US3497597A - Fungicidal composition and method containing 5-nitro-1,3,4-thiadiazoles - Google Patents

Fungicidal composition and method containing 5-nitro-1,3,4-thiadiazoles Download PDF

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US3497597A
US3497597A US657502A US3497597DA US3497597A US 3497597 A US3497597 A US 3497597A US 657502 A US657502 A US 657502A US 3497597D A US3497597D A US 3497597DA US 3497597 A US3497597 A US 3497597A
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nitro
thiadiazole
water
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mixture
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Andrew Stephen Tomcufcik
Howard Newman
Arlene May Hoffman
Ednelvyn Lezette Evans
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Wyeth Holdings LLC
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American Cyanamid Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • compositions of matter and method of administration are described.
  • the compositions contain as the active components Z-nitro-1,3,4-thiadiazole and S-substituted derivatives thereof.
  • the compositions are useful as topical antifungal agents.
  • This invention relates to new pharmaceutical compositions of matter and methods of administration to warmblooded animals. More specifically, the invention relates 3,497,597 Patented Feb. 24, 1970 "ice amino, morpholino, 2 (methylthio) 2 imidazolin-ly1, phenylthio and phenylsulfonyl.
  • the active ingredients of the compositions of this invention are, in general, yellow or orange colored, crystalline solids having characteristic melting points. They are relatively soluble in many organic solvents, such as, lower alkanols, acetone, ethyl acetate, and the like. Generally, however, they are insoluble in water.
  • compositions of this invention have shown high activity against a variety of fungi.
  • the in vitro antifungal activity of representative compounds is presented in Table I below which shows the minimal inhibitory concentration required to inhibit the growth of representative microorganisms in a nutrient medium.
  • the compounds of this invention have been found to be active against M icrosporum cards when tested in guinea pigs. Briefly, the test is described as follows: Male albino guinea pigs, 300500 g. (five animals per test group and five controls) are infected dermally with 0.5 ml. of a 10- dilution of a standard M. canis infective hair suspension. The test compounds are incorporated into ointments at concentrations of 5, 1, 0.25, and 0.06 percent in a mixture of solid polyethylene glycols having a molecular weight averaging about 4-00 and about 4,000.
  • compositions useful as topical antifungals containing as the active ingredient a compound of the formula:
  • R is hydrogen, lower alkyl, phenyl, p-methoxyphenyl, p-formylphenyl, p-carboxyphenyl, p-nitrophenyl, p-tolyl, p-benzaldiacetate, bromo, amino, diloweralkyl- Griseofulvin (1 percent) in the same polyethylene glycol mixture is included in the procedure as a positive control.
  • Treatment is applied to the infected lesion once daily for 5 days starting on day 3 postinfection. About 0.5 g. of ointment containing a particular test compound is applied topically at each treatment. Test animals are scored on day 10 and 17 postinfection as to the relative concentration of viable organisms per hair sample. Table II lists the results obtained with representative compounds of the present invention.
  • the excellent activity against dermatophytic Tricophyton and Microsporum species make them useful in the treatment of fungal infections of the skin of warm-blooded animals.
  • these compounds may be formulated with appropriate topically useful carriers such as wetting agents, stabilizing agents, dusting powders, ointments, creams, lotions, etc.
  • the formulated compounds can be applied topically to the infected skin area.
  • the topical compositions may contain from 0.2% to 5% of active component with a topically acceptable carrier.
  • the compounds of the present invention can be prepared by methods described herinafter in the examples and in the prior art.
  • the method most general for pre paring the majority of the compounds is by the conversion of the amino group of the substituted 5-amino-1,3,4-thiadiazole to a nitro group proceeding by the intermediate diazonium salt. Details are described in the examples.
  • EXAMPLE 2 Preparation of 2-phenyl-5-nitro-1,3,4-thiadiazole
  • the cupro-cupri sulfite is prepared by adding a solution If 25.2 g. (0.20 mole) of anhydrous sodium sulfite in 400 ml. of water to a solution of 33.6 g. (0.21 mole) of nhydrous cupric sulfate in 400 ml. of water.
  • the mixture s magnetically stirred at room temperature for 30 ninutes, and filtered through a layer of diatomaceous arth covered with a piece of filter paper.
  • the red-brown upro-cupri sulfite is washed with three 200 ml. portions f water.
  • the cupro-cupri sulfite is removed from the unnel and slurried with 300 ml. of water. This mixture filtered through a layer of diatomaceous earth (covered ith filter paper), and the cupro-cupri sulfite is Washed Iith another 600 ml. of water. The thoroughly washed upro-cupri sulfite is slurried in 200 ml. of water, and 1e mixture is added to a solution of 40 g. (0.58 mole) f sodium nitrite in 100 ml. of water. A warm solution f 35.4 g.
  • EXAMPLE 8 Preparation of 2-n-butyl-5-nitro-1,3,4-thiadiazole
  • the cupro-cupri sulfite is prepared from a solution of 8.85 g. (0.07 mole) of anhydrous sodium sulfite in 200 ml. of water and 12.0 g. (0.075 mole) of anhydrous cupric sulfate in 200 ml. of water as described in Example 2.
