CA1155857A - 1-phenethylimidazole derivatives - Google Patents

Abstract

ABSTRACT

1-Phenethylimidazole compounds of the formula:

wherein R4 and R5 are independently hydrogen or halogen, and Z is a mono or disubstituted phenyl moiety of the formula:

Description

l-PHENETHYLIMIDAZOLE DERIVATIVES
-I. Description:

This invention relates to certain novel l-phenethylimidazole derivatives and their antimicrobial acid addition salts, antimicrobial compositions containing the same, and methods of employing such derivatives, salts and compositions for inhibiting the growth of fungi and bacteria.

A large number of antifungal and antibacterial agents have been previously described which contain a ~ aryl)ethyl-lH-imidazole moiety of the formula: ~
N

N

- 2 1 a For example, in U.S. 3,7i7,655 and E. F. Godefroi et al, J. Med. Chem. 12, 784 (1969), compounds of formula 1 are disclosed in which Ra is:

-X(CH2)n-wherein X is O or NH

-2~ 5 ~ ~ 7 In U.S. 3,991,201 and J. Heeres et al, J. Med.
Chem. 20, 1511 (1977), ~uch compounds are disclosed in which Ra is -(CH2)n-Ar.

In J. Heeres et al, J. Med. Chem. 20, 1516 (1977), such compounds are disclosed in which Ra is -(CH2)nO-Ar.

In U.S. 4,055,652 and 4,039,677, such compounds are disclosed in which Ra is -SR2 wherein R2 is H, benzyl, phenyl, etc.

In U.S. 4,039,677 and 4,038,409, such compounds are disclosed in which Ra is -XICl-R3 wherein X and Y are O or S and R3 is H, alkyl, cycloalkyl, phenalkyl, phenalkenyl, or -XR4 wherein R4 is alkyl, halophenyl, etc.

In U.S. 4,006,243, such compounds are disclosed in which Ra is H, alkyl or phenyl.

An entirely new class of compounds of formula 1 has now been discovered which have very good anti-fungal and antibacterial activity, namely those in which Ra is an optionally nuclearly substituted group of the formula~
A -X-(CH2)n-Y-(CH2)m ~
wherein X and Y are independently sulfur or oxygen, m is zero or 1 and n is 1, 2 or 3, with the proviso that when n=l, X and Y cannot both be oxygen, and the CH
bonded phenyl ring is also optionally nuclearly sub-stituted, and including the antimicrobial acid additionsalts of such compounds.

The products of the present invention are named as derivatives of l-(ethyl)-lH-imidazole with the substituents Rl and R2 located at position 2 of the ethyl side chain, as in the following formula 2:

1 ~S~a ~

2 ~ ~
Il 2 CH2 FH- Rl Alternatively, the products can be named as derivatives of l-(phenethyl)-lH-imidazole where the substituent Rl is attached 3 to the imidazole ring, as in the following formula 3: .

I ~

3 CH2CH-Rl As indicated above, a primary feature of the present invention is the provision of novel compounds of formula 1 above in which Ra has the formula A above and the CH
bonded phenyl ring is optionally nuclearly substituted, and including the antimicrobial, i.e. antifungal and antibacterial, acid addition salts of such compounds, especially compounds of the formula:

4 c~f~-x (C~2,n~Y~(C~2,. ~ F~2 R5 - ~

~1 5~ 7 including the antimicrobial acid addition salts thereof, wherein:

X and Y are independently sulfur or oxygen; m is zero or l; n is l, 2 or 3, with the proviso that when n=l, X
and Y cannot be both oxygen; Rl and R2 are independently hydrogen, halogen or alkyl or taken together the atoms necessary to complete a naphthalene ring; R3 is hydrogen, halogen such as chlorine or fluorine, CF3, SCF3, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, pyrrolidinyl, piperidinyl, piperazinyl, alkanoylpiperazinyl, morpholinyl, alkylamino, dialkylamino, alkanoylamino, amino, nitro, carboxy, carboalkoxy or an aryl radical selected from the group consisting of phenyl, benzyl, benzoyl, phenylthio, phenylsulfonyl, phenylamino and benzoylamino, said aryl radical being optionally nuclearly substituted by one or more halogen, CF3, alkyl or alkoxy radicals' and R4, R5 and R6 are independently hydrogen, halogen, CF3, alkyl, alkoxy or phenyl optionally nuclearly substituted by one or more halogen, CF3, alkyl or alkoxy radicals;

and wherein with reference to the above, alkyl, alkoxy and alkanoyl radicals contain 1 to 6 carbon atoms, alkenyl and alkynyl radicals contain 2 to 12 carbon atoms, and cycloalkyl radicals contain 5 to 8 carbon atoms.

The subject compounds of formula 4 above exhibit antifungal and antibacterial activity against animal and human pathogens as well as antifungal activity against fungi of primarily agricultural importance. Thus, the subject compounds are found to be u-seful antimicrobials, having not only pharmaceutical but also agricultural and industrial applications. Thus, a further feature of the present invention relates to methods of inhibiting the growth of fungi and bacteria ~.

by applyin~ to a host object containing, or subject to attack by, fungi or bacteria, a fungicidally or bactericidally effective amount of a compound of this invention. A still further feature of the S present invention relates to compositions for pharma-ceutical, agricultural, and industrial use, which compositions comprise the subject compounds of formula 4 in combination with a suitable carrier.
Preferred embodiments of the invention include 1-phenethylimidazole compounds of the formula:
~3 N

~ ~4 (I) ~' wherein R4 and R5 are independently hydrogen or halogen, and Z is a mono or disubstituted phenyl moiety of the formula:

~ R2 wherein Rl and R2 are independently hydrogen, halogen, (lower) alkyl, or trifluoromethyl, with the proviso that Rl and R2 can not both be trifluoromethyl and the antimicrobial acid addition salts thereof.

,. ,~
.

-5~-Still another eature of this invention ~ 8 the provision of compounds useful as intermediates for pro-ducing the compounds of formula 4 above, such inter-mediates having the formula:

N
CH2( 'H-X(CH2)n- Z
B

R5~ ~~R6 wherein Z is a member selected from the group con-sisting of YM, halo, COOalkyl, methanesulfonate and -S2 ~ CH3, M is ~ or alkali metal, and X, Y, R4, R , and R and n have the values defined above.

As employed herein and in the appended claims, ~alkyl", "alkoxy" and "alkanoyl" groups contain a saturated, branched or unbranched acyclic hydro-carbon group of 1 to about 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl and hexyl and isomeric forms thereof. I'Alkenyl'' groups contain a branched or unbranched acyclic hydrocarbon group , j, having carbon-carbon double bond unsaturation and about 2 to about 12 carbon atoms such as allyl ethenyl, 2-hexenyl, 3-octenyl, 2-octenyl, 2-decenyl, l-dodecenyl and the like. "Alkynyl" groups are similar to "alkenyl" but with carbon-carbon triple bonds instead of double bonds. "Cycloalkyl" groups contain a saturated monocyclic hydrocarbon group of about 5 to about 8 carbons such as cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. "Halogen"
or "halo" refers to iodo, fluoro, bromo and most preferably chloro. The term "antimicrobial acid addition salts" refers to the crystalline salts of the subject compounds which possess the desired antimicrobial activity and which are neither biologically nor otherwise undesirable. Such salts are formed by contacting the subject compounds with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and phosphoric acids, and organic acids such as fumaric, oxalic, maleic, acetic, pyruvic, citric, tartaric, methanesulfonic, ethane-sulfonic, p-toluenesulfonic, hydroxyethanesulfonic, sulfamic, malic, succinic, ascorbic, levulinic, propionic, glycolic, benzoic, mandelic, salicylic, lactic, p-aminosalicylic, 2-phenoxybenzoic, 2-acetoxy-benzoic, 1,4-naphthalene disulfonic acids and the like.

The subject compounds of formula 4 are organic bases, the majority of which are viscous oils in the free base form. The free bases are usually purified by column chromatography on either silicic acid or alumina and may then be converted to their solid acid addition salts by contacting them with one of the above salt-forming acids, usually in a solvent such , 1'~;~S~ ~

as water, ethanol, l-propanol, ethyl acetate, ace-tonitrile or diethyl ether. Upon cooling or dilution with a less polar solvent the acid addition salts usually crystallize.

Such compounds of formula 4 contain a chiral or asymmetric center, i.e. the carbon atom in the depicted CH link, and therefore may exist as enantiomers which may if desired be separated by known procedures such as by conventional resolution means employing optically active acids such as the optically active forms of camphor-10-sulfonic, ~-bromocamphor-~-sulfonic, camphoric, menthoxyacetic, tartaric, malic, di-acetyltartaric, pyrrolidone-5-carboxylic acids and the like. It will be understood that this invention is inclusive of such optical isomers and the racemic mixtures thereof.

PREPARATION OF ANTIMICROBIAL PRODUCTS

The compounds of formula 4 are prepared utilizing the inherent variations of the Williamson Ether Synthesis (Houben-Weyl, Methoden Der Organischen Chemie, VI (Part 3)1975~.

As shown in Scheme I tosylate 5 is reacted with phenoxides (6, m=O, Y=O), thiophenoxides t6, m=O, Y=S), or the sodium or lithium salts of benzyl alcohols (6, m=l, Y=O) or benzyl mercaptans (6, m=l, Y=S) to provide the ethers 7 ~Y=O or S, m=O or 1).

Similarly, tosylate 8 has been reacted with thiophenoxides (9) to afford the dithio ethers 10.

11~S~'7 ~
~.
:C
-C `
~J
~Z~

l ~
Z~Z_~

~D ~
U~

+ Z+ ~ I

o o ~ I ~ O ~ I ~D
U~

~ ~ ~r ~\z~ z-~ ~

g Sch can be combined as follows:

Rl, 2, 3 CII~C~I-X-C~12CE12S2~ C~13+6 '> CH211 -X-CEl2cH2-y-(c l2) ~3R4 ~ 5 ~ 6 \ R'4' 5 ~ 6 Formation of the ethexs _ is accomplished by intimately contacting a solution of the tosylate 11 in an inert solvent such as tetrahydrofuran or tetrahydrofuran/N,N-dimethylformamide mixture, with an alkali metal salt 6 (sodium or lithium) of the requisite alcohol or mercaptan, usually in the same solvent, or containing an additional co-solvent at temperatures of about 25-100C and for periods of about 1 hour to several days. Of course the optimum temperatures and times will vary according to the nucleophilicity of the alcohol or mercaptan salt 6.

Preparation of the alkali metal salt 6 is effected by contacting the alcohol or mercaptan with a base such as sodium hydride and the like or n-butyl lithium in the presence of organic solvents such as tetra-hydrofuran and N,N-dimethylformamide at temperatures of from -78C, when n-butyl lithium is used, and about 0-100C when sodium hydride is used, and for periods of about 15 minutes to several hours.

Additional suitable solvents for the formation of the alkali metal salts 6, as well as for running -the reaction 11 ~ 12 include benzene, diglyme, hexamethylphosphoramide, dimethoxyethane and toluene.

Additional leaving groups as alternatives to the r p-toluenesulfonate anion (13, Z = -OS02- ~ CH3) include such conventional leaving groups as Z = chloro, bromo, iodo, methanesulfonate and the like.
CN~
x c~12c~l2z 4,5,6 Alcohol 14, from which tosylate 5 is derived, has been alkylated with benzyl halides 15, as shown in Scheme II, to ethers 16, thus confirming that the roles of alcohol and alkylating species can be interchanged in Williamson Synthesis.

Alcohol 17, from which tosylate 8 is derived, may be alkylated with the benzyl halides 15 to provide the ethers 18.

