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US3651054A - 3 5-disubstituted 1 2 4-oxadiazoles - Google Patents

3 5-disubstituted 1 2 4-oxadiazoles Download PDF

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US3651054A
US3651054A US612778A US3651054DA US3651054A US 3651054 A US3651054 A US 3651054A US 612778 A US612778 A US 612778A US 3651054D A US3651054D A US 3651054DA US 3651054 A US3651054 A US 3651054A
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nitro
furyl
ethanol
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Aldo Joseph Crovetti
Anne Mary Von Esch
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/14—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 three or more hetero rings

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  • non-toxic salts thereof such as the hydrochloride, hydrobromide, sulfate, and quaternary ammonium salts such as, for example, methyl bromide, methyl iodide, benzyl chloride, and methyl sulfate.
  • the compounds of the present invention have the formulas M It (B) and O OO N O omit Lit-t wherein R in these and succeeding formulas may be any of the previously enumerated radicals except 5-nitro-2- furyl.
  • these compounds are useful as anthelmintic agents when administered intraperitioneally to mice infected with Schistosomiasis mansoni.
  • the compounds are effective aaginst Trichomonas vaginalis in concentrations of 10 parts per million when applied topically.
  • a compound of the Formula B or C where R is halomethyl (the preparation of which is hereinafter described) is dissolved in an appropriate solvent such as benzene, toluene, acetonitrile, chloroform, or ethanol, and an appropriate nucleophile is added and refluxed. (A few milliliters of N,N-dimethylformamide may be added to assist displacement.) After several hours of refluxing, the solution is cooled; and if a hydrohalide salt of the nucleophile has been formed in the reaction, it is filtered. Upon concentration of the filtrate, the product separates either as a solid or a viscous oil. The compound can be converted to a salt if this is necessary for a solid product. Purification is obtained by recrystallization from a solvent such as ethanol, isopropanol, n-butanol, or acetonitrile, among others.
  • an appropriate solvent such as benzene, toluene, acetonitrile,
  • the compounds of Formula B wherein R is halomethyl (chloro or bromo) and which are the starting materials for the preparation of the compounds of the present invention can be readily prepared by heating at or above the melting point a compound of the formula wherein R is halomethyl, in the absence or presence of a solvent to liberate water and effect ring closure.
  • the preparation of compounds of Formula D will hereinafter be described in detail and is fully described in U.S. Pat. No. 3,272,828.
  • the compound thus formed, if a solid, is then crystallized from a suitable solvent such as ethanol, nitromethane, or acetonitrile. If the compound is a liquid, it is isolated by distillation under reduced pressure.
  • an R-substituted amidoxime where R is halomethyl, preferably chloro, and 5-nitro-2- furoyl chloride or bromide
  • an inert solvent such as acetone, toluene, xylene, dimethylformamide, or benzene
  • a hydrohalide acceptor such as pyridine, potassium carbonate, or triethylamine or in acetic acid without acid acceptor to form the intermediate compound designated in Formula D above in situ and without actually isolating said intermediate continuing the reaction at reflux temperature to close the ring.
  • the reaction mixture is then concentrated and the residue recrystallized or distilled to obtain the desired oxadiazole.
  • the compounds of Formula C wherein R is halomethyl can be readily prepared by heating at or above the melting point a compound of the formula in the absence or presence of a solvent to liberate water and effect ring closure.
  • the preparation of compounds of Formula B will hereinafter be described in detail and is fully described in US. Pat. No. 3,272,833.
  • the compound thus formed ' is then crystallized from a suitable solvent such as ethanol, nitromethane, or acetonitrile.
  • equimolar amounts of -nitro-2-furylamidoxime and a compound of the formula RCOX, where R is halomethyl, preferably chloro, and wherein X is a halogen, preferably chlorine or bromine, may be refluxed in an inert solvent such as toluene, xylene, dimethylformamide, or benzene in the presence of a hydrohalide acceptor such as pyridine, potassium carbonate, or triethylamine or in acetic acid without acid acceptor to form the intermediate compound designated in Formula E above in situ and without actually isolating said intermediate continuing the reaction at reflux temperature to close the ring.
  • the reaction mixture is then concentrated and the residue recrystallized to obtain the desired oxadiazole as a crystalline solid.
  • an excess of the compound RCOX can be employed as the solvent.
  • R and R may be any of the previously enumerated radicals with the proviso that both R and R cannot be 5-nitro-2-furyl.
  • R or R represents dialkylaminoloweralkyl, acylaminoalkyl, or acylthioloweralkyl, this method is more convenient than the previously-described method.
  • This ring closure can be readily carried out by heating the starting material (the preparation of which is hereinafter described) at or above its melting point or in the presence of a solvent to liberate water.
  • Solvents such as n-butanol, benzene, toluene, or N,N-dimethylformamide are suitable for the procedure. Upon cooling the melt or the solvent, the desired product crystallizes. Purification is achieved by recrystallization from ethanol, butanol, ethyl acetate, or other suitable solvents.
  • the compounds of Formula F may be made by the known acid halide procedure as disclosed in US. Pat. Nos. 3,272,828 and 3.272833. Alternatively, these compounds can be made in accordance with the following scheme:
  • equimolar quantities of ethylchloroformate and an acid acceptor i.e., triethylamine, pyridine, and the like, may be employed to form the intermediate mixed anhydride of the acid which acylates the amidoxime.
