United States Patent 0 Igatented Oct

2,767,173 United States Patent 0 igatented Oct. 16, 1955

2 the 4-chloro, S-chloro, 4-bromo, S-bromo, 3,5-dichloro, 3,5—dibromo, the various trichloro and tribrorno and tetrachloro thiosalicylhydrazides, the corresponding disul 2,767,173 ?des (dithiosalicylhydrazides), as well as benzyl and BACTERICIDAL AND FUNGICIDAL COMPOUNDS 5 benzal (benzylidene) and hydroxy, halogen, alkoxy and lower-alkylsulfonyl-substituted benzyl and benzal hy Leon Katz, Spring?eld, N. 3., assignor to Sehenley Indus drazides of thiosalicylic and the halogen-substituted thio tries, 130-, New York, N. Y., a corporation of Delaware salicylic acids and the corresponding disul?des of these No Drawing. Application April 22, 1953, hydrazides. The new benzal-substituted thiosalicylhy~ Serial No. 350,510 drazides may be represented by the general formula: 6 Claims. (Cl. 260-441))

HS The present invention relates to new compounds which 15 Y are derivatives of thiosalicylhydrazide, possessing re markably high fungicidal and bactericidal activity. I have found that, whereas the known salicylhydrazide in which X and Y are optional substituents; X may be one has little or no antifungal activity in vitro against such or more (maximum of four) halogen substituents of the organisms as Trichophyton menmgrophytes, Microspor 20 group consisting of chlorine and bromine and Y may be um gypsezzm, and Nocardia asteroides, its sulfur isologue, one or more (maximum of ?ve) substituents of the group thiosalicylhydrazide, surprisingly is remarkably active consisting of chlorine, bromine, loWer-alkyl and lower against these organisms. I also have found that 2,4-di alkoxy substituents, including particularly those required chlorobenzalthiosalicylhydrazide, having the formula to produce the 2,4-dichloro, 3,4-dichloro and Z-methoxy 25 benzal hydrazides of thiosalicylic and substituted dithio salicylic acids. Included also are the disul?des repre sented by the general formula HS

30 X X S-S is even more active than thiosalicylhydrazide itself and that thiosalicylhydrazide is readily oxidized to the disul ?de (dithiosalicylhydrazide) which itself is even more 35 active than the parent thiol against these organisms. The bactericidal and fungicidal activities of both the thiols and the disul?des are increased and other desirable pro perties are imparted thereto by the presence of various in which X and Y have the signi?cance hereinbefore as substituents in the compounds, as more speci?cially 40 signed. pointed out hereinafter. Compounds in which the phenyl portion of the benzal By the terms “thiosalicylhydrazide” and “dithiosalicyl radicals of the foregoing formulae are replaced by hydrazide,” as used throughout this speci?cation, I refer quinolyl radicals, such as are formed by the reaction of to, as thiosalicylhydrazide, the compound represented by a formylquinoline (quinolinecarboxaldehydes), particu the formula: 45 larly 2 and 4-formylquinolines, with thiosalicylhydrazide or dithiosalicylhydrazide, are also characterized by excellent bactericidal and fungicidal properties. Q-o O-NH—NH2 The corresponding benzyl compounds, obtained by I SN reduction of the benzal compounds, are also active 50 bactericides and fungicides. and, as dithiosalicylhydrazide, the compound represented The compounds of the present invention may be repre by the formula: sented by the following skeletal formula:

55 in which R is an ortho-phenylene radical which may be substituted by one or more chlorine or bromine atoms: I W is an amino, benzalimino (benzylidenimino, CeHsCH=H—) .by analogy with such designations as salicylamide and salicylanilide. Related compounds are referred to by 60 or benzylamino radical that may be substituted by one similar designations. or more hydroxy, chlorine, bromine, lower-alkyl, lower The thiol (thiosalicylhydrazide) is also known as thio alkoxy or lower-alkylsulfonyl radicals, or it may be a salicylic acid hydrazide, thiosalicyloylhydrazine, l-(or radical of the formula —N=CI-I——Q in which Q is a thomercaptobenzoyl)hydrazine and similar designations, quinolyl radical such as a 2 or 4-quinolyl radical; and while the disul?de (dithiosalicylhydrazide) is also re 65 Z is a hydrogen atom or a radical identical with the ferred to as bis-(benzoic acid hydrazide) ortho disul?de, —S—-R—CO—NH—W radical. 2,2.’-bis-carbohydrazinodiphenyl disul?de, and similar By virtue of the bactericidal and fungicidal activities resignations. possessed by the compounds of the present invention, The compounds of the present invention include thio and their comparatively low toxicities to humans, they salicylhydrazides, including thiosalicylhydrazide itself, 70 are especially adapted for use in therapeutic compositions 2,767,173 _ p i k ‘H " ‘ I} . d V _ for topical application. They may, however, be used, as acids, the following thiosalicylic acids have been_pre

are other ‘fungicides, in compositions for the preservation pared: . V ' t of wood, textiles and other ?bres that are subject to mold attack. .These compounds are also starting materials for the production of N-benzylidene and N-quinolylmeth Thiosalieylic Acid ' M.P , °o.