_Sche;ne II;
R~ 3 C~12CI~OC-12 2 (C~2)m~3 ~4, 5, 6 Z-CI"3r [~4, 5, 6 14 m--l 5 v ~ ~
Schcm~ I I ( Con~2 12C~ISC112C~120}1 2. 15 ;3~ ~}~2Ci~sc}~2c~-20 \<R45,6 ~\R 4 ,5,6 The alkylating agents 15 are added either neat or in solution to a preformed alkali metal salt (preferably sodium, but may be lithium or potassium) of alcohol _ in a suitable solvent at about 0. The resulting mixture is then heated at 25-100 to accelerate the rate of reaction for periods of 30 min. to 24 hours. With the reactive benzyl halides the reaction is complete in about 1-2 hours at about 60. Suitable solvents or solvent mixtures include tetrahydrofuran, N,N-dimethylformamide, hexamethylphosphoramide, benzene, toluene, diglyme, dimethoxyethane and the like. The alkali me~al salts of 14 are formed by contacting 14 with a strong base, e.g. sodium hydride and the like in the above solvents at 0-100 for periods of 15 min.
to several hours.

Products 22 of this invention may be synthesized as shown in Scheme III.

1 ~ 7 ~ 7 Scheme II I
_ ~1' (C2H)2 C

~ 4,5,6 l ~R4 5,6 20 + Z- (CH2) ~ ~-Y (CH2) m~
21 ~N~ pl,2,3 or 2CHS (CH2)n-Y-(CH
- C2~5~l ~ 22 ~4,5,6 U.S. 4,038,409 and 4,039,677 disclose the general methodology for the synthesis of the required xanthate salt 19 and for its hydrolysis to give thiol salt 20, which is then utilized in the instant syntheses.
Thiol salt 20 is advantageously stockpiled as the solid xanthate 19 and is generated in situ as needed, under nitrogen to minimize oxidation. The alkylating species 21 are then introduced and the mixture stirred at 25-80 for periods of 0. 5-24 hours to afford the desired products 22.

~ 1~50~7 The reaction of 20 with 21 (n=2, Z-Cl, Y=S) resulted largely in eliminating of HCl from 21 to afford 23.

Rl,2,3 _ ~ SCH=CR2 Compounds of type 22 where n=2, Y=S and m=O are therefore best synthesized according to the procedure outlined in Scheme I.

As shown in Scheme IV, al~ylation of 24 with chloro-methyl phenyl ulfides (21, Z=Cl, n=l, Y~S, m=O) or benzyl chloromethyl sulfides (21, Z=Cl, n=l, Y=S, m=1) provides the corresponding ethers 25 (n=l, Y=5, m=O or 10 1).

Scheme IV

C~ ¢ ~ ~ ,2,3 ~3 ~ 21 ~ C~12Ci!O-(C~2)~~Y~(CH2)m <
,5,6 ~ 25 2~ \p4,5,6 Ethers of general structure 25, wherein n=2, Y=O and m=O are preferably synthesized according to the procedure outlined in Scheme I.
-tj~ 7 -13a-In a preferred process the compounds of formula I
are prepared as shown in the following chart.

1H~C~SCOC2H5 C~N ~ e e (II) ~ N

(III) + CICH SCH - Z ~ l (IV)~ 4 (I) The starting xanthates II and their acid addition salts are known compounds and are readily prepared and hydrolyzed to afford the thiol salts III by the procedures disclosed in U.S. Pat. Nos. 4,038,409 and 4,039,677. The hydrolysis of the Xanthate II or an acid addition salt of the xanthate II
and the subsequent alkylation of the thiol salt III are usually conducted under an atmosphere of nitrogen to minimize oxidation. To the resulting alcoholic solution of the thiol salt III is added an approximately equimolar amount of the appropriately substituted chloromethyl arylmethyl sulfide IV, (Z=phenyl or thienyl). The reaction mixture is then stirred for periods of about 1-24 hours at temperatures of about 20 - 80C. Removal of the solvent leaves the crude ,. ~
~.~

-13b-product I, which is usually a viscous oil. The oil can be purified by conversion to a solid acid addition salt, which is then recrystallized, or the oil can be purified by chromato-graphic techniques using silicic acid or alumina. If de-sired, the purified oils can then be converted to suitableacid addition salts by methods commonly employed in the art.
Although we prefer ~o use the xanthates II and the chloromethyl arylmethyl sulfides IV (Z=phenyl or thienyl) in the instant syntheses, the preferred compounds I can also be prepared according to the following general procedure:

N

CH2CH--S--W -- > 1H2CH--SM

R4 ~/~5~ ~R4 R (~I ) (V) (VI) + L-CH2SCH2 - Z > (I) (VII) wherein W is a group which when treated with an alkali metal hydroxide (M=sodium, lithium, potassium), in the presence of a suitable solvent, is cleaved by hydrolysis to afford the alkali metal thiolates VI. W, for example, can be one of the groups disclosed in U.S. Pat. Nos. 4,038,409 and 4,039,677, `. 1 ;' -13c-or can be a group such as, for example, amidino hydrochloride : ~ NH

- C \ .HCl or N-methyl-2-pyridinium chloride '~1 1H3C1 e~

Treatment of the metal thiolate VI with the alkylating species VII, wherein L is a conventional leaving group such as halo (preferably chloro) mesyloxy or tosyloxy, in the presence of a suitable inert solvent, affords the products I. The starting compounds V, wherein M = amidino hydrochloride or N-methyl 2-pyridinium chloride, can be prepared by con~acting an imidazole of formula VIII in the presence of a suitable solvent with thiourea or N-methyl-2(1~I)-pyridine thione, respectively.
r N
~ N
I

CH2cH-cl (VIII) ~ R4 :

1~55857 -13d-The l~ chlorophenethyl)imidazoles VIII are known compounds and are described in ~.S. Pat. No. 3,679,697. As depicted below, the preferred compounds I can also be pre-pared by contacting an imidazole of formula VIII with a hemi-mercaptal of formula IX, in the presence of an inert solvent such as methanol, ethanol, N,N-dimethylformamide, benzene, toluene and the like, containing an acid binding agent such as sodium or potassium carbonate.

(VIII3 + HSCH2SCH2 - Z ) (I) (IX) Alternatively, the alkali metal salt of IX can be preformed with bases such as sodium ethoxide, sodium methoxide or an alkali metal hydride such as sodium hydride and the preformed salt of IX contacted with VIII preferably in the same solvent in which it was formed, to yield the sub~ect compounds I. The hemi-mercaptals IX are prepared by the procedure of H.
15 Bohme, H. Fischer and R. Frank [Ann. Chem. 563, 54, (1949)]
which essentially consists of treating a chloromethyl sulfide, such as IV with potassium sulfhydrate at low temperature.
Several of the chloromethyl arylmethyl sulfides IV
(Zs phenyl or thienyl) are described in the prior art. Those which are not previously described can be prepared by well-established techniques. For example, a mercaptan with the formula HSCH2 Z, is treated with hydrogen chloride and formaldehyde to afford IV, or the procedure of Goralski and Burk [J. Org. Chem., 42,3094(1977)] can be utilized, in which a mixture of the mercaptan, HSCH2 Z, in bromochloromethane C~

~155857 -13e-is stirred with powdered potassium hydroxide and a phase transfer catalyst to afford IV after workup.

~,,,~

PREPARATION OF INTE~.DIAT~S
Alcohol~ and Tosylates Starting from the know alcohol 26, the novel ester 28, alcohol 14 and its corresponding tosylate 5 are prepared as shown in Scheme V.

Scheme V

2 ~rCE2CD2C H > ~ ~ 4 ) ~ \~

H2CHOH CE~2CHOCH2C02C2H5 CH2,~HOCH2CH2-OH

4,5,6 ~ p~4,5,6 ~ ~ p4,5,6 C~3 ~ SO2C

N 3 TEa, CE12C12 CH2CHC~I2C~I2S2 ~ CH3 ~4,5,6 Treatment of the anion of 26 (see U.S. 3,717,655 and Godefroi et al, supra for this and other operative alcohols) with ethyl bromoacetate 27 proceeds smoothly to give ester 28. The ester may be isolated and purified as the solid nitrate salt, or can be -15- i 155857 reduced, in a crude state, with lithium aluminum hydride to provide the starting alcohol 14. Other hydride reducing agents such as aluminum hydride, diisobutylaluminum hydride and sodium bis(2-methoxy-ethoxy) aluminum hydride and the like may be employed.Diethyl ether, tetrahydrofuran, diglyme and benzene are suitable solvents.

Alcohol 14 is a viscous gum and is isolated, purified and stockpiled as its solid nitrate salt.
The nitrate salt may also be used in Williamsor.
Synthesis, provided that an additional equivalent of base, e.g. NaH is used.

Treatment of a solution of the alcohol 14, or its nitrate salt, in methylene chloride containing triethylamine with p-toluenesulfonyl chloride provides tosylate 5 in good yield. The tosylate is a viscous oil and is usually used shortly after preparation.
If desired the tosylate can be purified by filtration through alumina with methylene chloride, but the crude material is satisfactory. The tosylate should be stored in the refrigerator.

Alcohol 14 may be activated by other reactants.
For example, it may be mesylated with methanesulfonyl chloride or perhaps chlorinated with thionyl chloride to provide additional alcohol 14 derivatives for Williamson Synthesis.

Sodium thiolate 20 (see Scheme III) has been alkylated with either chloro- or bromoethanol (29, Z=Cl or Br) to afford alcohol 17. Alcohol 17 is then converted to its corresponding tosylate 8 as shown in Scheme VI.

~ 15~857 Scheme VI

t ~ ~ CH3~:02Cl ¢
\ e ~ \ CH cl2, TEA
~H2CHS~7a + 2c~H2c~2(~ ~I2CHSCH2~20H ~ cl'2cl~;CH2cH25~3 29 ~ ~ 8 R4~5~6 R4~5~6 R4~5r6 Tosylate 8 is also a viscous oil and is used without rigorous purification. Alcohol 17 can be purified by chromatography on silicic acid, or can be isolated and purified as its hydrogen fumarate salt.
A great number of phenols, thiophenols, benzyl alcohols, benzyl mercaptans and benzyl halides with which to practice this invention, are available from commercial sources, or are known in the literature and are readily synthesized.
For example, p-trifluoromethylthiobenzyl chloride 31 and the benzyl alcohol 30 ~ may be prepared as follows:

/==\ BH3-~7F C ~~~ SOC12 A
2 ~ SCF3 ~ 3 ~ 2~IDMF, CH2C12~ 3 ~ ~2 29a 30 3l ' Both the alcohol 30 and the chloride 31 are suitable substrates for Williamson Synthesis. Numerous benzoic acids or benzoate esters are available for such re-actions.
Operative alkylating agents may be prepared as shown below. These agents are used to alkylate 20 (see Scheme III).
fl ~Cl -OH 1. NaH, diglyme ~ ~ CH2CH2Cl 2. TsOCH2CH2Cl Cl llQ Cl 33 Cl f l ~ 1. NaH, DMF ~
Cl~ ------OH ~ Cl ~ \ / ~ OCH2CH2Cl ~ 2. TsOCH2CH2Cl ,~1 1. NaOEt, EtOH
34 2. Br(CEI2)3Cl ~~ Cl ~ O(CH2)3 reflux 36 ~ 1~ MaOEt, E~tOH ~r~~
C1-~ -SH ) 1 - / \ ~ S
2. BrC~12C~12CH2Cl C ~ (CH2)3c reflux 38 J

1 ~SS857 Thiophenols are also readily synthesized as illustrated by the synthesis of the following known compounds 40 and 42 which are utilized in preparing the subject antimicrobials.

Cl Çl ~ /
~ ~ 1. NaNO2, HCl Cl ( ~--NH
2- KSIC~c2~5 C1 ~ S~

3. NaOH

r 1 Mg, THF \ ~ 1H

From the foregoing description, it will be understood that in general, the compounds of formula 4 may be prepared, for example, by either:
Scheme VII reacting a compound of the formula:
r ~'~

CH ~
~ ~ R4~5~6 with an equimolar , ~
am~unt ~ mpound ~ ~he .~oxmula: ~1,2,3 4,4 ~ ~CH~,) n Y ~CF~) m --lg--wherein Wl is either (a) XM, M being hydrogen or an alkali metal such as Na, K, or Li, or (b) a leaving group such as Cl, Br, OS2P 2tolyl or 0S02CH3, and W is the other of (a) or (b) or Scheme VIII reacting a compound of the formula:

N

N
_ CH21HX(CH2)nW3 ~R4~5~6 ~ with an equimolar amount of a compound of the formula:
~ ,3 46 W (CH2)m -wherein W3 is either (c) YM, M being as defined in Scheme VII or (d) a leaving group as defined in Scheme VII, and W4 is the other of (c) or (d), X, Y, m, n, and Rl 6 being as defined in formula 4.