  • This reaction is run at 0-5 C. initially, followed by ambient temperatures.
  • the proper reactants must be selected in order to obtain the desired starting material of Formula F.
  • EXAMPLE 2 2-[ [5- (5-nitro-2-furyl -1 ,2,4-oxadiazol-3-yl] methyl] -2- thiopseudourea
  • the oil residue is mixed with ether and the ether extracts are washed with water.
  • the ether layer is stirred with decolorizing charcoal, filtered, and the resulting pale yellow filtrates dried over magnesium sulfate. After filtering from the drying agent, the ether solution is concentrated to dryness under vacuo.
  • the oil residue is the crude acetoxy derivative as shown by infrared analysis. Weight 3.80 grams.
  • the crude oil was taken into solution with 50 ml. of ethanol and 10 ml. of concentrated hydrochloric acid added. The mixture is heated at reflux for 6 hours. The mixture is concentrated under vacuo. The resulting oil is triturated with ether, the ether solution washed with water until no longer acidic and then dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrates when taken to dryness yield 2.31 g. of tacky solid. By taking the oil up in hot toluene and with the use of decolorizing charcoal, the product is obtained as a white solid, M.P. 114-115.
  • EXAMPLE 23 EXAMPLE 27 2-[ [3- (-nitro-2-furyl) -l,2,4-oxadiazol-5-yl] 3- (5-nitro-2-furyl) -1,2,4-oxadiazole-5-methanol methyl]am1no]ethanol 5
  • R CH2OH in Formula C
  • R CHZNHCH2CH2OH m
  • Formula C 4.6 g. of 5-chloromethyl-3-(S-nitro-Z furyl) 1,2,4- 4.6 g, of 5-(chloromethyl)r3-(5-nitro-2-furyl)-l,2,4- oxadiazole and 1.7 g. of sodium acetate in 100 m1.
  • the white quaternary salt is YU-L A- dlssolved in 9 1111- Of bBnZene filtered from the solution.
  • the solid is suspended in 40 ml. Containing 5 Of dlmlllylfofmamldeof ethanol containing 15 ml. of concentrated hydrochloric mole) of yla mi e is added to the benzene solution acid and allowed to stand for 48 hours at room temperaand rQfluXcd ovemlght- The hydfochlonde 0f dlmethylture.
  • azidoloweralkyl may be accomplished by reacting the appropriate halomethyl derivative, previously described, with a slight excess of sodium azide (a small amount of dimethylformamide or sodium iodide may be added to facilitate reaction) in acetonitrile, "ethanol, isopropanol,
  • R and R is 5-nitro-2-fu1'yl
  • the other is a member of the group consisting of diloweralkylclohexylaminoloweralkyl, morphilinoloweralkyl, azidoloweralkyl, benzylaminoloweralkyl, thiuionium loweralkyl, hydroxyloweralkyl, aminoloweralkyl, cycloaminoloweralkyl, acylaminoloweralkyl, N-loweracylamino-N- cyelohexylaminoloweralkyl, N acyl-N-loweralkylaminoloweralkyl, acylthiolowera lk-yl; hydroxyloweralkylaminoloweralkyl, bis(hydroxyloweralkyl)aminoloweralkyl, polyhydroxyloweralkylaminoloweralkyl, phenylaminoloweralkyl,
  • diloweralkylaminoloweralkyl ing of diloweralkylaminoloweralkyl, monoloweralkylaminoloweralkyl, cyclohexylaminoloweralkyl, morphilinoloweralkyl, azidoloweralkyl, benzylaminoloweralkyl, thiuronium loweralkyl, hydroxyloweralkyl, aminoloweralkyl, cycloaminoloweralkyl, acylaminoloweralkyl, N- lower-acylamino-N-cyclohexylaminoloweralkyl, N acyl- N-loweralkylaminoloweralkyl, acylthioloweralkyl, hydroxyloweralkylaminoloweralkyl, bis(hydroxyloweralkyl)aminoloweralky1, polyhydroxyloweralkylaminoloweralkyl, phenylaminoloweralkyl,
  • R is monoloweralkylaminoloweralkyl
  • R is acylthioloweralkyl
  • acy is a member of the group consisting of the acetyl, propionyl and benzoyl radicals.
  • R is S-nitro-Z-furyl and R is a member of the group consisting of diloweralkylaminoloweralkyl, monoloweralkylaminoloweralkyl, cyclohexylaminoloweralkyl, morpholinoloweralkyl, azidoloweralkyl, benzylaminoloweralkyl, thiuronium loweralkyl, hydroxyloweralkyl, aminoloweralkyl, cycloaminoloweralkyl, acylaminoloweralkyl, N- loweracylamino-N-cyclohexylaminoloweralkyl, acylthioloweralkyl, hydroxyloweralkylaminoloweralkyl, his(hydroxyloweralkyl)aminoloweralkyl, polyhydroxylower alkylaminoloweralkyl, phenylaminoloweralkyl, phenylalkyl
  • R is 5-nitro-2-furyl and R is aminoloweralkyl.
  • R is S-nitro-Z-furyl and R is N-acyl-N-loweralkylaminoloweralkyl
  • acyl is a member of the group consisting of the acetyl, propionyl and benzoyl radicals.