  • the cupro-cupri sulfite is slurried in 100 ml. of water and the mixture is added to a solution of 12.5 g. (0.18 mole) of sodium nitrite in 100 ml.
  • the mixture is filtered, and the benzene filtrate washed with water and saturated sodium chloride solution.
  • the benzene layer is dried, decolorized, and evaporated to leave 12.7 g. of red crystalline residue.
  • the residue is triturated with methanol to yield 4.2 g. (41%) of yellow crystals, .melting point 185l94 C.
  • the analytical sample was recrystallized twice from acetone, melting point 202-204 C.
  • the cooled filtrate gives a second crop of product of lesser purity.
  • the first crop of crystals weighs 324 mg. (72.7% yield), melting point 173175 C.
  • a recrystallization from methylene chloride yields purified 4-(5-nitro-1,3,4-thiadiazol- 2-yl)benzaldehyde, melting point 174.5176 C.
  • EXAMPLE 17 F'reparation of 2-(p-nitrophenyl)-5-nitro-1,3,4-thiadiazole 4 m1. of water, 1.1 g. of sodium nitrite, 144 mg. coper and 180 mg. of cupric oxide are mixed and heated 0 C. with constant agitation. 504 mg. of Z-(p-nitroahenyl)-5-amino-1,3,4-thiadiazole [see Helv. Chim. Acta E3, 1935 (1950)], 1.0 g. of 4850% fiuoboric acid 4 n1. acetic acid, and 5 ml. Water are mixed and heated in a steam bath until a clear solution is obtained.
  • the olution containing the amine is added dropwise but apidly to the nitrite suspension described above.
  • the esulting suspension is stirred for two and one-half hours tt temperatures ranging from 70 to C.
  • the solution is cooled and the solid colected by filtration, washed with water and extracted with everal portions of methylene chloride.
  • the methylene :hloride extracts are combined and evaporated to a resdue which is then slurried several times with ether.
  • the nsoluble material is collected, wt. mg. Sublimation tf this material at 185 C.
  • EXAMPLE 20 The compounds of this invention may be incorporated into a topical jelly according to the following formulation.
  • the parabens and methocel are dissolved in about twothirds of the final volume of distilled Water 80 C. with stirring.
  • the gel is cooled to below 40 C. and is then added with stirring to a solution to the active ingredient in propylene glycol.
  • the final gel is adjusted to volume with distilled water.
  • a 5 ml. portion of this gel contains 50 mg. of active ingredients.
  • EXAMPLE 21 A cream incorporating a compound of this invention may be formulated as follows:
  • the parabens are dissolved in about two-thirds of the final volume of distilled water at 80 C. with stirring.
  • the solution is cooled to about 50 C. and glycerine is added.
  • Light liquid petrolatum, cetyl alcohol and emulsified are heated together to about 50 C., blended well, and added with stirring to the warm aqueous solution.
  • the emu s on is cooled to room temperature and the active ingredient is then added with stirring.
  • the volume is adjusted with distilled water.
  • EXAMPLE 22 The compounds of this invention may be incorporated into a topical carbowax base ointment according to the following formulation.
  • the vehicles are blended together at about 60-65 C.
  • the active ingredient is suspended in the mixture with stirring and the slurry is passed through a suitable mill.
  • the ointment is agitated while cooling to room temperature to assure homogeniety.
  • EXAMPLE 23 The compounds of this invention may be incorporated into a topical grease-base ointment according to the following formulation.
  • the white petrolatum and lanolin are melted at 50-60 C. and blended together.
  • the active ingredient is suspended in the mixture with stirring and the slurry is passed through a suitable mill.
  • the ointment is agitated while cooling to room temperature as assure homogeniety.
  • a fungicidal composition in the form of oinlments, dusting powders, creams and lotions for controlling fungi consisting essentially of a topically acceptable carrier and from 0.2% to of a nitrothiadiazole of the formula:
  • R is selected from the group consisting of hydrogen, lower alkyl, phenyl, p-methoxyphenyl, p-formylphenyl, p-carboxyphenyl, p-nitrophenyl, p-tolyl, p-benzaldiacetate, bromo, amino, di-loweralkylamino, morpho- Rl J-Nm wherein R is selected from the group consisting of hydrogen, lower alkyl, phenyl, p-methoxyphenyl, p-formylphenyl, p-carboxyphenyl, p-nitrophenyl, p-tolyl, p-benzaldiacetate, bromo, amino, di-loweralkylamino, morpholino Z-(methylthio)-2-imidazo1in-l-yl, phenylthio and phenylsulfonyl.
  • nitrothiadiazole is 2-(4-methoxyphenyl) -5-nitro-l,3,4- thiadiazole.
  • nitroimidazole is 2-nitro-1,3,4-thiadiazole.
  • a fungicidal method according to claim 6, wherein the nitroimidazole is 2-phenyl-S-nitro-l,3,4-thiadiazole.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Description

United States Patent O US. Cl. 424-270 10 Claims ABSTRACT OF THE DISCLOSURE New compositions of matter and method of administration are described. The compositions contain as the active components Z-nitro-1,3,4-thiadiazole and S-substituted derivatives thereof. The compositions are useful as topical antifungal agents.