Table I below is only illustrative of some of the compounds of formula 4 which have been prepared.

~able_I
General_ Formula R
N~ ~/

~1 R-ll \Rl 'rABLE I

Cpd. Acid* Addition , ._ _ __ __ No . Salt . ~ R ~ R9 Rl R-l 4 44 -SCH2S- H H Cl H H
2 C4H404 H2CH2S H H Cl H H
3 Hh~03 -SCH2C~2S-Cl H Cl H H

C4H404 -scH2cH2cH2s- H H Cl H E~

6 HNC3 -OCH2CH20- H CF3 EI H H

7 HN03 2CH20 Cl H Cl H H

8 HN03 2CH20 Cl H H H Cl

9 HN03 -OCH2CH20- Cl H Cl Cl H
C2H24 -OCH2CH20- H H tert- H H
ll C2H24 -OCH2CH20- H H C6 5 H H
12 C2H24 -OCH2CH20- Cl H C6H5 H H

L4 C2H24 -OCH2CH20- -C6H5 H Cl H H
L5 C2H24 -CH2cx2-- H H -CH2C6H5 E~ H
. L6 C2H24 -OC~2CH20- H H -52C6H5 H E~

TABLE I (Cont'd.) _ . . . . _ _ Cpd. Acid* Addition No. Salt A R7 R8 R9 R10 . . . _ _ . _ 1l 19 C4H404 2 2 Cl H H H Cl C4H404 -SCH2CH2CH20- Cl H Cl H H

22 HN03 -OCH2CH2S- H H Cl H H
23 HN03 -OCH2CH2S- Cl H Cl H H
24 C2H24 -OCH2CH2S- Cl H Cl Cl H

26 C2H24 -OCH2CH2SCH2- H H Cl H H
27 C2H24 -OCH2CH2SCH2- Cl H Cl H H

29 C2H24 -OCH2CH20CH2- H H Cl H H
C2H24 -OCH2CH20CH2- Cl H Cl H H
31 free base -OCH2CH20CH2- H H SCF3 H H

33 C4H404 -SCH2S- Cl H Cl H H

1l 35 free base -OCH2CH20- H H N~_JN-CCH3 H H

38 HN03 -OCH2CH20- H H Cl **~
~/
39 C4H404 -SCH2S- Cl H H H Cl O C4H404 -OCH2S- H H Cl H H
1 1-5 C4H404 -SCH20- H H Cl H H
2 C4H404 -SCH2SCH2- H H Cl H H
43 C2H24 -OCH~scH2- H H Cl H
* C4H404 = fumaric acid, C2H204 = oxalic acid ** R10 and Rll together form with the benzene moiety a naphthalene ring.

The antifungal act~ity of compounds of general structure A Were determined using a broth dilution technique, against several strains of the ollowing human and an~mal pathogenic fungi: Candida albicans, Candida tropIcalis, Candida krusei, Trichophyton rubrum, Trichophyton mentagrophytes and Microsporum canis.

Two-fold serial dilutions are made with Sabouraud's liquid medium from stock solutions of the test compounds, usually in dimethyl sulfoxide, N,N-dimethylformamide or water. The Minimum Inhibitory Concentrations ~MIC's), which are considered to be the minimum concentrations of the test compounds in micrograms per milliliter which prevent grossly detectable growth of the test organisms, are then determined after inoculation of the medicated broths with the test organisms, and incubation at the appropriate temperature and for the appropriate time interval.

Candida species are incubated for 24 hours at 37, and five days at 28 for the dermatophytes Trichophyton rubrum, Trichophyton mentagrophytes and Microsporum canis.

The available antifungal MIC's of Compounds 1-32 in Table I are tabulated in Table II.

_ _ _ . A 0~ U~ o~
,~ ~ oo_ _oa~_ oo-~-o UO~ ~ ~ ' ~
~ ~ ~ n`o .u~ o S cn O o o r _ o ~o _ o o _ ~ ~o o o o c~, o _ _ _ V o c ~ ~ o c~
~ _ _ ooo C~OO~_O oo_~ocoe~J_o 1~ E 1- c~
_E ~ c~
_ _ ~ ~_ o o o o _ _ ~ ~ _ _ _ ...... _. .
o~ .r _ N
C~
~'~ o _ o c~ o ~ _ ~ o o ~ o o o o _ ~
_ C~
U O
~ ~n _ _ _ "~ s .
el . o ooc~ o_o_~_oo~r o C _ U~ ~ ' C ~7 O C~ O ~ _ _ O' O O ~

10 O U'>' ' U~ C:
5 ~ ~ ~~ N C`.l C~J ~11 ~ a- o c~ _ o' ~ ~ _ ~- _ o _ ~ _ o o ~ ~t _ _ ~ o ~
_ V~ _ _ Z
C _ N ~ 0 ~ 0 1~ CO C O -- C~l E _ _ _ _ _ _ _ _ _ _ ~ ~ c~
_ ~

--2~---I ~
_ _ _ ~

~ ~ o ~

~ ~'~
~, I *~
~ ~o - ~ _ o ~ o ~
_ *~

,~ O ~
_ _ ~ ~oo_ ~r ~ e' ~
~ o~ ~ ~ r o o -- o ~ ~o _ ~, _ _ ~ ~ O~q~

~ 1558~7 -~5-The antibacterial activity of compounds of general structure 4 has also been established. Table III lists the antibacterial activity in MIC's of some of the compounds described in Table I against gram-position organisms.

Table III

_ MIC (~g/m] )a Steptococcus Staphylococcus aureus Cpd pneumoniae pyogenes faecalis No.A9585* A9604* A20688* A9537* A9606* A15097*

11 125 125 8 8 8 8 26 ~125 ~125 2 2 2 2 29 >125 )125 4 2 2 2 31 >125 >125 ~ 4 4 4 *Strain number.

a. S. pneumoniae and S. pYogenes were tested in 50% Mueller-Hinton Broth + 45% antibiotic assay broth + 5% human serum, whereas S. faecalis and S aureaus were tested by the agar dilution test in Mueller-Hinton medium.

1~558~7 The following examples are only illustrative of certain preferred embodiments of the intermediates and antimicrobial compounds of this invention, the structures of which as disclosed herein are supported by satisfactory infrared and proton magnetic resonance spectra. As employed herein and in the appended claims, all amounts and proportions are by weight unless otherwise indicated, temperatures are in C, and melting and boiling points are uncorrected.

Example 1 Ethyl 2-[1-t2,4-dichlorophenyl)-2-(lH-l-imidazolyl) ethoxy]acetate (Scheme V, ~, R4'''5=2',4-dichloro). A
solution of l-(2,4-dichlorophenyl)-2-(lH-l-imidazolyl) ethanol* (3.0 g, 0.0118 mole) in N,N-dimethylformamide (DMF, 7 ml) was added to a stirred, cooled (ice-water) mineral oil suspension of 57% sodium hydride (0.55 g, 0.013 mole) in tetrahydrofuran (THF, 15 ml). The mixture was refluxed for 1.25 hours to complete salt formation. The cooling bath was replaced and a solution of ethyl bromoacetate (1.5 ml, 0.014 mole) in THF (5 ml) was added dropwise during ten minutes.
The mixture was refluxed for eighteen hours, cooled and diluted with diethyl ether. The ethereal solution was washed with water (3x) followed by brine and dried (Na2SO4). After removal of the ether, the residue was dissolved in acetonitrile and the mineral oil removed with two n-pentane washes. Removal of the acetonitrile left 2.55 g of the desired ester as a clear oil, which is suitable for reduction.

*U.S. 3,717,655 and Godefrei et al, supra ~ddition of O.S ml of 70~ nitric acid (d-1.42) to a solution of the ester (2.55 g) in diethyl ether (50 ml) containing ethanol (10 ml) af~orded colorless crystals (2.1 g) of the nitrate salt, mp 82-87.
Recrystallization ~rom eth~l acetate provided the analytical sample,' mp 102-104.

- Anal- Calc'd for C15H16C12N23 HNO3 H, 4.22; Cl, 17.45; N, 10.34.
Found: C, 44.38; H, 4.15; Cl, 17.12; N, 10.72.

Example 2 1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)-ethyl]--lH-imidazole nitrate ~ cheme V, _, R4'5 -2,4-dichloro). A solution of ethyl 2-[1-(2,4-dichlorophenyl)-2-(lH-l-imidazolyl)ethoxylacetate (6.4 g, 0.019 mole) in diethyl ether (100 ml) was rapidly added dropwise to a cooled (ice-water), stirred mixture of lithium aluminum hydride (0.76 g, 0.02 mole) in diethyl ether ~150 ml). The mixture was refluxed for sixteen hours, cooled (ice-water) and the excess hydride and aluminum complexes decomposed by the successive dropwise additions of water (5 ml) in THF (50 ml), 15% aqueous sodium hydroxide (10 ml) and water (5 ml). The mixture was stirred for an additional thirty minutes and filtered into a separatory funnel.
The aqueous layer was extracted with diethyl ether (3x) and the combined ethereal layers washed with water, followed by brine (2x~. After drying (Na2SO4) and removal of the ether there remained 5.12 g of the desired alcohol as a viscous oil.

Treatment of an ethereal solution o~ the free base with 70% nitric acid afforded the nitrate salt which melted at 97.5-98.5 after recr~stallization from acetonitrile-ether.

Anal. Calc'd for C13H14C12N2O2 3 Cl, 19.47; N, 11.54.
Found: C, 43.02; H, 4.13; Cl, 19.29; N, 11.57.

Example 3 Tosylate of 1-[2-(2,4`-dichlorophenyl)-2-(2-hy4droxy-ethoxy)ethyl]-lH-imidazole (Schemes I and V, 5, R '5 =
2,4-dichloro). The nitrate salt of 1-~2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole (6.0 g) was Partitioned between methylene chloride (CH2C12) and 0.5 N NaOH (40 ml). The CH2C12 layer was washed (brine) and dried (Na2SO4). Removal of the CH2C12 left the free base (5.02 g), of the alcohol. p-Toluenesulfonyl chloride (3.50 g, 0.0184 mole) was added to a cooled (ice-water), stirred solution of the alcohol (5.02 g, 0.0167 mole) in CH2C12 (60 ml) containing triethylamine (2.56 ml, 0.0167 mole). Stirring was continued at ice-bath temperature (one hour) and then at 25 (one hour).
The mixture was successively washed with cold water, cold aqueous Na2CO3 (2x), water and brine. The CH2C12 solution was dried (Na2SO4) and concentrated to dryness to afford 7.15 g of the tosylate as a viscous oil.
If desired, a solution of the tosylate in CH2C12 can be filtered through alumina to remove traces of starting alcohol. The latter operation is, however, not necessary for subsequent reactions.

The nitrate salt of 1-~2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole may be directly utilized in tosylate formation provided that an ad-ditional e~uivalent of triethylamine is added.

Example 4 1-[2-(4-biphenylyloxyethox~)-2-(2,4-dichlorophenyl) ethyl]-lH-imidazole hydrogen oxalate (Table I, Compound No. 11). A solution of 4-hydroxybiphenyl (2.42 g, O.0142 mole) in DMF (15 ml) was added dropwise to a cooled (ice-water) stirred, mineral oil suspension of 57% NaH (0.658 g, 0.0156 mole) in DMF (25 ml). Stirring was continued at 70 (20 minutes) and then at 100 (10 minutes) to complete salt formation. The cooling bath was replaced and a solution of the tosylate of 1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole (6.47 g, 0.0142 mole) in THF (15 ml) added.
The mixture was stirred for eighteen hours at an oil bath temperature of 75 under nitrogen and concentrated to dryness. The residue was partitioned between diethyl ether and water. The ethereal layer was washed with water (2x), followed by brine and dried (Na2SO4). After removal of the ether the residue was dissolved in ace-tonitrile and the mineral oil removed with two n-pentane washes. Removal of the acetonitrile left the crude free base (5.2 g), as a viscous oil which afforded 4.2 g, of pure base after chromatography on silicic acid (150 g) with methylene chloride-acetone (10:1).