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  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

COMPOUNDS COMPRISING 3,5-DISUBSTITUTED-1,2,4-OXADIAZOLES WITH ONE OF THE SUBSTITUENTS BEING 5-NITRO-2-FURYL. THE COMPOUNDS ARE USEFUL AS ANTIBACTERIAL, ANTHELMINTIC, AND ANTI-TRICHOMONAS AGENTS.

Description

United States Patent 3,651,054 3,5-DISUBSTITUTED 1,2,4-0XADIAZOLES Aldo Joseph Crovetti, Lake Forest, and Anne Mary Von Esch, North Chicago, Ill., assignors to Abbott Laboratories, North Chicago, Ill. No Drawing. Filed Jan. 31, 1967, Ser. No. 612,778 Int. Cl. C07d 85/52, 87/38 U.S. Cl. 260247.5 R 12 Claims ABSTRACT OF THE DISCLOSURE Compounds comprising 3,5-disubstituted-1,2,4-oxadiazoles with one of the substituents being S-nitro-Z-furyl. The compounds are useful as antibacterial, anthelmintic, and anti-trichomonas agents.
SUMMARY This invention relates to compounds of the formula 0 N/ CR Bri l-I' l Formula A In this formula, when R is 5-nitro-2-furyl, R represents Likewise, when R is S-nitro-Z-furyl, R may be any of the enumerated radicals except 5-nitro-2-furyl. The term loweralkyl includes the straight and branched alkyl radicals containing from 1-5 carbon atoms. It is also intend ed to include the non-toxic salts thereof such as the hydrochloride, hydrobromide, sulfate, and quaternary ammonium salts such as, for example, methyl bromide, methyl iodide, benzyl chloride, and methyl sulfate.
More particularly, the compounds of the present invention have the formulas M It (B) and O OO N O omit Lit-t wherein R in these and succeeding formulas may be any of the previously enumerated radicals except 5-nitro-2- furyl.
3,651,054 Patented Mar. 21, 1972 "ice These compounds are useful as antibacterial and antifungal agents and can be employed as active toxic constituents or disinfectant compositions for the control of microorganisms such as Salmonella typhimirium, Proteus vulgaris, Escherichia coli, Staphlococcus aureus, Chaetomium globosum, and Alternaria. In such use, the compounds are dispersed on an inert solid or in a liquid such as water and applied as a dust or spray. In a typical application, the compound wherein R of Formula C is hydroxymethyl completely inhibited the growth of the abovenamed microorganisms when employed as an aqueous composition in a concentration of parts per million. Additionally, these compounds are useful as anthelmintic agents when administered intraperitioneally to mice infected with Schistosomiasis mansoni. In another typical application, the compounds are effective aaginst Trichomonas vaginalis in concentrations of 10 parts per million when applied topically.
DETAILED DESCRIPTION The new compounds can be readily prepared by the following method.
A compound of the Formula B or C where R is halomethyl (the preparation of which is hereinafter described) is dissolved in an appropriate solvent such as benzene, toluene, acetonitrile, chloroform, or ethanol, and an appropriate nucleophile is added and refluxed. (A few milliliters of N,N-dimethylformamide may be added to assist displacement.) After several hours of refluxing, the solution is cooled; and if a hydrohalide salt of the nucleophile has been formed in the reaction, it is filtered. Upon concentration of the filtrate, the product separates either as a solid or a viscous oil. The compound can be converted to a salt if this is necessary for a solid product. Purification is obtained by recrystallization from a solvent such as ethanol, isopropanol, n-butanol, or acetonitrile, among others.
In the special case where R is Formula B or C is hydroxymethyl, the acetoxy compound obtained in the reaction described above is treated with ethanolic hydrochloric acid under reflux. The product crystallizes from the reaction mixture and is purified by recrystallization.
The compounds of Formula B wherein R is halomethyl (chloro or bromo) and which are the starting materials for the preparation of the compounds of the present invention can be readily prepared by heating at or above the melting point a compound of the formula wherein R is halomethyl, in the absence or presence of a solvent to liberate water and effect ring closure. The preparation of compounds of Formula D will hereinafter be described in detail and is fully described in U.S. Pat. No. 3,272,828. The compound thus formed, if a solid, is then crystallized from a suitable solvent such as ethanol, nitromethane, or acetonitrile. If the compound is a liquid, it is isolated by distillation under reduced pressure. If desired, equimolar amounts of an R-substituted amidoxime, where R is halomethyl, preferably chloro, and 5-nitro-2- furoyl chloride or bromide can be refluxed in an inert solvent such as acetone, toluene, xylene, dimethylformamide, or benzene in the presence of a hydrohalide acceptor such as pyridine, potassium carbonate, or triethylamine or in acetic acid without acid acceptor to form the intermediate compound designated in Formula D above in situ and without actually isolating said intermediate continuing the reaction at reflux temperature to close the ring. The reaction mixture is then concentrated and the residue recrystallized or distilled to obtain the desired oxadiazole. Likewise, the compounds of Formula C wherein R is halomethyl can be readily prepared by heating at or above the melting point a compound of the formula in the absence or presence of a solvent to liberate water and effect ring closure. The preparation of compounds of Formula B will hereinafter be described in detail and is fully described in US. Pat. No. 3,272,833. The compound thus formed 'is then crystallized from a suitable solvent such as ethanol, nitromethane, or acetonitrile. If desired, equimolar amounts of -nitro-2-furylamidoxime and a compound of the formula RCOX, where R is halomethyl, preferably chloro, and wherein X is a halogen, preferably chlorine or bromine, may be refluxed in an inert solvent such as toluene, xylene, dimethylformamide, or benzene in the presence of a hydrohalide acceptor such as pyridine, potassium carbonate, or triethylamine or in acetic acid without acid acceptor to form the intermediate compound designated in Formula E above in situ and without actually isolating said intermediate continuing the reaction at reflux temperature to close the ring. The reaction mixture is then concentrated and the residue recrystallized to obtain the desired oxadiazole as a crystalline solid. Alternatively, an excess of the compound RCOX can be employed as the solvent.