ylene-substituted Z-aminobenzisothiazolones, such as are 1. 4 Chloro -__-_-__- 195‘196 described and claimed in my copending applications ‘with 2. 193-194 William Schroeder, Serial No. 478,507 and 478,508, ?led 3. ' 196-198 4. 210-211 December, 29, 1954. 5. 3,5-D1bromo- ______221-222 6. 4-Methylsulfonyl- ______180-181 10 7. 4-Methoxy- ______.1 ______I...... __ 240 , Preparation of thiosalicylic and substituted ' thiosalicylicr acids. ' Preparation of dithiosalicylic acids 7 7' _ Thiosalic'ylic acid and its‘ hydrazide and‘ their deriva v Dithiosalicylic acid,’fromwhichthiosalicylic acid may V15 tives oxidize to the corresponding disul?desonexposure be obtained, can be prepared by known methods. ‘ ' to air. ‘However, for purpose of complete. conversion ' Thios‘alicylic acid can be“ prepared by the method de-. a and preparation of thecorresponding disul?des, the re ' scribed in Organic Syntheses, vol. 12 (1932), page 77, action can be hastened'with mild oxidizing agents such which involves a reduction of dithiosalicylic acid with as halogens, particularly iodine. The preparation of 5,5,’- ' .zinc and acetic acid, or preferably, with sodium hydro 20 dichlorodithiosalicylic acid, which is a typical procedure, sul?te in alkaline solution- Thiosalicylic acid can also may be conducted as follows: , ' a ' ‘ be- prepared by diazotization of anthranilic acid with Three (3) grams, of ‘5-chlorothiosalicylic acid, pre sodium nitrite; and condensation of the diazonium solu- ' pared as described hereinbefore, is dissolved in 50 mil! 1 7 tion with potassium ethyl xanthate, followed by hy liliters of methanol and slightly more than one equivalent . drolysis; 'This latter general method i'srused for the 26 (approximately 2.1 grams) of iodine crystals are, added prepartion of substituted thiosalicylicracids because sub thereto. The solution is allowed to stand at room tem-, ' stituted anthranilic acids are more readily available or perature for several minutes and the precipitated 5,5'-di can be more easily prepared than the substituted di chlorodithiosalicylic acid is separated by ?ltration. ;The thiosalicylic acids. The preparation of S-chlorothiosali product has a melting point of 326-328" C., and; weighs ' cylic acid 30 approximately 2.8 grams. On recrystallization from’ a mixture of methyl cellosolve, methanol and Water, its melting point is increased to 330° C. Its formula is

