NZ194829A - 1-phenethylimidazole derivatives;antibacterial and fungicidal compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 94829 cf rriority C-?.

(P* i"\TV^TTii ^ O ■ -. j" -r '^V- ' --■ .'0■ ~ ' %0 vw) S ioi'wi.O 4»vlwU4(ij,^L.'..vi J • ■ ■ ■ a a a a Co-ioa-b-?,; LC?T oto^; QS-StSSI a a •■ FijEjIecaucn Data: .....

B9.0Cl.iat P.O. Journal, Wo: .... - . m mmmmrns :^r. 2 zSEPfisg keih-,-.::> No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION 1-PHENETHYLIMIDAZOLE DERIVATIVES iQCwe, BRISTOL-MYERS COMPANY of 345 Park Avenue, New York, New York 10022, United States of America, a Corporation of the State of Delaware, United States of America hereby declare the invention for whichXJO^ we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (T,\y u - >Ct- 1-PHENETHYLIMIDAZOLE DERIVATIVES I. Description: This invention relates to certain novel 1-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 1-(3-aryl)ethyl-lH-imidazole moiety of the formula: For example, in U.S. 3,717,655 and E. F. Godefroi et al, J. Med. Chem. 12^, 784 (1969), compounds of formula 1 are disclosed in which R„ is: — a ■N 1 CH^-CH-R 2 < a wherein X is 0 or NH In U.S. 3,991,201 and J. Heeres et al, J. Med.

Chem. 2)0, 1511 (1977) , such compounds are disclosed in which R is -(CH-) -Ar. a z n In J. Heeres et al, J. Med. Chem. _20, 1516 (1977), such compounds are disclosed in which R^ is -(CI^^O-Ar.

In U.S. 4,055,652 and 4,039,677, such compounds are disclosed in which R& 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 R is -XC-R-, a || 3 Y wherein X and Y are O or S and R^ is H, alkyl, cycloalkyl, phenalkyl, phenalkenyl, or -XR^ wherein R^ is alkyl, halophenyl, etc.

In U.S. 4,006,243, such compounds are disclosed in which R is H, alkyl or phenyl. a An entirely new class of compounds of formula 1^ has now been discovered which have very good antifungal and antibacterial activity, namely those in which R is an optionally nuclearly substituted group of the d formula: A -X-(CH,) -Y-(CH-)-— i n 2 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 substituted, and including the antimicrobial acid addition salts of such compounds.

The products of the present invention are named as derivatives of 1-(ethyl)-lH-imidazole with the substituents R^ and R2 located at position 2 of the ethyl side chain, as in the following formula 2y 1 948 / N . o | 1 2 CH0CH-R. 2| 1 . R2 Alternatively, the products can be named as derivatives of 1-(phenethyl)-lH-imidazole where the substituent R^ is attached $ to the imidazole ring, as in the following formula 3: As indicated above, a primary feature of the present invention is the provision of novel compounds of formula 1 above in which R has the formula A above and the CH __ cl bonded phenyl ring is optionally nuclearly substituted, and including the antimicrobial, i.e. antifungal and 10 antibacterial, acid addition salts of such compounds, especially compounds of the formula: 194829 including the antimicrobial acid addition salts thereof, wherein: X and Y are independently sulfur or oxygen; m is zero or 1; n is 1, 2 or 3, with the proviso that when ~1 2 n=l, X and Y cannot both be oxygen; R and R are independently hydrogen, halogen or alkyl or taken together the atoms necessary to complete a naphthalene ring; 3 .

R is hydrogen, halogen , CF^, SCF^, alkyl, alkenyl, alkynyl, cyclo- alkyl, alkoxy, alkylthio, pyrrolidinyl, piperidinyl, piperazinyl, alkanoylpiperazinyl, morpholinyl, alkyl- amino, dialkylamino, alkanoylamino, amino, nitro, carboxy, carboalkoxy or an aryl radical selected from the group consisting of phenyl, benzyl, benzoyl, phenylthio, phenylsulfonyl, phenylamino and benzoyl- amino, said aryl radical being optionally nuclearly substituted by one or more halogen, CF_, alkyl or 4 5 6 alkoxy radicals; and R , R and R are independently hydrogen, halogen, CFalkyl, alkoxy or phenyl optionally nuclearly substituted by one or more halogen, CF^, 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 useful 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 ' i v l-*\ y < , * V J // by applying 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 5 present invention relates to compositions for pharmaceutical, agricultural, and industrial use, which compositions comprise the subject compounds of formula •4 in combination with a suitable carrier.

Still another feature of this invention is the 10 provision of compounds useful as intermediates for producing the compounds of formula £ above, such intermediates having the formula: As employed herein and in the appended claims, "alkyl", "alkoxy" and "alkanoyl" groups contain a saturated, branched or unbranched acyclic hydro-20 carbon group of 1 to about 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl and hexyl and isomeric forms thereof. "Alkenyl" groups contain a branched or unbranched acyclic hydrocarbon group B wherein Z is a member selected from the group consisting of YM, halo, COOalkyl, methanesulfonate and CH^, M is K or alkali metal, and X, Y, R 4 <1 —> c/ 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, 1-dodecenyl and the like. "Alkynyl" groups are 5 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" 10 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 15 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, 20 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-25 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 30 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 94 S as water, ethanol, 1-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 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 10 optically active acids such as the optically active forms of camphor-10-sulfonic, a-bromocamphor-Tr-sulfonic, camphoric, menthoxyacetic, tartaric, malic, di-acetyltartaric, pyrrolidone-5-carboxylic acids and the like. It will be understood that this invention 15 is inclusive of such optical isomers and the racemic mixtures thereof.

PREPARATION OF ANTIMICROBIAL PRODUCTS Thet compounds of formula £ are prepared utilizing the inherent variations of the Williamson Ether 20 Synthesis (Houben-Weyl, Methoden Der Organischen Chemie, VI (Part 3)1975).

As shown in Scheme I tosylate 5_ is reacted with phenoxides (£, m=0, Y=0), thiophenoxides (([, m=0, Y=S), or the sodium or lithium salts of benzyl alcohols 25 (6^, m=l, Y=0) or benzyl mercaptans (£, m=l, Y=S) to provide the ethers 7. (Y=0 or S, m=0 or 1) .