A solution of the free base (4.0 g, 0.00882 mole) in ethyl acetate tlO0 ml) was treated with a solution of oxalic acid (0.794 g, 0.00882 mole) in ethyl acetate (S0 ml) to provide, upon cooling, 4.28 g of the hydrogen oxalate salt, mp 122-124 (decomp.).

Anal. Calc'd for C25H22cl2o2N2 c2 2 4 H, 4.45; Cl, 13.04; N, 5.16.
Found: C, 59.39; H, 4.51; Cl, 13.24; N, 5.16.

Replacement of the 4-hydroxybiphenyl in the above procedure with 4-chloro-2-phenylphenol, 2-chloro-4-phenylphenol, 2-phenylphenol, 4-benzylphenol, 2,6-dichlorophenol, 4-fluorothiophenol, 4-mercaptobiphenyl, 4-chlorobenzyl mercaptan, and 4-methylbenzyl mercaptan and use of the suitable salt-forming acid,; gave the following crystalline acid addition salts, respectively:

1-[2-(4-chloro-2-phenylphenoxyethoxy)-2-(2,4-dichlorophenyl)ethyl]-lH-imidazole hydrogen oxalate, mp 88-91 (Table I, Compound No. 14).

Anal. Calcld for C25H21C13N2O2-C2 2 4 H, 4.01; N, 4.85.
Found: C, 56.24; H, 4.19; N, 5.01.
1-[2-(2-chloro-4-phenylphenoxyethoxy)-2-(2,4-dichloro-phenyl)ethyl]-lH-imidazole hydrogen oxalate, mp 93-95 (Table I, Compound No. 12).
-Anal. Calc'd for C25H21C13N2O2-C2 2 4 C, 56.12; H, 4.01; N, 4.85.
Found: C, 56.00; H, 4.15; N, 5.16.

1-[2-(2,4-dichlorophenyl)-2-(2-phenylphenoxyethoxy)ethyl]-lH-imidazole hydrogen oxalate, mp 140-141 (Table I !_ Compound No. 13).
Anal. Calc'd for C25H22C12N2O2.C2H2o4:
C, 59.68; H, 4.45; Cl, 13.05; N, 5.16.
Found: C, 59.28; H, 4.55; Cl, 12.86; N, 5.27.

1-[2-(4-benzylphenoxyethoxy)-2-(2,4-dichlorophenyl)ethyl]-lH-imidazole hydrogen oxalate, mp 117-118 (Table I, Compound No. 15).

-`` ' 11S58S7 Anal. Calc'd for C26H24C12N22 1 ( 2 2 4 C, 57.82; H, 4.52~ Cl, 11.77; N, 4.65.
Found: C, 57.58; H, 4.62; Cl, 11.43; N, 4.56.

1-~2-(2,6-dichlorophenoxyethoxy)-2-(2,4-dichlorophenyl)-ethyl]-lH-imidazole nitrate, mp 106-108 (Table I, Compound No. 8).
Anal. Calc'd for ClgH16C14N2O2 3 C, 44.82; H, 3.37; Cl, 27.85; N, 8.25.
Found: C, 44.84; H, 3.38; Cl, 27.47; N, 8.28.

1-12-(2,4-dichlorophenyl)-2-(4-fluorothiophenoxyethoxy)-ethyl]-lH-imidazole hydrogen oxalate, mp 107-108 (Table I, Compound No. 21).
Anal. Calc'd for ClgH17C12FN2OS.C2H2O4:
C, 50.31; H, 3.82; Cl, 14.14; N, 5.59; S, 6.40 Found: C, 50.38; H, 3.93; Cl, 14.01; N, 5.78;
S, 6.88 1-(2-[2,4-dichlorophenyl]-2-[(4-biphenylthio)ethoxy]ethyl)-lH-imidazolehydrogen oxalate (Table I, Compound No. 25).
nal. C lc d for C25H20C12N2S C2H24 C, 57.96; H, 4.32; N, 5.01; S, 5.73.
Found: C, 57.68; H, 4.35; N, 5.15; S, 5.25 1-(2-[(4-chlorobenzylthio)ethoxy]-2-[2,4-dichlorophenyl]
ethyl)-lH-imidazole hydrogen oxalate, mp 98-100 (Table I, Compound No. 26).
2g Anal- Calc'd for C20Hl9Cl N2S C2H24-C, 49.68; H, 3.98; Cl, 20.00; N, 5.27; S, 6.03.
Found: C, 49.94; H, 3.95; Cl, 19.81; N, 5.38;
S, 6.37.

1-(2-[2,4dichlorophenyl]-2-[(4-methylbenzylthio)ethoxy]-ethyl)-lH-imidazole nitrate, mp 107-108 (Table I, Compound No. 28).
Anal- Calc'd for C21H22C12N2S-HN3 C, 52.07; H, 4.79; Cl, 14.64; N, 8.67; S, 6.62.
Found: C, 51.85; H, 4.68; Cl, 14.71; N, 8.64;
S, 6.49~

115$857 Example 5 1-[2-(2~4-dichlorophenyl~-2-(2,4,5-trichloro-phenoxyethoxy)ethyl]-lH-imidazole nitrate (Table I, Compound No. 9). A solution of 2,4,5-trichlorophenol (3.41 g, 0.0173 mole) in DMF (10 ml) was added dropwise during five minutes to a ~tirred, cooled (ice-water) mixture of 57% sodium hydride in mineral oil (0.727 g, 0.0173 mole) in DMF (25 ml). Stirring was continued at 50-120 for 0.5 hour to complete salt formation. The ice-bath was replaced and a solution of the tosylate of l-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole (7.15 g, 0.0157 mole) in THF (25 ml) added dropwise during five minutes. The mixture was heated under gentle reflux for eighteen hours and concentrated to dryness.
The residue was partitioned between diethyl ether and water. The ethereal layer was washed (water, brine) and dried (Na2SO4). After removal of the ether the residue was dissolved in acetonitrile and the solution washed with n-pentane (2x) to remove the mineral oil. Removal of the acetonitrile left a gum (6.23 g) which was dissolved in a mixture of diethyl ether (100 ml) and ethyl acetate (25 ml).
Addition of 70% nitric acid (d=1.42) caused the titled nitrate salt to separate, mp 100-110. Two recrystallizations from ethyl acetate, the latter with the addition of decolorizing carbon, provided beige crystals of the analytical sample, mp 143-144.5.
Anal- Calc'd for Cl9H15C15N22 HN3 C, 41.98; H, 2.97; N, 7.73.
Found: C, 42.27; H, 3.06; N, 7.64.

By proceeding in a similar manner and replacing the 2,4,5-trichlorophenol with 4-tert-butylphenol, 4-phenylsulfonylphenol*, 4-hydroxybenzophenone, 2,4,5-trichlorothiophenol, and 4-methoxybenzyl alcohol, the following compounds were prepared, and characterized *Szmant und Suld, J. Amer. Chem. Soc., 78, 3400 (1956).

as hydrogen oxalate salts, respectively:
1-[2-(4-tert-butylphenoxyethoxy)-2-(2,4-dichlorophenyl) ethyl]-lH-imidazole, mp 141-143 (decomp) (Table I, Compound No. 10).
Anal. Calc'd for C H Cl N O .C H O :

C, 57.37; H, 5.39; Cl, 13.55; N, 5.35.
Found: C, 56.71; H, 5.06; Cl, 13.47; N, 5.06 1-[2-(2,4-dichlorophenyl)-2-(4-phenylsulfonylphenoxyethoxy)-ethyl]-lH-imidazole, mp 169-171 (decomp) (Table I, Compound No. 16).
Anal- Calc'd for C25H22C12N24S C2H24 C, 53,39; H, 3.98; Cl, 11.67; N, 4.61; S, 5.28.
Found: C, 53.39; H, 3.98; Cl, 11.70; N, 4.83;
S, 5.42.

1-~2-(4-benzoylphenoxyethoxy)-2-(2,4-dichlorophenyl)-ethyl]-lH-imidazole, mp 118-124 (Table I, Compound No. 17).
Anal. Calc'd for C26H22C12N2O3.C2H2O4:
C, 57.72; H, 4.37; Cl, 12.19; N, 4.89.
Found: C, 58.09; H, 4.46; Cl, 12.41; N, 4.85.
1-[2-(2,4-dichlorophenyl)-2-(2,4,5-trichlorothiophenoxy-ethoxy)ethyl]-lH-imidazole, mp 108.5-109.5 (Table I, Compound No. 24).
Anal- Calc d for Cl9H15C15N2S C2H24 C, 42.99; H, 2.92; Cl, 30.31; N, 4.77; S, 5.47.
Found: C, 42.90; H, 2.78; Cl, 30.08; N, 5.10;
S, 5.30.

1-[2-(2,4-dichlorophenyl)-2-(4-methoxybenzyloxyethoxy)-ethyl]-lH-imidazole, mp 155.5-157.5 (Table I, Compound No. 32).
Anal. Calc'd for C21H22C12N2O3.C2H2O4:
C, 54.02; H, 4.73; Cl, 13.87; N, 5.48.
Found: C, 53.90; H, 4.78; Cl, 13.82; N, 5.77.

Example 6 1-[2-(4-chlorothiophenoxyet oxy)-2-(2,4-dichloro-phenyl)ethyl]-lH-imidazole nitrate (Table I, Compound No. 22). 50~ Sodium hydride dispersion in mineral oil (0.21 g, 4.4 mmoles) was added to a stirred solution of 4-chlorothiophenol (0.64 g, 4.4 mmoles) S in DMF ~25 ml) at 20. Stirring was continued at ambient temperature for 1.5 hours and then at 50-60 for 0.5 hour. The solution was cooled to 20 and a solution of the tosylate of l-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole (2.0 g, 4.4 mmoles) in DMF ~10 ml) added. The mixture was heated at an oil bath temperature of 75 for three hours and concentrated to dryness. The residue was partitioned between CH2C12 and water and the aqueous layer extracted with CH2C12. The combined CH2C12 layers were evaporated to dryness and the residue dissolved in acetonitrile. The mineral oil was removed with two n-pentane washes. Removal of the acetonitrile left 2 g of a viscous oil which afforded 0.87 g of the pure base, after chromatography on neutral alumina (50 g) with CH2C12. A solution of the free base (0.87 g) in diethyl ether (100 ml) was converted to the nitrate salt by adding 70% nitric acid (d=1.42) until precipitation was complete.
Recrystallization from acetonitrile ether provided an analytical sample of the title compound, mp 98-Anal- Calc'd for Cl9H17C13N2S-HN3 C, 46.49; H, 3.70; Cl, 21.67; N, 8.56; S, 6.53.
Found: C, 46.76; H, 3.65; Cl, 21.58; N, 8.42;
S, 6.56.

By proceeding in a similar manner and replacing the 4-chlorothiophenol with 2,4-dichlorothiophenol, 2,4-di-chlorophenol and 3-trifluoromethylphenol, the followin~-compounds were prepared and characterized as nitrate salts:
1-[2-(2,4-dichlorophenyl)-2-(2,4-dichlothiorophenoxy-ethoxy)ethyl]-lH-imidazole, mp 172-173 (Table I, Compound No. 23).

ClgH16Cl4N2Os-HNO3 C, 43.44; H, 3.26; N, 8.00; S, 6.10.
Found: C, 43.75; H, 3.24; N, 8.14; S, 6.00.

1-[2-(2,4-dichlorophenoxyethoxy)-2-(2,4-dichlorophenyl)-ethyl-lH-imidazole, mp 173.5-174.5 (Table I, Compound No. 7).
ClgH16Cl4N2O2-HNO3 C, 44.81; H, 3.17; N, 8.25.
Found: C, 44.86; H, 3.36; N, 8.47.

1-[2-(2,4-dichlorophenyl)-2-(3-trifluoromethylphenoxy-ethoxy)ethyl]-lH-imidazole, mp 105.5-107.5 (Table I, Compound No. 6).
Anal. Calc'd for C20Hl7C12F3N2 2 3 C, 47.26; H, 3.57; N, 8.27.
Found: C, 46.98; H, 3.48; N, 8.53.