01 Cl 85

which is a typical method ‘of preparing substituted thio OOOH ' JJOOH V > salicylic acids, may be e?ected as follows : Preparation of alkyl esters of thiosulicylic and . .A solution of 94 grams (0.545 mole) of 5-chloroan 40 substituted thiosalicylic acids. - , thranilic acid, 23 grams (0.55 mole) of sodium hydroxide Alkyl esters of thiosalicylic and substituted thio and 34.5 grams (0.545 mole) of sodium nitrite in 650 milliliters of water is added slowly and with good agita salieylic acids can be readily prepared ‘by. conventional: procedures of esteri?cation with alkanols. A preferred tion to a mixture of 150 milliliters of concentrated hy method is that typi?edby the following preparation of drochloric acid'ancl 200 grams of ice in a beaker im methyl thiosalicylate: . ' 7 mersed in an ice bath, while the temperature is main 'Into a solution of thiosalicylic acid in approximately tainedfbetween 0 and 5° C. After completion of the 7 addition of the solution, 10 volumes of methanol, which is heated to and ,heldjat' the mixture is stirred for 30 a‘ temperature su?icient to maintain’ a gentle re?ux, a minutes and neutralized to Hydrion paper with potassium stream of dry hydrogen chloride gas is passed slowly ,for acetate. The cold diazonium solution is then charged, 50 in a thin stream, into a beaker containinga solution'of a period between approximately 8 and approximately 10 250 grams (1.55 moles) of potassium ethyl xanthate in hours. The excess methanol is then evaporated‘and the 800 milliliters of water that has been heated to 75~80° ester is recovered by vacuum distillation. The ester is, 7 thus obtained in a yield of approximately 80 to 85% of C. andris stirred vigorously. The temperature is main the theoretical. Its boiling point is 115-119" C. at a tained at 7,5-80° C. during the addition, which is ac cm companied by a copious evolution of nitrogen. Some .0. pressure of 1 .to 2 millimeters. Small proportions of oily material may separate during the reaction. The re methyl dithiosalicylate, which has a melting point of: action mixture is cooled, acidi?ed to approximately pH 130-132° C., may be recovered from the residue, 7 3 with concentrated hydrochloric acid and the aqueous In this manner the methyl esters of each of the fore phase is decanted from the semi-solid ‘sludge that forms. , 1 going thiosalicylic acids'were prepared. The melting ' points of those which were characterized, were as “The sludge is dissolved in 400 milliliters of 10% follows: aqueous sodium hydroxide solution and'heated on a steam bath for approximately 2 hours. In order to in sure that the thiol compound is present, 50 grams of Methyl Ester of Thiosalicylic Acid M. P., ° C. sodium hydrosul?te is added and the solution is main 65 tained at a temperature of 80 to 90° C. for 10 minutes; 1.. 5-Chloro- ______44-45 2. '3,-5~Dibrom0- ______v 88-89 ' a this addition of reducing agent may be omitted or a smaller amount'may be used, dependent upon the par ' Thiosalicylhydrazider and its ring-substituted derivatives ticular conditions in ‘di?erent'reaction' mixtures. The can be prepared ‘by the reaction of an alkyl es‘ter'of solution is then ?ltered, cooled, acidi?ed with concen trated hydrochloric acid to a pH between 4 and 5, and , thiosalicylic acid or substituted thiosalic'ylic acid with ' the solid collected quickly. hydrazine hydrate in accordance with the conventional ~ The ?lter cake is then ' method for the preparation of benzhydrazide, , The 'r'e-l washed with water and is sucked as dry as possible with the aid of'a rubber dam. sulting thiols (thiosalicylhydrazides) oxidizeislo'wly in, the air to. disul?des (dithiosalicylhydrazides) but they In the foregoing manner, from appropriate anthranilic 75.. may be converted completely to disul?dejs. by reaction} 2,767,173 . 6 » . ‘with iodine and other mild oxidizing agents, as referred in one portion. The iodine reacts as rapidly as it dis solves and a clear light-yellow solution is obtained. The to hereinbefore. ' In place of thiosalicylic acid esters, alkyl esters of solution is diluted with an equal volume of water and halogen-substituted thiosalicylic acids may be used to sodium bicarbonate solution is added for neutralization, produce corresponding halogen-substituted thiosalicyl whereupon a white precipitate forms. This precipitate is hydrazides. Thiosalicylhydrazides and dithiosalicyl collected by ?ltration, washed with water, and dried at hydrazides may be condensed with aldehydes to obtain 50° C. The yield is approximately 10.5 grams of dithio compounds characterized by a high’ order of activity salicylhydrazide, which corresponds to 79% of the theo against the fungi Trichophyton mentagrophytes, Nocardia . retical. The product has a melting point of 206-208“ C., asteroides, and Microsporum gypseum. 10 which, upon recrystallization from a mixture of dimcthyl The following is a typical method of preparing thio formarnide and methanol, is raised to 214-—215° C. The salicylhydrazide: melting point of its dihydrochloride is 220—222° C. EXABLPLE l. THIO SALICYLHYDRAZIDE Preparation of alkoxybenzaldehydes 15 Various alkoxybenzaldehydes are known, and methods C O —NH—NH2 for their preparation have been described. I prefer to prepare these compounds by the reaction of a hydroxy H benzaldehyde (salicylaldehyde or 4-hydroxybenzalde-' Thiosalicylhydrazide is readily prepared from an alkyl hyde) with an excess of an alkyl halide (or, in the prepa ester of thiosalicylic acid in accordance with the general ration of Z-formylphenoxyacetic acid, with chloroacetic acid) in the presence of an alkali-metal hydroxide. In method used heretofore for the preparation of the hy this manner the following alkoxybenzaldehydes have drazide of benzoic acid. Into a 300-milliliter round-bottomed ?ask provided with been prepared: a Glascol heater and re?ux condenser are placed 30 25 grams (0.177 mole) of methyl thiosalicylate, 75 grams Benzaldehyde B. P., ‘’ C. (1.27 moles) of 85% hydrazine hydrate and 15 milliliters of isopropyl alcohol. The mixture is heated to re?ux 2-l\/Iethoxy-______199/250 mm. 2-Ethory- ______._ 143-5/25 mm. and held at that temperature for approximately 31/2 hours. Z-n-Propoxy. ______37/03 mm. After cooling in an ice bath, the yellow solution is diluted 2-n-Butoxy_____ 105/02 mm. 2-Isobutoxy- 117/1-2 mm. with 200 milliliters of water and acidi?ed with 6N sul 2 sec.-Butoxy 78/005 mm furic acid to a pH between 6.5 and 7.0. The light-lemon 2-n-Amyloxy 112/04 mm 2-Isoamyloxy______94/01 mm. yellow-colored solid which separates is collected on a 2-Garboxymetl1oxy- ______(M. P. 129° C ) Buechner funnel and washed with 100 milliliters of cold 2-(2-Cl1loroethoxy)- ______103/015 mm 2-(2-Diethylaminoethoxy 118/008 mm. water. Approximately 22 grams of thiosalicylhydrazide 4-(2-Ohloroethorry)-____ _ 11010.1 mm having a melting point of 112-116" C. and corresponding 4-(2-Diethylaminoethoxy) ______._ 106/01 mm to a yield of 74% of the theoretical, is obtained. The melting point of the product is raised to 115-116° 'C. by EXAMPLE 3. SALICYLIDENETHIOSALICYLHYDRAZIDE two recrystallizations from 10 parts of water. Preparation of dithiosalicylhydrazides I Hydrazides of dithiosalicylic acids may be prepared by SH OH reaction of a lower-alkyl ester of the dithiosalicylic acid with at least three molecular proportions of hydrazine Into a ‘100-milliliter beaker are placed 100 milliliters hydrate followed by a subsequent oxidative procedure. of methanol, 2 milliliters of glacial acetic acid and 10 In such reaction, the lower-alkyl ester of dithiosalicylic grams (0.0595 mole) of thiosalicylhydrazide. The mix ture is heated to boiling. To the then clear solution is acid is converted to the hydrazide of the thiosalicylic acid, added 7.59 grams (0.0615 mole) of salicylaldehyde and which is then oxidized to the disul?de, namely, the dithio the boiling is continued for an additional 5 minutes. salicylhydrazide. These reactions may be represented as Upon cooling to 10° C., glistening crystals begin to sepa follows: 50 rate. The crystals are then collected on a Buechner fun nel, washed with 20% aqueous methanol (20 water to 80 methanol) and dried at 60° C. A yield of approxi mately 14.9 grams (95% of theory) of salicylidenethio ODOR OOOR salicylhydrazide, having a melting point of 172-176", is 2®-srr + znorr + arm + %Nm thus obtained. | EXAMPLE 4. ETHYLSULFONYLBENZALTHIOSALICYL HYDRAZIDE