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

I oo i 9'S^ 01 S—^HO^HOStfO^llO ' e'z'i* 9'S'fr>l s *;uGU0 - 0 - 0S0ZllD?lI0S110Zlin £'Z'l I 1 z'z'v VI 7 7 7 7 ( H0)-A 110 HODIIOHq X "ouiaips o » 1; 4 4 B 2 Scheme I can be combined as follows: V'5'6 -> 'CH0CH-X-CIl CH2-Y-(CH )r 0 1 \R-%5,6 12 Formation of the ethers 12_ is accomplished by intimately contacting a solution of the tosylate 11 in an inert solvent such as tetrahydrofuran 5 or tetrahydrofuran/N,N-dimethylformamide mixture, with an alkali metal salt S_ (sodium or lithium) of the requisite alcohol or mercaptan, usually in the s.ame ' solvent, or containing an additional co-solvent at temperatures of about 25-100°C and for periods of about 10 1 hour to several days. Of course the optimum temperatures and times will vary according to the nucleophilicity of the alcohol or mercaptan salt Preparation of the alkali metal salt 6^ is effected by contacting the alcohol or mercaptan with a base 15 such as sodium hydride and the like or n-butyl lithium in the presence of organic solvents such as tetrahydrofuran and N,N-dimethylformamide at temperatures of from -78°C, when n-butyl lithium is used, and about 0-100°C when sodium hydride is used, and for 20 periods of about 15 minutes to several hours.

Additional suitable solvents for the formation of the alkali metal salts £, as well as for running the reaction 1_1—^ 12 include benzene, diglyme, hexamethylphosphoramide, dimethoxyethane and toluene. \ v; >,*• V- Additional leaving groups as alternatives to the p-toluenesulfonate anion (13^ Z = -OSO~\^ yy"CH3) include such conventional leaving groups as Z = chloro, bromo, iodo, methanesulfonate and the like.

O CH CH-X-CH2CH2Z Alcohol 1^4, from which tosylate 5 is derived, has been alkylated with benzyl halides L5, as shown in Scheme II, tc ethers 16_, thus confirming that the roles of alcohol and.alkylating species can be interchanged in Williamson Synthesis.

* Alcohol 1T_, from which tosylate {3 is derived, may be alkylated with the benzyl halides lj5 to provide the ethers 18.

CII CHOCII CH OH 21 2 2 4,5,6 14 Scheme IT 1. NaH -> 2. /= O- 12 1 K'' 2 m Z=C1} Br m=l >1/2/3 CU2CH0CH2CH20(CH2) 16 r4,5,6 Schcrne II (Cont'd) The alkylating agents L5 are added either neat or in solution to a preformed alkali metal salt (preferably sodium, but may be lithium or potassium) of alcohol 14 in a suitable solvent at about 0°. The resulting 5 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 10 include tetrahydrofuran, N,N-dimethylformamide, hexamethylphosphoramide, benzene, toluene, diglyme, dimethoxyethane and the like. The alkali metal salts of 14_ are formed by contacting 14^ with a strong base, e.g. sodium hydride and the like in 15 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. 4 I « Schema III 1 94S r~~ n // \\ - (CO 11) V s I li CH2-C!!SC0C 1! Ka OH. Ci! OH or CHOH \-<,5,6 19 ,1,2,3 * Z- (CH2 )n-Y-<f Hz )m- 21 h \\ I CH OH > or C H.OH I 2 ' G (5 Ci! ClI-S KaU II "\\ . \ i I CH, CHS-(CH_) -Y-(CH?) 2 n c 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 5 the instant syntheses.

Thiol salt 2() is advantageously stockpiled as the solid xanthate 1_9 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.

C-, / " •' O <f5) The reaction of 20 with 21 (n=2, Z=C1, Y=S) resulted largely in eliminating of HCl from 21^ to afford 23.

SCH=CH, ,1,2,3 23 Compounds of type 22^ where n=2, Y=S and m=0 are therefore best synthesized according to the procedure outlined in Scheme I.

As shown in Scheme IV, alkylation of 24 with chloro-methyl phenyl sulfides (21, Z=C1, n=l, Y=S, m=0) or benzyl chloromethyl sulfides (21, Z=C1, n=l, Y=S, m=l) provides the corresponding ethers 25 (n=l, Y=S, m=0 or 1) .

Scheme IV Ll0CH^fta® + 21 4,5,6 24 II w .v i I 1,2,3 CH C-IO-CCH ) -Y-(CH2) ^ I Tl V.5.6 Ethers of general structure £5, wherein n=2, Y=0 and m=0 are preferably synthesized according to the procedure outlined in Scheme I.

I # PREP ARATION OF INTERMEDIATES Alcohols and Tosylates Starting from the known alcohol 26the novel ester 28, alcohol 1£ and its corresponding tosylate _5 are 5 prepared as shown in Scheme V.

Scheme V 1. NaH, TllF-DMF A 2. BrCII C02C2H5 27 4,5,6 LiAlIl, en cuoca co2c7u5 / N K» ' t CH CHOCH CH^OH r4,5,6 o R4- 5.6 TEA, CH.Cl. » 2 2 CH2CH0CU2CH2OSO9-^ CH.

V'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 2jB. The ester may be isolated and purified as the solid nitrate salt, or can be 1 94 S reduced, in a crude state, with lithium aluminum hydride to provide the starting alcohol 14k Other hydride reducing agents such as aluminum hydride, diisobutylaluminum hydride and sodium bis(2-methoxy-5 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. 10 The nitrate salt may also be used in Williamson 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 15 triethylamine with p-toluenesulfonyl chloride provides tosylate f5 in good yield. The tosylate is a viscous oil and is usually used shortly af*ter preparation. If desired the tosylate can be purified by filtration through alumina with methylene chloride, but the 2 0 crude material is satisfactory. The tosylate should be stored in the refrigerator.

» Alcohol 1£ may be activated by other reactants. For example, it may be mesylated with methanesulfonyl chloride or perhaps chlorinated with thionyl chloride 25 to provide additional alcohol 1£ derivatives for Williamson Synthesis.

Sodium thiolate 20^ (see Scheme III) has been alkylated with either chloro- or bromoethanol (_29, Z=C1 or Br) to afford alcohol L7. Alcohol _T7 is then 30 converted to its corresponding tosylate 8_ as shown in Scheme VI. f-* ^ V S £ "2/ Tosylate £ 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 5 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 10 and are readily synthesized.

For example, p-trifluoromethylthiobenzyl chloride 31 and the benzyl alcohol 30 ) may be prepared as follows: /=\ BII -TUF S0C12 /^X C-V^"SCF3 CP3S-W-CH2OH ——> 29a 30 31 % Scheme VI Both the alcohol 30^ and the chloride 31 are suitable substrates for Williamson Synthesis. Numerous benzoic acids or benzoate esters are available for such reactions .

Operative alkylating agents may be prepared as shown below. These agents are used to alkylate 2J) (see Scheme III) .