Example 7 1-(2-[(2,4-dichlorobenzylthio)ethoxy]-2-[2,4-dichlorophenyl]ethyl)-lH-imidazole hydrogen oxalate (Table I, Compound No. 27). A 1.6 M solution of n-butyl lithium in hexane (6.3 ml, 0.01 mole) was added dropwise to a stirred solution of 2,4-dichloro-benzyl mercaptan (1.93 g, 0.01 mole) in THF (65 ml) at -78. Stirring was continued at -78 for 0.5 hour and a solution of the tosylate of l-[2-(2,4-dichloro-phenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole (4.55 g, 0.01 mole) in THF (35 ml) added dropwise. The mixture was stirred an additional 0.5 hour at -78 and then for 1.5 hours at ambient temperature. The ~olvents were removed in vacuo and a mixture of the residue in water extracted with CH2C~2 (3x). The combined CH2C12 extracts were washed with brine (3x), then water and dried (Na2SO4). Removal of the ~ 1 155857 solvent, after treatment with decolorizing carbon, afforded 4.~ g of oil which gave 2.99 g of pure free base after chromatography on 9ilicic acid (100 g) with CH2C12acetone ~20:1). Addition of oxalic acid to a solution of the free base in ethyl acetate gave the titled salt (2.77 g), mp 85-88.
1. C lc d for C20H18C14N2OS.C2H2O4:
C, 46.66; H, 3.56; N, 4.95.
Found: C, 46.49; H, 3.55; N, 5.17.

Example 8 1-[2-(4-chlorobenzyloxyethoxy?-2-(2,4-dichloro-phenyl)ethyl]-lH-imidazole hydro~en oxalate (Table I, Compound No. 29). A solution of 1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole nitrate (2.5 g, 6.87 mmoles) in DMF (15 ml) was added dropwise during fifteen minutes to a stirred, cooled (ice-water) mineral oil suspension of 57% sodium hydride (0.61 g, 14.4 mmoles) in a mixture of`DMF (10 ml) and THF (10 ml) under nitrogen.
Stirring was then continued for 0.5 hour at 25 and for 0.25 hour at 50. The cooling bath was replaced and the 4-chlorobenzyl chloride (1.22 g, 7.56 mmoles) radidly added. The mixture was stirred at ambient temperature for 35 minutes and then at an oil bath temperature of 65 for 1.5 hours. The mixture was concentrated to dryness and the residue partitioned between diethyl ether and water. The athereal layer was washed (water, brine), dried (Na2SO4) and concentrated to dryness. The residue was dissolved in acetonitrile and the mineral oil ramoved by washing with n-pentane (3x). The residue (2.35 g) was chromatographed on alumina (130 g) with CH2C12-ethanol (25:1) to give the pure free base (1.26 g) as a yellow oil. Treatment of a solution of the free base (1.2 g) in ethyl acetate with oxalic acid ~0.254 g) afforded the title compound, mp 103-105.
Anal. Calc'd for C~oHlgC13N202~C2H404 C, 51.23; H, 4.10; Cl, 20.62; N, 5.43.
Found: C, 51.35: H, 4.02; Cl, 20.60; N, 5.68.

In a similar manner, replacing the 4-chlorobenzyl chloride with 2,4-dichlorobenzyl chloride and 4-tri-fluoromethylthio benzyl chloride provided, respectively:
1-~2-(2,4-dichlorobenzyloxyethoxy)-2-(2,4-dichlorophenyl)-ethyl]-lH-imidazole hydrogen oxalate, mp 100-103 tTable I, Compound No. 30).
Anal- Calc'd for C20H18C14N22 C2 2 4 C, 48.02; H, 3.66, Cl, 25.77; N, 5.09.
Found: C, 48.10; H, 3.65; Cl, 25.66;
N, 5.34.

1-[2-(2,4-dichlorophenyl)-2-t4-trifluoromethylthio-benzyloxyethoxy)ethyl]-lH-imidazole, mp 51-52 tTable I, Compound No. 31).
Anal. Calc'd for C21HlgC12F3N2O2S:
C, 51.33; H, 3.90; Cl, 14.43; N, 5.70.
Found: C, 51.60; H, 3.75; Cl, 14.38; N, 5.80.

Example 9 4-trifluoromethylthiobenzyl alcohol t30). A 1.02 M solution of borane in THF t56.9 ml, 0.058 mole) was added dropwise during 0.25 hour to a stirred solution of 4-carboxyphenyl trifluoromethyl sulfide (10.0 g, 0.045 mole) in THF (25 ml) at -5. The cooling bath was removed and stirring continued for three hours at 25. The cooling bath was replaced and 30 ml of water -THF (1:1) cautiously added. The aqueous phase was saturated with potassium carbonate and the layers separated. The aqueous phase was extracted with diethyl ether (4 x 25 ml). The ethereal extracts were combined with the THF layer and the combination washed (water) and dried (Na2SO4). Removal of the solvents left an oil which crystallized when triturated with 6 N HCl. Recrystallization from Skellysolve-B
provided the alcohol (6.5 g), mp 52-53.
Anal. Calc'd for C8H7F3OS: C, 46.15; H, 3.39.
Found: C, 46.44; H, 3.51.

Example 10 4-trifluoromethylthiobenzy-l-chloride (31). Thionyl chloride (2.48 g, 0.0208 mole) was added dropwise to a stirred solution of 4-trifluoromethylthiobenzyl alcohol (4.0 g, 0.0192 mole) in CH2Cl (40 ml) at 5. One drop of DMF was then added and the solution stirred for eighteen hours at 25. The solution was concentrated and the residue triturated with ice-water and extracted with CH2C12. The CH2C12 solution was washed (water) and dried (Na2SO4). Removal of the solvent left 4.0 g of the titled product as a mobile oil.
Anal. Calc'd for C8H6ClF3S: C, 42.39; H, 2.67; Cll 15.65.
Found: C, 42.31; H, 2.76; Cl, 15.26.

Example 11 .
1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethyLthio)ethyl]-et4hyl]-lH-imidazo~e hydrogen fumarate (Schemes II and VI, 17, R ' = 2,3-dichloro). To a stirred solution of sodium hydrox-ide (5.8 g, 0.145 mole) in ethanol (650 ml) at 25 under a blanket of nitrogen, was added 1-[2-(2,4-dichlorophenyl)-2-(ethoxythiocarbonylthio)ethyl]-lH-imidazole hydrogen ~39 oxalate* (13.1 g, 0.029 mole?. After stirring for an additi~onal 0.75 hour at 25 a solution of 2-bromoethanol (3.87 g, 0.031 mole) ln ethanol ~10 ml) was added.
Stirring was continued for one hour and the ethanol removed. The residue was partitioned between diethyl ether and water. The aqueous layer was extracted with several portions of ether and the combined ethereal layers washed with water followed by brine. Removal of the ether, after drying with Na2SO4, left 9.3 g of the free base as a viscous oil. Addition of fumaric acid (3.40 g~ to a solution of the free base (9.3 g) in l-propanol (30 ml~ provided, after removal of the 1-propanol and two recrystallizations from acetonitrile, colorless crystals (8.8 g) of the titled salt, mp 124-125 (foamingl.Anal- Calc'd fr C13H14C12N2~S-C4H404 C, 47.12; H, 4.19; Cl, 16.37; N, 6.47; S, 7.40.
Found: C, 47.07; H, 4.00; Cl, 16.31; N, 6.80;
S, 7.40.

A similar procedure using 2-chloroethanol in place of the 2-bromoethanol provided the free base as a viscous oil after chromatography on silicic acid with chloroform-acetone tl:l).

Example 12 1-[2-(4-chlorothiophenoxyethylthio)-2-(2,4-di-chLorophenyl)ethyl]-lH-imidazole hydrogen fumarate (Table I, Compound No. 2). p-Toluenesulfonyl chloride t930 mg., 4.9 mmoles) was added to a cooled (ice-water), stirred solution of l-[2-(2,4-dichlorophenyl)-2-(2-hydroxy-ethylthio)ethyl]-lH-imidazole tl.4 g, 4.41 mmoles) in CH2C12 (20 ml) containing triethylamine (0.61 ml, 4.41 mmoles~. Stirring was continued at ice bath temperature ~0.75 hour~ and then at 25 ~0.75 hour).

*U.S. 4,038,409 and 4,039,677 , The mixtUre was then successi~ely wa8hed With the following cold aqueous solutions: water ~2x], 2~
K2CO3-water ~2x), ~ater ~2x? and ~rine. Removal of the solvent, after drying with Na2SO4, left 2.03 g of the tosylate of 1-[2-~2,4-dichlorophenyl)-2-~2-hydroxyethylthio)ethyl]-lH-imidazole as a viscous oil.

A solution of 4-chlorothiophenol (0.67 g, 4.66 mmoles) in DMF ~3 ml) was added during five minutes to a cooled (ice-water), stirred suspension of 57%
sodium hydride in mineral oil tl96 mg, 4.66 mmoles) in DMF (8 ml). The mixture was then heated at an oil bath temperature of 110 for 0.5 hour. The cooling bath was replaced and a solution of the aforesaid tosylate (2.03 g, 4.3L mmoles) in THF (8 ml) added during five minutes. The mixture was gently refluxed for six hours and concentrated to dryness in vacuo.
The resulting oil was diLuted with water and the - mixture extracted with several portions of diethyl ether. The combined ethereal extracts were washed (water, brine), dried tNa2SO4) and concentrated to leave an oil which was dissolved in acetonitrile ~CH3CN). The CH3CN solution was washed with n-pentane (2x). Removal of the CH3CN left the free base ~1.29 g) of the title compound. A solution of the free base 25 ~1.29 g) in CH3CN was treated with fumaric acid ~0.31 g) to provide the title compound ~0.85 g), mp 95-98 (foaming). Recrystallization from CH3CN gave colorless crystals of the analytical sample, mp 96-98.
A~a;l. Calc'd for Cl9H17C13N2S2-C4 4 4 C, 49.33; H, 3.78; Cl, 19.00; N, 5.40; S, 11.45 Found: C, 49.47; H, 3.86; Cl, 18.72; N, 5.08;
S, 11.48.

In a similar manner, replacement of the 4-chlorothiophenol with 2,4-d~chlorothiophenol and 4-mercaptobiphenyl, and use of the suitable salt-forminq acid, gave respectively:
1-[2-(2,4-dichlorothiophenoxyethylthio)-2-(2,4-di-chlorophenyL)ethyl]-lH-imidazole nitrate, mp 104-105 (Table I, Compound No. 3).
Anal. Calc d for ClgH16C14N2S2 HN3 C, 42.15; H, 3.17; Cl, 26.20; N, 7.76.
Found: C, 42.34; H, 2.78; Cl, 25.97; N, 8.12.

1-[2-(4-biphenylylthioethylthio)-2-(2,4-dichlorophenyl)-ethyl]-lH-imidazole hydrogen fumarate, mp 116-119 (Table I, Compound No. 4).
Anal. Calc'd for C25H22C12N2S2 C4 4 4 Cl, 11.79; N, 4.66; S, 10.66.
Found: Cl, 12.20; N, 5.00; S, 10.38.

Example 13 1-[2-(2~4-dichlorophenyl)-2-(4-chlorophenylthio-propylthio)ethyl]-lH-imidazole hydrogen fumarate (Table I, Compound No. S~. To a stirred solution of sodium hydroxide (1.55 g, 0.0388 mole) in ethanol (176 ml) at 25 under a blanket of nitrogen, was added 1-~2-(2,4-dichlorophenyl)-2-(ethoxythiocarbonylthio)ethyl]-lH-imidazole hydrogen oxalate* (3.5 g, 7.7 mmoles).
After stirring at 25 for 0.75 hour, 4-chlorophenyl 3-chloropropyl sulfide (1.8 g, 8.1 mmoles) was added dropwise during five minutes. The mixture was refluxed for eighteen hours and concentrated to dryness. The residue was diluted with water and the mixture extracted with several portions of diethyl ether. The combined *As in Example 11.

ethereal layers were washed (water) and dried tNa2SO4).
Removal of the ether left a viscous oil (3.8 g).
Fumaric acid (0.96 g) wa~ added to a hot solution of the oil in CH3CN(10 ml). Upon cooling colorless crystals (3.3 g) of the titled compound separated, mp 116-117.
Anal- Calc'd for C20Hl9C13N2S2 4 4 4 C, 50.22, H, 4.04; Cl, 18.53; N, 4.88.
Found: C, 50.19; H, 4.06; Cl, 18.66; N, 5.05.