By proceeding as described in Example 3, but substitut ing an equimolecular proportion of 4-ethylsulfonylbenz 65 aldehyde (Bernstein et al., J. Amer. Chem. Soc., 1951, A convenient method of preparing dithiosalicylhydra vol. 73, page 909) for salicylaldehyde and using 25% zides consists in the oxidation of thiosalicylhydrazides, aqueous acetic acid as the solvent, 4-ethylsulfonylben'2al which may be effected with iodine, as typi?ed by the thiosalicylhydrazide is obtained in approximately 90% of following preparation of dithiosalicylhydrazide: the theoretical yield. its melting point is 168-170“ ‘C. EXAMPLE 2. DITHIOSALICYLHYDRAZIDE 70 EXAMPLE 5. ‘2,4-DICHLOROBENZALTHIOSALICYL Thirteen and four-tenths grams (0.08 mole) of thio HYDRAZIDE salicylhydrazide is dissolved in 100 milliliters of 50% aqueous methanol by warming. The solution is cooled to approximately room temperature and, while agitating I it vigorously, 10.1 grams (0.04 mole) of iodine is added 75 SH Cl 2,767,173 8 .By -,substituting an, equimolecular “proportion” of‘ 2,4 The identical .compqundihaving ‘the [same charadeds dichloro‘benzaldehyde for ‘the salicyla'ldehyde of Example tics, can also ‘be made'by condensation?of ,th' “liQYl-i 3,]and'li’sopropyl alcohol for methanol, ZA-dichlordbenzeil hydrazide and 72,4-dichlorobenzaldehyde as jd'esc bedlin thiosa'licylhydrazideis obtained in a‘yield cf_approximately Example 5 and subsequent oxidation of thecond 95% of ‘the ‘theoretical. The melting point of the prod; 2 product inpyridine with an equivalent amount of uctcis 2111—2'16° C. l EXAMPLE '9; 1131s(3,4-DICHLOROBENZAL‘)nrmnro- Y 6. BI‘S- (‘l-QUINOLYLMETH‘YLENE)DITHIO SALIGYLHYDRAZIDE SALICYLHYDRAZIDE

