US 3269904 A
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United States Patent 3,269,904 HYDROXY-PYRIDINE OXIDES IN AN ANTIFUNGAL METHOD Jack Bernstein, New Brunswick, James Ling Chen, East Brunswick, and Gilman Norman Cyr, New Brunswick, NJ., assignors, by mesne assignments, to E. R. Squibb 8: Sons, Inc, New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 11, 1965, Ser. No. 479,005
6 Claims. (Cl. 167-58) This application is a continuation-in-part of a prior application, Serial No. 278,406, filed May 6, 1963, which application is now abandoned.
This invention relates to and has as its objects the provision of new compositions of matter, and more particularly, to new pharmaceutically active compositions useful as topically administrable fungicides.
The new fungicidal composition of this invention comprises essentially a principal active ingredient selected from the group consisting of compounds of the formula and the non-toxic, pharmaceutically acceptable heavy metal and amine salts thereof, wherein each R is selected from the group consisting of hydrogen and lower alkyl; said principal active ingredient intimately dispersed in a substantial amount of a suitable extending agent.
Preferably, the non-toxic pharmaceutically acceptable salts of the principal ingredient which are employed in the practice of this invention are such heavy metal salts as the zinc salt, and such amine salts as the higher alkylamine salts. By the term higher alkyl it is meant an alkyl either straight or branched chain of more than nine carbon atoms and preferably ten to eighteen carbon atoms. These salts may be prepared by reacting the respective principal ingredient compounds with such reactants as zinc oxide or (higher alkyl) amine (e.g., dodecyl amine), respectively.
The compositions of this invention are useful in the topical treatment of dermatophylic fungal infections of animals and may be employed for the treatment or prevention of conditions caused by such microorganisms as Trichophyton mentagrophytes, for example, athletes foot, fungally caused odors, dermatitis, middle ear infections, vaginal infections, ringworm infections caused by Microsporum canis and other like fungus infections.
In this disclosure and in the claims appended thereto, the term dispersed is used in its widest possible sense. When it is said that the compounds of this invention are dispersed, it means that the particles may be molecular in size and held in true solution in a suitable solvent. It means further, that the particle may be colloidal in size and dispersed through a liquid phase in the form of suspension or emulsions or in the form of particles held in suspension by wetting agents. It also includes particles which are dispersed in a semi-solid viscous carrier such as petrolatum or soap in which they may be actually dissolved in the carrier or held in suspension in the carrier.
The term dispersed also means that the particles may be mixed with and spread throughout a solid carrier so that the mixture is in the form of powder or dust. The term dispersed also includes mixtures which are suitable for use as aerosols including solutions, suspensions or emulsions of the agents of this invention in a car- Patented August 30, 1966 rier such as Freon which boils below room temperature weight of the final composition, preferably from 0.05
to 5%, and optimally, in an amount of from 0.25% to 5.0% by weight of the final product. This concentra tion is effective when the dispersing agent is a liquid but it is preferred to use more concentrated mixtures when the dispersing agent is a semi-solid or a solid. This is because liq-uid dispersions which are of course suitable for use as sprays give a more intimate contact with the area being treated than the solid dispersions and, therefore, lower concentrations are more effective with liquid dispersions.
There are a number of pharmaceutically acceptable solvents which can be utilized for the preparation of solutions, suspensions or emulsions of the compounds of this invention. High boiling oils of vegetable origin such as castor oil, corn oil, sesame oil or olive oil have been found to be suitable. Esters such as isopropyl palmitate or dioctyl sebacate and low boiling, more volatile solvents such as acetone, alcohols, such as methanol and ethanol and the like are also useful. For certain applications it may be advantageous to resort to mixtures of solvents.