CI 1. NaH. diglyrr.e ' > —OCl^CH CI. 2. TsOCH2CH2C1 110° 1. HaH, DMF 2. TsOCII2CH2C1 C1— OCH CH CI 2 2 34 35 3.4 l. u.iOEt, ECO:-: 2. Br(CH2>3Cl C1 , oCCIl2)3Cl reflux .36 A A 1. NaOEC, EtOH // \\ C1 SU 2. BrCH2CH2CH2Cl " CI / S(CH2)3C1 reflux 3T 38 Thiophenols are also readily synthesized as illustrated by the synthesis of the following known compounds £0 and £2 which are utilized in preparing the subject antimicrobials.

CI- Nil. 39 1.

NaNO KC1 2.

KSCOC Kc I! 2 5 s 3, NaOH CI— 40" — Br 41 1. Kg, TKF 2. S w /r \ // 42 SH From the foregoing description, it will be understood that in general, the compounds of formula £ may be prepared, for example, by either: Scheme VII reacting a compound of the formula: /; N > 43 N I 1 CH2CHW 4 5 6 R ' ' with an equimolar amount of a compound of the formula: _R1,2,3 44 W (CH2)n Y <CH2)m wherein W^" is either (a) XM, M being hydrogen or an alkali metal such as Na, K, or Li, or (b) a leaving group roaotivc with M such as Cl, Br, OSC^p-tolyl or OSC^CH^/ and is the other of (a) or (b) or Scheme VIII reacting a compound of the formula: .c CH^CHX(CH_)_W~ 45 2| 2 n "R 4,5,6 with an equimolar amount of a compound of the formula: ,1/2,3 46 W (CH„) — 2 m -/ ^ 3 wherein W is either (c) YM, M being as defined in Scheme VII or (d) a leaving group as defined in Scheme VII, and W is the other of (c) or (d) , X, Y, m, n, and R ^ being as defined in formula 4 i V44 '£ Table I below is only illustrative of some of the compounds of formula £ which have been prepared.

Table I General Formula TABLE I Cpd. no.

Acid* Addition Salt a r7 00 r9 r10 h11 1 1.5 C.H.O. 4 4 4 caha°'a 4 4 4 -sch2s- h h ci h h 2 -sch2ch2s- h h ci h h 3 hno3 -sch2ch2s- ci h ci h h 4 c4h4°4 c4h4°4 -sch2ch2s--sch2ch2ch2s- h h h h -c6h5 ci h h h h • 6 hno3 -0ch2ch20- h cf3 h h h 7 8 9 hno3 hno3 hno3 -gch„ch_0-z 2 -0ch2ch20- -och2ch2o- ci ci ci h h h ci h cl h h Cl h Cl h c2h2°4 -och2ch2o- h h tert-butyl h h 11 c2h2°4 -0ch2ch20- h h "c6h5 h h 12 c2h2°4 -0ch2ch20- ci h "c6h5 h h l3 c2*2°4 -0ch2ch20- -c6h5 h h h h l4 c2h2°4 -och2ch2o- -c6h5 h cl h h l5 1.5 c2h 0 -0ch2ch20- h h -ch2c6h5 h h l6 c2h2°4 -0ch2ch20- H H -so2c6h5 H .

H % (J /' u ■ ^ TABLE I (Cont'd.) Cpd. No.

Acid* Addition Salt A R7 R8 R9 0 I—1 R11 17 C2H2°4 -och2ch2o- H H 0 II -CC6H5 h h 18 C4H4°4 -sch2ch2o- H h h h h 19 C4H4O4 -sch2ch2o- Cl h h h Cl W4 -sch2ch2ch2o- Cl H Cl H H 21 C2H2°4 -och2ch2s- H H F H H 22 hno3 -och2ch2s- H H Cl H H 23 hno3 -och2ch2s- Cl H Cl H h 24 C2H2°4 -och2ch2s- cl H Cl Cl H C2H2°4 -och2ch2s- h H ~C6H5 H H 26 C2H2°4 -och2ch2sch2- h H Cl h h 27 C2H2°4 -och2ch2sch2- Cl H Cl h h 28 hno3 -och2ch2sch2- h h ch_ H h 29 C2H2°4 -och2ch2och2- h h C1 h h W4 -och2ch2och2- Cl H cl H H 31 free base -och2ch2och2" h H scf3 H h 32 C2H2°4 -och2ch2och2- H h och3 h h 33 C4H4°4• -sch2s- Cl H Cl h h 34 C2H2°4 -0ch2ch20- h h -nhcgh5 H H 0 free base -0ch2ch20- h H /"""A ii n n-cch h H 36 hno3 -och2ch2sch2- h h Vh3 H h 37 hno3 -och2ch2och2- h H C6H5 H h 38 . hno3 -0ch2ch20- h h Cl **/ 3 \ 39 C4H4°4 -sch2s- Cl h h h Cl 40 C4H4°4 -och2s- h h Cl H h 41 1-5 C4H404 -sch2o- h h Cl H h 42 c4h4°4 -sch2sch2- h h Cl h h 4-3 C2H2°4 -och2sch2" h h Cl h h C4H4°4 = fumaric acid, C2H2°4 = oxalic acid Rl® and rH together form with the benzene moiety a naphthalene ring. ; 1i ^ a The antifungal activity of compounds of general structure £ were determined using a broth dilution technique, against several strains of the following human and animal pathogenic fungi: Candida albicans, 5 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 10 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 15 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 20 rubrum, Trichophyton mentagrophytes and Microsporum canis.

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

Table II MIC (yg/ml) Compound No.

Candida Trichophyton albicans troplcalls krusei rubrum mentagrophytes Microsporum canis 9540* 15049* 15050* 15051* 22493* 15052* 22492* T-233* 9870* 9872* 22494* 0.5 0.5 0.5 8 1 0.032 0.063 0.13 0.25 2 2 0.5 16 •TV 0.5 0.25 0.25 0.25 1 2 2 16 2 0.25 0.5 1 0.25 16 2 2 4 4 32 16 2 . 2 4 2 0.25 0.25 1 1 1 8 4 2 4 0.5 0.25 0.063 1 0.5 0.5 16 1 8 16 8 1 2 1 8 2 0.25 1 1 1 0.5 2 0.5 1 0.5 0.13 0.13 1 2 1 4 0.25 0.5 0.25 2 4 2 16 2 0.25 0.25 ,0.063 0.25 1 1 1 16 0.5 0.5 1 1 0.25 1 0.5 4 0.25 1 1 2 4 0.25 0.5 0.5 2 0.5 8 16 16 16 0.5 4 4 0.5 1 2 0.5 1 4 16 4 4 4 0.25 0.5 0.5 1 32 8 8 0.5 1 16 2 2 2 4 8 4 1 0.25 0.25 0.5 4 1 0.13 0.063 1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 * Strain number.