C1 01 This compound can be made“ by the oxidation of 3,4 dichlorobenzalthiosalicylhydrazide {(M. .P. 155-160" C.) 2) with an equivalent lquantityrofaioldine. Its meltingpoint 'This compound was prepared 'by reaction of dithio is 220—‘222° ‘C. after recrystallization from n-butanolQ 7 salicylhydriazide dihydrochloride (Example 2') with -a EXAMPLE 10. 5,5'-DIBROMODITHIOSALICYLHYDRA stoichiornetrical quantity of 4-formylquinoline (4-quino line vcarboxaldehydelin methanol, substantially as de 25 scribed hereinabove for the preparation of related benzal thiosalicylhydrazides. It hasamelting point-of 224-225 ° C. after recrystallization from aqueous dimethylform amide. The melting point of its'dihydrochloride is 212 215° C. with decomposition. ' v ' EXAMPLE 7. BIS’-(Z-QUINOLYLMETHXLENE)DITHIO 'Thishcormpound wasprepared in 80% yield by oxidation SALICYLHYDRAZIDE ' (with the —stoichimetrically equivalent amount of iodine in aqueous lpyridine) of Sébromothiosalicylhydrazide; H which .was‘ prepared ‘from hydrazine hydrate and methyl 54bromothiosalicylate. 7 .After recrystallizing twice from O methanolie dimethylformamide, 'its lmeltinglpwoint was

249—.25.Q° ' V , a _ - i 7 EXAMPLE :11. BIVS-(2;4=—DICHLQROBEN»ZAL)—5,5’7DI CHLOTRODITHIOSALICKLHYDBAZIDE

‘This-compound may be prepared in exactly thersame to to manner " as the ‘corresponding 4-quinolyl derivative by in; in; ' a i - substituting "2-rformylquinoline for 4-formylquinoline. Its melting point, after recrystallization from aqueous methylcellosolvads 167-.170° C. vltszdihydrochloride has amelting pointtof.228—230°i C. _ (in iin©.-o1 ' O1 01 i EXAMPLE s. BIS; (2 ,~1—'DICHLO~ROBENZAL ) DITHIO— Condensation of S-chlorothiosalicylhydrazide wi_t_h>,2_,4 - 'SALICYLH-YDRAZIDE dichlorobenzaldehydeinisopropanol produceda-yield of 90% of the theoretical quantity of “2,4-dichlorobenzal-5 O' chlorothiosalicylhydrazide. On recrystallization from methylcellosolve, this was converted to the. desired disul O ?de whichltad avmeltingpoint of.;245i—247° C.;and was H identical with the product obtained by condensation of 5,5’-dichlorodithiosalicylhydrazide (melting point, 249 250° C.) with 2, 4-dichlorobenzaldehyde. ' 60 EXAMPLE 12. BIS-(Z-METHQXYBENZAL)-5;5'-DI CELORODITHIOSALICYLHYDRAZIDE Thiscompound can be prepared as follows: ' q"Five‘hundred'milligrams of 2,4-‘dichlorobenzaldehydeV was added to 'a hot solution ‘of 1334 milligrams of di thiosalicylhydrazide in’5 milliliters of glacial aceticacid. ' 7 After a vfew minutes, ‘crystals started to separate from the‘hot solution. The mixture was vcooled and the crys tals werercollected and washed successively with acetic acid and methanol. “The melting point of the crystals 70 wasi253—255° v.C.'and‘505 milligrams. ofwthem, equivalent to a yield of 78% of the theoretical, was obtained. After ' Thiswcompound wasma'de rbyjcondensation (til-meth two recrystallizations form a mixture of vdimethylform oxybenzaldehyde I and 5,5 ’-ldichlo1_'odithiosalicylhydrazide amide and water, *the mielting "point was raised to (melting pointf249—‘25{)° 'C.), which was; prepared from 266—267° C. ' V 75 hydrazine hydrate and vmethyl "S-chIOwthiQSaIiQYlate 2,767,173 9 10 {melting point 44-4546 C.). Its melting pointwas 245- The compounds described in the examples of this in‘ vention were tested against various species of bacteria 24770 c. _ - and fungi, to determine their activity. In these tests a glycerol solution or suspension containing 2500 gammas EXAMPLE 13; 3,3355'-TETRACHL0R0D1TH10SALL (2.5 milligrams) of the compound per milliliter was,