SUMMARY OF THE INVENTION This invention relates to new pharmaceutical compositions of matter and methods of administration to warmblooded animals. More specifically, the invention relates 3,497,597 Patented Feb. 24, 1970 "ice amino, morpholino, 2 (methylthio) 2 imidazolin-ly1, phenylthio and phenylsulfonyl.
The active ingredients of the compositions of this invention are, in general, yellow or orange colored, crystalline solids having characteristic melting points. They are relatively soluble in many organic solvents, such as, lower alkanols, acetone, ethyl acetate, and the like. Generally, however, they are insoluble in water.
The active ingredients of the compositions of this invention have shown high activity against a variety of fungi. The in vitro antifungal activity of representative compounds is presented in Table I below which shows the minimal inhibitory concentration required to inhibit the growth of representative microorganisms in a nutrient medium.
Additionally, the compounds of this invention have been found to be active against M icrosporum cards when tested in guinea pigs. Briefly, the test is described as follows: Male albino guinea pigs, 300500 g. (five animals per test group and five controls) are infected dermally with 0.5 ml. of a 10- dilution of a standard M. canis infective hair suspension. The test compounds are incorporated into ointments at concentrations of 5, 1, 0.25, and 0.06 percent in a mixture of solid polyethylene glycols having a molecular weight averaging about 4-00 and about 4,000.
TABLE I.IN VITRO ANTIFUNGAL ACTIVITY (MINIMAL INHIBITORY CONCENTRATIONS) (MCGJ'MLJ O rganism 1 Compound Name 1 2 3 4 5 6 7 8 9 10 11 12 2-nitro-1,3,4-thiadiazo1e 8 8 8 4 4 8 0. 5 4 8 4 2 8 5-nitro-2-methyl-1,3,4-thiadiazole 15 15 15 31 31 15 2 NT 8 4 15 l5 l5 5-nitro-2-phenyl-1,3,4-thiadiazole 3 1. 5 3 6 6 3 0. 5 0. 5 3 6 0. 5 3 5-nitro-2-(-methoxyphenyl)-1,3,4-thiadiazole 3 3 3 250 6 6 0. 5 1. 5 6 6 1. 5 62 5-nitro-2-bromo-l,3,4-thiadiazole 2 2 2 2 2 1 0. 12 0. 5 2 2 1 2 5-nitro-2-amino-1,3,4-thiadiazole. 62 62 125 62 62 125 15 62 125 62 62 125 5-nitro-2-morpholino-l,3,4-thiadiazole 250 125 31 62 62 62 15 31 NT NF NT NT 2-[2-(methylthio)-2-imidazolm-l-yll-S-nitro-l,3,4-
thiadiazolc 15 62 62 62 15 15 31 62 62 62 5-nitro-2-dipropylamino-l,3,4-thiadiazole 250 NT 125 125 125 250 62 62 250 250 62 NT 1 See the following:
Candida albicans-Bergen Strain, E-3. Candida mycoderma-ATCC 9888. Saccharomyces cerevisiae-ATCC 4100. Mucor ramannianux-M143. F usarium episphaeria-F-105j Hormodendrum cladosporoides-Z-Slfi. Trichophyton mentagrophytes-El1. Microsporum gypseumE-28. Penicillium digitatum-P-308B. 10. Memnoniella echinataZ-583. 11. Chaetomium gZobosumH-7l, QM 6694. 12. Aspergillus fumigatus-S246. 2 Not Tested.
to new compositions useful as topical antifungals containing as the active ingredient a compound of the formula:
Bl SJ-NOz wherein R is hydrogen, lower alkyl, phenyl, p-methoxyphenyl, p-formylphenyl, p-carboxyphenyl, p-nitrophenyl, p-tolyl, p-benzaldiacetate, bromo, amino, diloweralkyl- Griseofulvin (1 percent) in the same polyethylene glycol mixture is included in the procedure as a positive control. Treatment is applied to the infected lesion once daily for 5 days starting on day 3 postinfection. About 0.5 g. of ointment containing a particular test compound is applied topically at each treatment. Test animals are scored on day 10 and 17 postinfection as to the relative concentration of viable organisms per hair sample. Table II lists the results obtained with representative compounds of the present invention.
TABLE II.-HAIR CULTURE SCORES OF TEST COMPOUNDS TESTED IN THE 111. cams INFECTION IN GUINEA PIGS Hair Culture Score, day 10, day 17 Compound Name 5% 1% 0.25% 0.06%
2nitro- ,3,4-thiadiazole 2-nitro-1,3,4-thiadiazole (repeat) 2-phenyl-5-nitro-1,3,4-thiadiazole 0, NT 2-methy1-5-nitro-1,SA-thiadiazole- NT NT 2-11-butyl5-nitr0-1,BA-thiadiazole NT NT NT 2-(p-methoxyphenyl)-5-nitro-l,3,4-tliiadiazole NT NT NT 5-nitro-2 bromo-1,3,4-thiadiazole NT NT NT Griseofulvin (combined results) T Control (combined results) Hair culture score indicates the concentrations of viable spores per hair sample (0; +=1-10; 11-100; +++=1011, 000; and ++++=1,000). The hair culture score at the beginning of the treatment the third day after infection, ranged from to NT indicates not tested.
