3,798,258 United States Patent Office Patented Mar. 19, 1974 1. 2 X is hydrogen or halogen; 3,798,258 Xs is hydrogen or halogen; SALCYLANILDES Q is oxygen or sulfur; Arthur A. Patchett, Cranford, Helmut Mrozik, Matawan, Z is hydrogen, halogen, or loweralkyl containing 1-4 and Dale R. Hoff, Basking Ridge, N.J., assignors to carbons; NoMerck Drawing. & Co., Continuation-in-part Inc., Rahway, N.J. of application Ser. No Z is hydrogen, halogen, trifluoromethyl, loweralkyl con 634,442, Apr. 28, 1967, which is a continuation-in-part taining 1-4 carbons, such as methyl, ethyl, or butyl, or of application Ser. No. 573,474, Aug. 10, 1966, which cyano; in turn is a continuation-in-part of application Ser. No. Z, is hydrogen, halogen, cyano, nitro, trifluoromethyl, 555,694, June 7, 1966, all now abandoned. This appli O loweralkyl containing 1-4 carbons, such as methyl, cation Mar. 13, 1970, Ser. No. 19,487 ethyl, or butyl, or loweralkoxy containing 1-4 carbons; int, C. CO7c 103/30 Z5 is hydrogen, halogen, or trifluoromethyl; and U.S. C. 260-479 R 10 Claims Zs is hydrogen or halogen; provided that Ring C is linked to Ring B at either the ABSTRACT OF THE DISCLOSURE 15 3 or 4 position of Ring B, and that no more than three substituents other than hydrogen are present on any Salicylanilides having an aromatic ring linked to the one of the aromatic rings at any one time, i.e., at least aniline moiety by one or more non-metallic atoms. Proc one of X, Y and Z is hydrogen. The term "halogen' is esses for the preparation of novel salicylanilides. Com intended to include bromine, chlorine, iodine and fluo positions useful in the treatment of parasitic diseases con 20 rine. Where Ring C is attached to Ring B at the 3' taining a substituted salicylanilide as an active ingredient. position, the substituent X is in the 4' position. This application is a continuation-in-part of our appli Also within the scope of the present invention are the cation Ser. No. 634,442, filed Apr. 28, 1967 now aban pharmaceutically acceptable replacement or amine addi doned, which latter application is a continuation-in-part tion salts of Compound I, such as metal salts, exemplified of our application Ser. No. 573,474, filed Aug. 10, 1966, 25 by sodium, potassium, calcium, copper, iron, and the like, now abandoned, which in turn is a continuation-in-part and amine salts such as the pyridine, piperazine, methyl of application Ser. No. 555,694, filed June 7, 1966, now amine, ethanolamine salts, and the like. It is also contem abandoned. plated that the novel salicylanilides of this invention can be employed in combination with other known, non DESCRIPTION OF THE PREFERRED 30 antagonistic anthelmintic agents such as thiabendazole, EMBODIMENTS tetramisol, organo phosphorous compounds, piperazine, This invention relates to a novel class of chemical com phenothiazine, certain antimony compounds, or with cer pounds described as salicylanilides. More specifically, it tain antibacterial agents such as the sulfonamides, certain relates to novel salicylanilides which carry an aromatic penicillin preparations, certain antibiotics, and the like. ring on the anilide moiety linked thereto through one or 35 The type of combination to be employed would depend more non-metallic atoms. Furthermore, it relates to novel upon the type and degree of infection to be combatted and salicylanilides useful in the treatment of parasitic diseases, the mode of administration. to methods of preparing and using them, and to composi As can be seen from the foregoing structural formula, tions containing them. 40 the compounds of the present invention are tricyclic in The novel salicylanilides of the present invention are which each ring is variously substituted. Those compounds structurally depicted as follows: wherein Q is either oxygen or sulfur, namely the phenoxy salicylanilides and phenylthiosalicylanilides, and X, Y and OA X Xs Z are halogen, hydroxy, nitro or trifluoromethyl represent 65 45 a preferred subclass of the compounds of the present Y 4\ast- B4 0 invention. Also within the scope of the present invention Y 33 Y X X Q-(Co mP Z. are the sulfinyl and sulfonyl salicylanilides which can be 2. 2. prepared from those compounds where Q is sulfur by Ys s techniques known in the art. The point of attachment 50 between the anilide ring moiety B and the nuclear ring (I) moiety can be at a carbon either para or meta to the wherein nitrogen or the anilide, i.e., at the 3 or 4 position of Ring A is hydrogen or loweralkanoyl containing 2-4 carbon B. The para position is the preferred point of attachment. atoms, such as acetyl, propionyl or butyryl; Typical of the compounds within the scope of the pres Ya is hydrogen, halogen, such as bromine, chlorine, iodine 55 ent invention wherein the total substituents other than or fluorine, cyano, nitro, loweralkyl containing 1-4 hydrogen in Rings B and C is 0 or 1 are: carbons such as methyl, ethyl and butyl; Y is hydrogen or trifluoromethyl; 3,5-dibromo-4'-phenoxysalicylanilide Ys is hydrogen, halogen, or nitro; 