US3828056A - (2-(2-methyl-5-nitro-1-imidazolyl)ethyl)heteroaryloxy ethers - Google Patents

(2-(2-methyl-5-nitro-1-imidazolyl)ethyl)heteroaryloxy ethers Download PDF

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US3828056A
US3828056A US00288111A US28811172A US3828056A US 3828056 A US3828056 A US 3828056A US 00288111 A US00288111 A US 00288111A US 28811172 A US28811172 A US 28811172A US 3828056 A US3828056 A US 3828056A
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E Kreider
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GD Searle LLC
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Priority to AU60142/73A priority patent/AU478094B2/en
Priority to BE135496A priority patent/BE804666A/en
Priority to DE19732345521 priority patent/DE2345521A1/en
Priority to NL7312458A priority patent/NL7312458A/xx
Priority to CA180,630A priority patent/CA1006873A/en
Priority to ZA737188A priority patent/ZA737188B/en
Priority to GB4256273A priority patent/GB1386210A/en
Priority to AR250031A priority patent/AR197526A1/en
Priority to FR7332655A priority patent/FR2208657B1/fr
Priority to JP48102571A priority patent/JPS4962480A/ja
Priority to ES418666A priority patent/ES418666A1/en
Priority to CH1299173A priority patent/CH582694A5/xx
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • the present invention relates to a group of [2-(2-methyl-S-nitro-1-imidazolyl)ethyl]heteroaryloxy ethers of the general formula.
  • R is a mono or binuclear heteroaromatic radical.
  • the position of oxygen attachment to the carbon of the heteroaromatic is optional and mono and poly substitution pattern on the aromatic nucleus among halo, lower alkyl, and nitro substituents are likewise optional.
  • the preferred heteroaromatic nuclei are pyridyl and benzo(b) pyridyl.
  • Preferred embodiments of the pyridyl derivatives are those in which -R is pyridyl and 2-bromo-3-pyridyl.
  • Preferred embodiments of benzo(b)pyridyl are those in which -R is 4 (8-chlorobenzo(b)pyridyl), and 8 (5-nitrobenzo'(b)pyridyl), 8- (5,7-dichlorobenzo(b)pyridyl), and 8- 2-methyl-5,7-dichlorobenzo (b pyridyl)
  • the compounds of the present invention are heteroaryloxy ether derivatives of 1-(2-hydroxyethyl)-5-ni'troimidazole, which is described as a potent bactericidal agent in US. Pat. 2,994,061.
  • the present compounds are prepared by the general method of Scheme I.
  • a dimethylformamide solution of '1-(2-chloroethyl)- 2-methyl-5-nitroimidazole and sodium iodide is added to a dimethylformamide solution of 3-hydroxypyridine and sodium ethox-ide to form 2-methy1-5-nitro-1[2-(3-pyridyloxy ethyl) imidazole.
  • the compounds of the present invention are useful in view of their anti-microbial activity. They are especially effective in inhibiting the growth of protozoa and bacteria.
  • a modified Diamond medium is prepared by mixing 1200 parts of trypticase (Baltimore Biological Laboratories), 600 parts of yeast extract (Difco), 300 parts of maltose, 60 parts of L-cysteine hydrochloride, 12 parts of L-ascorbic acid, 48 parts of dibasic potassium phosphate, 48 parts of monobasic potassium phosphate and 54,000 parts of distilled water. The pH is adjusted to 6.8 with 40% sodium hydroxide solution and 30 parts of agar (Baltimore Biological Laboratories) is incorporated.
  • the mixture is boiled for one minute to dissolve the agar and is then sterilized in an autoclave.
  • To volumes of the resultant medium is aseptically added 20 volumes of sterile Dubos medium serum.
  • the resultant medium is inoculated with 1% by volume of a 72 hour culture of T. vaginalis, whereupon 1 ml. of the inoculated medium is mixed with 10 mg. of test compound.