Table II (Cont'd) Candida 3 Trichophyton Compound No. albicans troplcalls 9540*' 15049* 15050 15051* 22495 krusei rubrum 15052* 22492* T-233* mentagrophytes 9870* Microsporum canis 9872* 22494* 23 24 26 27 28 29 31 32 2 4 1 4 0.5 0.5 1 0.5 4 [16 8 4 1 2 1 2 16 2 16 0.5 0.5 1 4 4 16 32 8 4 16 8 8 4 16 63 1 8 1 0.5 2 1 1 0.5 4 8 1 0.25 0.5 1 0.25 0.13 0.25 0.25 0.25 16 32 1 0.25 . 0.25 0.5 0.25 0.25 16 32 0.5 0.5 0.5 16 8 * Strata number.

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

Table III.

^ MIC (ur/EI Da • Steptococcus Staphylococcus.aureus cpa pneumoniae pyogenes fno. calls A1509^ Hi).

A95S5* A9604 * A206S3* , AS537* A9606 * 7 63 63 2 2 2 2 8 63 63 4 2 2 . 2 9 | 63 63 2 1 1 . 1 11 125 125 8 8 8 8 18 125 125 32 16 16 16 125 125 2 1 1 2 21 63 - 63 2 2 2 2 22 125 125 2 2 2 1 24 125' 125 4 1 2 2 26 >125 >125 2 2 2 2 29 >125 ■>125 4 2 2 2 . 63 63 1 1 1 .1 31 >125 4 >125 8 4 4 4 * Strain number. a. pneumoniae and 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 10 in Mueller-Hinton medium. 1 94 8 »• I 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 5 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-(2,4-dichlorophenyl)-2-(lH-l-imidazolyl) 4 5 ethoxy]acetate (Scheme V, 2fi, R ' =2,4-dichloro). A solution of 1-(2,4-dichlorophenyl)-2-(lH-l-imidazolyl) ethanol* (3.0 g, 0.0118 mole) in N,N-dimethylformamide 15 (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 20 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 25 (Na2SO^). 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 1 C: /' M >; i 4/ <~\i' 4es Addition of 0.5 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) afforded colorless crystals (2.1 g) of the nitrate salt/ mp 82-87°. 5 Recrystallization from ethyl acetate provided the analytical sample, mp 102-104°.

Anal. Calc'd for C15H16C12N203•HN03: C, 44.35; 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)- 4 5 ethyl]-1H—imidazole nitrate (Scheme V, 14, R ' = 2,4-dichioro). A solution of ethyl 2-[l-(2,4-dichlorophenyl)-2-(lH-l-imidazolyl)ethoxy]acetate 15 (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) 20 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 25 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 (Na2SO^) and removal of the ether there 30 remained 5.12 g of the desired alcohol as a viscous - oil.

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

Anal. Calc'd for C13H14C12N202.HNC>3: C, 42.87; H, 4.15; 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-hydroxy- 4 5 ]_q ethoxy)ethyl] - 1H-imidazole (Schemes I and V, 5^, R ' = 2,4-dichloro). The nitrate salt of l-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-1H-imidazole (6.0 g) was partitioned between methylene chloride (CH2C12) and 0.5 N NaOH (40 ml). The CH2C12 15 layer was washed (brine) and dried (Na2SC>4). 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 20 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 Na2CC>3 (2x), water and brine. The CH2C12 25 solution was dried (Na2S04) 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 30 for subsequent reactions. 1 948 2 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 additional equivalent of triethylamine is added.

Example 4 1-[2-(4-biphenylyloxyethoxy)-2-(2,4-dichlorophenyl) ethyl]-lH-imidazole hydrogen oxalate (Table I, Compound No. 11). A solution of 4-hydroxybiphenyl (2.42 g, 0.0142 mole) in DMF (15 ml) was added dropwise to a 10 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 l-[2-15 (2,4-dichlorophenyl) -2-(2-hydroxyethoxy)ethyl]-1H- 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 20 ether and water. The ethereal layer was washed with water (2x), followed by brine and dried (Na2SO^). 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 25 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 (100 ml) was treated with a solution of 30 oxalic acid (0.794 g, 0.00882 mole) in ethyl acetate (50 ml) to provide, upon cooling, 4.28 g of the hydrogen oxalate salt, mp 122-124° (decomp.). i v ; x Anal. Calc'd for t2^2'£''l-p-p2'C2A'P 4' C' 59*67; 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 5 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 10 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. Calc'd for C_cH0,Cl_N_0o.C0H00.: C, 56.12; 25 21 3 2 2 2 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 C0t-H0, Cl_N_0o .CoHo0„ : 25 21 3 2 2 2 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 CocHo-Cl-No0_.C„H«0.: 25 22 2 2 2 2 2 4 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). .11 >/*L; O .;■■■ ^ J 9 4 -a Anal. Calc'd for C0£.H0>1C10N«00 .1. 5 (C_H_0-) : 26 24 2 2 2 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)-5 ethyl]-lH-imidazole nitrate, mp 106-108° (Table I, Compound No. 8) .

Anal. Calc'd for C,QH.,C1«No0o.HNO-: 19 16 4 2 2 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-[2-(2,4-dichlorophenyl)-2-(4-fluorothiophenoxyethoxy)- ethyl]-lH-imidazole hydrogen oxalate, mp 107-108° (Table I, Compound No. 21).

Anal. Calc'd for C,nH._C1_FN_0S.CoHo0. : 19 17 2 2 2 2 4 C, 50.31; H, 3.82; Cl, 14.14; N, 5.59; S, 6.40 15 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)- IH-imidazole hydrogen oxalate (Table I, Compound No. 25).

Anal. Calc'd for CncH„nCl~N_0S.C„HnO.: —— 25 20 2 2 2 2 4 ' 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).

Anal. Calc'd for C_-H..oCl_No0S.CoH„0.: - 20 19 3 2 2 2 4 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] -30 ethyl)-lH-imidazole nitrate, mp 107-108° (Table I, Compound No. 28) .

Anal. Calc'd for C21H22Cl2N2OS.HN03: 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; 35 S, 6.49.

