl]imidazole~ nitrate salt, m.p. 133.5-137C.;
~ 25 1-~2,4-dichloro-~-(3-(4'-tert-butylphenyl)prop 2-enyl
i: .
. thio)phenethyl]imidazole, nitrate salt, m.p. 147-153 D 5C.;
2,4-dichloro~ 4-phenylbut-3-enylthio)phen-
ethyl]imidazole;
[2,4-dlchloro-3-(3-(4'-chl.orophenyl)propy:lthio)p}len-
ethyl~imidaæole, oxala~e salt, m.p. 111-113C.;.
2~4-dichloro-~-(prop-2-ynylthio)phenet~lyl]imidazole;
.'~; ' ' - . .
:
:~ -51~
~ i 3~ D~ y `
1-[4-methylthio-~-(3',~'-cLichlorobenzylth:io)phen-
- ethyl]imidazole;
l~[~-n-butylthio-~-(4'-chlorokerlzylthio)phenethyl]im~
idazole;
1--l2,4-dichloro-~-(n-hexylthio)E~henethyl]imidazole;
2,4-dibromo-~ (n-hexylthio)p~ienethyl]imidazole;
1-[2,4-dibromo-~ (n-octylthio)phenethyl]imida~ole;
1~ - .
[2,4-difluoro-~-(n-octylthio)phenethyl]imicLazole; and
.
1=~2,4~difluoro-~-(n-decylthio)phenethyl]imidazoleO
.
,~ . . .
:~ ''' ' ' ' ' .
.
.
3~ . .
92 ~ .
EX~MPLE 16
1-[4-chloro-~-t4'-chlorophenylthio)phenethyl]im-
. idazole nitrate (1 g.) in 100 ml. of dichloromethane is
shaken with excess dilute potassium c~rbonate solution
until the salt is completely dissolved. The organic layer
is then separated, washed with water and dried over
magnesium sulfate~
Evaporation of the solvent yields 1-[4-chloro-~-(4'-chloro-
phenylthio)phenethyl]imidazole as a gum.
1~ In similar manner, the acid addition salts of all
compounds of Formula ~I) can be converted to the corres-
ponding compounds in base form, for example,
1-[2,4-dichloro-~-(3',4'-dichlorophenylthi.o)phen-
ethyl]imidazole,
1-[2,4-dichloro-~-(2',41-dichlorobenzylthio~phen-
-; . ethyl]imidazole;
[2,4-dichloro-~-(n-heptylthio)phenethyl]imidazole?
1-[2,4-dichloro-~-(4'-chlorophenylthio)phenethyl]im-
idaæole.
1-[2~-dichloro-~-~4'-chlorobenzylthio)phenethyl]im-
idazole, and so forth.
` 2~
, . . .
52a~
ExAMæLE 17
Nitric acid (70%; d=1.4Z) is added dropwise to a
stirred solution or 2.5 g. of 1-[4-chloro-~ (4'-chloro-
phenyl~lio)phenethyl]imidazole in 40 ml~ anhydrous ether
until precipitation is complete. The product is filtered
of, washed with ether and dried. Recrystallization from
ethyl acetate yields 1-[4-chloro-~-(4'-chlorophenylthio)phen-
ethyl]imidazole nitrate, m.p. 136.5-137.5~C
In similar manner, all compounds of Formula (I) in
base foxm can be converted to the acid addition salts by
tr~atment in the conventional manner with the appropriate
acid.
.
~ ~0 .,
. ~ .
~" ' .
,~ , , .
~; 2S ;
' . ' ' '
' ' . '
3~
~ -53-
; .
EX~MPLE 18
The anti-bacterial activity of certain compouncls of
th~ presentinvention and of Keflin* is illustrated in the
following procedure.
S Streptococcus faecalis, a gram~) bacteria, is
cultured at 37C. in Brain-Heart Infusion Broth (Difco).
After 24 hours the culture is diluted to a concentration
of lx108 cells/ml. with the growth medium. Of this
suspension, 0.05 ml. is added to various dilutions of the
test compounds.
The test compounds are dissolved in dimethyl sulfoxide,
ethanol or water at a concentratlon of 10 mg./ml. and
thereafter diluted with sterile water to give a stock solution
ha~ing a concentration of 100 ~g./ml. From this stock
lS solution, appropriate dilutions are made. Approximately
~4 ml. of each dilution is added to a sterile test tube
and 0.05 ml. of the above prepared inoculum is then added
~ .
to each tube. Incubation is then carried out for 24 hours
and the minimal inhibitory concentration (MIC), which is
~he concèntration at which no visible growth occ~rs,
is then determined.
. ~ ' .
~ ,
~ 25~
j
Y * sodium salt o~ 7-tthiophene-2-acetamido) cephalosporanic acid.
.1 .
.1, . . .
Y~ 30
53a-
~, . ,
:
'': ,
' , - ~ ~ . , . : ~ ' ' . . . .
' ' . ' . ' . , ~ , ' ~ , :
i f ~ f~ ~ ~`?