If the active agents are to be applied as aerosols, it
is convenient to dissolve them in a suitable solvent and to disperse the resulting solution in a liquid such as Freon which boils below room temperature. For such applications it is better to employ true solutions of the active agent although it is possible to employ suspensions or emulsions of the active agent.
i The agents of this invention are often dispersed either in the form of emulsions or suspensions, in an inert carrier with the aid of a surface-active substance. Such surface-active substances may be anionic, cationic or nonionic. There may be mentioned by way of example, natural or synthetic soaps, and the like. Other examples include high molecular weight quaternary ammonium compounds as well as condensation products of ethylene and propylene oxide with monohydric and polyhydric alcohols.
For use as a powder or dust the active ingredient of this invention may be mixed with any of a number of extending agents either organic or inorganic in nature which are suitable for the manufacture of rpulverulent preparations. In addition to mixing the ingredients directly the active compounds of this invention may first be dissolved in a suitable solvent and the dry extending agents may be treated with the resulting solution so that after the solvent evaporates off the active ingredient is effectively coated on the surface of the extending agent. The extending agents which may be employed include, for example, tricalcium phosphate, calcium carbonate, kaolin, bole, kieselguhr, talc, calcined magnesia, boric acid and others. Materials of vegetable origin such as powdered cellulose and starch are also useful. These mixtures may be used in the dry form or, by the addition of wetting agents, the dry powder can be rendered wettable by water so as to obtain stable aqueous dispersions suitable for use as sprays.
For special purposes the agents of this invention can be worked into the form of a paste or an ointment by the use of such semi-solid extending agents as soap or 3 petroleum jelly with or .without the aid of solubility promoters and/ or dispersing agents.
Generally, the principal active ingredients of this invention may be prepared according to the procedures set forth in U.S. Patent No. 2,540,218, issued Feb. 6, 1951. The compounds wherein R is lower alkyl may be prepared by reacting the appropriately substituted 2- bromopyridine-1-oxides with aqueous sodium hydroxide and recovering the correspondingly substituted 2-hydroxypyridine-l-oxide after acidification of the reaction mixture. Alternately, the appropriately substituted 2- bromo-pyridine-l-oxide may be reacted with sodium benzylate and the Z-benzyloxypyridiued-xide thus obtained converted to the desired 2-.hydroxypyridine-1- oxide by hydrogenolysis in the presence of a catalyst such as palladium on charcoal, or by hydrolysis with aqueous hydrochloric acid.
The zinc salts of these compounds are prepared by treating an aqueous hot solution of the appropriately substituted Lhydroxypyridine-l-oxide with a Warm aqueous suspension of an equivalent quantity of zinc oxide, filtering the hot solution and recovering the zinc salt by lyophilization or concentration of the solution under reduced pressure. The amine salts of these compounds are prepared by adding a warm solution of the appropriately substituted 2-hydroxypyridine-l-oxide in a solvent such as water or an organic solvent such as acetonitrile or a lower alcohol to a solution of the de sired amine in water or an organic solvent such as acetonitrile or a lower alcohol filtering the hot solution and cooling to precipitate the salt, which is then recovered by filtration. In those cases in which the salt is soluble in the solvent used, the salt may be recovered by concentration of the solvent under reduced pressure.
The following examples are illustrative of this invention:
Example 1.-2-hydr0xypyridine-1-0xide A solution of 14 g. of Z-bromopyridine-l-oxide hydrochloride in 100 cc. 10% sodium hydroxide is refluxed [for two hours. The cooled solution is acidified with concentrated hydrochloric acid and lyophilized to yield 21 lg. solid. This dry solid is extracted with boiling hexane to yield 3.6 g. product melting at 144-146". Alter recrystallization from 100 cc. hexane the product melts at 148-149".
Example 2 A solution of 31 g. of 2 benzyloxypyridine-l-oxide in 250 cc. abs. alcohol is shaken at room temperature in the presence of 2 g. of palladium on charcoal until the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off and the alcohol removed under reduced pressure. The residue is triturated with cold hexane to yield 12 g. of 2-hydroxypyridine-1-oxide melting at 146-148". After sublimati-on at ISO-160 and 0.75 mm. the product weighs 10.5 g. and melts at 148- 149.