In a similar manner, replacement of the 4-chloro-phenyl 3-chloropropyl sulfide with chloromethyl 4-chlorophenyl sulfide, and 2,4-dichlorophenyl 3-chloro-propyl ether gave, respectively:
1-[2-(4-chlorothiophenoxymethylthio)-2-(2,4-dichloro-phenyl)ethyl]-lH-imidazole sesquifumarate, mp 125-126 (foaming) (Table I, Compound No. 1).
Anal. Calc'd for C H Cl N S .1.5 C H O :

C, 47.73; H, 3.51; Cl, 17.61; N, 4.64; S, 10.62.
Found: C, 47.64; H, 3.59; Cl, 17.41; N, 4.92;
S, 10.29.
1-[2-(2,4-dichlorophenoxypropylthio)-2-(2,4-dichloro-phenyl)ethyl]-lH-imidazole hydrogen fumarate, mp 138-139.5 (Table I, Compound No. 20).
1. C lc d o C20H18 14N2OS-C4H404 C, 48.66; H, 3.74; Cl, 23.95; N, 4.73; S, 5.41.
Found: C, 49.04; H, 3.75; Cl, 23.41; N, 4.90;
S, 5.60.

Example 14 1-[2-t2,4-dichlorophenyl)-2-(phenoxyethylthio)-ethyl]-lH-imidazole hydrogen fumarate (Table I, Compound No. 18). 1-[2-(2,4-dichlorophenyl)-2-(ethoxythiocarbonylthio)-ethyl]-lH-imidazole hydrogen oxalate (1.1 g, 2.45 mmoles) was added to a stirred, cooled ~ice-water~ solution of sodium hydroxide (0.49 g, ~.0123 mole) in methanol t6Q ml) under nitrogen. The ice bath was removed after stirring for 0.25 hour. Stirring was continued at 25 for 0.5 5 hour and a solution of ~-bromophenetole tO.49 g, 2.42 mmoles) in methanol (10 ml) added. The mixture was stirred at room temperature for one hour and then refluxed for two hours. The methanol was removed and a mixture of the residue in water extracted with 10 two portions of diethyl ether. The combined ethereal extracts were washed with 5% aqueous K2CO3 (3x) followed by water. The ether layer was then extracted with dilute hydrochloric acid and the aqueous layer washed with several portions of ether. The aqueous layer 15 was made basic with aqueous sodium hydroxide and the free base extracted into ether. The ethereal layer was dried (Na2SO4) and concentrated to afford 700 mg of a viscous oil, a portion of which (520 mg), when chromatographed on silicic acid (20 g) with CH2C12-20 acetone (lOO:lS) gave 260 mg of purified free base.
Treatment of a solution of the free base in acetonitrile with fumaric acid, provided colorless crystals of the titled salt, mp 116-117.
o ClgHlgcl2N2Os-c4H4O4 C, 54.23; H, 4.35; N, S.S0.
Found: C, 53.48; H, 4.36; N, 5.51.

In a similar manner, replacement of the ~-bromo-phenetole with 2-chloroethyl 2,6-dichlorophenyl ether gave 1-[2-(2,6-dichlorophenoxyethylthio~-2-(2,4-30 d;chIorophenyl)ethyl]-lH-im~dazole hydrogen fumarate, mp 107-108 (Table I, Compound No. 19).
A C f ClgH16C14N2OS-c4H404 C, 47.76; H, 3.49; N, 4.84.
Found: C, 47.87; H, 3.50; N, 4.81.

Example 15 3-chloropropyl 2,4-dichlorophenyl ether* (36).
l-bromo-3-chloropropane (60 g, 0.38 mole) was added to a solution of 2,4-dichlorophenol (40.8 g, 0.25 mole) in 0.5 M ethanolic sodium ethoxide (500 ml). The mixture was refluxed for two hours, cooled and diluted with water (500 ml). The mixture was extracted with CH2C12. The CH2C12 layer was washed (aqueous NaHCO3), concentrated and the resulting oil distilled to provide 40.5 g of the title compound, bp 114-115 (0.2 mm).

In a similar manner, treatment of l-bromo-3-chloropropane with 4-chlorothiophenol provided 3-chloropropyl 4-chlorophenyl sulfide** (Scheme VI, 41), bp 107-108 (0.2 mm).

Example 16 2-_hloroethyl 2,6-dichlorophenyl ether (33).
A solution of 2,6-dichlorophenol (32.6 g, 0.20 mole) in diglyme (65 ml) was added to a cooled (ice-water), stirred mineral oil suspension of 57~ sodium hydride (9.3 g, 0.22 mole) in diglyme (90 ml) containing DMF (5 ml). The mixture was stirred for five minutes at 40 and the cooling bath replaced. A solution of 2-chloroethyl p-toluenesulfonate (47 g, 0.020 mole) in diglyme (20 ml) was then added during twenty minutes.
The mixture was heated at an oil bath temperature of 110 for nineteen hours, and partially concentrated.
The mixture was diluted with cold water and extracted with diethyl ether (2x 125 ml). The combined ethereal extracts were washed successively with ice cold 1 N

*Dutch Patent 94,934 (1960) **Bird and Stirling, J. Chem. Soc. (B), 111 (1968).

1 15585't NaOH, water and brine. The ethereal solution was dried (Na2SO4), concentrated and the residue distilled to provide 35.5 g of the title compound, bp 79-81 (0.1 mm).

2-chloroethyl 2,4-dichlorophenyl ether* (3S), bp 107-111 (0.75 mm) was similarly prepared.

Example 17 1-[2-(4-chloronaphthoxyethoxy)-2-(2,4-dichloroPhenvlj-ethyl]-lH-imidazole nitrate (Table I, Compound No.
_ 38). A solution of 4-chloro-1-naphthol (1.68 g, 9.4 mmoles) in DMF (5 ml) was rapidly added to a cooled (ice-water), stirred, mineral oil suspension of 57%
NaH (435 mg, 10.3 moles) in DMF (15 ml). The cooling bath was removed and stirring continued for five minutes at 5-35 to complete salt formation. The cooling bath was replaced and a solution of the tosylate of 1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)-ethyl]-lH-imidazole (4.28 g, 9.4 mmoles) in the THF
(15 ml) added. The mixture was stirred under gentle reflux for eighteen hours and concentrated to dryness.
The residue was partitioned between diethyl ether and water. The ethereal layer was successively washed with 1 N NaOH, water, brine and dried (Na2SO4).
After removal of the ether the residue was dissolved in acetonitrile and the mineral oil removed with two n-pentane washes. Removal of the acetonitrile left the crude free base (3.30 g), as a viscous brown oil which afforded 2.18 g of pure base after chromatography on silicic acid (120 g) with methylene chloride-acetone (10:1).

*Foldeak et al, Acta Phys. Chem. 9, 134 (1963) -46- 1 1558s7 Addition of 0.3 ml of 70% nitric acid (d-1.42) to a solution of the purified free base (2.18 g) in ethyl acetate provided the nitrate Ralt, mp 88-95. ~e-crystallization from ethyl acetate a~forded peach crystals of the analytical sample, mp 154-156.

alc d for C23H19C13N22 HN3 C, 52.64; H, 3.84; Cl, 20.27; N, 8.01.
Found: C, 52.45; H, 3.92; Cl, 20.30; N, 7.79.

In a similar manner, replacement of the 4-chloro-1-naphthol in the above expeximent with p-hydroxydiphenyl-amine, 4-(4-acetyl-1-piperazinyl)phenol* and p-methoxybenzyl mercaptan and use of the suitable salt-forming acid, gave the following products, respectively:

1-~2-(4-anilinophenoxyethoxy)-2-(2,4-dichlorophenyl)-ethyl]-lH-imidazole hydrogen oxalate, mp 131-135 (Table I, Compound No. 34).

Anal. Calc'd for C25H23C12N32 2 2 4 C, 58.07; H, 4.51; Cl, 12.70; N, 7.52.
Found: C, 57.71; H, 4.53; Cl, 12.45; N, 7.57.

1-(2-[4-(4-acetyl-1-piperazinyl)phenoxyethoxy]-2-[2,4-dichlorophenyl]ethyl)-lH imidazole, mp 128-130 (Table I, Compound No. 35).

Anal. Calc'd for C25H28C12N4O3:
C, 59.65; H, 5.61; Cl, 14.08; N, 11.13.
Found: C, 59.90; H, 5.64; Cl, 13.88; N, 10.92.

1-(2-[2,4-dichlorophenyl]-2-[(4-methoxybenzylthio)ethoxy~-ethyl)-lH-imidazole nitrate, mp 86-88 (Table I, Compound No. 36).
*German OLS 2804096 -47_ 1 155857 Anal. Calc'd for C21H22C12N2O2 3 C, 50.40; H, 4.637 Cl, 14.17; N, 8.40; S, 6.41.
Found: C, 50.23; H, 4.63; Cl, 14.27; N, 8.34;
S, 6.46.

Example 18 1-[2-(2~4-dichlorophenyl)-2-(2~4-dichlorothio-phenoxy~ethylthio)ethyi]-lH-imidazole hydrogen fumarate (Table I, Compound No. 33). To a stirred solution of sodium hydroxide (2.02 g, 0.050 mole) in ethanol (180 ml) at 25 under a blanket of nitrogen, was added l-[2-(2,4-dichlorophenyl)-2-(ethoxythiocarbonyl-thio)ethyl]-lH-imidazole hydrogen oxalate (4.51 g, 0.01 mole). After stirriny at 25 for 0.75 hour, chloromethyl 2,4-dichlorophenyl sulfide (2.5 g, 0.011 mole) was added. The mixture was refluxed for eighteen hours and concentrated to dryness. The residue was diluted with water and the mixture extracted with two portions of diethyl ether. The combined ethereal extracts were washed successively with dilute NaOH, H2O, brine and dried (Na2SO4).
Removal of the ether left a cloudy oil (4.2 g) which afforded 3.8 g of the pure free base after chromato-graphy on silicic acid (100 g) with methylene chloride -acetone (10:1).

The oily free base (3.8 g) was treated with fumaric acid (950 mg) to give, after dilution with acetonitrile, the fumarate salt which melted at 117-120 after two recrystallizations from acetonitrile.

~155857 Anal. Calc'd for C18H14C14N2S2 4 4 4 C, 45.53; H, 3.13; Cl, 24.44; ~, 4.83; S, 11.05.
Found: C, 45.35; H, 3.09; Cl, 24.10i N, 4.68;
S, 11.04.

Example 19 1-[2-~4-biphenyly}methoxyethoxy)-2-~2,4-dichloro-phenyl)ethyl]-lH-imidazole nitrate (Table I, Compound No. 37). A solution of 1-~2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyll-lH-imidazole nitrate (3.64 g, 0.01 mole) in DMF (22 ml) was added dropwise during ten minutes to a stirred, cooled (ice-water) mineral oil suspension of 57% sodium hydride (926 mg, 0.022 mole) in DMF (15 ml) under nitrogen.
Stirring was then continued at 40-45 for twenty lS minutes to complete salt formation. The cooling bath was replaced and a solution of 4-chloromethyl-biphenyl (2.03 g, 0.01 mole) in THF (10 ml) added.
The mixture was then heated at an oil bath temperature of 65 for three hours and concentrated to dryness.
The residue was partitioned between diethyl ether and water. The ethereal layer was washed (brine), dried (Na2SO4) and the ether removed. The residue was dissolved in acetonitrile and the mineral oil removed by washing with n-pentane (2x). The acetonitrile was removed and the residue chromatographed on silicic acid (120 g) with methylene chloride -acetone (10:1) to give the free base (1.56 g) as a yellow oil. A solution of the free base (1.56 g) in ethyl acetate was treated with oxalic acid (300 mg) to provide the hydrogen oxalate salt which melted at 113-121 after recrystallization from ethyl acetate followed by recrystallization from nitromethane.