Table I
. :............................. Minimal Inhibitory Concen-
Compound tration ~g./ml.
Keflirl ____ 33
l-[3,4-dichloro-~-(3',4'-dichloro- lO
;. phenylthio)phenethyl]imidazole
nitrate
l-12,4-dichloro-~-(4l-chlorobenzyl- lO
. . thio)phenethyl]imidazole nitrate
l-[4-chloro-~-(4' chlorophenylthio)-3.3
:~ . phenethyl]imidazole nitrate
~; 10
.. . . .
:. ,
.
: 15 . .
.~ , .
~`','~ . '
' . '
; 20
:~ . . . . .. -
.: . .
.. .
.. .
.. . .
,
;:~ 25
: '
: . .
.;
'~ . : . .. .- .
.. ... . .
O . ... .
k
53b-
.
:1
~,
,
~ ,æ~
EX~MPLE 19
The anti-fungal activity of certain compounds of the
present invention and of Mi,conazole* is illustrated in the
following procedure.
~richophyton rubrum i5 cultured on Sabourad Dextrose
agar (DifCo) at room temperatlure for 14 days. The fungi
mat is then removed from the agar slant and homogeniæed to
a fine suspension in Sabouraud Dextrose ~roth~ This
suspension i5 diluted to a uniform concentration (OD of 0.1
at 600 nm3 and 0.05 ml. is added to various dilutions of the
test compounds.
The test compounds are dissolved in dimethyl sul-
~oxide, ethanol or water at a concentration of 10 mg./ml.
and thereafter diluted with sterile water to give a con-
centration of 100 ~g/ml. From this stock solution
',,appropriate dilutions were made. Approximately 4 ml. of
each dilution is added to a sterile test tube and 0.05
ml. of the above prepared inoculum is then added to each tube.
', Incubation is carried out for 7 to 14 days depending on the
growth in the negative control.
The minimal inhibitory concentration (MIC), which
is the concentration at which no visible growth occurs,
is then determined for each test compound and for Miconazole.
~he results obtained are listed i~ Table I.
, ~5~
, ~ .
.
, . .
" ~
* 1-[2,4-dichloro-~ (2',4~-dichlorobenzyloxy)phenethyl~im-
`' idazole nitrate.
~ 53~-
.
Table I
Minimal Inhibitory Concen-
Compound tration llg./ml.
Miconazole _ 10
- ~ _
1-[2,4-dichloro-~-(2',4'-dichloro- 3
benzylthio)phenethyl~imidazole
nitrate
1-[2,4-dichloro-~-(g'-chlorobenzyl- 3
thio)phenethyl~imidazole nitrate
1-[2,4-dichloro-~-(n-heptylthio)phen- 3
ethyl~imidazole oxalate
; ,ln
. ' ' ' ' .
- - .
: lS
: '' ' '
.
. .
~" .
: . . .
i . i
~' ' ~" ' ' .
, : -.... ... : .
~ 25
: ;
I j - _ . -
,, ~ . . .
.~ . .
, 30
,' . .
~ 53d~
. ' .
~ .
.
: . .
' ~ '- ' , , ~ , ' :
: . , - ~. . ~ ~ : . .
Example 20
. The followin~ formulations are typical of topical, oral
and parenteral dosage forms for the compounds of the present
- inventionO
Cream:
a compound of the present invention 1.0 g.
stearic acid 10.0 g.
Span 60 (Tradename for commercial 5.2 g.
surfactant)
Span 80 (Tradename for commercial 1.0 g.
surfactant)
propylene glycol 5.0 g.
me~hyl paraben O.OS g.
propyl paraben 0.01 g.
distilled water qs. to 100.0 g.
The constituents are mixed at 60~C. and cooled with agitation
- to produce a smooth cream.
Tablet:
; a compound of the present invention 100 mg.
~ lactose USP 80 mg.
., .
; 20 cornstarch 16 mg.
; polyvi~ylpyrrolidone 5.6 mg.
magnesium stearate 0.4 m~.
,.' . ~00.0 Ing.
The constituents are mixed and granu1ated with an appropriate
solvent, e.g~ methanol, dried, then formed into tablets using
-~ suitable tableting equipment.
Suppository o
a compound of the present inventionOol g.
.;; .
polye~hylene glycol 1000 1~0 gO
; 30 polyethylene glycol 4000 0~
10 2 g~
~ ~ -53e-
,:
. . . , .. . , . .. - ~ : ; .
The constituents are mixed together at 50C., then poured
into molds and allowed to cool to room temperature.
Iniectable Solution:
a compound of the present invention0.5 g.
propylene glycol 30.0 g.
sodium chloride 0.8 g.
distilled water qs. to 100 ml.
A solution of the active compound hereof in the propylene
glycol is mixed with the sodium chlor.ide in water, brought to
lD final volume, and filtered through 0.2~ membrane filter and
.packaged under s~erile conditions.
.
.'
~ 20
,, .
,,
~, .
," .
'.
, :
.,1 . .
. 3~
-53~-
~.
,: .: ., . . . ~. . .