  • the mixture is incubated anaerobically at 37 C. for 48 hours and then examined microscopically for the presence of motile trichomonads. If any are observed the compound is considered inactive. If no motile trichomonads are observed, 0.1 ml.
  • incubated mixture is serially diluted and mixed with quantities of the inoculated medium sufficient to produce concentrations of 1000, 100, 10 and 1 micrograms of test compound per ml. and the resulting mixtures are incubated anaerobically as before at 37 C. for 48 hours and then examined microscopically for the presence of motile trichomonads. Controls are provided by concurrent incubations identical with the foregoing except for the absence of test compound.
  • EXAMPLE 1 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and the solution is added to a stirring mixture of 1.08 parts of sodium methoxide and 3.6 parts of 4-hydroxy-8-chloroquinoline in 25 parts by volume of dimethylformamide. The reaction rnixture is refluxed under anhydrous conditions for 24 hours, cooled, diluted with parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide.
  • the chloroform solution is dried over anhydrous sodium sulfate and then one-half of the solvent is removed by evaporation at reduced pressure. The addition of hexane causes precipitation of the product. The product is treated with decolorizing charcoal and recrystallized from chloroformhexane. This procedure provides 2 methyl-5-nitro-1- ⁇ 2- [4- 8-chlorobenzo (b pyridyloxy) ethyl] ⁇ imidazole, melting at 198-20l.
  • the reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with parts by volume of water.
  • the product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide.
  • the chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with chloroform and the product is eluted with chloroform.
  • the product is treated with decolorizing charcoal and recrystallized from chloroformhexane. This procedure provides Z-methyl-S-nitro-l- ⁇ Z- [8 (2 methyl-5,7-dichlorobenzo(b)pyridyloxy)ethyl] ⁇ imidazole, melting at 124-125.
  • the chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with benzene and the product is eluted with 5% ethanol in benzene. The product is treated with decolorizing charcoal and recrystallization from chloroformhexane provides 2 methyl 5 nitro-1-[2-(2-bromo-3- pyridyloxy)ethyl]imidazole, melting at -167".
  • the formula of this compound is 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 30 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 1.91 parts of 3-hydroxypyridine in 25 parts by volume of dimethylformamide.
  • the reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water.
  • the product is extracted with chloroform, then is precipitated by addition of hexane to the chloroform.
  • the precipitate is treated with decolorizing charcoal and recrystallized from ethyl acetate-hexane.
  • This procedure provides 2 methyl-5-nitro-1-[2-(3 -pyridyloxy)ethyl]imidazole, melting at 122123.
  • the formula of this compound is l CH EXAMPLE 7 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 30 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 1.19 parts of 4-hydroxypyridine in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water.
  • the product is extracted with chloroform and it is precipitated by addition of hexane to the chloroform.
  • the precipitate is treated with decolorizing charcoal and recrystallized from ethyl acetate-hexane.
  • This procedure provides 2-methyl 5 nitro-l-[2-(4-pyridyloxy)ethyl]imidazole.
  • the formula of this compound is 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimid azole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 1.19 parts of 2-hydroxypyridine in 25 parts by volume of dimethylformamide.
  • reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water.
  • the product is extracted with chloroform, then is precipitated by addition of hexane to the chloroform solution.
  • the precipitate is treated with decolorizing charcoal and recrystallized from ethyl acetate-hexane. This procedure provides Z-methyl-S-nitro-l-[2-(2-pyridyloxy) ethyl]imidazole.
  • the chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with benzene and the product is eluted with 5% ethanol in benzene. The product is treated with decolorizing charcoal and recrystallization from chloroform-hexane provides 2 methyl-5-nitro-1-[2-(6- bromo 2 pyridyloxy)ethyl]imidazole.
  • the formula of this compound is 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.48 parts of 4-chloro-2-hydroxypyridine in 25 parts by volume of dimethylformamide.
  • the reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water.
  • the product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide.
  • the chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel.
  • the reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water.
  • the product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide.
