US2731386A - Antifungal composition - Google Patents

Description

United States Patent ANTIFUNGAL COMPOSITION Laszlo Reiner, Essex Fells, N. 1., assignor to Wallace & Tiernan Company, Inc., a corporation of New Jersey No Drawing. Application September 6, 1951, Serial No. 245,431

6 Claims. (Cl. 167-58) For antifungal purposes, i. e. to prevent or inhibit mold growth, both in non-therapeutic circumstances and in the prevention or treatment of fungus infections, salicylanilide has had considerable use. Although some chloro deriva tives of salicylanilide have been known, and although such derivatives of the compound might be expected to exhibit antifungal properties, it does not appear that any one of them has received extensive use for the purpose. The absence of acceptance of the chloro derivatives as antifungal agents is presumably occasioned by the fact (confirmed by the investigations reported below) that each of these derivatives of salicylanilide appears to be quite specific in its action against various fungi. That is to say, these derivatives have been found to be relatively inactive against a number of fungi, which are usually considered resistant, whereas the derivatives will inhibit the growth of other fungi, even at relatively low concentrations of the agent, such other fungi being deemed to be characterized by low resistance to agents of this sort. In other words, the selective action of the chloro derivatives of salicylanilide has imposed a serious limitation on the utility of such compounds for inhibiting or preventing growth of mold organisms, so that there has apparently been no practical use of them.

In arriving at the discovery upon which the present invention is predicated, and at the same time in taking account of the above facts, the following hypothesis was conceived, namely that the apparently selective action of various chloro derivatives of salicylanilide is not due, or at least is not solely due, to any inherent specificity in the compounds with respect to their antifungal action on various organisms, but is, in some manner, determined by certain physico-chemical characteristics of the compounds, or more particularly by special factors such as theirlow solubility, e. g. in water or other aqueous media in which they are called upon to function. That is to say, it is now conceived that the chloro derivatives of salicylanilide may actually have a high intrinsic activity toward any one of the organisms in question, but because of one or more factors such as just mentioned, the compounds cannot effectively exert their action toward certain organisms or under certain conditions. Itwill be understood that the term intrinsic activity is used to mean the activity which a compound exhibits or which it can be expected to exhibit at a certain concentration, irrespective of whether or not this concentration can be realized under the given condition of the test. As a further illustration of this concept and as an illustration of the procedure by which the value of the intrinsic activity can be experimentally approximated by extrapolation: supposing that a compound is. capable of killing 1% of the population of a particular micro-organism, one can determine by extrapolation, using some of the known functional relationships between the death rate of micro-organisms and concentration, the concentration which would be needed to kill 50% of the same population under the same conditions even though the concentration thus determined with approximation cannot be realized because of the low solubility of the compound in question. Furthermore, even if the value of the intrinsic activity cannot be determined its existence can be postulated.

The present invention, as more fully explained below, is believed to make it possible to utilize the high intrinsic activity of chlorinated salicylanilide derivatives; in any event, whether the above hypothesis andthe assumption of the existence of high intrinsic activity are correct or not, the discovery of the present invention has yielded compositions of marked effectiveness and utility for the prevention of fungus growth, and particularly in the case of so-called resistant organisms, where these compounds have not heretofore been deemed satisfactory agents.

In general, the chlorinated salicylanilides with which the present invention is concerned are the following: salicylanilide derivatives in which the ring of the salicylic acid moiety of the molecule is substituted by a chlorine atom in the 5-position or in the 3-position, or by chlorine atoms in both positions, although derivatives in which only the 5-position is chlorinated appear now to be of special superiority (in the invention) and are therefore preferred; salicylanilide derivatives in which the ring of the aniline moiety of the molecule is substituted by one or more chlorine atoms in the ortho-, paraand metapositions; and finally, salicylanilide derivatives in which both rings are chlorinated, each in one or more of the positions mentioned. Thus in a generic sense, the chloro derivatives to which the invention relates are those which involve one or more chlorine atoms substituted in either or both of the rings respectively of the salicyclic acid and aniline moieties, although as will appear below, certain specific chloro derivatives or classes of same are believed to be specially advantageous in the antifungal compositions. By way of example of chloro derivatives to which the invention relates, mention is made of the following, notably useful and more or less readily producible compounds; anilides derived from salicyclic acid and 4-chloroaniline, 3-chloroaniline, 2-chloroaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 3,5-dichloroaniline, and 2,4,6- trichloroaniline; 3-chlorosalicylanilide, S-chlorosalicylanilide, and 5,3-dichlorosalicylanilide; 5, 4-dichlorosalicylanilide, 5,3-dichlorosalicylanilide, 5,2'-dichlorosalicylanilide, 5,2',4'-trichlorosalicylanilide, 5,3,4-trichlorosalicylanilide, 5,3',5-trichlorosalicylanilide, and 5,2',4,6- tetrachlorosalicylanilide.