' V ‘ CYLHYDRVAZIDE ' used. Aliquot portions of this solution were then dis pensed into preselected volumes of ?uid nutrient medium. ' ' ' C1 C1 (Brainheart, Sabouraud or a yeast-extract medium) in _ - V . 1- I r test tubes, so as to prepare media having concentrations‘ of the compound of respectively 250, 125, 50 and 25-‘ gammas per milliliter of nutrient 'medium. These media 7 ~ ([30 ‘ V (130 were then inoculated with a loop (0.01 milliliter) of a viable culture of the speci?ed organism and incubated. IETHNH: 11THNH: at a temperature of 37° C. for 24 hours. In the case of 15 the fungi (Trz'chophyton mentagrophytes and the others), the incubation was at prevailing room temperatures for This compound was prepared by the reaction of hy a period of at least 4 days. drazine hydrate with methyl 3,5-dichlorothiosalicylate The values reported in the tables are approximately the (prepared from 3,5-dichlorothiosalicylic acid having a minimal concentrations or ranges of concentrations in melting point of 196—198° C.) and oxidation of the 20 gammas per milliliter that completely inhibit the growth resulting 3,S-dichlorothiosalicylhydrazide with iodine. of the organism. A value “over” a speci?ed value is Its melting point was 233—234° C. without special signi?cance since the compound may be inactive at even higher values. The organisms used are EXAMPLE 14, BIS-[N-(2,4aDICHLOROBENZYL)] DITHIO those listed at the head of the respective tables, and the SALICYLHYDRAZIDE 25 values for the three Microsporum species represent the range obtained in separate tests with each of three species, namely, gypseum, auodouini and canis, while those of’ the three Trichophyton species similarly represent the range obtained in separate tests with the species rubrum,‘ 30 schoenleini and mentagrophytes. ('30 +0 A mixture of undecylenic acid and its zinc salt, which IYIH 1TH are the active constituents of several commercially avail able products for treatment of fungous infections of the 1TH IIIH skin, was used as a control. The inhibiting concentra 01 —OH: GHQ-Cl 35 tions of this composition for various fungi are repre 1 01 sented in the table of fungi opposite the heading “Com mercial Composition A.” The activities of another com This compound was made by the electrolytic reduction pound commercially available for the treatment of “ath of 2,4-dichlorobenzalthiosalicylhydrazide (Example 5, lete’s foot” (epidermophytosis interdigium), namely, melting point 2ll—2l6° C.) in 50% aqueous piperidine 2 - dimethylamino - 6 - 18 - diethylaminoethoxybenzo using a mercury cathode and a carbon anode. The prod thiazole, against the test bacteria and fungi, are listed uct, recrystallized from aqueous dimethylformamide, had opposite the heading “Commercial Composition B” in‘ a melting point of 255~257° C. both tables. EXAMPLE 15. BIS-(4—B-CHLOROETHOXYBENZAL)DI THIO SALICYLHYDRAZIDE

I N GHQ-O-CHaCHaClll This compound was prepared from 4-(?-chloroethoxy) benzaldehyde (boiling point 110° C. at 0.1 mm.) and dithiosalicylhydrazide. Its melting point was 237-238” The compounds of the present invention whose activi C. after recrystallization from methanolic dimethyl ties are speci?ed in the tables are as follows: formamide. 60 EXAJSLE’LE 16. 315- (Z-N-PROPOXYBENZAL )DITHIO SA LICYLHYDRAZIDE Example Compound Thiosalioylhydrazide. Dithiosalicylhydrazide. @"S -s Q 2,4-Dichlorobenzalthiosalicylhydrazide. Bisl-lgdt-qéiinalylmethylene)dithiosalicylhydrazide dihydro ([50 +0 Bis-(2~quinolylmethylene)dithioswcylhydrazidec on e. dihydro , chloride. ' 11THN NITIH Bis-(2,4-dichl0robenzal) dithiosalicylhydrazide. 1 H H Bis-(3,4-dichlorobenzal) dithiosalicylhydrazide. —CH CH 5,5’-Dibromodithiosalicylhydrazide. ' 70 Bis - (2,4 - dichlorobenzal) - 5,5’ - dichlorodithiosalicylhydra - Bis-(Z-methoxybenzal)-5.5’-dichlorodithiosalicylhydrazide.zide. (BCaHk (3:111 3,3’,5,5’-Tetrach1orodithiosalicylhydrazide. This compound was prepared from 2-n-propoxybenzal Bis-[N-(2,4-dichlorobenzyl)]dithiosalicylhyd.razide. Bis-(tehloroethoxybenzal) dithiosalieylhydrazide. dehyde (boiling point 87° C. at 3 mm.) and dithiosalicyl Bis-(2‘n-propoxybenzal) dithiosalicylhydrazide. hydrazide. Its melting point was 224~225° C. after recrystallization from aqueous ethanol. 75 2,767,173 1 1 ' 12' ' 5 ' BACTERIA ,sabeeh?ment base. are then added with Sin-Ties the £2.17 lowing solids as ?nely ground powders: - Activitiesin gamma; per-militate?‘ Parts by Weight