The excellent activity against dermatophytic Tricophyton and Microsporum species (see Tables I and II), coupled with the relative chemical stability of the compounds of this invention, make them useful in the treatment of fungal infections of the skin of warm-blooded animals. For such use these compounds may be formulated with appropriate topically useful carriers such as wetting agents, stabilizing agents, dusting powders, ointments, creams, lotions, etc. The formulated compounds can be applied topically to the infected skin area. The topical compositions may contain from 0.2% to 5% of active component with a topically acceptable carrier.
The compounds of the present invention can be prepared by methods described herinafter in the examples and in the prior art. The method most general for pre paring the majority of the compounds is by the conversion of the amino group of the substituted 5-amino-1,3,4-thiadiazole to a nitro group proceeding by the intermediate diazonium salt. Details are described in the examples.
The invention will be described in greater particularity in conjunction with the following specific examples.
EXAMPLE 1 Preparation of 2-phenyl-5-nitro-1,3,4-thiadiazole A mixture of 9.0 g. (0.05 mole) of 2-amino-5-phenyl- 1,3,4-thiadiazle [prepared as described in Chem. Ber. 96, 1059 (1963)], 85 ml. of 40% fluoroboric acid and 50 ml. of water is heated to give a clear solution. This mixture is added, during a 20 minute period, to a stirred suspension of 10 g. (0.126 mole) of cupric oxide, 28 g. (0.4 mole) of sodium nitrite and 80 ml. of water which has been treated with 1 to 2 drops of fluoroboric acid [5 minutes before addition of the amine. After the mix- :ure is stirred for 2.5 hours the solid is collected and lried, then extracted with methylene chloride. The ex- ;racts are concentrated to a small volume and chromatographed on an aluminum oxide column using methylene :hloride as eluant, yield 1.6 g. of crude material. The :rude material is recrystallized from methylene chloride md petroleum ether to give 1.1 g. yield) of prodict, melting point 158160 C.
EXAMPLE 2 Preparation of 2-phenyl-5-nitro-1,3,4-thiadiazole The cupro-cupri sulfite is prepared by adding a solution If 25.2 g. (0.20 mole) of anhydrous sodium sulfite in 400 ml. of water to a solution of 33.6 g. (0.21 mole) of nhydrous cupric sulfate in 400 ml. of water. The mixture s magnetically stirred at room temperature for 30 ninutes, and filtered through a layer of diatomaceous arth covered with a piece of filter paper. The red-brown upro-cupri sulfite is washed with three 200 ml. portions f water. The cupro-cupri sulfite is removed from the unnel and slurried with 300 ml. of water. This mixture filtered through a layer of diatomaceous earth (covered ith filter paper), and the cupro-cupri sulfite is Washed Iith another 600 ml. of water. The thoroughly washed upro-cupri sulfite is slurried in 200 ml. of water, and 1e mixture is added to a solution of 40 g. (0.58 mole) f sodium nitrite in 100 ml. of water. A warm solution f 35.4 g. (0.20 mole) of 2-amino-5-phenyl-l,3,4-thiaiazole in 100 ml. of fluoboric acid (37-40%) and 150 ll. of water is added slowly (about 10 ml. portions) the mechanically stirred mixture of cupro-cupri sulfite nd sodium nitrite in a three-necked 3-liter flask. Foaming ccurs after each addition, and either is added to break 1e foam. The addition takes about one hour. The mixlre is then stirred for 2 hours with no external heating. he reaction temperature rises to 35 C. and then slowly rops to 25 C. The mixture is filtered, and the solid and 1e filtrate are extracted with three 250 ml. portions of enzene. The benzene extract is dried, decolorized and Japorated to leave 10.3 g. of crystalline residue. A soluon of the residue (10.3 g.) in 200 ml. of benzene is chromatographed on an activated magnesium silicate column. The column (3.8 x 36 cm.) is prepared from 200 g. of 60200 mesh activated magnesium silicate slurry packed in benzene. The column is eluted with 1700 ml. of benzene, and ml. fractions are collected. Fractions 6 through 15 are combined and evaporated to give 3.4 g. (8% yield) of pale yellow crystals. One recrystallization from 300 ml. of methanol yield 1.6 g. (4%) of 2-phenyl- 5-nitro-1,3,4-thiadiazole, melting point 157l59 C.
EXAMPLE 3 Preparation of 2- (p-methoxyphenyl) -5-nitro-1,3,4-
thiadiazole To 7 g. of 2 amino 5 p methoxyphenyl-1,3,4-thiadiazole, and 14.8 g. of warm 50% fluoboric acid hot water is added until the solution is practically clear. Insoluble material is filtered off and the solution is heated on the steam bath until its temperature is approximately 80 C. It is then added rapidly in portions, with good stirring to a mixture of 16.2 g. of sodium nitrite, 2.65 g. copper oxide, 2.13 g. copper in 60 ml. of water, in a 3-neck flask at 80 C. After 20 minutes between 8097 C., the solid is collected from the hot mixture. The solid is dissolved in methylene chloride and the solution filtered to separate the insoluble material. The methylene chloride solution is dried over magnesium sulfate and filtered. The filtrate is concentrated and chromatographed on an alumina oxide column using methylene chloride as eluting solvent. The product obtained is washed with etherpetroleum ether (boiling point 3060 C.): Yield, 1.25 g. (15.7%), melting point 181-183.5 C.