  • the chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with benzene and the product is eluted with 5% ethanol in benzene.
  • the product is treated with decolorizing charcoal and recrystallization from chloroform-hexane provides 2-methyl-5-nitro 1 ⁇ 2-(4-chloro- 3-pyridyloxy)ethyl] imidazole.
  • the formula of this compound is EXAMPLE 14 2.70 parts of 1- (2-chloroethyl)-2-methyl-5-nitr0imidazole and 2.15 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirred mixture of 0.85 part of sodium methoxide and 3.25 parts of 2-propyl-8-hydroxy-5,7-dibromo-quiuoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with dilute sodium hydroxide.
  • the chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with chloroform and the product is eluted with chloroform. The product is treated with decolorizing charcoal and recrystallized from chloroformhexane. This procedure provides 2-methyl-5-nitro-1- ⁇ 2- propyl 5,7 dibromobenzo(b)pyridyloxy)ethyl] ⁇ imidazole. The formula of this compound is CiaH7 1 CH3 Br EXAMPLE 15 dium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel.
  • EXAMPLE 16 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.81 parts of 5-propyl-8-hydroxyquinoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, diluted with parts by volume of water. The product is extracted With chloroform and the chloroform is removed by evaporation at reduced pressure. The resulting solid is chromatographed on neutral silica gei.
  • the reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water.
  • the product is extracted with chloroform and the chloroform is removed by evaporation at reduced pressure.
  • the resulting solid is chromatographed on neutral silica gel. Development of the column is initiated with chloroform and the product is eluted with 2% ethanol in chloroform.
  • the product is treated with decolorizing charcoal and recrystallized from chloroform hexane. This procedure provides 2-methyl-5-nitro-l- ⁇ 2- [8 (5 bromobenzo(b)pyridoxy)ethyl] ⁇ imidazle.
  • the chloroform solution is dried over anhydrous sodium sulfate and then one-half of the solvent is removed by evaporation at reduced pressure. The addition of hexane causes precipitation of the product. The product is treated with decolorizing charcoal and recrystallized from chloroform-hexane. This procedure provides 2- methyl 5 nitro 1 ⁇ 2- [4-(8-nitrobenzo(b)pyridyloxy) ethyl] ⁇ imidazole.
  • the chloroform solution is dried over anhydrous sodium sulfate and then one-half of the solvent is removed by evaporation at reduced pressure; The addition of hexane causes precipitation of the product.
  • the product is treated with decolorizing charcoal and recrystallized from chloroform-hexane. This procedure provides 2- methyl 5 nitro 1 ⁇ 2-[4-(8-propylbenzo(b)pyridyloxy)ethyl] ⁇ imidazole.
  • the formula of this compound is 3.72 parts of 1-(2-chloroethyl) 2 methyl 5 nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirred mixture of 1.08 parts of sodium methoxide and 3.6 parts of 4-hydroxy-8-methylquinoline in 25 parts by volume of dimethylformamide.
  • the reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water.
  • the product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide.
  • the chloroform solution is dried over anhydrous sodium sulfate and then one-half of the solvent is removed by evaporation at reduced pressure.
  • the reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water.
  • the product is extracted with chloroform and the chloroform extracts are washed with diluted sodium hydroxide.
  • the chloroform solution is dried over anhydrous sodium sulfate and then one-half of the solvent is removed by evaporation at reduced pressure.
  • the addition of hexane causes precipitation of the product.
  • the product is treated with decolorizing charcoal and recrystallized from chloroform-hexane.
  • This procedure provides Z-methyl 5 nitro 1 ⁇ 2-[4-(8-bromobenzo(b)pyr- 1 1 r 1 2 idy1oxy)ethyl] ⁇ imidazo1e.
  • the formula of this compound 2 As in claim 1, the compound which is Z-methyl-S- is nitro-1-[2-(2-bromo-3-pyridyloxy)ethyl]imidazole.