Investigation has further revealed that the chloro derivatives of salicylanilide not only exhibit the apparent specificity mentioned above, but also seem to have activity which varies with conditions in a different manner, respectively for different organisms. For instance, against the organism T richophyton interdigitale all of the chlorinated compounds show a growth preventing action in lower concentration than the unsubstituted salicylanilide, such action being influenced in a particular way by the hydrogen ion concentration. Thus Within the over-all range of pH values at which the organism grows well, the activity of the chloro derivatives is observed to be less at higher pH values (i. e. smaller hydrogen ion concentrations) than at lower values. As the same time none of these chloro compounds has been found to show activity of practically useful character, at any attainable concentration, against certain organisms such as Momlia albicans or Saccharomyces cerevisiae. Even with respect, however, tosuch activity as may be detected, a different relation to pH is noted. For example, if the pH of the medium is increased (i. e., the hydrogen ion concentration reduced), an increase has been observed in the slight activity which each of the chloro derivatives exhibits toward Saccharomyces cerevisiae.

Thus these compounds behave, qualitatively, in a different way toward different mold organisms, such as T. interdigilale on the one hand and S. cerevisiae on the other. The apparent contradiction may now be explained, however, in a manner substantiating the hypothesis mentioned above. That is to say, the chloro derivativesappear to have a greater solubility at highr' pH values, indeed such that a concentration of each individual compound can be reached which may even be high enough to inhibit the growth of Saccharomyces cerevisiae; yet at the higher pH values the intrinsic activity of the compound, e. g. as observed against Trichophyton interdigitale (for which the effective concentrations are low and well within the limits of solubility of the com- It might therefore seem that this phenomenon could be put to actual antifungal use, as by employing a selected chloro-derivative of salicylanilide in a medium providing a high pH, the concept being that the compound would then be sufliciently soluble (i. e. in the aqueous medium) as to attain a dissolved concentration where it would be effective against the organisms toward which it has heretofore been deemed inactive. Under practical conditions, however, attainment of a sufficiently high pH is often not possible; even if the difficulty in that respect were overcome, there remains a serious potential disadvantage in that a composition having a very high pH may be harmful to fabrics, leather, living skin or tissues, hair and similar materials upon which antifungal treatment is desired.

To the end of avoiding such difficulties while providing improved antifungal agents having new and special advantages in a variety of respects, the present invention embraces the discovery that compositions comprising the combination of two or more compounds selected from the class that consists of the chlorosalicylanilides and unsubstituted salicylanilide, will prevent growth of even the most resistant fungus which cannot be effectively inhibited in growth by any amount of the chloro derivatives when used singly and which is sensitive to unsubstituted salicylanilide by itself only when used in much higher concentrations, i. e. greater than the total concentration of the combination of these compounds in the new composition. Preferably at least two chlorosalicyl anilides are included; indeed especially satisfactory results, representing a notable, specific improvement, are

achieved where the composition embraces several substances of the stated class, for instance at least three of the chloro derivatives, or the combination of the unsubstituted compound with at least two of the chloro compounds. Thus combined in suitable proportions, the ingredients of the composition appear to coact in accordance with the hypotheses explained above, e. g. in that whereas each chloro derivative may be present only in no more than the low concentration attainable at a convenient pH, the combined effect is equal to the theoretical, high intrinsic activity which each derivative might achieve but for the practical limitations on its reaching an appropriately large concentration.