' ~ - r ' Bis - .(4 - quinolylntethylepe)tiithipsalicylliyslrazide - CQmPOImd Staphylw P Paeugzp- I E ‘Z, .9 dihydroc'hloride (Compound of Example 6) _ '__ . 5.0 ' cocci/.8 roteus monas- ‘ 1066,11 _ - ' ' ' ' . ' aureus vuigd'n's . aerugi- ~ abortus Ethyl P anlmobenzoate ------"T ------'"‘ 5'0 > new ?-Phenylethylralcohol ______r______0.05 ’ ‘ " These ingredients are intimately incorporated by grind- ' , over 1,000 over 1,000 01,911,000v over 1,000 10' mg, either by stirring whlle the base is maintained at ap_ uhgbiiila ---- "56115-5; .- 125%? ' 50-1-25 ' proximately 70° 1C. or while the base is maintained at 50-125 ' 125-250 over 250 "" “511L105 approximately 70° C. or while cold in a roller 0r ointment 6. 25-12. 5 12, 5.-'25 ; 125 1. 25-2. 5 mil . 50 125v 125 1.2525 . . . ' . ' 25. 50 25.150‘ 125. 250 25250 Ointments containing one or a mixture of two or more over 250.‘ over 250. over'250 5-121'5. ‘ ' - ' ' 125 V _ 125‘ over 250 5425 15 of the fungicidal compounds of the lnventlonmay be 50 ' 5;)v over 250 5.115 7 prepared in a similar manner. The ?-phenylethyl alcohol . Over Hill-2g may be partially or completely replaced by ,geraniol 'or 50 ‘125 over 250 125-25 other suitable perfuming ingredient, or may be omitted. 125 125 Over 250 125-25 Other surface anesthetics such as ~2-dimethylaminoethyl 1 ' p-butylaminobenzoate hydrochloride may be used to .re

FUNGI ' ‘

Activities in gammas per milliliter

‘Compound Micro- 'l‘n-.1 e v Nocmjdzaw _- Hzstoplasma_ ~., Aspergillus_ _. Candida sporum chophyton _ ostermdes capsulatum fumigatus albz'cans. (3 species) . (3 species) »

Commercial Compound A__ :50-125 50-250 ‘ 250 z 250 over 250 _.__v__.>___.__ Commercial-Compound B-.- 7 12. 5-100 > 12.5-100 vover 1,000 , 100-200 over 1,000 over 1,000 Example 2. 5-25 2 '5-12. 5 . ‘125-25 5-12. 5 250 25:50 Example 7 12. 5-50 0.25-50' '12. -5-25 6. 25-12. 5 50 250 Example 8 50 12. 5.—25 250 5-12. 5 250 50-125 Example 9 12. 5-25 5-25 125 5-12. 5 250 125 Example 10 _ 5-50 5-25 5-12. 5 5-12. 5 125-250 over 250 Example 11 ______.1 _ 12. 5-25 v5-125 12. 5-25 12. 5-25 50-125 250 Example 12.. _ 125-250 2 5-12. 5 12.5-2. 5 12. 5-25 50-125 250 Example 13.- _ v5-50 5-25 50-125 5-12. 5 50-125 , 250 Example 14.__ ; 125-125 12. 5-25 1. 25-2. 5 5-12. 5 125' ' over 250 Example 15“ _; ' 12. 5-50 I 6. 25-25 6. 25-12. 5 6. 25-12. 5 over 250 over 250 Example 16 ______50 12. 5-50 V " 50 6. 25-12. 5 50 250

The compounds of the present invention may be dis pensed in various conventional forms for use as bacteri place the ethyl peaminohenzoate. The sorbitan mono eides and fungicides. ‘Salts of thiosalicylhydrazide, di 49 palmitate dispersing agent may be replaced by sodium. thiosalicylhydrazide and the .bis-(quinolylmethylene) di > lalll'yl sulfate. ’ i ' thiosalicylhydrazides of :Examples 6 and '7, such as the EXAMPLE >18.’ BACTERIClDA-L AND FUNGICIDAL" ‘respective dihydrochlorides, sulfates,vand salts with simi Aounousisu'snnu'siolv lar strong acids, are used in preference to the free tbiol 0r ,disul?de. For use in the treatment. of epidennophy 45 An aqueous suspensionrof tone .ofuthe'compounds of tosis interdigium, the compounds or-their salts may be this invention that ‘is .thixotropic, that is, that sodi?ies applied to the affected part in the form of ointments in on standing but becomes ?uid -'when shaken, and that conventional ointment bases or as aqueous suspensions. dries to a smooth thin -?lm when applied to the skin A suitable ointment is one composed of 90% petrolatum similar to a hand llotion, may be prepared from. the fol lowing ingredients: ' and 5% by Weight of one or a mixture of tWo or more of 50 the active compounds of this invention. The proportion Bis ‘- (2,4 - dichlorobenzal)dithiosalicylhydrazide of the active compounds may be varied, for example, (Compound of Example 8) “__par_ts by Weight__ 5 between the range of l to 10%Vby weight, dependent upon its activity. Other ointment bases, such as polyethylene .Complex colloidal magnesium aluminum “sili glycol compounds, may be substituted for petrolatum. 55 cate ____,______parts :by weight__ 1.5 An example of such ointments is the following: liqlyethylem .slyeob as (axetase zmqleqular weight a .1500) -- ‘ parts'byIWeisht-- .29 :EXAMRLE 171 :BACTER'ICIDAL AND 'EUNGICIDAL ."_.-.->-.1-_-.—-f_q' '_S'.—. OINTMENT The complex colloidal magnesium aluminum silicate An ointment base is prepared from-the following sub 00 (which may be the v09mmvial PYQQHQt 591d by .lR- T stances in the specified proportions by weight: Vanderbilt ‘Co. under ;thegtrade_nan1e ,Veegum HV), is ,Parts .by ,weight suspended in water.’ vA suspension of the powdered ac Polyethylenebetween 3000 glycol and wax 3700;,solidif'ying (averagegmolecular>weiglit range jSO-to tive compound is .made with the‘aid of a-small amount of water. These two suspensions are -_-then combinedand >