Example 5 1 94 S 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 5 (3.41 g, 0.0173 mole) in DMF (10 ml) was added dropwise during five minutes to a stirred, 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 10 salt formation. The ice-bath was replaced and a solution of the tosylate of 1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-IH-imidazole (7.15 g, 0.0157 mole) in THF (25 ml) added dropwise during five minutes. The mixture was heated under gentle 15 reflux for eighteen hours and concentrated to dryness. i The residue was partitioned between diethyl ether and water. The ethereal layer was washed (water, brine) and dried (Na^O^) . After removal of the ether the residue was dissolved in acetonitrile and 20 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 7 0% nitric acid (d=1.42) caused the 25 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 C^gH^5Cl5N202.HNO^: 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, 4-35 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., 7J3, 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_oHocCl_N_0o.CoH_0.: 23 26 2 2 2 2 2 4 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 C^H^Cl^N^O^S .C^Hn04: 25 22 2 2 4 2 2 4 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 C^H^Cl^O., .C^O,: 26 22 2 2 3 2 2 4 C, 57.72; H, 4.37; Cl, 12.19; N, 4.89. 20 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 C,QHncClcNo0S.C-H-O.: 19 15 5 2 2 2 4 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 C_,H_oCloNo0_.C_H_0.: 21 22 2 2 3 2 2 4 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-chlorothiophenoxyethoxy)-2-(2,4-dichloro- I A / ' o -34- b " 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) 5 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 1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole (2.0 g, 4.4 10 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 CI^C^ and water and the aqueous layer extracted with CI^C^- The combined CI^C^ 15 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 20 neutral alumina (50 g) with Cf^C^- 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 25 an analytical sample of the title compound, mp 98-99° .

Anal. Calc'd for C^H^Cl^OS .HNC>3: 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; 30 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 following compounds were prepared and characterized as nitrate 35 salts: 1-[2-(2,4-dichlorophenyl)-2-(2,4-dichlothiorophenoxy-ethoxy)ethyl]-lH-imidazole, mp 172-173° (Table I, Compound No. 23).

Anal. Calc'd for C, QH. /.Cl>1No0S .HNO_ : 19 16 4 2 3 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)-5 ethyl-IH-imidazole, mp 17 3.5-174.5° (Table I, Compound No. 7).

Anal. Calc'd for C^gH^gCl^^C^-HNOj: 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 C2qH^C12F3N202.HNO^: C, 47.26; H, 3.57; N, 8.27. 15 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-20 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 1-[2-(2,4-dichloro-25 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 solvents were removed in vacuo and a mixture of the 30 residue in water extracted with C^C^ (3x) . The combined CH2CI2 extracts were washed with brine (3x), then water and dried (Na2S04). Removal of the solvent, after treatment with decolorizing carbon, afforded 4.8 g of oil which gave 2.99 g of pure free base after chromatography on silicic acid (100 g) with Cl^C^acetone (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°.

Anal. Calc'd for C0-HnQC1„N_0S.C»Ho0.: 20 18 4 2 2 2 4 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-dichlorophenyl) ethyl] -lH-imidazole hydrogen oxalate (Table I, Compound No. 29). A solution of l-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-1H-15 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. 20 Stirring was then continued for 0.5 hour at 25° and for 0.2-5 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 25 bath temperature of 65° for 1.5 hours. The mixture was concentrated to dryness and the residue partitioned between diethyl ether and water. The ethereal layer was washed (water, brine), dried (Na2SO^) and concentrated to dryness. The residue was dissolved in acetonitrile 30 and the mineral oil removed by washing with n-pentane , (3x) . The residue (2.35 g) was chromatographed on alumina (130 g) with CH^^-ethanol (25:1) to give the pure free base (1.26 g) as a yellow oil. Treatment 1 9 4-1 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 COAH. 0C1,N„O..C0H.O,: 20 19 3 2 2 2 4 4 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]-1H-imidazole hydrogen oxalate, mp 100-103° (Table I, Compound No. 30).

Anal. Calc'd for C_ftH_QC1.N.O..CoH_0 .: 20 18 4 2 2 2 2 4 C, 48.02; H, 3.66; Cl, 25.77; N, 5.09. 15 Found: C, 48.10; H, 3.65; Cl, 25.66; N, 5.34. 1- [2- (2,4-dichlorophenyl)-2-(4-trifluoromethylthio-benzyloxyethoxy)ethyl]-lH-imidazole, mp 51-52° (Table I, Compound No. 31).

Anal. Calc'd for c21HigCl2F3N202S: 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-trifluoromethyithiobenzyl alcohol (30). A 1.02 25 M solution of borane in THF (56.9 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 30 25°. The cooling bath was replaced and 30 ml of water -THF (1:1) cautiously added. The aqueous phase 1 - a n 2 f 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 (Na2SO^). Removal of the solvents left an oil which crystallized when triturated with 6 N HC1. Recrystallization from Skellysolve-B provided the alcohol (6.5 g), mp 52-53°.

Anal. Calc'd for CgH^OS: C, 46.15; H, 3.39.

Found: C, 46.44; H, 3.51.

Example 10 4-trifluoromethyithiobehzyl 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 C^Cl (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 C^C^. The CH2CI2 solution was washed (water) and dried ,(Na2S04) . Removal of the solvent left 4.0 g of the titled product as a mobile oil.

Anal. Calc'd for CgHgClF^: C, 42.39; H, 2.67; Cl, 15.65.

Found: C, 42.31; H, 2.76; Cl, 15.26.

Example 11 1-[2-(2,4-dichlorophenyi)-2- (2-hydroxyethyithio)ethyl]-e thy1]-1H-imidazole hydrogen fumarate (Schemes II and VI, 17, r4 /5_ 2 f3-dichloro). To a stirred solution of sodium hydroxide (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 oxalate* (13.1 g, 0.029 mole). After stirring for an additional 0.75 hour at 25° a solution of 2-bromoethanol (3.87 g, 0.031 mole) in 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 ^280^, 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 1-propanol (3 0 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° (foaming).

Anal. Calc'd for C,^H.,.CloNo0S.C,H.0,: 13 14 2 2 4 4 4 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 (1:1).

Example 12 1-[2-(4-chiorothiophenoxyethylthio)-2-(2,4-di chlorophenyl) ethyl]-1H-imidazole hydrogen fumarate (Table I, Compound No. 2). p-Toluenesulfonyl chloride (930 mg. , 4.9 mmoles) was added to a cooled (ice-water), stirred solution of 1-[2-(2,4-dichlorophenyl)-2-(2-hydroxy-30 ethylthio)ethyl]-IH-imidazole (1.4 g, 4.41 mmoles) in CH2CI2 (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 ? 94-8 '2 9 The mixture was then successively washed with the following cold aqueous solutions: water (.2x1, 2% I^CO^-water (2x), water (2x) and brine. Removal of the solvent, after drying with Na2SO^, left 2.03 g 5 of the tosylate of 1-(2- (2 ,4-dichlorophenyl)-2-(2- hydroxyethylthio)ethyl]-IH-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 (19 6 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, 4.31 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 (Na2SO^) and concentrated to leave an'oil which was dissolved in acetonitrile (CH^CN). The CH^CN solution was washed with n-pentane (2x). Removal of the CH^CN left the free base (1.29 g) of the title compound. A solution of the free base (1.29 g) in CH^CN was treated with fumaric acid (0.31 g) to provide the title compound (0.85 g), mp 95-98° (foaming). Recrystallization from CH^CN gave colorless crystals of the analytical sample, mp 96-98°.