  • ALAN L. ROTMAN Primary Examiner What is ciaimed is: 10 US. Cl. X.R. A the 260296 AB, 288 R; 424258, 263
  • Y is hydrogen or halogen

Abstract

HETEROARRYLOXY ETHERS OF 1-(2-HYDROXYETHYL)-5NITROIMIDAZOLE ARE HEREIN DESCRIBED. THESE COMPOUNDS ARE POTENT ANTI-MICROBIAL AGENTS. THEY ARE PREPARED BY THE REACTION OF A HETEROAROMATIC ALCOHOL WITH 1-(2-CHLOROETHYL)-2METHYL-5-NITROIMIDZABLE IN APROTIC POLAR SOLVENTS IN THE PRESENCE OF BASE AND SODIUM OR POTASSIUM IODIDE.

Description

United States Patent Office 3,828,056 Patented Aug. 6, 1974 3,828,056 [2-(2-METHYL-5-NITRO-1-]MIDAZOLYL)ETHYL] HETEROARYLOXY ETHERS Eunice M. Kreider, Chicago, Ill., assiguor to G. D. Searle & Co., Chicago, Ill.
No Drawing. Filed Sept. 11, 1972, Ser. No. 288,111 Int. Cl. C07d 31/42 US. Cl. 260-296 R 3 Claims ABSTRACT OF THE DISCLOSURE Heteroaryloxy ethers of 1-(2-hydroxyethyl)-5-nitroimidazole are herein described. These compounds are potent anti-microbial agents. They are prepared by the reaction of a heteroaromatic alcohol with l'(2-chloroethyl)-2 methyl-S-nitroimidazole in aprotic polar solvents in the presence of base and sodium or potassium iodide.
The present invention relates to a group of [2-(2-methyl-S-nitro-1-imidazolyl)ethyl]heteroaryloxy ethers of the general formula.
N NCH7 CHIO'R wherein R is a mono or binuclear heteroaromatic radical. The position of oxygen attachment to the carbon of the heteroaromatic is optional and mono and poly substitution pattern on the aromatic nucleus among halo, lower alkyl, and nitro substituents are likewise optional. The preferred heteroaromatic nuclei are pyridyl and benzo(b) pyridyl. Preferred embodiments of the pyridyl derivatives are those in which -R is pyridyl and 2-bromo-3-pyridyl. Preferred embodiments of benzo(b)pyridyl are those in which -R is 4 (8-chlorobenzo(b)pyridyl), and 8 (5-nitrobenzo'(b)pyridyl), 8- (5,7-dichlorobenzo(b)pyridyl), and 8- 2-methyl-5,7-dichlorobenzo (b pyridyl) The compounds of the present invention are heteroaryloxy ether derivatives of 1-(2-hydroxyethyl)-5-ni'troimidazole, which is described as a potent bactericidal agent in US. Pat. 2,994,061. The present compounds are prepared by the general method of Scheme I.
Base (K)NaI ROH N N-GH1-CHg-C1 Aprons I Polar Solvent IIIO An aprotic polar solvent solution of '1-(2-chloroethyl) 2- methyl-S-nitroimidazole (J. Med. Chem, 11, 370, 1968) and sodium or potassium iodide is added to a basic aprotic polar solvent solution of a heteroaromatic alcohol. Dimethylsulfoxide, dimethylformamide, dimethylacetamide, and acetonitrile are suitable solvents and alkali metal lower alkoxide salts and sodium hydride are suitable bases. Thus, a dimethylformamide solution of '1-(2-chloroethyl)- 2-methyl-5-nitroimidazole and sodium iodide is added to a dimethylformamide solution of 3-hydroxypyridine and sodium ethox-ide to form 2-methy1-5-nitro-1[2-(3-pyridyloxy ethyl) imidazole.
The compounds of the present invention are useful in view of their anti-microbial activity. They are especially effective in inhibiting the growth of protozoa and bacteria.