EXAMPLE 4 Preparation of 2-p-tolyl-5-arnino-1,3,4-thiadiazole A mixture of 58.2 g. (0.29 mole) of ethyl p-methylbenzimidate hydrochloride, 22.1 g. (0.242 mole) of thiosemicarbazide and 300 ml. of pyridine is heated toboiling in an open flask for 1.75 hours. The flask, which then contains very little solvent, is cooled and ice water is added. The solid which has formed is collected by filtration, washed with water, slurried with ether and the mixture is filtered again; yield, 24.3 g., melting point -205 C. After recrystallization from acetonitrile, 16.5 g. (36% yield) of the purified product is obtained, melting point 215219 C.
EXAMPLE 5 Preparation of 2-p-tolyl-5-nitro-1,3,4-thiadiazole A hot solution of 3.82 g. (0.02 mole) of 2-p-tolyl-5- amino-1,3,4-thiadiazole, 8.8 g. of 50% fluoboric acid and 40 ml. of acetic acid is added dropwise, but rapidly, to a vigorously stirred suspension of 10 g. of sodium nitrite, 40 ml. of water, 1.2 g. of copper powder and 1.4 g. of cupric oxide at 80 C. (Two or three drops of 50% fluoboric acid had been added to the latter suspension immediately preceding the addition.) A concentrated aqueous solution of 5 g. of sodium nitrite is added and the mixture is stirred at 70-85 C. for 2 hours. The mixture is cooled, diluted with water and filtered and the solid, after drying, is extracted with ether. The ether extracts are evaporated to dryness and the residue is chromatographed on alum-inum oxide using methylene chloride as carrier solvent; yield 1.3 g. (14% melting point 177179 C. A-sublimed sample melts at 179182 C. In a number of runs, the yield has varied from 14 to 22%.
EXAMPLE 6 Preparation of 4-[S-nitro-l,3,4-thiadiazole-2-yl]- benzaldiacetate 126 mg. (0.0005 mole) of 2-tolyl-5-nitro-1,3,4-thiadiazole in 3 ml. of acetic anhydride is cooled and treated with 0.2 ml. of concentrated sulfuric acid and stirred a few minutes while cooling below 10 C. A mixture of 139 mg. of chromium trioxide in 4 ml. of acetic anhydride is added dropwise with constant stirring below C. After 2 hours, the addition of ice water produces a solid which is collected, washed with water, slurried in 2% sodium carbonate and again washed with water; yield 118 mg., melting point 168-177 C. Recrystallization from benzene-hexane gives a pure product; yield, 42 mg. (25%), melting point 184-187 C.
EXAMPLE 7 Preparation of 2-methyl-5-nitro-1,3,4-thiadiazole A solution of 2.88 g. (0.024 mole) of 2-arnino-5-methyl- 1,3,4-thiadiazole in 4.5 g. (3.4 ml.) of 48-50% fiuoboric acid is diluted with an additional 13 ml. of the fiuoboric acid, and the solution cooled to 05 C. Sodium nitrite, 1.67 g., (0.024 mole) is added slowly during fifteen minutes. The red slurry is stirred at 0-5 C. for an additional twenty minutes, and is then added in small portions to a vigorously stirred suspension of 4.9 g. (0.077 atom) of copper powder in a solution of 24.7 g. (0.36 mole) of sodium nitrite in 50 ml. of water (temperature, 25 C.). The addition requires twenty minutes, and a noticeable amount of nitrous oxide is liberated during the addition. The reaction mixture becomes green during the addition, and is accompanied by vigorous gas evolution (ether is used to break the foam). After thirty minutes, gas evolution is no longer evident. The reaction mixture is filtered and the filtrate is extracted with three 150 ml. portions of benzene. The benzene extracts are combined and dried over magnesium sulfate. Removal of the benzene under reduced pressure gives 1.75 g. (50% crude yield) of a yellow syrup that crystallizes on standing. Recrystallization from 50% aqueous acetone yields 0.95 g. (27%) of pure product, melting point 6566 C.
EXAMPLE 8 Preparation of 2-n-butyl-5-nitro-1,3,4-thiadiazole The cupro-cupri sulfite is prepared from a solution of 8.85 g. (0.07 mole) of anhydrous sodium sulfite in 200 ml. of water and 12.0 g. (0.075 mole) of anhydrous cupric sulfate in 200 ml. of water as described in Example 2. The cupro-cupri sulfite is slurried in 100 ml. of water and the mixture is added to a solution of 12.5 g. (0.18 mole) of sodium nitrite in 100 ml. of water in a three-necked 2-liter flask fitted with a mechanical stirrer and a thermometer. A solution of 10.0 g. (0.06 mole) of 2-amino-5-n-butyl- 1,3,4-thiadiazole in 80 ml. of fluoboric acid is added dropwise during 20 minutes. The reaction temperature rises from 18 to 30 C. The mixture is stirred for 30 minutes, and is then filtered. The solid and the filtrate are extracted with three 250 ml. portions of benzene and the extracts are washed with water. Magnesium sulfate and activated charcoal are added, and the mixture is filtered. Evaporation of the benzene leaves 7.2 g. of 'a brown oil which is dissolved in 200 ml. of benzene. The benzene solution is chromatographed on an activated magnesium silicate column (3.8 x 36 cm.) which is prepared from 200 g. (60- 200 mesh) activated magnesium silicate slurry packed in benzene. Fractions of 100 ml. are collected, and the column is developed with 2 liter of benzene. Fractions 7 through 20 are combined and evaporated to leave 1.3 g. (10% yield) of a yellow oil. The product is recrystallized twice from ether-hexane (at -10 C.) to give 100 mg. (1% yield) of 2-n-butyl-5-nitro-1,3,4-thiadiazole, melting point approximately 20 C.