1 1~5~S ~

The hydrogen oxalate salt was partitioned between diethyl ether and dilute aqueous sodium hydroxide. The ethereal layer was washed (water, brine), dried (Na2SO4) and concentrated. Treatment of a solution of the re-sulting free base in ethyl acetate with 70% nitric acid~d=1.42) provided the titled nitrate salt mp 114-116.5.
Recrystallization from ethyl acetate gave colorless crystals of the analytical sample, mp 115-118.5.

Anal- Calc d for C26H24C12N22-HN3 C, 58.88; H, 4.75; Cl, 13.37; N, 7.92.
Found: C, 58.67; H, 4.98; Cl, 12.89; N, 7.73.

Example 20 Chloromethyl 2,6-dichlorophenyl sulfide (Scheme III, 21, Z=Cl, n=l, Y=S, m=o, Rl'2=2,6-dichloro). Utilizing the general method of Goralski and Burk*, benzyltriethyl-ammonium bromide (0.6 g, 2.2 mmoles) was added to a stirred mixture of 2,6-dichlorothiophenol (12.0 g, 0.067 mole) and powdered 85~ potassium hydroxide (4.42 g, 0.067 mole) in bromochloromethane (300 ml) at 22. An immediate exotherm ensued, the temperature rising to 38. Stirring was continued at ambient temperature for two hours. The mixture was filtered and the excess bromochloromethane removed in a rotary evaporator to leave an amber oil. A solution of the oil in diethyl ether was dried (Na2SO4) and concentrated to leave the crude product as a crystalline solid. Recrystallization from Skellysolve-B afforded chunky crystals (11.9 g) of the title compound, mp 52.5-55.5.

* J. Org. Chem., 42, 3094 (1977).

--so--Example 21 1-12-(2~4-Dichlorophenyl)-2-(2 ! 6-dichlorophenYlthio-methylthio)ethyll-lH-imidazole hydrogen fumarate (Table I, Compound No. 39). To a stirred solution of ~odium hydroxide (2.02 g, 0.050 mole) in ethanol (180 ml) at 25 under a blanket of nitrogen, was added 1-12-(2,4-dichlorophenyl)-2-(ethoxythiocarbonylthio)ethyl]-lH-imidazole hydrogen oxalate (4.51 g, 0.01 mole).
After stirring at 25 for 0.75 hour, chloromethyl 2,6-dichlorophenyl sulfide (2.5 g, 0.011 mole) was added. The mixture was refluxed for eighteen hours and concentrated to dryness. The residue was diluted with water and the mixture extracted with two portions of diethyl ether. The combined ethereal extracts lS were washed successively with dilute NaOH, H2O, brine and dried (Na2SO4). Removal of the ether left a cloudy oil (4.4 g) which afforded 2.56 g of the pure free base after chromatography on silicic acid (150 g) with methylene chloride-acetone (10:1).

A solution of the free base (2.56 g) in acetonitrile was treated with fumaric acid (632 mgs) to afford color-less crystals (2.22 g) of the hydrogen fumarate salt, mp 134-136. Recrystallization from acetronitrile gave the analytical sample, mp 133-136.

Anal. Calc'd for C18H14C14N2S2.C4H4O4 H, 3.13; Cl, 24.44; N, 4.83; S, 11.05.
Found: C, 45.36; H, 3.02; Cl, 24.29; N, 5.00;
S, 11.03.

Example 22 1-12-(4-Chlorophenoxymethylthio)-2-(2,4-dichloro-phenyl)ethyl]-lH-imidazole sesquihydrogen fumarate -51- 1 1~5~ ~

(Table I, Compound No. 41). In a manner similar to that described in Example 21, replacement of the chloromethyl 2,6-dichlorophenyl sulfide with chloromethyl 4-chlorophenyl ether gave the title compound, mp 158-160.

Anal- Calc d for C18H15C13N2S 1-5(C4H4O4) C, 49.04;
H, 3.60; Cl, 18.09; N, 4.77; S, 5.45.
Found: C, 49.28; H, 3.74; Cl, 17.74; N, 4.85;
S, 5.51.

Example 23 1-{2-[(4-Chlorophenylthio)methoxy]-2-[2,4-dichloro-phenyl]ethyl}-lH-imidazole hydrogen fumarate (Table I, Compound No. 40). 1-(2,4-Dichlorophenyl)-2-tlH-l-imidazolyl)ethanol* (2.57 g, 0.01 mole) was added to a stirred mixture of. a mineral oil suspension of 57%
sodium hydride (463 mgs, 0.011 mole) in DMF (15 ml) and THF (10 ml), under nitrogen. The mixture was heated under gentle reflux for 0.75 hour to complete salt formation. The mixture was cooled in an ice-water bath and a solution of chloromethyl 4-chlorophenyl sulfide (1.93 g, 0.01 mole) in THF (3 ml) added. The mixture was heated under gentle reflux for eighteen hours and concentrated. A solution of the residue in diethyl ether was washed successively with water, Na2CO3-water, brine and then dried (Na2SO4) and concentrated.

The residue was dissolved in acetonitrile and the mineral oil removed by washing with n-pentane (2x).
Removal of the acetonitrile left a dark oil which was chromatographed on silicic acid (120 g) with methylene chloride-acetone (20:1) to afford a brown oil (1.79 g) which crystallized. Recrystallization from cyclohexane gave 1.5 g of the free base, mp 95-97.

*U.S. 3,717,655 and Godefroi et al, supra.

Treatment of an acetonitrile ~olution of the free base with umaric acid provided the hydrogen fumarate salt, mp 128-130. Two recrystallizations from ethyl acetate -Skellysolve-B - gave the analytical sample, mp 129-133.

Anal- Calc'd for C18H15C13N2S C4H4 4 H, 3.61; Cl, 20.07; N, 5.29; S, 6.05.
Found: C, 49.80; H, 3.60; Cl, 19.99; N, 5.17;
S, 6.20.

Example 24 1-[2-(4-Chlorobenzylthiomethylthio)-2-(2,4-dichlorophenyl)ethyl]-lH-imidazole hydrogen fumarate (Table I, Compound No. 42). To a stirred solution of sodium hydroxide (2.02 g, 0.05 mole) in ethanol (180 ml) at 25 under a blanket of nitrogen, was added 1-[2-(2,4-dichlorophenyl)-2-(ethoxythiocarbonylthio) ethyl]-lH-imidazole hydrogen oxalate t4.51 g, 0.01 mole). After stirring at 25 for 0.75 hour a solution of 4-chlorobenzyl chloromethyl sulfide (2.07 g, 0.01 mole) in ethanol (2 ml) was added. The mixture was refluxed for twenty hours and concentrated to dryness.
The residue was partitioned between diethyl ether and water. The ethereal layer was washed successively with H2O, Na2CO3-H2O, H2O, brine and dried (Na2SO4).
Removal of the ether left the free base (3.3 g~ as a viscous brown oil. Treatment of a solution of the free base (3.3 g) in acetonitrile with fumaric acid (0.78 g) provided 2.5 g) of the title compound, mp 120-125. Recrystallization from ethyl acetate gave colorless crystals, mp 121-123, of the analytical sample.

Anal. Calc d for ClgH17Cl3N2s2-c4H4O4 C~ 49-34; H~
3.78; Cl, 19.00; N, 5.00; S, 11.45.
Found: C, 49.70; H, 3.90; Cl, 18.94; N, 5.24;
S, 11.39 Example 25 1-(2-[(4-Chlorobenz~lthio)methoxy]-2-[2 ! 4-dichloro-phenyl]e~y_)-lH-imidazole hydrogen oxalate (Table I, Compound No. 43). 1-~2-(2,4-Dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole (2.57 g, 0.01 mole) was added to a stirred mineral oil suspension of 57%
sodium hydride (463 mg, 0.011 mole) in a mixture of DMF (15 ml) and THF (10 ml). The mixture was heated under gentle reflux for 0.5 hr to complete salt formation. A solution of 4-chlorobenzyl chloromethyl sulfide (2.07 g, 0.01 mole) was added and the mixture heated under gentle reflux for twenty hours. The mixture was partitioned between diethyl ether and water. The ethereal was filtered to remove starting alcohol (1.3 g~. The ethereal filtrate was concentrated.
A solution of the residue in acetonitrile was washed with n-pentane (2x~ to remove the mineral oil. The acetonitrile was removed and the residue chromatographed on silicic acid (30 g) with methylene chloride -acetone (25:3) to give the free base (190 mg) as a viscous brown oil. Treatment of a solution of the free base (190 mg) in ethyl acetate with oxalic acid (40 mg) provided colorless crystals of the title compound, mp 148-150. The product melted at 153.5-154 after recrystallization from acetonitrile.

Anal. Calc'd. for C1gH17C13N2OS.C2H2O4: C, 48.71; H, 3.70;
Cl, 20.54; N, 5.41; S, 6.19.
Found: C, 49.21; H, 3.71; Cl, l9.9S; N, 5.30; S, 6.73.

The antimicrobial compounds of this invention exhibit antifungal and antibacterial activity against a wide variety of human and animal pathogens in addition to those referred to in Tables II and III above and are accordingly useful not only in pharmaceutical appli-cations but also in agricultural, industrial, household and other applications in which such activity i~ required.
In general, antimicrobial compositions may contain such compounds in any concentrations, i.e. from about 0.1%
to about 99.9% in a suitable or conventional carrier adapted for the intended use. For example, from about 10% to 90% concentrates may be supplied for dilution by the user to concentrations generally ranging from about 0.1% to 10%.

lS In pharmaceutical formulations compositions may be solid, semi-solid or liquid in for~ such as tablets, capsules, powders, suppositories, liquid solutions, suspensions, creams, lotions, gels, ointments and the like. Pharmaceutically acceptable non-toxic carriers, or excipients normally employed for solid formulations include tricalcium phosphate, calcium carbonate, kaolin, bentonite, talcum, gelatin, lactose, starch and the like; for semi-solid formulations there may be mentioned, for example, polyalkylène glycols, vaseline, petrolatum and other cream bases; for liquid formulations there may be mentioned, for example, water, oils of vegetable origin and low boiling solvents such as isopropanol, hydrogenated naphthalenes and the like. The pharma-ceutical compositions containing the compounds of the present invention may be subjected to conventional pharmaceutical expedients such as sterilization and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, emulsifying agents, salts for the adjustment of osmotic pressure and buffers.
The compositions may also contain other therapeutically active materials.

11~5857 The pharmaceutical compositions of this invention typically comprise a pharmaceutically acceptable, non-toxic carrier in combination with one or more compounds represent0d by formula 4 in an amount effective for relief or prevention of the specific condition being treated. Since the active compounds of this invention exhibit anti-fungal and anti-bacterial activity over a wide range of concentration, the efective amount may vary. For example, in topical formulations the amount may be about 0.1% to about 10~ of the total pharmaceutical formulation while in other formulations the amount may be about S to 95% or more. Preferably the pharmaceutical compositions of this invention are formulated in unit dosage form to facilitate administration (unit dosage being the amount of active ingredients administered on one occasion).

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. "Topical" ad-ministration includes intravaginal application while parenteral administration includes intramuscular as well as subcutaneous and intravenous injection. Intra-venous injection of imidazole derivatives for certain systemic conditions has been demonstrated to be effective (see for example, Drugs 9, 419-420 (1975), which describes the intravenous administration of Miconazole, i.e.
1-[2,4-dichloro-~-(2',4'-dichlorobenzyloxy)phenethyl]-imidazole nitrate, to patients with systemic candidiasis).
Topical application is the preferred method of admin-istration in pharmaceutical applications. For such treatment, an area having an existing fungal or bacterial growth, or to be protected against attack by fungi or bacteria, may be treated with the subject compounds of formula 4 or compositions containing them by, for example, dusting, sprinkling, spraying, rinsing, brushing, dipping, smearing, coating, impregnating and the like.