Anal. Calc'd for C,nHn„C1_N_S_.C,H.O.: 19 17 3 2 2 4 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. m /*v- In a similar manner, replacement of the 4-chlorothiophenol with 2,4-dichlorothiophenol and 4-mercaptobiphenyl, and use of the suitable salt-forming acid, gave respectively: 5 1-[2-(2,4-dichlorothiophenoxyethylthio)-2-(2,4-dichlorophenyl) ethyl] -lH-imidazole nitrate, mp 104-105° (Table I, Compound No. 3).

Anal. Calc'd for C^gH1gCl4N2S2.HNO^: C, 42.15; H, 3.17; Cl, 26.20; N, 7.76. 10 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 .C^H^jO^ : Cl, 11.79; N, 4.66; S, 10.66. 15 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 20 l_, Compound No. 5) . 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). 25 After stirring at 25° for 0.7 5 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 30 with several portions of diethyl ether. The combined *As in Example 11. -42- < ethereal layers were washed (water) and dried (Na2S04). Removal of the ether left a viscous oil (3.8 g).

Fumaric acid (0.96 g) was added to a hot solution of the oil in CH^CNdO ml). Upon cooling colorless 5 crystals (3.3 g) of the titled compound separated, mp 116-117°.

Anal. Calc'd for C,nH.0C1_N0S0.C.H.O .: 20 19 3 2 2 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]-IH-imidazole sesquifumarate, mp 125-126° (foaming) (Table I, Compound No. 1).

Anal. Calc'd for C,QH,cCl_N„S0.1.5 C.H.O.: 18 15 3 2 2 4 4 4 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; 20 ~ S, 10.29. 1-[2-(2,4-dichlorophenoxypropylthio)-2-(2,4-dichlorophenyl^ ethyl]-lH-imidazole hydrogen fumarate, mp 138-139.5° (Table I, Compound No. 20).

Anal. Calc'd for CoriH. 0C1 .N_OS .C-H.O.: 20 18 4 2 4 4 4 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- (2,4-dichlorophenyl)-2-(phenoxyethylthio) -30 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-waterI solution of sodium hydroxide (0.49 g, 0.0123 mole) in methanol (60 ml) under nitrogen. The ice bath was removed after stirring for 0.25 hour. Stirring was continued at 25p for 0.5 hour and a solution of p-bromophenetole (0.49 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 two portions of diethyl ether. The combined ethereal extracts were washed with 5% aqueous I^CO^ (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 was made basic with aqueous sodiiom hydroxide and the free base extracted into ether. The ethereal layer was dried (Na2S04) and concentrated to afford 700 mg of a viscous oil, a portion of which (520 mg), when chromatographed on silicic acid (20 g) with CI^C^- acetone (100:15) 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°.

Anal. Calc'd for C.nH. oCl_Nn0S.C.H.O. : 19 18 2 2 4 4 4 C, 54.23; H, 4.35; N, 5.50.

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 l-[2-(2,6-dichlorophenoxyethylthio)-2-(2,4- dichlorophenyl)ethyl]-IH-imidazole hydrogen fumarate, mp 107-1089 (Table I, Compound No. 19).

Anal. Calc'd for C. QH. ^Cl.N^OS.C.H-O-: 19 16 4 2 444 C, 47.76; H, 3.49; N, 4.84.

Found: C, 47.87; H, 3.50; N, 4.81.

Example 15 1 94 3'2 9 3-chloropropyl 2,4-dichlorophenyl ether* (36). 1-brorao-3-chloropropane (60 g, 0.38 mole) was added to a solution of 2,4-dichlorophenol (40.8 g, 0.25 5 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 CI^C^. T^e CH2C^"2 laYer was washed (aqueous NaHCO^) , concentrated and the resulting oil distilled to provide 10 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-chloroethyl 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 20 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 " r. *?' a ■ ,:/ -y NaOH, water and brine. The ethereal solution was dried (Na2S04), 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* (35), bp 107-111° (0.75 mm) was similarly prepared.

Example 17 1-[2-(4-chloronaphthoxyethoxy)-2-(2,4-dichlorophenylj-ethyl]-lH-imidazole nitrate (Table I, Compound No. 10 38). A solution of 4-chloro-l-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 15 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 20 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 (Na^O^).

After removal of the ether the residue was dissolved 25 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-30 acetone (10:1).

*Foldeak et al, Acta Phys. Chem. 9^, 134 (1963) 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 salt, mp 88-95°. Recrystallization from ethyl acetate afforded peach 5 crystals of the analytical sample, mp 154-156°.

Anal. Calc'd for C23H19C13N202.HNC>3 : 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-l-10 naphthol in the above experiment with p-hydroxydiphenyl-amine, 4-(4-acetyl-l-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) 15 ethyl]-1H-imidazole hydrogen oxalate, mp 131-135° (Table I, Compound No. 34) .

Anal. Calc'd for C25H23C12N3C>2 .C2H204: C, 58.07; H, 4.51; Cl, 12.70; N, 7.52.

? Found: C, 57.71; H, 4.53; Cl, i2.45; N, 7.57. 1-(2-[4-(4-acetyl-l-piperazinyl)phenoxyethoxy]-2-[2,4— dichlorophenyl]ethyl)-1H imidazole, mp 128-130° (Table I, Compound No. 35).

Anal. Calc'd for C25H28C^"2N4^3: C, 59.65; H, 5.61; Cl, 14.08; N, 11.13. 25 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 I q> O Anal. Calc'd for C21H22C12N2C>2S .HN03 : C, 50.40; H, 4.63; 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-phenoxymethylthio)ethyl]-lH-imidazole hydrogen fumarate (Table I, Compound No. 33). To a stirred solution of sodium hydroxide (2.02 g, 0.050 mole) in ethanol 10 (18 0 ml) at 25° under a blanket of nitrogen, was added 1-[2-(2,4-dichlorophenyl)-2-(ethoxythiocarbonyl-thio)ethyl]-lH-imidazole hydrogen oxalate (4.51 g, 0.01 mole). After stirring at 25° for 0.75 hour, chloromethyl 2,4-dichlorophenyl sulfide (2.5 g, 15 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 20 with dilute NaOH, H20, brine and dried (Na2SO^).