55°C») --- , .7 _. _ __ 354.0 .65 ‘homogenized by passing the mixture through a hand Polyethylene glycol liquid (averagermolecul 1' weight homogenizer or a colloid'mill. V between 300 and 400)‘___’______'_: ______'__ 42.5‘ The foregoing aqueous suspension was tested to de Sorbitan monopalmitate (dispersing agent) ._>__,.__.-. 085 termine whetherit produced any irritation tothe skin or

Water ' _ ' V _‘__,__,_7,§_‘5/ any allergic/reactions. ~ in patch tests?-onihumans, not one The polyethylene glycol wax and liquid ‘together with instance of anysuch reactions was observed. ' ’ the 'sorbitan mpnopalmitate are ‘(stirred together and l Similar aqueous suspensions mayqbe zJmade with-the othsrsetnpaun._ 59f’ this invention by 'suitable iimoéi?i?- ' heated to a temperature of ~approximately70 tionof he roportions, TifsuspensioIns that arethixotropicr water is then vadded and the stirring :is ‘continued until - are; esiredJ the base congeals. To 85_pa1ts by weight of the fore .75; ~The compounds may also he .ptili‘zted 15in .l-lthhe Lil of 2,767,173 13 14 vaginal suppositories prepared from conventional in Inasmuch as the foregoing speci?cation comprises pre gredients in conventional manners. A suitable composi ferred embodiments of the invention, it is to be under tion for the preparation of such suppositories consists of stood that the invention is not restricted thereto and that 90 parts by weight of cocoa butter, 5 parts of spermaceti modi?cations and adaptations thereof may be made in wax and 5 parts by weight of one or a mixture of two or conventional manner. The invention is accordingly re more of the active compounds. The proportions, as is stricted only by the scope of the appended claims. obvious, may be varied rather widely to obtain products I claim: having the desired activity. The preparation of a vaginal 1. A compound of the group represented by the suppository is described in the example which follows: formula 10 EXAMPLE l9. VAGINAL SUPPOSITORY A suppository base is prepared by mixing together at CO C O approximately 50° C., the following ingredients: NE NE Parts by weight a 1% Spermaceti 5 . 0 15 Cocoa butter _ 95.0 in which each R is a radical of the group consisting of To this base (100 parts by weight) is then added 5 2-phenylene and 4-chloro-2-phenylene radicals, and each parts by Weight of bis-(3,4-dichlorobenzal) dithiosalicyl Q is a radical of the group consisting of 2,4-dichloro hydrazide (Compound of Example 9) and the same is phenyl, 3,4-dichlorophenyl, 2-(lower alkoxy) phenyl, 4 ground together until a homogeneous uniform dispersion 20 (B-c loroethoxy) phenyl and 2 and 4-quinolyl radicals. is obtained. The dispersion is then moulded, preferably . Bis-(4-quinolylmethylene) dithiosalicylhydrazide. by a cold extrusion process, into suppositories of conven . Bis-(Z-quinolylmethylene) dithiosalicylhydrazide. tional size and shape. . Bis-(2,4-dichlorobenzal) dithiosalicylhydrazide. Instead of the base described above, an emulsifying 25 . Bis-(3,4-dichlorobenzal) dithiosalicylhydrazide. grade of propylene glycol monostearate may be used. 6. Bis-(2~methoxybenzal) - 5,5’ - dichlorodithiosa'licyl Perfuming ingredients such as geraniol or B-phenylethyl alcohol, with or without chlorophyllin, may also be added hydrazide, if desired. References Cited in the ?le of this patent Other useful preparations containing the compounds of the invention are dusting powders, which may be pre 30 UNITED STATES PATENTS pared, for example, by mixing together 70 parts of talcum 2,603,617 Hook et al ______Iuly15, 1952 powder, 25 parts of colloidal kaolin and 5 or more parts OTHER REFERENCES of one or more of the active compounds. Such powders may be used in place of ointments for the treatment of Kaltz et al.; J. Org. Chem., vol. 18, No. 10, October epidermophytosis interdigium and may also be applied to 85 1953. (Received April 9, 1953). shoes and other footwear that are carriers of the in fecting organisms.