Example 3.-2-hydr0xy-4-methylpyridine-I-oxide A solution of 12 g. (0.055 M) of 2 benzyloxy-4-methyl-pyridine-l-oxide in 200 cc. absolute alcohol is shaken atroorn temperature in the presence of 500 mg. of 5% palladium on charcoal until the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off and the alcohol removed under reduced pressure. The residue is triturated with hexane to yield 6.1 g. product melting at 130-132". The product is purified by sublimation at 80 and 0.3 mm. to yield a white crystalline solid melting at 131-132.
This compound can also be prepared by refluxing a solution of 22.4 g. 2 brom-4wmethylpyridine-l-oxide hydrochloride in 200 cc. sodium hydroxide for two hours. The solution is cooled and acidified with 2% hydrochloric acid to yield the desired product.
4 Example 4.2-hydr0xy-6-methylpyridine A solution of 22.4 g. (0.1 M) 2-brom-6-methylpyridined-oxide hydrochloride is refluxed for two hours with 10% sodium hydroxide. The solution is cooled and made strongly acid with concentrated hydrochloric acid to yield a crystalline solid melting at 138-141". After recrystallization from 40 cc. benzene the product is constant melting at 141-142.
This compound is also prepared by shaking a solution of '2-benZyl-oxy-6-methyl-pyridine-l-oxide in absolute alcohol in the presence of 5% palladium on charcoal for forty minutes when the theoretical amount of hydrogen is absorbed. The catalyst is filtered oil and the alcohol removed under reduced pressure. The crystalline residue is purified by sublimation at and 3 mm. to yield the product melting at 141-142".
Example 5.Zinc salt of Z-hydroxypyridine-l-oxide A solution of 10 g. of 2-hydroxypyridine-l-oxide in 200 cc. water is added to a suspension of 3.7 g. zinc oxide in 400 cc. water. The mixture is heated to boiling and a clear solution formed. This solution is filtered and lyophilized to yield 12 g. product. The solid is triturated with dry ether and dried overnight at 1 mm. to yield the desired product.
Example 6.2hydr0xypyridine-1-0xide salt with dodecylamine A hot solution of 7.4 g. 2-hydroxypyridine-l-oxide in 250 cc. acetonitrile is added to a solution of 12.9 g. dodecylamine in 250 cc. acetonitrile. The hot solution is filtered, cooled, and the crytalline solid filtered to yield the desired product melting at 53-545".
Similarly, substituting an equivalent amount of cetyldimethylamine for the dodecylamine in Example 3, there is obtained the cetyldimethylamine salt of 2-hydroxypyridine-l-oxide.
Example 7.-Preparation of the cetyltrimethyl-ammonium salt of Z-hydroxypyridz'ne-l-0xide To a solution of cetyltrimethyl-ammonium hydroxide in water (prepared by treatment of an aqueous solution of cetyltrimethyl ammonium bromide with excess silver oxide) there is added an equiv-alent amount of an aqueous solution of 2-hydroxypyridine-l-oxide. The solution is then lyophilized to recover the desired salt.
Example 8 (A) A composition of the fol-lowing formula is prepared:
G. Zinc salt of 2-hydroxypyridine-1-0xide 1.0 Corn oil 5.0 Ethanol 12.0
The zinc salt of Z-hydroxypyridine-l-oxide is suspended in a solution of the ethanol and corn oil.
(B) The foregoing composition is then introduced into a pressure packaged disperser of known type along with 82 g. of a suitable propellent such as a mixture of fifty parts trichloromonofluoromethane (Freon 11, Dupont) and fifty parts dichlorodifluoromethane (Freon 12, Du pont) or similar propellents either alone or as a mixture. The pressure pack is capped with a suitable value. Suitable dispersers are disclosed, for example, in US. Patent No. 1,892,750 dated January 3, 1933 and in US. Patent No. 2,440,915 dated May 4, 1948.