Removal of the ether left a cloudy oil (4.2 g) which afforded 3.8 g of the pure free base after chromatography 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.

Anal. Calc'd for ciqH14C14N2S2,C4H4°4: C, 45.53; H, 3.13; Cl, 24.44; N, 4.83; S, 11.05.

Found: C, 45.35; H, 3.09; Cl, 24.10; N, 4.68; S, 11.04.

Example 19 1-[2-(4-biphenylylmethoxyethoxy)-2-(2,4-dichlorophenyl) ethyl]-lH-imidazole nitrate (Table I, Compound No. 37). A solution of 1-[2-(2,4-dichlorophenyl)-2-(2-hydroxyethoxy)ethyl]-lH-imidazole nitrate (3.64 10 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 (92 6 mg, 0.022 mole) in DMF (15 ml) under nitrogen.

Stirring was then continued at 40-45° for twenty 15 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), i dried (Na2SO^) and the ether removed. The residue was dissolved in acetonitrile and the mineral oil removed by washing with n-pentane (2x). The acetonitrile 25 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) 30 to provide the hydrogen oxalate salt which melted at 113-121° after recrystallization from ethyl acetate followed by recrystallization from nitromethane. 1 948 29 The hydrogen oxalate salt was partitioned between diethyl ether and dilute aqueous sodium hydroxide. The ethereal layer was washed (water, brine), dried (Na2S0^) and concentrated. Treatment of a solution of the resulting 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 CocH_.C10N000.HNO.: 26 24 2 2 2 3 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=C1, n=l, Y=S, m=0, R"*"' ^=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 (Na2S04) 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). / v . ■ -i 'o L ' "• > Example 21 1-[2-(2,4-Dichlorophenyl)-2-(2,6-dichlorophenylthio-methylthio)ethyl]-lH-imidazole hydrogen fumarate (Table I, Compound No. 39). To a stirred solution of sodium 5 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-(ethoxythiocarbonylthio)ethyl]-1H-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 were washed successively with dilute NaOH, 1^0, brine and dried (Na2SO^). 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 colorless 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 C,0H..C1.N-S-.C.H.O.: C, 45.53; 18 14 422444 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-[2-(4-Chlorophenoxymethylthio)-2-(2,4-dichloro phenyl) ethyl] -lH-imidazole sesquihydrogen fumarate (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 158-5 160°.

Anal^ Calc'd for C18H15C13N20S.1.5(C4H404): 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 l-{2-[(4-Chlorophenylthio)methoxy]— 2 —[2,4-dichlorophenyl] ethyl}-lH-imidazole hydrogen fumarate (Table I, Compound No. 40). 1-(2,4-Dichlorophenyl)-2-(lH-l-imidazolyl)ethanol* (2.57 g, 0.01 mole) was added to 15 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-20 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, 25 Na^O^-water, brine and then dried (Na2S04) 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 30 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.

I / Treatment of an acetonitrile solution of the free base with fumaric acid provided the hydrogen fumarate salt, mp 128-130°. Two recrystallizations from ethyl acetate -Skellysolve-B - gave the analytical 5 sample, mp 129-133°.

Anal. Calc'd for C^H^Cl^OS.C4H404: C, 49.87; 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 sodiiom hydroxide (2.02 g, 0.05 mole) in ethanol (180 15 ml) at 25° under a blanket of nitrogen, was added 1-[2-(2,4-dichlorophenyl)-2-(ethoxythiocarbonylthio) ethyl]-lH-imidazole hydrogen oxalate (4.51 g, 0.01 mole). After stirring at 25° for 0.75 hour a solution of 4-chlorobenzyl chloromethyl sulfide (2.07 g, 0.01 20 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 1^0, Na2C03-H20, 1^0, brine and dried (Na2S04). 25 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 N (0.78 g) provided 2.5 g) of the title compound, mp 120-125°. Recrystallization from ethyl acetate gave 30 colorless crystals, mp 121-123°, of the analytical sample. 1948 29" Anal. Calc'd for C,QHn_C1,N„S0.C,H.0.: C, 49.34; H, 19 17 3 2 2 4 4 4 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-Chlorobenzylthio)methoxy]-2-[2,4-dichlorophenyl] ethyl) -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 C19H17C13N20S : C, 48.71; H, 3.70; Cl, 20.54; N, 5.41; S, 6.19.

Found: C, 49.21; H, 3.71; Cl, 19.95; N, 5.30; S, 6.73. # i 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 5 accordingly useful not only in pharmaceutical applications but also in agricultural, industrial, household and other applications in which such activity is required. In general, antimicrobial compositions may contain such compounds in any concentrations, i.e. from about 0.1% 10 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%.

In pharmaceutical formulations compositions may be solid, semi-solid or liquid in form such as tablets, capsules, powders, suppositories, liquid solutions, suspensions, creams, lotions, gels, ointments and the like. Pharmaceutically acceptable non-toxic carriers, 2 0 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, polyalkylene glycols, vaseline, petrolatum 25 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 pharmaceutical compositions containing the compounds of the 30 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. 35 The compositions may also contain other therapeutically active materials. € c'>\ /I. q i ; ^ - ,/ ' "-i ' The pharmaceutical compositions of this invention typically comprise a pharmaceutically acceptable, nontoxic carrier in combination with one or more compounds represented by formula £ in an amount effective for 5 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 effective amount may vary. For example, in topical formulations the amount 10 may be about 0.1% to about 10% of the total pharmaceutical formulation while in other formulations the amount may be about 5 to 95% or more. Preferably the pharmaceutical compositions of this invention are formulated in unit dosage form to facilitate administration (unit dosage 15 being the amount of active ingredients administered on one occasion).