The exact regimen for pharmaceutical administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the in-dividual subject being treated, the type of treatment, e.g., whether preventative or curative, the type or organism involved and, of course, the judgment of the attending practitioner. In general, for systemic (e.g., oral or parenteral) administration it is expedient to administer the active ingredient in amounts of between about 1 and 100 mg/kg body weight per day (preferably between about 5 and 50 mg/kg body weight per day) preferably distributed over several applications (e.g., in 3 individual doses) in order to achieve effective results. For localized (e.g., topical) administration, however, proportionately less of the active ingredient is required.

In agricultural 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 various mineral silicates, e.g., mica, talc, pyrophyllite, and clays. The subject compounds may also be applied to the seeds in admixture with a conventional surface-active wetting agent with or without additional solid carrier. Surface-active wetting agents that can be used are any of the conventional anionic, non-ionic, amphoteric or cationic types. As a soil treatment for fungi and the like, the subject compounds can be applied as a dust in admixture with sand, soil or a powdered solid carrier such as mineral silicate with or without additional surface-active agent, or the subject compounds can be applied as an aqueous spray optionally containing a surface-active dispersing agent and a powdered solid carrier. As a foliage treatment, the subject compounds can be applied to growing plants as an aqueous spray which contains a surface-active dispersing agent with or without a S powdered solid carrier and hydrocarbon solvents.

In industrial applications, the subject compounds may be used to control bacteria and fungi by contacting the pathogens with the compounds in any known manner.
Materials capable of supporting bacteria and fungi may be protected by contacting, mixing or impregnating these materials with the subject compounds. In order to increase their effect, the subject compounds may be combined with other pesticidal control agents such as fungicides, bactericides, insecticides, miticides and the like. A particularly important industrial/
agricultural use for the subject compounds of the present invention is as a food preservative against bacteria and fungi which cause deterioration and spoilage of foods.

This invention has been disclosed with respect to certain preferred embodiments, and it will be understood that modifications and variations thereof obvious to those skilled in the art are to be included within the spirit and perview of this application and the scope of the appended claims.

Claims (49)

1. A process for producing a compound of the formula (I) including the pharmaceutically acceptable antimicrobial acid addition salts thereof, wherein R4 and R5 are independently hydrogen or halogen and Z is a mono-or disubstituted phenyl moiety of the formula wherein R1 and R2 are independently hydrogen, halogen, (lower) alkyl or trifluoro methyl, with the proviso that R1 and R2 may not simultaneously both be trifluoromethyl, comprising (1) reacting an alkali metal thiolate of the formula (VI) wherein M is sodium, potassium or lithium and R4 and R5 are as previously defined, with a compound of the formula L-CH2SCH2-Z (VII) wherein Z is as previously defined and L is a conventional leaving group, in the presence of a reaction inert solvent to produce the compound of formula I or (2) reacting an imidazole compound of the formula (VIII) wherein R4 and R5 are as previously defined, with a hemi-mercaptal of the formula HSCH2SCH2-Z (IX) wherein Z is as previously defined, in the presence of a reaction inert solvent containing an acid binding agent, to produce the compound of formula I; then, if desired, converting the compound of formula I to its corresponding pharmaceutically acceptable acid addition salt.

2. The process of claim 1 wherein the compound of formula I is produced by the reaction of the alkali metal thiolate of formula VI with the compound of formula VII.

3. The process of claim 2 wherein M is Na and the reaction is carried out under inert atmosphere to minimize oxidation; L is chloro; and the alkali metal thiolate of the formula VI is reacted with an approximately equimolar amount of the compound of formula VII.

4. The process of claim 2 wherein the alkali metal thiolate of the formula VI is produced by reacting a compound of the formula (V) with an alkali metal hydroxide of the formula MOH in the presence of a suitable solvent, and wherein R4 and R5 are as previously defined, M is sodium, potassium or lithium and W
is a group which is cleaved by the alkali metal hydroxide.

5. The process of claim 4 wherein in said compound of the formula V W is .

6. A compound of the formula (I) including the pharmaceutically acceptable antimicrobial acid addition salts thereof, wherein;
R4 and R5 are independently hydrogen or halogen and Z
is a mono or disubstituted phenyl moiety of the formula wherein R1 and R2 are independently hydrogen, halogen, (lower) alkyl or trifluoromethyl, with the proviso that R1 and R2 may not simultaneously both be trifluoromethyl, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

7. The compound of claim 6 when prepared by the process of claim 2 or 3 or by an obvious chemical equivalent thereof.

8. The compound of claim 6 when prepared by the process of claim 4 or 5 or by an obvious chemical equivalent thereof.

9. A process of claim 1 including converting the compound of formula (I) into a pharmaceutically acceptable antimicrobial acid addition salt selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, phosphate, fumarate, oxalate, maleate, acetate, pyruvate, citrate, tartrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, hydroxyethanesulfonate, sulfamate, malate, succinate, ascorbate, levulinate, propionate, glycolate, benzoate, mandelate, salicylate, lactate, p-aminosalicylate, 2-phenoxy benzoate, 2-acetoxy benzoate and 1,4-naphthalene disulfonate salt.

10. The compound of claim 6 wherein the antimicrobial pharmaceutically acceptable acid addition salt is the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, phosphate, fumarate, oxalate, maleate, acetate, pyruvate, citrate, tartrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, hydroxyethanesulfonate, sulfamate, malate, succinate, ascorbate, levulinate, propionate, glycolate, benzoate, mandelate, salicylate, lactate, p-aminosalicylate, 2-phenoxy benzoate, 2-acetoxy benzoate or 1,4-naphthalene disulfonate salt, when prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

11. A process of claim 1, wherein one of the R4 or R5 substituents is chloro and the other is chloro or hydrogen, and R1 and R2 are independently hydrogen, fluoro, chloro, (lower) alkyl or trifluoromethyl, with the proviso that R1 and R2 may not simultaneously both be trifluoromethyl.

12. The compound of the formula I or antimicrobial acid addition salt thereof, as claimed in claim 6, wherein one of the R4 or R5 substituents is chloro and the other is chloro or hydrogen, and R1 and R2 are independently hydrogen, fluoro, chloro, (lower) alkyl or trifluoromethyl, with the proviso that R1 and R2 may not simultaneously both be trifluoromethyl, when prepared by the process of claim 11 or by an obvious chemical equivalent thereof.

13. A process of claim 1, wherein one of the R4 or R5 substituents is chloro and the other is chloro or hydrogen and R1 and R2 are independently hydrogen, chloro or (lower) alkyl.

14. The compound of the formula I or antimicrobial acid addition salt thereof, as claimed in claim 6, wherein one of the R4 or R5 substituents is chloro and the other is chloro or hydrogen and R1 and R2 are independently hydrogen, chloro or (lower) alkyl, when prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

15. A process of claim 1 wherein R5 is chloro, R4 is hydrogen or chloro and Z is 4-chlorophenyl or 2,4-dichlorophenyl.

16. The compound of the formula I or antimicrobial acid addition salt thereof, as claimed in claim 6, wherein R5 is chloro, R4 is hydrogen or chloro and Z is 4-chlorophenyl or 2,4-dichlorophenyl, when prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

17. A process of Claim 1 wherein R4 and R5 are chloro and z is 4-chlorophenyl or 4-methylphenyl.

18. The compound of the formula I or antimicrobial acid addition salt thereof, as claimed in claim 6, wherein R4 and R5 are chloro and Z is 4-chlorophenyl or 4-methylphenyl, when prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

19. A process of claim 1 wherein R4 and R5 are chloro and Z is 4-chlorophenyl.

20. The compound of the formula I or antimicrobial acid addition salt thereof, as claimed in claim 6, wherein R4 and R5 are chloro and Z is 4-chlorophenyl, when prepared by the process of claim 19 or by an obvious chemical equivalent thereof.

21. A process of claim 19 including converting the reaction product into the fumarate salt.

22. The fumarate salt of the compound of the formula I as claimed in claim 6, wherein R4 and R5 are chloro and Z
is 4-chlorophenyl, when prepared by the process of claim 21 or by an obvious chemical equivalent thereof.

23. A process of claim 19 including converting the reaction product into the hydrochloride salt.

24. The hydrochloride salt of the compound of the formula I as claimed in claim 6, wherein R4 and R5 are chloro and Z is 4-chlorophenyl, when prepared by the process of claim 23 or by an obvious chemical equivalent thereof.

25. A process of claim 1 wherein R4 and R5 are chloro and Z is 4-methylphenyl.

26. The compound of the formula I or antimicrobial acid addition salt thereof, as claimed in claim 6 wherein R4 and R5 are chloro and Z is 4-methylphenyl, when prepared by the process of claim 25 or by an obvious chemical equivalent thereof.

27. A process of claim 25 including converting the reaction product into the fumarate salt.

28. The fumarate salt of the compound of the formula I
as claimed in claim 6, wherein R4 and R5 are chloro and Z is 4-methylphenyl, when prepared by the process of claim 27 or by an obvious chemical equivalent thereof.

29. A process of claim 1 wherein R4 and R5 are chloro and Z is 2,4-dichlorophenyl.

30. The compound of the formula I or acid addition salt thereof, as claimed in claim 6, wherein R4 and R5 are chloro and Z is 2,4-dichlorophenyl, when prepared by the process of claim 29 or by an obvious chemical equivalent thereof.

31. A process of claim 29 including converting the reaction product into the fumarate salt.

32. The fumarate salt of the compound of the formula I
as claimed in claim 6, wherein R4 and R5 are chloro and Z is 2,4-dichlorophenyl, when prepared by the process of claim 31 or by an obvious chemical equivalent thereof.

33. A process of claim 1 wherein R4 and R5 are chloro and Z is 2,6-dichlorophenyl.

34. The compound of the formula I or acid addition salt thereof, as claimed in claim 6, wherein R4 and R5 are chloro and Z is 2,6-dichlorophenyl, when prepared by the process of claim 33 or by an obvious chemical equivalent thereof.

35. A process of claim 33, including converting the reaction product into the hydrochloride salt.

36. The hydrochloride salt of the compound of the formula I as claimed in claim 6, wherein R4 and R5 are chloro and z is 2,6-dichlorophenyl, when prepared by the process of claim 35 or by an obvious chemical equivalent thereof.

37. A process of claim 1 wherein R4 is hydrogen, R5 is chloro and Z is 4-chlorophenyl.

38. The compound of the formula I or acid addition salt thereof, as claimed in claim 6, wherein R4 is hydrogen, R5 is chloro and Z is 4-chlorophenyl, when prepared by the process of claim 37 or by an obvious chemical equivalent thereof.

39. A process of claim 37, including converting the reaction product into the fumarate salt.

40. The fumarate salt of the compound of the formula I as claimed in claim 6, wherein R4 is hydrogen, R5 is chloro and Z is 4-chlorophenyl, when prepared by the process of claim 39 or by an obvious chemical equivalent thereof.

41. A process of claim 1, wherein R4 is hydrogen, R5 is chloro and Z is 2,4-dichlorophenyl.

42. The compound of the formula I or acid addition salt thereof, as claimed in claim 6, wherein R4 is hydrogen, R5 is chloro and Z is 2,4-dichlorophenyl, when prepared by the process of claim 41 or by an obvious chemical equivalent thereof.

43. A process of claim 41, including converting the reaction product into the fumarate salt.

44. The fumarate salt of the compound of the formula I
as claimed in claim 6, wherein R4 is hydrogen, R5 is chloro and Z is 2,4-dichlorophenyl, when prepared by the process of claim 43 or by an obvious chemical equivalent thereof.

45. A process of claim 1 including the step of recovering the dextrorotatory optical isomer of the compound of formula I.

46. The dextrorotatory optical isomer of the compound of the formula I or antimicrobial acid addition salt thereof, as claimed in claim 6, when prepared by the process of claim 45 or by an obvious chemical equivalent thereof.

47. A process of claim 1 including the step of recovering the levorotatory optical isomer of the compound of formula I.

48. The levorotatory optical isomer of the compound of the formula I or antimicrobial acid addition salt thereof, as claimed in claim 6, when prepared by the process of claim 47 or by an obvious chemical equivalent thereof.

49. A method of inhibiting the growth of fungi or bacteria comprising applying to a host object containing, carrying or subject to attack by fungi or bacteria an antimicrobially effective amount of a compound as defined in claim 6, said host object being selected from plants and inanimate objects.