In any event, and whether or not these theoretical considerations represent a true explanation of the phenomena, the unusual results and advantages achieved by the described compositions have been abundantly dem onstrated by actual test. For example, in one series of experiments the growth inhibiting action of salicylam'lide and various chloro derivatives of salicylanflide toward a resistant organism were tested, and by comparison test was made of the action of combinations of such compounds, i. e. in accordance with the present invention. The test organism was saccharomyces cerevisiae, and the medium was Sabourauds broth containing 1% ethanol, the tests being performed at a pH of 6.3. The following 5 table sets forth the successive tests and results obtained,

including the quantities of salicylanilide or its chloroderivative employed in each case:

TABLE I n a I Amount used (mg/100 cc.) of Salzcylamlzde or it derivative Unsubsti- 5,4- 5,2'- 5,4',2' 5 tuted 5-Chloro' dichloro dichloro trichloro Result No growth. Growth.

Do. Do. Do. Do. No growth significance (since .even when larger amounts of each substance were introduced, no antifungal activity was noticed), except to show that an amount of each substance generally e'qual to or greater than the total concentration in the combined composition, was ineffective to inhibit propagation of the organism.

Thus from the foregoing table, it appears that no concentration of any one of these chloro compounds was found which would prevent mold growth when used alone. However, when the four compounds are simultaneously present, each in a concentration which is not more than one-quarter of the concentration which fails (by itself) to influence growth, the combination will prevent mold growth completely. Furthermore, if as little as oneeighth of the concentration of unsubstituted salicylanilide which is required by itself to prevent growth, is also incorporated in a mixture of the four derivatives, growthinhibiting activity can be achieved with even smaller concentrations of the derivatives, i. e. in the last-mentioned combination.

In addition to the important advantage demonstrated above, namely that in the present invention low concentrations of chloro-derivatives can be generally used for preventing the growth of mold organisms against which such derivatives could not heretofore be employed, there are further advantages of a specific character to be realized. Thus it is found that the new antifungal compositions also show improved activity against those organisms toward which the individual compounds of the stated class could be shown to have growth inhibiting activity by themselves. Under such circumstances, the new compositions can be employed with greater safety or less likelihood of irritation or other undesirable results; indeed against any of a wide variety of organisms, the compositions may be effective with a total concentration of active agents which is so slow as to be harmless to living tissue. It will be understood that other advantages, including economy of the active agents, similarly flow from the improved activity which the combination exhibits against various organisms. These results are further and is itselfsensitive to the individual chlorosalicylanilides, by

and the PH being 6.2.

specifically shown, e. g. in relation to an organism which TABLE II Amounts used (mg. per I cc.) of Salicylkznilid'e derivative 4'- 5,2'- 5,2 4'- i" dichloro. dichloro tricbloro Results No growth. Growth. N0 growth. Growth. No growth. Growth. No growth. Growth. 0.0 Nogrowt-h, 0.02 0.0013 0.0013 Growth.

It will be seen at once that a condition of growth inhibit io'n was achieved with the combination or four substances, at concentrations of each which are much below the concentration required separately of each for preventing organism growth; Furthermore, the total concentration (in this particular series of experiments) needed to inhibit growth with the combination was only 0.03 milligram per 100 cc. of the medium, whereas in the case of S-chldrosalicylanilide alone, growth was still evident in the presence of 0.04 milligram and could only be inhibited by a still larger concentration, i. e. 0.08 milligram.

Another advantage of the compositions of the invention is that more effective, actual concentrations can be reached in materials such as leather, fabrics, live skin, hair, mucous membranes, fruits, plants and similar possible sites of fungus contamination, such improved results being attainable by the simultaneous and independent diffusion or penetration of the individual agents (which compose the composition) into the various materials described. A still further feature of notable utility in the compositions is that they possess powerfulantibacterial properties, a valuable attribute in therapeutic or like application of the composition, such properties thus being exhibited along with the described universality of antifungal action, which in itself has not heretofore been attained with these chloroderivatives of salicylanilide.