In pharmaceutical applications, the subject compounds and compositions may be administered to humans and animals by conventional methods, e.g. topically, 20 orally, parenterally and the like. "Topical" administration includes intravaginal application while parenteral administration includes intramuscular as well as subcutaneous and intravenous injection. Intravenous injection of imidazole derivatives for certain 25 systemic conditions has been demonstrated to be effective (see for example, Drugs jJ, 419-420 (1975), which describes the intravenous administration of Miconazole, i.e. 1-[2,4-dichloro-3-(2',4'-dichlorobenzyloxy)phenethyl]-imidazole nitrate, to patients with systemic candidiasis). 30 Topical application is the preferred method of administration 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 35* 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 individual subject being treated, the type of treatment, 5 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 10 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., 15 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 20 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 25 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 30 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 1 9482 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 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)

WHAT WE CLAIM IS

1. A compound of the formula: r 1 2 I CH-CH-X (CH_) -Y-CCH.)-^ z n z m r r 3 R 5 R 6 including the antimicrobial acid addition salts thereof, wherein; X and Y are independently sulfur or oxygen; m is zero or 1; n is 1, 2 or 3, with the proviso that when n=l, X and Y cannot both be oxygen; 1 2 R and R are independently hydrogen, halogen or alkyl or, taken together the atoms necessary to complete a naphthalene ring; 3 R is hydrogen, halogen, CF3, SCF3, alkyl, alkenyl, alkynyl, cycloalkyl alkoxy, alkylthio, pyrrolidinyl, piperidinyl, pipera-zinyl, 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 4 or more halogen, CF_ , alkyl or alkoxy radicals; and R , 5 6 R and R are independently hydrogen, halogen, CF3, alkyl, alkoxy or phenyl optionally nuclearly substituted by one or more halogen, CF3, alkyl or alkoxy radicals; -59- 194829 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 5 8 carbon atoms.

2. A compound of claim 1 wherein X and Y are both oxygen, and n is 2 or 3.

3. A compound of claim 1 wherein X and Y are both sulfur. 10

4. A compound of claim 1 wherein X is oxygen and Y is sulfur.

5. A compound of claim 1 wherein X is sulfur and Y is oxygen. 4

6. A compound of claim 1 wherexn R is 2-chloro, 15 R^ is 4-chloro and R^ is H.

7. A compound of claim 6 wherein X and Y are both oxygen, and n is 2 or 3.

8. A compound of claim 7 wherein n is 2 and m is zero. 1 2

9. A compound of claim 8 wherein R and R are H 3 and R is CF^, alkyl, phenyl, phenylsulfonyl, benzyl, benzoyl, phenylamino, or 4-acetyl piperazinyl.

10. A compound of claim 8 wherein R^" is chloro. 3 .

11. A compound of claxm 10 wherexn R xs chloro or phenyl. 25febs982 RECEIVED 194829 -60- 2 3

12. A compound of claim 10 wherein R and R are chloro. 1 2

13. A compound of claim 8 wherein R and R are in the 2- and 3-positions and joined together to complete 5 a naphthalene ring, and R^ is 4-chloro.

14. A compound of claim 7 wherein n is 2 and m is 1. 3

15. A compound of claim 14 wherein R is chloro,

SCF^, alkoxy or phenyl. 1 2 10 16. A compound of claim 14 wherein R and R are chloro.

17. A compound of claim 6 wherein X and Y are both sulfur.

18. A compound of claim 17 wherein n is 2 and m 15 is zero. 3

19. A compound of claim 18 wherein R is chloro or phenyl. 1 2

20. A compound of claim 18 wherein R and R are chloro. 20

21. A compound of claim 17 wherein n is 3, m is zero and R^" is chloro.

22. A compound of claim 17 wherein n is 1 and m is zero. 25feb1982 | 194829 -61-

23. A compoxond of claim 22 wherein R is 2 chloro and R is chloro or H.

24. A compound of claim 17 wherein n is 1 and m is 1. / 5

25. A compoxond of claim 6 wherein X is oxygen and Y is sulfur.

26. A compound of claim 25 wherein n is 2 and m is zero. 3 ■

27. A compound of claim 26 wherein R is F, 10 chloro, or phenyl. 1 2

28. A compoxond of claim 26 wherein R and R • 3 are chloro and R is chloro or H.

29. A compound of claim 25 wherein n is 2 and m is 1. 3 15

30. A compound of claim 29 wherein R is chloro, alkyl or alkoxy. 1 2

31. A compoxond of claim 29 wherein R and R are chloro.

32. A compound of claim 25 wherein n is 1 and 20 m is zero.

33. A compoxind of claim 32 wherein R1 is Cl. 1 2

34. A compoxond of claim 24 wherein R and R are 3 both hydrogen and R is 4-chloro. 25 FEB3982 f PECETVED *§;194829;-62-;

35. A compound of claim 6 wherein X is sulfur and Y is oxygen.;

36. A compound of claim 35 wherein n is 2 and m is zero.;1 2;5

37. A compound of claim 36 wherein R and R;are chloro.;

38. A compound of claim 35 wherein n is 3 and m is zero.;1 2;

39. A compound of claim 38 wherein R and R 10 are chloro.;

40. A compound of claim 35 wherein n is 1 and m is zero.;

41. A compound of claim 40 wherein R^" is chloro.;15

42. A composition for inhibiting the ;;growth of fungi or bacteria comprising an antimicrobially effective amount of a compound as defined in claim 1 in admixture with a suitable carrier.;

43. A composition of claim 42 for pharmaceutical 20 use wherein the carrier is a pharmaceutically acceptable non-toxic carrier.;

44. A composition of claim 43 for topical administration wherein said compound is present in an amount ranging from 0.1 to 10 weight percent.;25;,'..v j ctfkcb;2 3 FEBI982;- 63 -;194829;

45. A method of inhibiting the growth of fungi or bacteria (but excluding the pharmaceutical treatment of humans) 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 1.;

46. The method of claim 45 applied topically.;

47. A compound having the formula:;wherein Z is a member selected from the group consisting of YM, halo, COO alkyl, methanesulfonate;CH-CH-X(CH_) Z;z i n d;4;4 5 6;M is H or alkali metal, and X, Y, R , R , R and n have the values defined in claim 1.;- 64 -;.194829;

48. A method for the preparation of a compound defined in Claim 1 which comprises;(i) reacting a compound of the formula;O;' 1;CH2CHW;R;r with an equimolar amount of a compound of the formula w2(ch2)n-y-(ch2)m-^j£r3;wherein W"^" is either (a) XM, M being hydrogen or an alkali metal, or (b) a leaving group, and;2;W is the other of (a) or (b),;and X, Y, m, n, and R"*" to R^ are as defined in Claim 1; or (ii) reacting a compound of the formula o R R" vn' i CH2CHX(CH2) W- r t juls984 with an equimolar amount of a compound of the formula - 65 - 191829 txy1 w4(ch2»m \_v 3 wherein W is either (c) YM, M being hydrogen or an alkali metal, or (d) a leaving group, and 4 W is the other of (c) or (d), and X, Y, m, n, arid R"^ to R^ are as defined in Claim 1.

49. A method for the preparation of a compound defined in Claim 1 whenever performed substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 8, 11 to 14, 17 to 19 and 21 to 25. DATED THIS IStk DAY OP 19^2 A. J. PARK & SON Pr.'H ^ ^ AGENTS FOR THE APPLICANT# 25FE&