Example 9 (A) A composition of the following formula is prepared:
G Dodecylamine salt of 2-hydroxypyridine-l-oxide 0.8 Polyethylene (mol. weight, 21,000) 0.95 Mineral oil 18.05
A polyethylene mineral oil dispersion is prepared as described in Example 1 of US. Patent No. 2,628,187, issued February 10, 1953, and the dodecylamine salt of 2-hydroxypyridine-l-oxide is incorporated therein.
Example (A) A composition of the following formula is prepared:
4-methyl-2-hydroxypyridine-1-0xide 1.0 Powdered talc 99 The 4-methyl-2-hydroxypyridine-l-oxide is added to the powdered talc and intimately mixed therewith.
(B) The foregoing composition may then be separated Heat the stearic acid, Span and Tween mixture to 80 Dissolve the Z-hydroxypyridine-l-oxide in the water heated to 85 and add to the mixture. Stir until the temperature has dropped to 35 and then add the perfume.
Example 12 A composition of the following formula is prepared:
2-hydroxypyridine-l-oxide 3.0 Stearic acid 1.4 Triethanolamine 0.6 Glyceryl monostearate 4.0 Lanoline 1.0 Cetyl alcohol 0.4 Mineral oil 2.0
Water 87.5 Perfume oil, q.s.
This forms a 3% cream lotion.
Heat the water to about 65 C. and add the 2-hydroxy pyridine-l-oxide. Add the triethanolamine and warm to 85 C. Melt together the glyceryl monostearate stearic acid, lanolin, cetyl alcohol and mineral oil and heat to 90 C. Incorporate this into the water phase; stir vigorously and continuously until cool. Add the perform oil when the temperature has dropped to about 45 C.
If a color cream lotion is desired, make a dilute solution of a water-soluble cosmetic color and add along with the perfume oil.
Example 13 A composition of the following formula is prepared.
G. Dodecylamine salt of 2-hydroxypy1idine-1-oxide 80 Sodium lauryl sulfate 10 Propylene glycol 100 Stearyl alcohol 225 White petrolatum 226 Water 360 This will make an 8% ointment.
Melt the stearyl alcohol and the white petrolatum on a water bath and adjust the temperature to about 75 C. Add the other ingredients previously dissolved in water and warmed to 75 C. Stir the mixture until it congeals.
Example 14 A composition of the following formula is prepared! G.
2-hydroxypyridine-1-oxide, zinc salt 50 Cholesterol 30 Stearyl alcohol 30 White Wax 70 White petrolatum 820 This will make a 5% ointment.
Melt the stearyl alcohol, white wax and white petrolatum together on a water bath. Add the cholesterol until it completely dissolves. Then add the finely powdered zinc salt to the solution, remove from the water bath and stir until the mixture congeals.
Example 15 A composition of the following formula is prepared:
2-hydroxypyridine-l-oxide, zinc salt 10 Polyethylene glycol 4000 45 Polyethylene glycol 400 35 Sorbitan monopalmitate 1 Water 9 This makes a 10% ointment.
Warm the sorbitan monopalmitate and the polyethylene glycols to 70 and add water at 70. Then add the finely pulverized zinc salt and stir until congealed.
solve the potassium hydroxide in a mixture of glycerine and cc. of distilled water, and add the solution while it is still hot, to the hot oil. Stir the mixture vigorously until an emulsion is formed, and heat on a hotplate until the mixture becomes homogeneous and a small portion dissolves completely in hot water. Add sufficient hot water to make total weight about 1000 g., and incorporate the water in soap. Add powdered 2-hydroxypyridine-l-oxide and distribute evenly throughout soap. This makes a soft soap, whose properties depend on the vegetable oil used. Oils derived from higher fatty acids and saponified with NaOh will give hard soaps.
Example 17 A cream base containing propylene glycol, cetyl alcohol, glyceryl monostearate, spermaceti, isopropyl palmitate, polyoxyethylene sorbitan monostearate, methyl paraben and propyl paraben is prepared in the same manner as set forth in Example 12. A 5% 2-hydroxypyriidine-l-oxide cream is prepared from this cream base by the addition of a suitable amount of the active ingredient.