Another method which may be employed is the ring closing of an O-substituted amidoxime, represented by the formula NHz R1 'J=N0 i'r-R, (F)
in which R and R may be any of the previously enumerated radicals with the proviso that both R and R cannot be 5-nitro-2-furyl. When R or R represents dialkylaminoloweralkyl, acylaminoalkyl, or acylthioloweralkyl, this method is more convenient than the previously-described method.
This ring closure can be readily carried out by heating the starting material (the preparation of which is hereinafter described) at or above its melting point or in the presence of a solvent to liberate water. Solvents such as n-butanol, benzene, toluene, or N,N-dimethylformamide are suitable for the procedure. Upon cooling the melt or the solvent, the desired product crystallizes. Purification is achieved by recrystallization from ethanol, butanol, ethyl acetate, or other suitable solvents.
The compounds of Formula F may be made by the known acid halide procedure as disclosed in US. Pat. Nos. 3,272,828 and 3.272833. Alternatively, these compounds can be made in accordance with the following scheme:
CHCH NH2 The reaction is nun in solvents such as acetonitrile, dimethylformamide, 1,2-dimethoxyethane, chloroform, ether, and the like. Equimolar quantities of the acid and the amidoxime are employed in the presence of 1.0 to 1.25 moles of a condensing agent such as dicyclohexylcarbodiimide, at ambient temperatures.
If desired, equimolar quantities of ethylchloroformate and an acid acceptor, i.e., triethylamine, pyridine, and the like, may be employed to form the intermediate mixed anhydride of the acid which acylates the amidoxime. This reaction is run at 0-5 C. initially, followed by ambient temperatures. Of course, the proper reactants must be selected in order to obtain the desired starting material of Formula F.
4 The examples which follow are presented as illustrations rather than limitations of the invention.
EXAMPLE 1 3- diethylamino) methyl] -5- (5-nitro-2-furyl) -1,2,4-
' oxadiazole R=CH N(C -H -'I-ICl in Formula B To 4.5 ml. of anhydrous diethylamine is added 2.58 g. (0.01125 mole) of 3-(chloromethyl)-5-(5-nitro-2-furyl)- 1,2,4-oxadiazole with stirring at room temperature. After solution is elfected, the reaction mixture is heated on a steam bath for 0.5 hours. The dark reaction mixture which forms is filtered and the residue washed with anhydrous benzene. The benzene filtrates are concentrated to dryness under vacuo and the residual oil taken up in anhydrous ether, the solution heated with decolorizing charcoal. After filtration of the latter mixture, the ether filtrates are treated with etheral HCl. The solid which precipitates is filtered and dried, weight 2.0 g. (59%), M.P. 159 dec. The product is purified by crystallization from absolute alcohol. The pure product melts at 170l71 dec.
Analysis.-Calc. for C H ClN O (percent): C, 43.64; H, 5.01; N, 18.54; Cl, 11.73. Found (percent): C, 43.67; H, 5.02; N, 18.66; Cl, 11.77.
EXAMPLE 2 2-[ [5- (5-nitro-2-furyl -1 ,2,4-oxadiazol-3-yl] methyl] -2- thiopseudourea EXAMPLE 3 5-(5-nitro-2-furyl)-1,2,4-oxadiazole-3-methanol R=CH OH in Formula B A mixture containing 5.0 g. (0.0218 mole) of 3-(chloromethyl)-5-(5-nitro-2 furyl) 1,2,4 oxadiazole, 1.79 g. 0.0218 mole) of anhydrous sodium acetate, 60 ml. of absolute ethanol, and 4 drops of dimethylformamide is heated at reflux for 24 hours. The reaction mixture is filtered and the filtrate taken to dryness. The oil residue is mixed with ether and the ether extracts are washed with water. The ether layeris stirred with decolorizing charcoal, filtered, and the resulting pale yellow filtrates dried over magnesium sulfate. After filtering from the drying agent, the ether solution is concentrated to dryness under vacuo. The oil residue is the crude acetoxy derivative as shown by infrared analysis. Weight 3.80 grams.
The crude oil was taken into solution with 50 ml. of ethanol and 10 ml. of concentrated hydrochloric acid added. The mixture is heated at reflux for 6 hours. The mixture is concentrated under vacuo. The resulting oil is triturated with ether, the ether solution washed with water until no longer acidic and then dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrates when taken to dryness yield 2.31 g. of tacky solid. By taking the oil up in hot toluene and with the use of decolorizing charcoal, the product is obtained as a white solid, M.P. 114-115.
Analysis.Calc. for C H N O (percent): C, 39.82; H, 2.39; N, 19.90. Found (percent): C, 39.94; H, 2.33; N, 19.73.