EXAMPLE 9 Preparation of 2-bromo-5-nitro-1,3,4-thiadiazole 900 mg. (0.005 mole) of 2-arnino-5-bromo-1,3,4-thiadiazole, 1 ml. of concentrated hydrochloric acid and 2 ml. of water are mixed and heated on the steam bath to dissolve. This solution is added dropwise in a minute period to a vigorously stirred suspension of copper metal powder in a solution of 1 g. sodium nitrite (0.015 mole) in 10 ml. of water. [The sodium nitrite, copper is first treated with one or two drops hydrochloride acid to initiate nitrous oxide and stirred 15 minutes before starting the addition described above] During addition, the mixture becomes green, evolves gas, and a yellow solid separates. The mixture is stirred for 2 hours, filtered and the solid is dried. The solid is extracted with ether. Evaporation of the ether gives 500 mg. of dark yellow crystals, melting point 102-103 C. Recrystallization gives 450 mg. (43%) of product, melting point 102-103 C.
EXAMPLE 10 Preparation of 2-dipropylamino-5-nitro-1,3,4-thiadiazole A solution of 6.1 g. (0.06 mole) of di-n-propylamine in 50 ml. of ether is added dropwise during 10 minutes to a suspension of 6.3 g. (0.03 mole) of 2-brorno-5-nitro- 1,3,4-thiadiazole in 700 ml. of ether in an ice bath at 20 C. The mixture is magnetically stirred at 20 C. for 30 minutes, and the di-n-propylamine hydrochloride is removed by filtration. The ether filtrate is washed with saturated sodium chloride solution, dried and decolorized. Evaporation of the ether gives 1.9 g. of a red oil which is dissolved in 50 mll of benzene. The benzene solution is placed on an aluminum oxide column. (150 g. aluminum oxide slurry packed in benzene to give a column 2.7 x 27 cm.). The development of the column with 250 ml. of benzene gives 4.2 g. of a yellow oil. A solution of this oil in ml. of ether and 100 ml. of hexane is chilled in a Dry Ice-acetone bath. The resulting yellow crystals are collected (at 5 C.) by filtration and are washed with cold hexane. The crystals melted at 15 C. The resulting yellow oil, 2.8 g. (40% yield) is dried under reduced pressure at 25 C. over phosphorus pentoxide and paraflin.
EXAMPLE 11 Preparation of 2-morpholino-5-nitro-1,3,4-thiadiazole A solution of 1.9 ml. (0.022 mole) of morpholine in 15 ml. of ether is added dropwise during 20 minutes to a solution of 2.1 g. (0.01 mole) of 2-bromo-5-nitro-1,3,4- thiadiazole in 75 ml. of ether. The resulting yellow mixture is stirred at room temperature for 2 hours and filtered. The yellow precipitate is washed with ether and water and air dried to give 1.65 g. of a yellow solid, melting point 149-152 C. This material is recrystallized twice from ethanol to yield 1.46 g. (68%) of pure product, melting point 151-152 C.
EXAMPLE 12 Preparation of Z-dimethylamino-S-nitro-1,3,4-thiadiazole A solution of 2.1 g. (0.01 mole) of 2-bromo-5-nitro- 1,3,4-thiadiazole in ml. of ether is chilled in a salt-ice bath, and 5.0 ml. (0.75 .mole) of dimethylamine is added. The mixture is stirred (salt-ice bath cooling) for 2 hours and then filtered. The orange precipitate is washed with ether and water and dried yielding 1.3 g. of the crude product, melting point 138-140 C. An additional 0.3 g. orange crystals, melting point 139-142 C. is obtained from the filtrate. The two solids are combined and recrystallized twice from ethanol to yield 1.1 g. (63%) of the purified compound, melting point 141.5-142.5 C.
EXAMPLE 13 Preparation of 2-amino-5-nitro-1,3,4-thiadiazole Ammonia is bubbled through a magnetically stirred solution of 4.2 g. (0.02 mole) of 2-bromo-5-nitro-1,3,4- thiadiazole in 100 ml. of dioxane. The dioxane had been purified by passing it through an aluminum oxide column before use. After fifty minutes, the mixture is filtered. The brown precipitate is washed with ether and water and dried at 50 C. to give 1.36 g. (46%) of crude product, melting point decomposition above 230 C. (capillary). A sample prepared in a similar experiment is recrystallized once from water and twice from ethyl acetate to EXAM PLE 14 Preparation of 2- 2- (methylthio -2-imidazolin-l-yl] -5- nitro-1,3,4-thiadiazole A solution of 9.5 g. (54 mmoles) of 2-bromo-5-nitro- 1,3,4-thiadiazole in 150 ml. of benzene is added during minutes to a stirred solution of 10.6 g. (92 mmoles) of Z-methylthioimidazoline in 200 ml. of benzene. The mixture is stirred under nitrogen at 2227 C. for 3.5 hours. The mixture is filtered, and the benzene filtrate washed with water and saturated sodium chloride solution. The benzene layer is dried, decolorized, and evaporated to leave 12.7 g. of red crystalline residue. The residue is triturated with methanol to yield 4.2 g. (41%) of yellow crystals, .melting point 185l94 C. The analytical sample was recrystallized twice from acetone, melting point 202-204 C.