3,5-dichloro-4'-phenoxysalicylanilide Y is hydrogen, halogen, hydroxy, loweralkoxy contain 60 3,5-diiodo-4'-phenoxysalicylanilide ing 1-4 carbons, such as methoxy, ethoxy, and butoxy, 3,5-dibromo-4-(m-trifluoromethylphenoxy)-salicylanilide or loweralkanoyloxy containing 2-4 carbons, such as 3,5-dibromo-4'-(p-methoxyphenoxy)-salicylanilide acetoxy, propionyloxy, or butyryloxy; 3,5-dichloro-4-(m-ethoxyphenoxy)-salicylanilide X is hydrogen, hydroxy, halogen, nitro, trifluoromethyl, 3,5-dichloro-4-(methoxyphenoxy)-salicylanilide or loweralkoxy containing 1-4 carbons, such as me 65 3,5-dibromo-4'-(p-nitrophenoxy)-salicylanilide thoxy, ethoxy, or butoxy; 3,5-diiodo-4'-(o-nitrophenoxy)-salicylanilide X is hydrogen, halogen, trifluoromethyl, nitro, amino, 3,5-dibromo-4'-(p-cyanophenoxy)-salicylanilide or loweralkoxy containing 1-4 carbons, such as me 3,5-dibromo-4'-(p-bromophenoxy)-salicylanilide thoxy, ethoxy, or butoxy; 3,5-dichloro-4'-(p-bromophenoxy)-salicylanilide X is hydrogen, halogen, trifluoromethyl, nitro, amino, or 70 3,5-dibromo-4'-(p-chlorophenoxy)-salicylanilide loweralkoxy containing 1-4 carbons, such as methoxy, 3,5-dichloro-4'-(p-chlorophenoxy)-salicylanilide ethoxy, or butoxy; 3,5-diiodo-4'-(o-chlorophenoxy)-salicylanilide 3,798,258 5 6 The preferred compounds among the foregoing are: agent such as thionyl chloride, thionyl bromide, phosphor ous trichloride, phosphorous oxychloride, phosphorous tri 3,5-dibromo-3'-chloro-4-(p-chlorophenoxy)- bromide, phosphorous pentachloride, phosphorous penta salicylanilide bromide, oxalylchloride, silicon tetrachloride, and the like. 3,5-dibromo-3'-chloro-4-(op-dichlorophenoxy)- The temperature of the reaction is not critical, suitable re salicylanilide sults being obtained at temperatures ranging from room 3-nitro-5-bromo-3'-chloro-4'-(p-chlorophenoxy)- temperature to the reflux temperature of the reaction salicylanilide mass. It is preferred, however, to conduct the reaction at 3,5-dibromo-3'-bromo-4-(p-bromophenoxy)- elevated temperatures (since room temperature reactions salicylanilide may be uneconomical and the time consuming) and most 3,5-dibromo-6-hydroxy-4-chloro-3'-(p-chlorophenoxy)- 0. preferably at the reflux temperature of the system. As suit salicylanilide able solvents there may be employed aromatic compounds 3,5-dibromo-2'-chloro-4-(p-chlorophenoxy)- such as benzene, toluene, xylene; halogenated aromatic salicylanilide compounds such as chlorobenzene and dichlorobenzene; 3,5-dibromo-6-hydroxy-4-(p-fluorophenylthio)- halogenated hydrocarbons such as chloroform, tetra salicylanilide 5 chloroethane, carbon tetrachloride, methylene chloride; 3,5-dibromo-4-(mp-dichlorophenoxy)-salicylanilide ethers such as dioxane, diethylether, dimethoxyethane; and salicylanilide the like. Halogenated aromatic solvents are preferred with 3,5-dibromo-4-(m-trifluoromethylphenoxy)- chlorobenzene being most preferred. The final product is salicylanilide obtained in solution and may be recovered by filtration 3,5-dibromo-2',5'-dichloro-4-(p-chlorophenoxy)-salicyl 20 where crytallization has already occurred, or the entire anilide mixture may be filtered and the filtrate concentrated to the 3,5-dibromo-4'-(p-fluorophenylthio)-salicylanilide, and point of crystallization or by other techniques known in 3,5-dibromo-4-(m-trifluoromethylphenylthio)-salicyl the art. anilide. The reaction may also be carried out by first forming The compounds of the present invention are prepared 25 the acid chloride of the substituted salicyclic acid com by condensing an appropriately substituted salicyclic acid pound by refluxing the acid in a solvent such as benzene, compound containing an activating group in the car toluene, or xylene with a halogenating agent such as thion boxylic acid sidechain (Compound II) with an aniline yi chloride, oxalyl chloride, or phosphorus trichloride. The compound substituted at the 3 or 4 position with a second solvent is then removed before reacting the acid halide aromatic ring, said rings being joined together by an oxy 30 with the amine. Any suitable method may be employed, gen or sulfur atom, with optional substitution on the re such as distillation in vacuo, particularly for the lower maining carbon atoms of each of the aromatic rings, boiling solvents. The residue is then redissolved in the hereinafter referred to as a substituted aniline compound same solvent and the solution is added to a stirred mix (Compound III) as shown by the following flow diagram: ture of the substituted aniline in an alkaline solution em 35 ploying, for example, sodium hydroxide. The addition is OA. generally carried out slowly to ensure the presence of COD X Xs excess alkali. After the addition of acid chloride is com plete, the reaction mixture is generally stirred for an addi -- NH 40 tional period of from 30-60 minutes to ensure complete reaction. The pH of the solution is then made neutral or barely acidic with a dilute acid such as hydrochloric acid, and the solid which separates is filtered off and purified by techniques known to those skilled in the art.