Analysis.-Calc. for C H N (percent): C, 53.51;
EXAMPLE 4 H, 3.21; N, 17.83; 0, 25.46. Found (percent): (3, 53.47; H, 3.51;N,17.86;0, 25.44. N-[ [5-(5 -11itro-2-furyl) -1,2,4-oxadiazol-3 -yl] methyl] benzamide 5 EXAMPLE 5 N-methyl-N-[[5-(5-nitro-2-furyl)-1,2,4-oxadiazol-3-yl] methyl]acetamide o R=CH NHH1- in Formula B 0 ll R=CH -l}ICCHa in Formula B One gram of 0-5 nitro-2-furoyl-N-benzoylaminoacetamidoxime (M.P. 188189) is heated at 190 under reduced pressure. After cessation of gas evolution, the 13,9 (0,049 mole) f O-aCyIamidQXime is refluxed melt is Poured into a cfystalliliflgdish- The glass is taken in 600 ml. of n-butanol overnight and then concentrated up in excess alcohol with heat, heated with decolorizto an oil. Recrystallization from ethanol gave the product ing charcoal and the mixture filtered. The filtrates are 20 with a melting point of 1l9-121 C. concentrated to 15 ml. and chilled. The product is fil- Using methods exemplified in the foregoing examples, tered and washed with cold alcohol. The product after the following compounds, wherein R refers to substitudrying weighed 0.61 g. (64.5%), M.P. 161162. tions in Formula B, were made.
Analysis Calculated Found M.P. in Recrystallization Mol. Example R degrees Salt solvent 0 H N C H N wt.
6 0H5N(01H5)5 170.5-171 H01 Abs. ethanol 43.64 5.01 18.54 43.67 5.02 18.66 302.72 7 CHg-N-(CaHrll): 146 H01 Iso-propanol 47.20 5.79 16.94 47.33 6.01 16.61 330.77
8 189-190 H01 CHaCN 45.79 4.81 17.80 45.96 4.88 17.60 314.73
GHQ-N 9 Abs. ethanol 47.14 4.32 19.99 47.10 4.34 19.79 280.24
CHrN
10 187 H01 166'- ro anol 43.96 4.36 18.65 44.80 4.76 18.46 300.70
CH? l p p 11 CHzNH-CHz-CeHb 201 HCl Abs. ethanol 49.93 3.89 16.64 49.99 3.92 16.45 336.73
12 lfiIH 220 H01 .--.-do 31.43 2.64 22.91 31.62 2.71 22.76 305.71
OH S--CNH;
13 GHQ-0H 1145-1155 Et]hy1acetate+petro- 39.82 2.39 19.90 39.94 2.33 19.73 211.13
8111118 81', 14 CHz-NH: 134-135 Abs. ethanol 26.66 25.95 210.15
15 -176 H01 CHaCN+ 47.49 5.21 17.04 47.75 5.20 17.21 328.76
CHg-NH- 8 diisopropylether.
16 (1H5 175-176 H01 ..do 53.90 5.05 14.79 53.89 5.05 14.79 378.81
CHg-N-(EHgCHzCBHB CH;
CH -NlEL-C-C H 18 134 Abs. ethanol 42.86 3.20 22.21 43.03 3.38 22.21 252.19
CH NHO-CHI 19 COCH; 110-111 Iso-butanoH- 53.88 5.43 16.76 54.06 5.52 16.90 334.33
cyclohexane:
20 GB 198 lso-propanol 46.69 2.94 18.15 46.53 2.99 18.23 308.70
CH -N diisopropylether;
21 119-121 Ethanol 45.11 3.79 21.05 45.25 4.07 20.97 266.21
cmmonoocm 22 97-98 chloroform 47.14 4.32 19.99 47.21 4.54 20.10 280.24
CHIN(C2H5) 60H:
EXAMPLE 23 EXAMPLE 27 2-[ [3- (-nitro-2-furyl) -l,2,4-oxadiazol-5-yl] 3- (5-nitro-2-furyl) -1,2,4-oxadiazole-5-methanol methyl]am1no]ethanol 5 R=CH2OH in Formula C R=CHZNHCH2CH2OH m Formula C 4.6 g. of 5-chloromethyl-3-(S-nitro-Z furyl) 1,2,4- 4.6 g, of 5-(chloromethyl)r3-(5-nitro-2-furyl)-l,2,4- oxadiazole and 1.7 g. of sodium acetate in 100 m1. of oxadiazole is dissolved in 100 ml. of benzene containing ethanol are refluxed for 72 hours. The resulting solution 5 ml. of N,N-dimethylformamide. 2.4 g. (0.04 mole) of is filtered, and ml. of concentrated hydrochloric acid ethanolamine is added in 25 ml. of benzene. The solution 10 is added. The solution is refluxed overnight and then is refluxed for 12 hours and then cooled. The ethanolfiltered. Upon concentration, a White solid crystallizes. A amine hyd l filtered, and the filtrate is recrystallization from boiling ethanol raises the melting centrated to an oil. The oil is then crystallized from boilpoint to 132-134 C. ing ethanol- M-P- 114*116 C. EXAMPLE 24 1 3-(5-nitro-2-furyl)-5-methylamino-1,2,4-oxadiazole 5-[(dimethylamino)methyl] -3-(5-nitro-2-fury 1,2, 4 oxa diazole R CH NH HCl in Formula Cth 9.2 g. of 3-(5-nitro-2-furyl)-5 