Evidence of the anti-protozoal utility of the present compounds is obtained from standardized tests designed to determine the capacity of test compounds to inhibit the growth Trichomonas vaginalis. These tests are carried out in the following manner. A modified Diamond medium is prepared by mixing 1200 parts of trypticase (Baltimore Biological Laboratories), 600 parts of yeast extract (Difco), 300 parts of maltose, 60 parts of L-cysteine hydrochloride, 12 parts of L-ascorbic acid, 48 parts of dibasic potassium phosphate, 48 parts of monobasic potassium phosphate and 54,000 parts of distilled water. The pH is adjusted to 6.8 with 40% sodium hydroxide solution and 30 parts of agar (Baltimore Biological Laboratories) is incorporated. The mixture is boiled for one minute to dissolve the agar and is then sterilized in an autoclave. To volumes of the resultant medium is aseptically added 20 volumes of sterile Dubos medium serum. The resultant medium is inoculated with 1% by volume of a 72 hour culture of T. vaginalis, whereupon 1 ml. of the inoculated medium is mixed with 10 mg. of test compound. The mixture is incubated anaerobically at 37 C. for 48 hours and then examined microscopically for the presence of motile trichomonads. If any are observed the compound is considered inactive. If no motile trichomonads are observed, 0.1 ml. of the incubated mixture is serially diluted and mixed with quantities of the inoculated medium sufficient to produce concentrations of 1000, 100, 10 and 1 micrograms of test compound per ml. and the resulting mixtures are incubated anaerobically as before at 37 C. for 48 hours and then examined microscopically for the presence of motile trichomonads. Controls are provided by concurrent incubations identical with the foregoing except for the absence of test compound.
Evidence of the antibacterial utility of the instant compounds is provided by standardized tests for their capacity to prevent the growth of Bacillus subtilis. In these tests, a. mixture of 5 mg. of compound with 5 ml. of sterile nutrient broth is heated at 80 C. for 20 minutes, then cooled to around 25 C., and finally serially diluted and mixed with sufiicient quantities of a mixture of sterile nutrient broth and 1% of a culture of B. subtilis to produce concentrations of approximately 400, 100, 25, and 6 rncgm. of compound per ml. The resultant mixtures are incubated for 20-24 hr. at 37 C. Controls are provided by concurrent incubations identical with the foregoing excepting that no compound is present. Activity is determined by gross examination; and potency is expressed as the minimum concentration, in rncgm. of compound per ml., at which no growth of the test organism is discernible.
The following examples are presented to further illustrate the present invention. They should not be construed as limiting it either in spirit or in scope. In these examples quantities are indicated in parts by weight unless parts by volume are specified, and temperatures are indicated in degrees Centigrade C.). The relationship between parts by weight and parts by volume is the same as that existing between grams and milliliters.
EXAMPLE 1 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and the solution is added to a stirring mixture of 1.08 parts of sodium methoxide and 3.6 parts of 4-hydroxy-8-chloroquinoline in 25 parts by volume of dimethylformamide. The reaction rnixture is refluxed under anhydrous conditions for 24 hours, cooled, diluted with parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform solution is dried over anhydrous sodium sulfate and then one-half of the solvent is removed by evaporation at reduced pressure. The addition of hexane causes precipitation of the product. The product is treated with decolorizing charcoal and recrystallized from chloroformhexane. This procedure provides 2 methyl-5-nitro-1-{2- [4- 8-chlorobenzo (b pyridyloxy) ethyl]}imidazole, melting at 198-20l. The formula of this compound is EXAMPLE 2 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.81 parts of 5-nitro-S-hydroxyquinoline in 25 parts by volume of dimethylforrnamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform is removed by evaporation at reduced pressure. The resulting solid is chromatographed on neutral silica gel. Development of the column is initiated with chloroform