Employing the method of Goss et al., reported in vol. 40 of the Journal of Investigative Dermatology, pp. 299- 304 (1963), male albino guinea pigs, weighing 400 to 600 gms. are inoculated cutaneously with T. mentagrophytes. Groups of five animals are used, and each animal is infected at three sites, making available fifteen lesion sites for each test formulation. Triamcinolone acetonide, 10 mg. is given subcutaneously starting on the day of inoculation and continued daily five days per Week for three weeks, then three times weekly for another three weeks. Topical treatment of the test animals with the 2%; 3%; and 5% 2-hydroxypyridien-l-oxide cream; and the cream base as a placebo, was started on the sixteenth day after infection and continued daily, five days The efficacy of the test formulations is evaluated by a week. Untreated animals are used as controls. The comparing, at appropriate time intervals, the appearance results are reported below in Table 1: and average size (area) of lesions in the treated and un- TABLE 1 treated animals.
. Example 18 (A) Fourteen days post infectrortr, betfore 2-hydroxypy'r1dme-1-ox1de ma men Utilizing the procedure set forth in Example 17 except NO Ofin Av Size that treatment was started on the animals fourteen days Test Formulation ocu'lation g if fi gif 15510115 after infection, and the number of animals treated was sltes (mm?) increased, the results obtained are as indicated in Table 2:
5% 2-hydroxypyridine-1- F 2 oxide cream 0 15 3 2 (A) Seventeen days post infection (ten treatments with Z-hydroxy- 3% 2-hydroxypyridine-1- pyridine-l-oxide, then three days without treatment) z yxziie eirreamnna. 15 0 15 343 y oxypyri ine-l- 15 0 15 416 o xide cream... 15 0 15 416 15 No. of in- N0. sites No. sites Avg. size Placebo cream. 15 0 15 396 Test Formulation oculation clear infected of lesions Untreated 15 o 15 37s sltes 1 (B) Twenty-one days post infection (four treatments with 2-hydroxy y ypy 92 34 3 7 pyridine-l-oxide starting sixteen days after infection) OX c c eam Placebo cream 96 0 96 323 5% Z-hydrcxypyridine-loxide cream 15 0 15 418 (B) Thirty-one days post infection (ten treatments with Z-hydroxy- 3% 2-hydroxypyridine-1- pyridine-l-oxide, then seveteen days Without treatment) oxide cream 15 O 15 468 2% Z-hydroxypyridine-loxide cream-. 15 0 15 562 3% 2-hydroxypyridine-1' Placebo cream- 15 0 15 596 oxide cream.- 86 51 35 74 Untreated l5 0 15 580 Placebo cream 90 0 90 259 (C) Thirty-two days post infection (ten treatments with 2-hydroxy- The figures include the total results from seven separate tests.
pyridine-l-oxide). 2 For 78 sites.
5% My droxypyri (mm The above data indicates the effectiveness of Z-hydroxy- 3;??? eirreamn 15 0 15 344 py v yp xide cream---- 15 0 15 355 Example 19 2% 2 -hydroxypyr oxid e cre im 8 :13 Example 18 was repeated utilizing a cream contaming 355 5153 2; 15 0 15 2 0.25%, 0.50% and 1% of 2-hydroxypyridine-l-oxide. Five animals injected at three sites were utilized in this (D) Fifty-twodays post infection (fourteen treatments with 2-hydroxyp and treatment Was pp on y fourteenpy -o then slxteen y wlthout treatment) Triamcinolone acetonide was continued to be applied from day fourteen to day twenty-eight. The results obtained 57 2-hydroxypyridine-1- 3;??? g fi q 15 5 110 40 are indicated in Table 3 y oxypyn ine- 5a eeam a 15 12 13 TABLE 3 y YDY ille-l h d f t f teend oite gxide cream n 15 3 12 u (A) Twenty erg t ays postm cc 1011, our ays r atment Body comgg;; g P1913913 No.0l'in- No. sites No. sites Avg. size covered. Test Formulation oculation clear infected oflcsions sites (mm?) 1 These sites represent relapses, since at the end of treatment they were almost clear. The relapses were pinpoint lesions and there was seldom (125% gh d p more than one in an original inoculation site, the rest of the area remaindi 1. id ean 15 0 15 157 e clear- 0.53% ah d ox ti- 15 13 -1- 2 01 At sixteen days post-infection, the lesion is unlformly, g i;gfi% 1 fully established and measures several square centimeters -32 i: g g in area. If left untreated, these lesions will spread to Placebo 555 1: 15 0 1 225 cover the entire skin.