chlorome yl 1,2,4- R CH2N(CH3)2 Hcl m Formula C oxadiazole and 5.6 grams of hexamethylene tetraamine mole) y were refluxed for 2 hours. The white quaternary salt is YU-L A- dlssolved in 9 1111- Of bBnZene filtered from the solution. The solid is suspended in 40 ml. Containing 5 Of dlmlllylfofmamldeof ethanol containing 15 ml. of concentrated hydrochloric mole) of yla mi e is added to the benzene solution acid and allowed to stand for 48 hours at room temperaand rQfluXcd ovemlght- The hydfochlonde 0f dlmethylture. The solution is then neutralized with sodium caramine is filtered and the filtrate is concentrated to an a bonate nd xt t d th time with th r, Th ether oil. The Oil is dissolve in 20 of ether f e 50111- is dried and ethereal hydrochloride is added. The hydrotion is washed with water and drlcd fo mmutes Over chloride precipitates as the product. Yield is 1.0 'g., M.P. .MgSQ Ethereal HCl is added. The hydrochloride of the goof-202 (2.. r product precipitates as a white solid. Yield of crude prod- 30 EXAMPLE 29 not is 86.6%. For analysis, the compound is recrystallized from boiling ethanol. M.P., 21o-21s c. i'
acetamlde EXAMPLE 25 o 4- [3-(5-nitro-2-furyl)-1,2,4- oxadiazol-5-yl] R=CH2NH g CH3 in Formula C methyl]morphol1ne 36.9 g. (0.1365 mole) of 5-mtro-2-furam1dox1me O- aceturate is heated above melting point for 10 minutes. CHI-CH2 A dark oil solidifies to black solid upon standing, produc- R=CHz-N o in Formula 0 ing 32.5 g. (94.2%) of the product. Recrystallization from CHFC 2 40 absolute ethanol gave 23.8 g. (68%) of product. M.P.,
156-158 c. 4.6 g. of 5-chloromethyl-3-(5-nitro-2-furyl)-1,2,4- I EXAMPLE oxadiazole was dissolved in 100 ml. of benzene containy y ing 1 ml. of dimethylformamide. 3.5 g. of morpholine is R=c added and refluxed for two hours. HZNHZ m Formula C The morpholine hydrochloride is filtered and the ben- Neutrallzatlon of a small afnount of Hcl salt of the zene solution is concentrated to an oil. The oil crystalcompound of E p 28 Wlth all equlvalent flm0 ll11t 0f lizes from ethanol. Yield is 68%. For analysis, the ma- NaHQOB solutlon gave the free 1 Becrystalllzaflon terial is recrystallized from ethanol. M.P., 125 126 C. from 'P P gave P meltlng P C. (dec.). EXAMPLE EXAMPLE26 1[[3 s 't at 1 124 151 m1 -n1ro--u -,,-oxa1azo-- m Diethylmethyl[[3-(5-n1tro-2-furyl)-1,2,4-oxad1azolpylgdinium d id y 1 e y 5-yl]methyl]ammonium iodide 63 R-CH I in Formula C CHz-CHg i R=CHZ7N\ 4.6 g. (0.02 mole) of 5-chloromethyl-3-(S-nitro 2- 5 (3112.9113 furyl)-l,2,4-oxadiazole is dissolved in 25 ml. of acetonitrile and 2.0 g. of pyridine is added. The solution is heated at 10.6 g. of S-diethlylamrnomethyl-Zi-(5-mtro-2-fu1fyl)- 55 C. for 2 hours, whereupon 3.1 g. of product is ob- 1,2,4-oxadiazole is dissolved in 50 ml. of ethanol. 10 g. tained. The product is recrystallized from ethanol for of methyl iodide is added and the solution is refluxed analysis. M.P., l95-l97 C. (dec.). for 1 hour. The solution is then cooled until crystals Using methods exemplified inthe foregoing examples, form. The final compound is crystallized from ethanol. the following compounds, wherein R refers to substitu- Recovery is 10 g. M.P., 158160 C. (dec.). tions in Formula C, were made.
Anaiysis M.P. in Recrystallization Calculated Found M01 Example R deg ees Salt solvent C H N C H N wt:
32 CHFITICHZCH3 215-220 HC1 Et anol 39.37 4.00 20.40 39,12- 4, 20 32 223810 1 H I CH ::NHT(QH2)JQH3 21H)-HQl,..ls -pr na .3-... Ami. ...4.54-.19.41. 41.50 4.68 19.41, 2253,05
34 CH -NH-CH:CH;OH 3. 97 22.04 42.48 3.95 31.98 2 254.2
See footnotes at end of table.
9 TABLECnflnued I 9 '7 Alialysis I w M.P.ln Recrystallization Calculated Found M01; Example R degrees Salt solvent 0 H N C H N wt.