and the product is eluted with 2% ethanol in chloroform. The product is treated with decolorizing charcoal and recrystallized from chloroform-hexane. This procedure provides 2 methyl 5 nitro-1-{2-[8-(5- nitrobenzo(b)pyridyloxy ethyl]}imidazole, 207.5-'8". The formula of this compound is EXAMPLE 3 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.25 parts of sodium methoxide and 4.28 parts of 5,7 dichloro-8-hydroxyquinoline in parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with dilute sodium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with chloroform and the product is eluted with chloroform. The product is treated with decolorizing charcoal and recrystallized from methanoldiethyl ether. This procedure provides Z-methyl-S-nitro- 1 {2 [8(5,7-dichlorobenzo(b)pyridyloxy)ethy1]}im=idazole, melting at 1515-153". The formula of this compound is parts by volume of dimethylformamide and this solution is added to a stirring mixture of 0.85 parts of sodium melting at methoxide and 3.25 parts of Z-methyl-'4-hydroxy-5,7-dichloroquinoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with chloroform and the product is eluted with chloroform. The product is treated with decolorizing charcoal and recrystallized from chloroformhexane. This procedure provides Z-methyl-S-nitro-l-{Z- [8 (2 methyl-5,7-dichlorobenzo(b)pyridyloxy)ethyl]} imidazole, melting at 124-125. The formula of this compound is 1 1 CH3 Cl EXAMPLE 5 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are disolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.48 parts of 2-bromo-3-hydroxypyridine in 25 parts by volume of dimethylformamide. The reaction mixture is refiuxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with benzene and the product is eluted with 5% ethanol in benzene. The product is treated with decolorizing charcoal and recrystallization from chloroformhexane provides 2 methyl 5 nitro-1-[2-(2-bromo-3- pyridyloxy)ethyl]imidazole, melting at -167". The formula of this compound is 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 30 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 1.91 parts of 3-hydroxypyridine in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform, then is precipitated by addition of hexane to the chloroform. The precipitate is treated with decolorizing charcoal and recrystallized from ethyl acetate-hexane. This procedure provides 2 methyl-5-nitro-1-[2-(3 -pyridyloxy)ethyl]imidazole, melting at 122123. The formula of this compound is l CH EXAMPLE 7 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 30 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 1.19 parts of 4-hydroxypyridine in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and it is precipitated by addition of hexane to the chloroform. The precipitate is treated with decolorizing charcoal and recrystallized from ethyl acetate-hexane. This procedure provides 2-methyl 5 nitro-l-[2-(4-pyridyloxy)ethyl]imidazole. The formula of this compound is 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimid azole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 1.19 parts of 2-hydroxypyridine in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform, then is precipitated by addition of hexane to the chloroform solution. The precipitate is treated with decolorizing charcoal and recrystallized from ethyl acetate-hexane. This procedure provides Z-methyl-S-nitro-l-[2-(2-pyridyloxy) ethyl]imidazole. The formula of this compound is EXAMPLE 9 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole end 3.0 parts of sodium iodide are dissolved in 40 parts of volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.48 parts of 3-chloro-4-hydroxypyridine in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral siilca gel. Development of the column is initiated with benzene and the product is eluted with 5% ethanol in benzene. The product is treated with decolorizing charcoal and recrystallization from chloroform-hexane provides 2-methyl-5-nitro-1-[2-(3-chloro- 4-pyridyloxy)ethyl]imidazole. The formula of this compound is l on, 1