. As indicated above, the several compounds of the stated class, with or without the unsubstituted salicylanilide, may be employed in any one of many combinations. For instance in the set of experiments reported in the followingftable, various combinations of four substances selected from a group of five were tested, in comparison with attempts to inhibit growth by using each of the substances alone. The test organism in these experiments was Saccharomyces cerevisiae, the medium being Sabourauds broth containing 0.5% ethanol, at a pH of 7.2.

TABLE III Amounts used, in mg. per 100 cc.

diehloro dichloro dichloto Results Growth. No Growth. Growth.

Do. No Growth Growth. No Growth. Trace. No Growth. 'lrace.*

No Growth.

Trace." No Growth. Trace.*

Iii-most cases no concentration of the individual compounds Could be rachd which WO'uldihhibit glowth of the organisms,-the sole exception being in the case of'the 5,4J-dichloro' derivative, where inhibition was achieved at a concentration of 2 milligrams per cc., this result being apparently due to the higher pH, as explained above. It will be apparent from Table III that various combinations of the agents were found to be effective, the results (marked. with an asterisk) which represent a trace of growth being referred to the final reading after hours. In the instances last mentioned, no growth was observed after only 48 hours. Hence it may be taken that in each of the combinations of 4 substances, completely effective results might be had with only slightly higher concentrations than specifically stated to have resulted in a trace of growth. It will also be noted that by a combination of two derivatives, the 5-chloro and 5,4',2- trichloro compounds, growth was inhibited whereas neither of: these substances alone could be shown to have any activity against the. test organism. It may also be noted from a comparison of Tables I and III, that the improved results are attainable independently of the hydrogen ion concentration of the medium.

While the relative amounts of the individual compounds embodied in the new compositions may vary considerably, it appears that in certain cases, especially where the composition contains only two or three compounds (of the stated class consisting of salicylanilide and chlorosalicylanilides), the advantages of combination are poorly realized if the ingredient or ingredients having greater intrinsic activity and being usually less soluble are present in substantially larger quantities than the less active and more soluble ingredient or ingredients. Indeed it is generally important, according to present understanding, that the selected substances be associated in at least equal amounts orif not, then in approximately inverse proportion to their intrinsic activity. That is to say, the activity (or at least, the intrinsic activity) may be deemed to increase with increase in the number or order of chlorine atoms, unsubstituted salicylanilide being considered as of zero, i. e. lowest order of chlorine content. Thus the un usually useful compositions are those wherein the total quantity of the compound (or of the compounds) of each lower order (i. e. each order lower than the highest present) is not appreciably less than (or in other words, is at least about as great as) the amount present of any one compound of a higher order.

Hence if the composition consists of salicylanilide and a single chlorsalicylanilide (of any order), the amount of the unsubstituted compound should be at least as. great as, or greater than, the amount of the chloro derivative. Likewise, for instance, if the composition comprises a monochloro salicylanilide and a chloro derivative of higher order (having two or more chlorine atoms), the amount of the monochloro derivative should be at least as large as that of the higher order derivative. In similar fashion, if the combination selected from the basic class consists of three or more compounds of different order the amount of the compound of lowest order should preferably be as much as, or more than, that of the chloro derivative of intermediate order, and the quantity of the latter should in turn be as much as, or more than, that of the higher order derivative. I

It is at present understood that these relationships of proportion among the several orders of compound are primarily requisite when the composition contains only two substances of the class, or not more 'than three substances, in the latter case particularly if one of the three is the unsubstituted salicylanilide and the other two are of V mutually different orders of chlorine content; although it may sometimes be disregarded (e. g. when three or more chloro derivatives are present), the relationship is nevertheless preferred and advantages in all cases, namely to have the total amount of compound material present of each lower order (there being ten possible orders' of chlorine content, from zero to nine) at least as 5 great as the amount present of any one individual compound of a higher order. A further example of a com position coming within this rule of proportionality is one that embodies one part of salicylanilide, one part of trichlorosalicylanlide, two parts of another trichlorosalicylanilide, and three parts of a tetrachlorosalicylanilide.