The leslons had attalned considerable Sim in three (B) Forty-two days after infection, fourteen days after treatment stopped groups f animals, as Shown i T bl 1 S ti A, b but tnamcmoloue acetomde contlnued. fore treatment. From Sections B and C it is seen that 0.257 Z-hydroxypyriafter ten topical treatments with hydroxypyridine 1 dhgedmide cream 15 4 11 155 oxide cream, there is a marked clearing of the lesions as 0.509; Z-hydroxypyriindicated by their decreased size. The 3% and 5% am- 15 3 12 91 1% Z-hydroxypyrldmeformulations of 2-hydroxypyrid1ne-1-ox1de were equally 0 1-oxidecream.. *12 2 10 61 effective Untreated. 15 0 15 235 Placebo cream. 12 0 12 142 When the lesions are examined sixteen days after the last of the fourteen topical treatments, some of the lesion 1 one animal died s1tes treated with 2-hydroxypyr1d1ene-l-oxlde showed an occasional pinpointed infection, but the remainder of the 5 Tflamclnolone acelonld Was glven after PP g treatareas were clear of infection. Animals not treated with Inent to 6011mm? the ll'lfectlonthis compound were entirely covered with the infection. The fofmula'tlons P fP accflrdlng to P Q In other words, the above data indicates that Z-hydroxyeXampleS can all be P Y PP t0 thefinlm'al belng pyridine-l-oxide controls the spread of the infection at treated for the control of T. men g p 1 I1f6t1011S- the beginning and thereafter reduces the lesions. This Th mventwn y be varlouslv otherwlse embodled is clearly pointed out by a comparison of Sections A, B Wlthm the scope of the appended claims. and C above. The average size of the lesions treated What IS clalmed IS with Z-hydroxypyridine-l-oxide remain in the three hun- 1. A method of treating animals for fungal conditions dred to low four hundred area whereas the lesions treated amenable to topical therapy which comprises topically otherwise spread out of control. applying a composition comprising from about 0.01 to about 10.0% of a principal active ingredient selected from the group consisting of compounds of the formula Ti -OH and the zinc and higher alkyl amine salts thereof having more than nine carbons; wherein each R is selected from the group consisting of hydrogen and lower alkyl, intimately dispersed in a substantial amount of a suitable topically administrable pharmaceutically acceptable extending agent.
2. A method of treating animals for fungal infections which comprises topically applying a composition comprising from about 0.01 to about 10.0% of 4-methyl-2- hydroxypyridine-l-oxide dispersed in a topically administrable pharmaceutically acceptable powder vehicle, to affected site.
3. A method for treating animals for fungal infections which comprises topically applying an aerosol composition comprising from about 0.01 to about 10.0% of the Zinc salt of 2-hydroxypyridine-l-oxide dispersed in a pharmaceutically acceptable liquid propellant.
4. A method of treating animals for dermatophylic fungal conditions which comprises topically applying a soap comprising from about 0.01 to about 10.0% of 2- hydroxypyn'dine-l-oxide dispersed in a topically administrable pharmaceutically acceptable soap base.
5. The method of claim 1 wherein the principal active ingredient is the zinc salt of Z-hydroxypyridine-l-oxide.
6. The method of claim 1 wherein the principal ingredient is the dodecylamine salt of Z-hydrroxypyridine-loxide.
References Cited by the Examiner UNITED STATES PATENTS 2/1951 Shaw 260297 6/1956 Cislak 260-297