6 EXAMPLE 10 3.72. parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.48 parts of 2-bromo-4-hydroxypyridine in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with benzene andthe product is eluted with 5% ethanol in benzene. The product is treated with decolorizing charcoal and recrystallization from chloroformhexane provides 2-rnethyl-5-nitro-1-[2-(2-bromo-4-pyridyloxy) ethyl]imidazole. The formula of this compound 18 EXAMPLE 11 3.72 parts of l-(2-chloroethyl) 2 methyl-S-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.48 parts of 6-bromo-2-hydroxypyridine in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with benzene and the product is eluted with 5% ethanol in benzene. The product is treated with decolorizing charcoal and recrystallization from chloroform-hexane provides 2 methyl-5-nitro-1-[2-(6- bromo 2 pyridyloxy)ethyl]imidazole. The formula of this compound is 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.48 parts of 4-chloro-2-hydroxypyridine in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with benzene and the product is eluted with 5% ethanol in benzene. The product is treated with decolorizing charcoal and recrystallization from chloroform-hexane provides 2 methyl -nitro-1-[2-(4-chloro-2-pyridloxy) ethyHimidazole. The formula of this compound is 3.72 parts of l- (2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.48 parts of 4-chloro-3-hydroxypyridine in parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with benzene and the product is eluted with 5% ethanol in benzene. The product is treated with decolorizing charcoal and recrystallization from chloroform-hexane provides 2-methyl-5-nitro 1 {2-(4-chloro- 3-pyridyloxy)ethyl] imidazole. The formula of this compound is EXAMPLE 14 2.70 parts of 1- (2-chloroethyl)-2-methyl-5-nitr0imidazole and 2.15 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirred mixture of 0.85 part of sodium methoxide and 3.25 parts of 2-propyl-8-hydroxy-5,7-dibromo-quiuoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with dilute sodium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated with chloroform and the product is eluted with chloroform. The product is treated with decolorizing charcoal and recrystallized from chloroformhexane. This procedure provides 2-methyl-5-nitro-1-{2- propyl 5,7 dibromobenzo(b)pyridyloxy)ethyl]}imidazole. The formula of this compound is CiaH7 1 CH3 Br EXAMPLE 15 dium hydroxide. The chloroform is removed by evaporation at reduced pressure and the residual solid is chromatographed on neutral silica gel. Development of the column is initiated With chloroform and the product is eluted with chloroform. The product is treated with decolorizing charcoal and recrystallized from methanol-diethyl ether. This procedure provides 2 methyl 5-nitro-1{2- [8 (5,7 dibromobenzo(b)pyridyloxy)ethyl]}imidazole. The formula of this compound is IIIO:
I CH:
EXAMPLE 16 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.81 parts of 5-propyl-8-hydroxyquinoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, diluted with parts by volume of water. The product is extracted With chloroform and the chloroform is removed by evaporation at reduced pressure. The resulting solid is chromatographed on neutral silica gei. Development of the column is initiated with chloroform and the product is eluted with 2% ethanol in chloroform. The product is treated with decolorizing charcoal and recrystallized from chloroform-hexane. This procedure provides 2-methyl-5-nitro1-{2-[8 (5 propylbenzo(b)pyridyloxy)ethyl]}imidazole. The formula of this compound is EXAMPLE 17 3.72 parts of l-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimcthylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.81 parts of S-methyl-S-hydroxyquinoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform is removed by evaporation at reduced pressure. The resulting solid is chromatographed on neutral silica gel. Development of the column is initiated with chloroform and the product is eluted with 2% ethanol in chloroform. The product is treated with decolorizing charcoal and recrystallized from chloroform-hexane. This procedure provides 2-methyl-5-nitro-1-{2-[8-(S-methylbenzo(b)pyridyloxy)ethyl]}imidazole. The formula of this compound is N O 3 l N\/ N-cmom0-Q om EXAMPLE 18 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxicle and 3.81 parts of 5-chloro-8-hydroxyquinoline this compound is EXAMPLE 19 3.72 parts of l-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirring mixture of 1.10 parts of sodium methoxide and 3.81 parts of 