The following are additional examples of particularly useful preparations according to the invention. One such compositon contains four parts of salicylanilide,

I two parts of a monochlorosalicylanilide and one part .of these compounds are at present preferred for inclusion in the compositions, e. g., by reason of availability, economy and greater solubility. For instance, an unusually satisfactory composition, in all of these respects and likewise in respect to effectiveness of antifungal action, is one wherein one of the plurality of compounds from the stated class is S-chlorosalicylanilide. Ingredients also presently found to be of special preference, for one or more of the same reasons, are 5,4-dichlorosalicylanilide, 5,3-dichlorosalicylanilide, and 5,2,4-trichlorosalicylanilide.

The salicylanilide derivatives which are employed in the compositions herein described can be prepared by various methods, e. g., procedures which will be well known. to, or readily understood by, those skilled in the art; hence it is believed necessary only to mention such procedures briefly, in the case of certain compounds as examples, with the understanding that corresponding operations, or other methods which maybe known or readily adopted in the art, may be employed in the case of other specific chloro derivatives as may be desired.

Thus, for example, 5,3-dichlorosalicylanilide can be prepared by heating S-chlorosalol with 3-chloroaniline to l80220 C. and continuously distilling the liberated phenol off during this process. It is advantageous to use reduced pressure for this distillation and to carry out the procedure in a nitrogen atmosphere. The crude reaction product is dissolved in alcohol to which an equivalent amount of sodium hydroxide is added in the form of approximately l0-n aqueous solution. The resulting solution of the sodium salt of 5,3'-dichlorosalicylanilide is then decolorized with charcoal and neutralized with dilute hydrochloric acid. The 5,3'-di'chlorosalicylanilide thus precipitated is filtered and recrystallized from ethyl alcohol, ethyl acetate, or some other suitable solvent.

As indicated, still other methods can be employed for preparation of these chloro derivatives. For instance, instead of the phenolic ester of S-chlorosalicylic acid (i. e., identified above by its common name, S-chlorosalol) other esters of S-chlorosalicylic acid may be used, such as the ethyl ester or the methyl ester. The chlorosalicylanilides can also be prepared in some instances by heating the salicylic acid and the aniline (one or both of which is substituted with one or more chlorine atoms) in the presence of small amounts of phosphorus pentachloride and a tertiary organic base such as dimethylaniline.

As explained, the essential active part or basis of the new compositions is the combination of a plurality of 7 compounds selected from the stated class. In all cases, it

is assumed that each of the selected active ingredients of the combination will be present in an effective amount, for example in amount equal to or greater than at least. 10% of the amount of that one of the compounds which is present in next larger quantity, the definition of the-composition herein being understood as disregarding minor or trace amounts of other members of the stated class which may happen to be present, for example'because 8 necessarily occurring as an impurity or impurities, so to speak ,.in the original production of one or another-of the compounds selected as primary ingredients.

It will be understood that in most cases the composition also actually includes a suitable carrier in uniform admixture with the active ingredients, e. g. appropriately distributing the ingredients while maintaining their mutually eifective'icombination with each other, and facilitating application of the active combination to the surface or other locality of use, e. g. for such spreading, penetration or other special access as maybe required of the active ingredients for the antifungal effect. Thus for therapeutic use, e. g. to prevent or to treat fungus infection, the combination with the carrier may be such as to provide a powder, liquid (i. e. lotion) or ointment, e. g. a spreadable preparation in which the active combination of ingredients is uniformly and smoothly distributed, preferably in stable suspension or solution. In therapeutic uses, the

total amount of combination here described (i. e. the effective combination of substances from the stated class) may ordinarily range from 0.1% to 30% of the complete composition, at least a major part (and often all) of the remainder of the composition being' usually an inert carrier material, which may itself comprise or include water in the case of lotions and ointments. In making up compositions with a suitable carrier, it will be understood that the individual compounds may be added or adsorbed to the carrier powder, or can be suspended or dissolved in a liquid or ointment.

In exceptional cases, larger proportions of the combination of salicylanilide compounds may be employed, there being utility in certain circumstances even for a preparation which consists wholly of the active ingredients, e. g. two or more compounds from the class of salicylanilide and chlorosalicylanilides. For antifungal purposes in non-therapeutic circumstances, as to prevent mold growth on fabrics, leather, and various other materials, it will be understood that powders or preferably solutions may be used, with or without additional carrier material, i. e. other'than water in the case of solutions.