EXAMPLE Preparation of 4-(S-nitro-1,3,4-thiadiazol-2-yl)- benzaldehyde 674 mg. (0.002 mOle) of 4-[5-nitro-1,3,4-thiadiazol-2- yl]benzaldiacetate (Example 6) is dissolved in hot ethanol, and 15 ml. of water and 0.2 ml. of concentrated sulfuric acid are added to the solution. The suspension is heated to reflux and additional ethanol is added until a clear solution is obtained. The clear solution is heated at reflux temperature for an additional fifty minutes after which time the condenser is removed and the ethanol is removed by evaporation. The yellow solid is collected by filtration while the aqueous solution is hot. The cooled filtrate gives a second crop of product of lesser purity. The first crop of crystals weighs 324 mg. (72.7% yield), melting point 173175 C. A recrystallization from methylene chloride yields purified 4-(5-nitro-1,3,4-thiadiazol- 2-yl)benzaldehyde, melting point 174.5176 C.
EXAMPLE 16 Preparation of 4-(S-nitro-1,3,4-thiadiazol-2-yl)- benzoic acid To 170 mg. of 4-(5-nitro-1,3,4-thiadiazol-2-yl)benzallehyde is added 10 ml. of peroxyacetic acid. The nixture becomes clear on warming over a steam bath, )ut shortly after a solid precipitates. The suspension is ieated 1 hour, diluted with water and the solid collected. The solid is dissolved in 5% sodium bicarbonate, filtered 1nd reprecipitated with 9 M sulfuric acid. 113 mg. of )roduct is obtained which when recrystallized from aceone-acetonitrile and dried, has a melting point of 248- 250 C. dec. with eff.
EXAMPLE 17 F'reparation of 2-(p-nitrophenyl)-5-nitro-1,3,4-thiadiazole 4 m1. of water, 1.1 g. of sodium nitrite, 144 mg. coper and 180 mg. of cupric oxide are mixed and heated 0 C. with constant agitation. 504 mg. of Z-(p-nitroahenyl)-5-amino-1,3,4-thiadiazole [see Helv. Chim. Acta E3, 1935 (1950)], 1.0 g. of 4850% fiuoboric acid 4 n1. acetic acid, and 5 ml. Water are mixed and heated in a steam bath until a clear solution is obtained. The olution containing the amine is added dropwise but apidly to the nitrite suspension described above. The esulting suspension is stirred for two and one-half hours tt temperatures ranging from 70 to C. At the end f this period the solution is cooled and the solid colected by filtration, washed with water and extracted with everal portions of methylene chloride. The methylene :hloride extracts are combined and evaporated to a resdue which is then slurried several times with ether. The nsoluble material is collected, wt. mg. Sublimation tf this material at 185 C. (0.1 mm.) and washing he sublimate with ether yields the desired Z-(p-nitro- 8 phenyl)-5-nitro-1,3,4-thiadiazole, melting point 204.5- 207 C. Additional product is obtained from residue of the ether wash by sublimation and washing the sublimate with ether. Combined yield of product is 64 mg. (11% yield).
EXAMPLE 18 Preparation of 2- (phenylthio) -5-nitro-1,3,4-thiadiazole 4.2 g. (0.02 mole) of 2-bromo-5-nitro-1,3,4-thiadiazole is dissolved in ethanol and 4.34 g. (0.02 mole) of the silver salt of thiophenol is added. After refluxing 36 hours, the solvent is evaporated and ether added. The insoluble material is filtered off and the filtrate evaporated. The residue is slurried repeatedly With very small quantities of cold ether to wash out impurities. Recrystallization of 2 g. from methylene-chloride ether gives 1.6 g. (33.6%) of analytically pure product, melting point 9294 C.
The filtrates from Washing and recrystallization are combined, concentrated and chromatographed to yield an additional 315 mg. of product. (Total yield 46%.)
EXAMPLE 19 Preparation of 2-(phenylsulfonyl)-5-nitro- 1,3,4-thiadiazole 104 m. of Z-(phenylthio)-5-nitro-1,3,4-thiadiazole is warmed on the steam bath for 30 minutes in 10 ml. of 40% peroxy-acetic acid. The original yellow solution becomes colorless. It is cooled and then diluted with ice and water to yield 66 mg. (50%) of product; melting point, 121-423". Analytically pure material, melting point 124126 C. is obtained either by sublimation [ca. 125 (0.1 mm.)] or recrystallization from ether-hexane.
EXAMPLE 20 The compounds of this invention may be incorporated into a topical jelly according to the following formulation.