CH; 210-215 HCl.. ...-00 39.17 4.00 20.40. 39.17 4.19 20.42 238.20
GE -N 36 CHQCHS 195 HGl --dO 43.64 4.99 18.51 43.55 5.21 18.32 266.25
CHr-N CHQCHI 37 CH CH; 158-160 Quilt .-do 35.31 4.20 13.73 35.73 4.28 13.73 408.21
38 CHzCHgOH 128-129 H01... Ethyl acetate 50.21 6.46 15.61 50.18 6.53 15.61 322.36
GHQ-N CHICHQOH 39 CH: 244 HCL. Ethanol 43.64 4.99 18.51 43.74 4.80 18.73 266.23
CHz-NH-(E-CH:
40---. CHICHEOH 128-130 .-do 44.30 4.73 32.18 44.31 4.94 32.20 298.25
CHI-N CH CH OH 41 CHgOH 126-128 .-do 42.04 4.49 17.83 42.28 4.50 17.66 314.25
CHzNH-C-CHgOH CH OH 42... CHzCH: 195 HO] ..do 43.94 4.36 18.63 44.19 4.45 18.57 264.23
GHQ-N CHZCH,
43.. GHQ-CHI 81-82 d0 51.79 5.07 20.14 51.85 5.30 19.95 278.26
CH1N --CHg GHQ-CH2 44 CHz-CH: 210 215 HG] -.dO 43.71 4.89 21.24 44.00 5.09 21.09 293.28
CH7N N-CH3 CHI-CH1 45-.. CHz-CH: 200-204 HC1------..(1O 47.49 5.21 17.04 47.53 5.48 16.93 292.29
CHgNH--CH CH GHQ-OH] 46 OHPNH Q EC] ..(10 48.38 3.44 17.36 50.14 3.29 17.21 322.71
47 CHz NH CHz Q I 85-88 do.-.. 56.00 4.03 18.66 56.04 4.05 18.81 300.27
48..':..' CH2C H\2 4.32 19.99 47.19 4.42 20.09 380.24
50-.'.'.-':.'.;:: CH 183484 HCl- .....d0.... 51.71 4.85 14.19 52.00 4.85 14.31 358.35
CHr-N-( IH-OH-Q Ha ()H 51 Y -197 Quat.:::;.do..-..:::::: 46.69 2.94 18.15 46.69 3.19 18.24 308. 69
See footnotes at end of table.
V Analysis M.P.ln Recrystallization"; Calculated Found Mo]. x m 1 degrees t. s e t .Q ;E. NH, .Nv w
52 CH2 N I 190 Quat;;--- .d0...; 42.22 4.36 26.59 42.32 4.38 26.55 369.7'
53 cur-011 132-134 ..do 39.82 2.39 19.90 40.09 2.35 19.76 211.13
54 NH 190 1101 ....do 31.43 2.64 22.91 31.58 2.65 22;71" 269.1
cm- -NH,
55 9 211-213 Quat --do 42.52 3.02 15.26 42.76 3.18 15.40 367.17 CH3CH-N: 1
57 CHI-NH; 88-89 Iso-propauol 40.00 2.88 26.66 40.08 2.97 26.81 "210.15
58 CHZNHI'HCI 200-202 EthanolisopropanoL. 34.09 2.86 22.73 33.90" 3.12 22.71 210.15
50 156-158 Iso-propanol 45.11 3.79 21.05 45.10 3.99 21.04 266.22
(CH2)1NH%CH3 V onus-191145011,
om-N
62 o 96-98 Ethanol-water 50.64 5.23 18.17 50.73- 5.46 19.22 306.20
(CHzh-NHHIOH;
63 113-115 Iso-propanol 37.71 2.46 19.55 37177 2.77 19.70 286.63
CH -NHPJCH Cl H,-N(oH. i 1cH;
65 cHr-NHcH, 58-59 0111016161111.-. 42.86 3.60 24.99 42.57 3.63 24.90 224.18
66-- cur-111102141101 292-204 Ethanol--. 36.86 3.48 21.50 36.71 3.36 21.55 224.18
Qua-19119101211015,
68 0 183-185 CHzCN 53.51 3.21 17.83 53.23 3.15 18.01 314.26 QHPNHg-Q i 69 0 141-143 chloroform 45.11 3.79 21.05 l38 4.05 21.16 266.21 CH3CHNH(IBCHI 70 112-114 Iso-propanol- 40.14 2.62 15.61 40:17 2.72 15.69 269.24
onr-si ion,
Dec. Free base.
The synthesis of the Formula B or C where R is aminoloweralkyl, monoloweralkylaminoloweralkyl, cy-
azidoloweralkyl may be accomplished by reacting the appropriate halomethyl derivative, previously described, with a slight excess of sodium azide (a small amount of dimethylformamide or sodium iodide may be added to facilitate reaction) in acetonitrile, "ethanol, isopropanol,
or the like, at reflux for 24-48 hours. Filtration of the reaction mixture followed by concentration and purification yields the desired product.