The composition can also advantageously be combined with fatty acids or their salts, especially substances having pronounced antifungal properties, some examples being propionic acid, caprylic acid, and likewise the unsaturated acids containing from 6 to 12 carbon atoms, notably undecylenic acid, as well as salts of these acids, such as sodium propionate and particularly zinc undecylenate. Other substances that may be included in the combination are anionic wetting agents. Both of these additives, i. e. fatty acids (or salts) and anionic wetting agents, have been found to enhance the activity of the preparation in practice. Whereas the anionic wetting agents are thus found beneficial, present experience has indicated that the non-ionic wetting agents, although they may be of utility as good solubilizing agents for these compounds (e. g. the chlorosalicylanilides), tend to decrease the effectiveness of the composition.

The following are a number of specific examples of preparations which are of special value in practical application under various circumstances as indicated. It will be understood, nevertheless, that these are simply set forth by way of example and that a variety of other combinations may be prepared, including various different combinations of the active ingredients and likewise a variety of carrier and other supplemental materials. In all cases, and indeed elsewhere in this specification, reference to parts or percentages are intended to mean values by weight, unless otherwise specifically indicated.

Example I An effective antimycotic ointment, adapted for. treatment of fungous infections, e. g. for topical application to treat such infections of the skin, is made according to the following formula:

Parts S-chlbrbsalicylanilide ;1 t s;a1 c--.. s 0.5 5,2-dichlorosalicylanilide -1; 0.5 5,4'-dichlorosalicylanilide 0.2 5,3-dichlorosalicylanilide 0.2 5,2,4'-trichlorosalicylanilide 0.2 Polyethylene glycol base N. F 93.0

Example II A dusting powder, particularly advantageous in the prevention and treatment of fungous infections,- is prepared in the following manner: h

Two pounds each of 5-chloro, 5,4'-dicliloro, and 5,3- dichlorosalicylanilides are dissolved in a sufficient amount 'of ethyl acetate to give a clear solution and to cover 200 pounds of talc which are added to the stated solution. The alcohol is then evaporated under continuous stirring and the powder dried. It now contains 1% of each of the salicylanilide derivatives and it is useful in the treatment and prevention of fungous infections.

Example III This is a liquid preparation which is of special value in treating fungous infections of the external auditory canal, and which may therefore be employed as ear drops, for such treatment:

Parts S-chlorosalicylanilide 0.5

5,3'-dichlorosalicylanilide 0.5

5,4'-dichlorosalicylanilide 0.5

Polyethylene glycol (400) 63.5

Glycerine 35.0 Example IV Another antimycotic preparation, in the form of a solution which is useful in the treatment of skin infections caused by fungi, has the following formula. Although this composition (like other examples, below) also includes a certain amount of another antifungal agent, e. g. undecylenic acid, the advantages of the invention respecting the combination of salicylanilide and two chlorosalicylanilides are abundantly realized, i. e. in obtaining activity, with an unusually small amount of active material, against organisms toward which each of the chloro compounds is not satisfactorily effective alone.

Parts 5,4'-dichlorosalicylanilide 0.5 5-chlorosalicylanilide 1.0 Salicylanilide 2.0 Undecylenic acid 2.0 'Iriethanolamine 0.5 n-Propanol 30.0 Acetone 30.0 Polyethylene glycol (300) 24.0 Sodium lauryl sulfate .1 Distilled water ad 100.0

Example V This preparation is of considerable utility as a scalp lotion, i. e. for treating fungous disorders of the scalp:

ExampleVI The following is an antirnycotic cream suitable for various purposes, for instance in the treatment of mucous @erhbranes infected by fungi, especially the species known as Monilia albicans:

Example VII Many other uses, as for antifung'al action on leather, fabrics, fruits, plants and other sites of undesirable mold growth, are contemplated for the described novel combinations of a plurality of substances selected from the class consisting of salicylanilide and the chlorosalicylanilides. For instance, one composition which thus embodies the invention and which may be employed for the moldproofing of fabrics, is prepared as follows:

A solution of the sodium salts of each of the following salicylanilide compounds: 5,2- and 5,3-dichloro-, and 5,2,4-trichlorosalicylanilide, is prepared by dissolving one pound of each of these three compounds in lbs. of an alcoholic sodium hydroxide solution containing gms. of sodium hydroxide, the liquid components of the solution being ethyl alcohol 30% and water 70%, but aqueous solutions of the sodium salts can also be used. This solution can be applied to a fabric in various ways, a convenient procedure being simply to pass the fabric through the solution. The fabric is then wrung or squeezed almost dry, and finally dried by evaporation. A deposit of the intimately mixed compounds remains in or upon the fibers, and is effective, over a long period of time, to prevent mold or mildew on the fabric. A similar solution, to be used in the same way and with like effect, can be made by dissolving the sodium salts of the salicylanilide derivatives in ethyl alcohol, e. g. commercial 95% ethanol.

Although it is preferred to use compositions which contain one or more chlorinated salicylanilides, and although the invention is in a principal or specific sense directed to the chlorosalicylanilides, results similar to those described throughout the foregoing specification can be obtained with derivatives of salicylanilide of which one or more hydrogens in the aromatic rings are replaced by a halogen of higher atomic weight than chlorine, such as S-bromosalicylanilide, 5-iodosalicylanilide, 5,4'-dibromosalicylanilide, 5,3-dibromosalicylanilide, and the corresponding di-iodosalicylanilides, and salicylanilides in which one or more hydrogen atoms of the aromatic ring of the salicyl moiety is replaced by a heavier halogen than chlorine, whereas one or more hydrogen atoms of the aromatic ring of the aniline moiety are replaced by chlorine and vice versa. These compounds may be defined as halogen derivatives of salicylanilide, the halogen being of greater atomic Weight than fluorine.

It is to be understood that the invention is not limited to the specific compositions herein described by way of example, but may be embodied in other forms without departure from its spirit.

I claim:

1. An antifungal composition comprising as active ingredients salicylanilide and at least three chlorosalicylanilides, each of which contains less than five chlorine atoms.

2. An antifungal composition comprising as active ingredients salicylanilide and at least two chlorosalicylanilides each of which contains less than five chlorine atoms.

3. An antifungal composition as defined in claim 2 in which the two chlorosalicylanilides are respectively S-chlorosalicylanilid and 5,4-dichlorosalicylanilide.

4. An. antifungal composition comprising as active ingredients: 5,3-dichlorosalicylanilide, 5,4-dichlorosalicylanilide; S-chlorosalicylanilide in amount at least as great as the amount of one of said first and secondmentioned 'chlorosalicylanilides; and salicylanilide in amount at least as great as the amount of said S-chlorosalicylanilide.

5. An antifungal' composition comprising as active ingredients at least three different compounds selected from the class consisting of salicylanilide and halogen derivatives of salicylanilide that contain less than five halogen atoms, the halogen atoms of said derivatives being of greater atomic weight than fluorine, and the entire halogen content in each derivative being of a single haolgen element.

6. An antifungal composition comprising as active ingredients salicylanilide and at least two halogen derivatives of salicylanilide that contain less than five halogen atoms, the halogen atoms of saidrderivatives being of greater atomic weight than fluorine, and the entire halogen content in each derivative being of a single halogen element. H i t v References Cited in the file of this patent UNITED STATES PATENTS Fargher Aug. 23, 1932 Wyman Dec. 4, 1951 OTHER REFERENCES 0 1953, page 1430.

Claims (1)

1. 5. AN ANTIFUNGAL COMPOSITION COMPRISING AS ACTIVE INGREDIENTS AT LEAST THREE DIFFERENT COMPOUNDS SELECTED FROM THE CLASS CONSISTING OF SALICYLANILIDE AND HALOGEN DERIVATIVES OF SALICYLANILIDE THAT CONTAIN LESS THAN FIVE HALOGOEN ATOMS, THE HALOGEN ATOMS OF SAID DERIVATIVES BEING OF GREATER ATOMIC WEIGHT THAN FLUORINE, AND THE ENTIRE HALOGEN CONTENT IN EACH DERIVATIVE BEING OF A SINGLE HAOLGEN ELEMENT.