Ingredient: Amount percent w./v. Substituted 5-nitro-1,3,4-thiadiazole 1.0 Methocel 00 2.75 Parabens (4:1 mixture of methyl and propyl) 0.1 Propylene glycol 20.0 Distilled water, q.s. 100.0
The parabens and methocel are dissolved in about twothirds of the final volume of distilled Water 80 C. with stirring. The gel is cooled to below 40 C. and is then added with stirring to a solution to the active ingredient in propylene glycol. The final gel is adjusted to volume with distilled water.
A 5 ml. portion of this gel contains 50 mg. of active ingredients.
EXAMPLE 21 A cream incorporating a compound of this invention may be formulated as follows:
Ingredient: Amount percent w./v. Substituted 5-nitro-1,3,4-thiadiazole 2.0 Liquid petrolatum (light) 20.0 Cetyl alcohol 5.0 Parabens (4:1 mixture of methyl and propyl) 0.1 Emulsifier 5.0 Glycerin 5.0 Distilled water, q.s. 100.0
The parabens are dissolved in about two-thirds of the final volume of distilled water at 80 C. with stirring. The solution is cooled to about 50 C. and glycerine is added. Light liquid petrolatum, cetyl alcohol and emulsified are heated together to about 50 C., blended well, and added with stirring to the warm aqueous solution. The emu s on is cooled to room temperature and the active ingredient is then added with stirring. The volume is adjusted with distilled water.
EXAMPLE 22 The compounds of this invention may be incorporated into a topical carbowax base ointment according to the following formulation.
Ingredient: Amount percent w./v. Substituted S-nitro-1,3,4-thiadiazole Polyethylene glycol having molecular weight of 400 32.0 Polyethylene glycol having molecular weight of 4000 q.s. 100.0
The vehicles are blended together at about 60-65 C. The active ingredient is suspended in the mixture with stirring and the slurry is passed through a suitable mill. The ointment is agitated while cooling to room temperature to assure homogeniety.
EXAMPLE 23 The compounds of this invention may be incorporated into a topical grease-base ointment according to the following formulation.
Ingredient: Amount percent w./v.
Substituted S-nitro-1,3,4-thiadiazole 2. Lanolin U.S.P. W 10.0 White petrolatum U.S.P., q.s 100.0
The white petrolatum and lanolin are melted at 50-60 C. and blended together. The active ingredient is suspended in the mixture with stirring and the slurry is passed through a suitable mill. The ointment is agitated while cooling to room temperature as assure homogeniety.
We claim:
1. A fungicidal composition in the form of oinlments, dusting powders, creams and lotions for controlling fungi consisting essentially of a topically acceptable carrier and from 0.2% to of a nitrothiadiazole of the formula:
wherein R is selected from the group consisting of hydrogen, lower alkyl, phenyl, p-methoxyphenyl, p-formylphenyl, p-carboxyphenyl, p-nitrophenyl, p-tolyl, p-benzaldiacetate, bromo, amino, di-loweralkylamino, morpho- Rl J-Nm wherein R is selected from the group consisting of hydrogen, lower alkyl, phenyl, p-methoxyphenyl, p-formylphenyl, p-carboxyphenyl, p-nitrophenyl, p-tolyl, p-benzaldiacetate, bromo, amino, di-loweralkylamino, morpholino Z-(methylthio)-2-imidazo1in-l-yl, phenylthio and phenylsulfonyl.
7. A fungicidal method according to claim 6, wherein the nitrothiadiazole is 2-(4-methoxyphenyl) -5-nitro-l,3,4- thiadiazole.
8. A fungicidal method according to claim 6, wherein the nitroimidazole is 2-nitro-1,3,4-thiadiazole.
9. A fungicidal method according to claim 6, wherein the nitroimidazole is 2-phenyl-S-nitro-l,3,4-thiadiazole.
10. A fungicidal method according to claim 6, wherein the nitroimidazole is 2-bromo-5-nitro-l,3,4-thiadiazole.
References Cited UNITED STATES PATENTS 8/1967 Kier 424270 8/ 1967 =Boesch et al. 424-270 XR ALBERT T. MEYERS, Primary Examiner D. R. ORE, Assistant Examiner US. Cl. X.R.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3598830A (en) * 1968-10-11 1971-08-10 American Cyanamid Co 5-substituted-1,3,4-thiadiazole-2-carboxaldehydes
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3337575A (en) * 1964-07-28 1967-08-22 Rhone Poulenc Sa Certain carbamoyl diazolones
US3337398A (en) * 1965-11-12 1967-08-22 Univ Ohio State Method of killing microorganisms

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3337575A (en) * 1964-07-28 1967-08-22 Rhone Poulenc Sa Certain carbamoyl diazolones
US3337398A (en) * 1965-11-12 1967-08-22 Univ Ohio State Method of killing microorganisms

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3598830A (en) * 1968-10-11 1971-08-10 American Cyanamid Co 5-substituted-1,3,4-thiadiazole-2-carboxaldehydes
US3794665A (en) * 1968-10-11 1974-02-26 American Cyanamid Co 2,5-disubstituted 1,3,4-thiadiazoles
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9453007B2 (en) 2010-12-22 2016-09-27 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9567355B2 (en) 2010-12-22 2017-02-14 Abbvie Inc. Hepatitis C inhibitors and uses thereof

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