, What is claimed is:
i 1. A compound of the formula:
wherein when one of R and R is 5-nitro-2-fu1'yl, the other is a member of the group consisting of diloweralkylclohexylaminoloweralkyl, morphilinoloweralkyl, azidoloweralkyl, benzylaminoloweralkyl, thiuionium loweralkyl, hydroxyloweralkyl, aminoloweralkyl, cycloaminoloweralkyl, acylaminoloweralkyl, N-loweracylamino-N- cyelohexylaminoloweralkyl, N acyl-N-loweralkylaminoloweralkyl, acylthiolowera lk-yl; hydroxyloweralkylaminoloweralkyl, bis(hydroxyloweralkyl)aminoloweralkyl, polyhydroxyloweralkylaminoloweralkyl, phenylaminoloweralkyl, -pyridinium loweralkyl, hexamethylene tetrammonium loweralkyl, and loweracyloxyloweralkyl; and non-toxic salts thereof, :acy1'is*a member of the group consisting of the acetyl, propionyl and benzoyl radicals,
and polyhydroxy including radicals containing from:
ing of diloweralkylaminoloweralkyl, monoloweralkylaminoloweralkyl, cyclohexylaminoloweralkyl, morphilinoloweralkyl, azidoloweralkyl, benzylaminoloweralkyl, thiuronium loweralkyl, hydroxyloweralkyl, aminoloweralkyl, cycloaminoloweralkyl, acylaminoloweralkyl, N- lower-acylamino-N-cyclohexylaminoloweralkyl, N acyl- N-loweralkylaminoloweralkyl, acylthioloweralkyl, hydroxyloweralkylaminoloweralkyl, bis(hydroxyloweralkyl)aminoloweralky1, polyhydroxyloweralkylaminoloweralkyl, phenylaminoloweralkyl, phenylalkylaminoloweralkyl, pyridium loweralkyl, hexamethylene tetrammonium loweralkyl, and loweracyloxyloweralkyl, acy is a member of the group consisting of the acetyl, propionyl and benzoyl radicals, and polyhydroxy including radicals containing from one to three hydroxyl groups.
3. A compound as claimed in claim 1 wherein when R is -nitro-2-furyl, R is morphilinoloweralkyl; and when R is 5-nitro-2-furyl, R is morphilinoloweralkyl.
4. A compound as claimed in claim 2 wherein R is hydroxyloweralkylaminoloweralkyl.
5. A compound as claimed in claim 2 wherein R is pyridinium loweralkyl.
6. A compound as claimed in claim 2 wherein R is monoloweralkylaminoloweralkyl.
7. A compound as claimed in claim 2 wherein R is acylthioloweralkyl, acy is a member of the group consisting of the acetyl, propionyl and benzoyl radicals.
8. A compound as claimed in claim 1 wherein R is S-nitro-Z-furyl and R is a member of the group consisting of diloweralkylaminoloweralkyl, monoloweralkylaminoloweralkyl, cyclohexylaminoloweralkyl, morpholinoloweralkyl, azidoloweralkyl, benzylaminoloweralkyl, thiuronium loweralkyl, hydroxyloweralkyl, aminoloweralkyl, cycloaminoloweralkyl, acylaminoloweralkyl, N- loweracylamino-N-cyclohexylaminoloweralkyl, acylthioloweralkyl, hydroxyloweralkylaminoloweralkyl, his(hydroxyloweralkyl)aminoloweralkyl, polyhydroxylower alkylaminoloweralkyl, phenylaminoloweralkyl, phenylalkylaminoloweralkyl, pyridinium loweralkyl, hexamethylene tetrammonium loweralkyl, and loweracyloxyloweralky, acy is a member of the group consisting of the acetyl, propionyl and benzoyl radicals, and poly hydroxy" including radicals containing from one to three hydroxyl groups.
9. A compound as claimed in claim 8 wherein R is thiuronium loweralkyl.
14 10. A compound of the formula:
wherein R is 5-nitro-2-furyl and R is aminoloweralkyl.
12. A compound of the formula:
wherein R is S-nitro-Z-furyl and R is N-acyl-N-loweralkylaminoloweralkyl, acyl is a member of the group consisting of the acetyl, propionyl and benzoyl radicals.
References Cited UNITED STATES PATENTS 3,264,318 8/1966 Eloy 260-307 3,337,541 8/1967 Haraoka et a1. 260307 FOREIGN PATENTS 1,025,439 4/1966 Great Britain 260-307 OTHER REFERENCES Chem. Abstracts, 1,2,4-Oxadiazoles, Palazzo et 211., vol. 60, 1964, 8020 h relied on.
ALEX MAZEL, Primary Examiner A. M. T. TIGHE, Assistant Examiner US. Cl. X.R.
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US3853893A (en) * 1973-04-02 1974-12-10 Squibb & Sons Inc Anthelmintic 5-(pyridyl)-3-(isothiocyanophenyl) oxadiazoles
US4007185A (en) * 1967-01-31 1977-02-08 Abbott Laboratories 3,5-Substituted-1,2,4-oxadiazole inner quaternary ammonium salts
US7728009B1 (en) 2005-02-18 2010-06-01 Neurogen Corporation Thiazole amides, imidazole amides and related analogues

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US5009608A (en) * 1990-07-12 1991-04-23 Amp Incorporated Separable connector assembly for an IC Chip Carrier
US7312337B2 (en) * 2004-09-30 2007-12-25 Eastman Kodak Company Oxadiazoles and their manufacture

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US3509170A (en) * 1967-06-12 1970-04-28 Du Pont Heterocyclic amino-oxazolines
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Cited By (3)

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US4007185A (en) * 1967-01-31 1977-02-08 Abbott Laboratories 3,5-Substituted-1,2,4-oxadiazole inner quaternary ammonium salts
US3853893A (en) * 1973-04-02 1974-12-10 Squibb & Sons Inc Anthelmintic 5-(pyridyl)-3-(isothiocyanophenyl) oxadiazoles
US7728009B1 (en) 2005-02-18 2010-06-01 Neurogen Corporation Thiazole amides, imidazole amides and related analogues

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