5-'bromo-8-hydroxyquinoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform is removed by evaporation at reduced pressure. The resulting solid is chromatographed on neutral silica gel. Development of the column is initiated with chloroform and the product is eluted with 2% ethanol in chloroform. The product is treated with decolorizing charcoal and recrystallized from chloroform hexane. This procedure provides 2-methyl-5-nitro-l-{2- [8 (5 bromobenzo(b)pyridoxy)ethyl]}imidazle. The formula of this compound is EXAMPLE 20 3.72 parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirred mixture of 1.08 parts of sodium methoxide and 3.6 parts of 4-hydroxy-8-nitroquinoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform solution is dried over anhydrous sodium sulfate and then one-half of the solvent is removed by evaporation at reduced pressure. The addition of hexane causes precipitation of the product. The product is treated with decolorizing charcoal and recrystallized from chloroform-hexane. This procedure provides 2- methyl 5 nitro 1 {2- [4-(8-nitrobenzo(b)pyridyloxy) ethyl]}imidazole. The formula of this compound is 10 EXAMPLE 21 3.72 parts of 1-(2-ch1oroethyl) 2 methyl-S-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirred mixture of 1.08 parts of sodium methoxide and 3.6 parts of 4-hydroxy 8-propylquinoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform solution is dried over anhydrous sodium sulfate and then one-half of the solvent is removed by evaporation at reduced pressure; The addition of hexane causes precipitation of the product. The product is treated with decolorizing charcoal and recrystallized from chloroform-hexane. This procedure provides 2- methyl 5 nitro 1 {2-[4-(8-propylbenzo(b)pyridyloxy)ethyl]}imidazole. The formula of this compound is 3.72 parts of 1-(2-chloroethyl) 2 methyl 5 nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to a stirred mixture of 1.08 parts of sodium methoxide and 3.6 parts of 4-hydroxy-8-methylquinoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with dilute sodium hydroxide. The chloroform solution is dried over anhydrous sodium sulfate and then one-half of the solvent is removed by evaporation at reduced pressure. The addition of hexane causes precipitation of the product. The product is treated with decolorizing charcoal and recrystallized from chloroform-hexane. This procedure provides 2-methyl 5 nitro l {2-[4-(8-methylbenzo(b)pyridyloxy)ethyl}imidazole. The formula of this compound is 3.72 parts of l-(2 chloroethyl) 2 methyl-S-nitroimidazole and 3.0 parts of sodium iodide are dissolved in 40 parts by volume of dimethylformamide and this solution is added to .a stirred mixture of 1.08 parts of sodium methoxide and 3.6 parts of 4-hydroxy-8-bromoquinoline in 25 parts by volume of dimethylformamide. The reaction mixture is refluxed under anhydrous conditions for 24 hours, cooled, and diluted with 100 parts by volume of water. The product is extracted with chloroform and the chloroform extracts are washed with diluted sodium hydroxide. The chloroform solution is dried over anhydrous sodium sulfate and then one-half of the solvent is removed by evaporation at reduced pressure. The addition of hexane causes precipitation of the product. The product is treated with decolorizing charcoal and recrystallized from chloroform-hexane. This procedure provides Z-methyl 5 nitro 1 {2-[4-(8-bromobenzo(b)pyr- 1 1 r 1 2 idy1oxy)ethyl]}imidazo1e. The formula of this compound 2. As in claim 1, the compound which is Z-methyl-S- is nitro-1-[2-(2-bromo-3-pyridyloxy)ethyl]imidazole.
N0, r '3. As in claim 1, the compound which is Zanethyl-S- I lab-m nitro-l-[2-(3-pyridyloxy)ethyl]imidazole- N N -CHgCHr-O- /N No references cited.
ALAN L. ROTMAN, Primary Examiner What is ciaimed is: 10 US. Cl. X.R. A the 260296 AB, 288 R; 424258, 263
wherein Y is hydrogen or halogen.
US00288111A 1972-09-11 1972-09-11 (2-(2-methyl-5-nitro-1-imidazolyl)ethyl)heteroaryloxy ethers Expired - Lifetime US3828056A (en)

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US00288111A US3828056A (en) 1972-09-11 1972-09-11 (2-(2-methyl-5-nitro-1-imidazolyl)ethyl)heteroaryloxy ethers
AU60142/73A AU478094B2 (en) 1972-09-11 1973-09-10 2-methyl-5-nitro-1-/2-(heteroaryloxy) ethyl-/ imidazole
BE135496A BE804666A (en) 1972-09-11 1973-09-10 METHYL-2 NITRO-5 (HETEROARYLUXY) -2 ETHYLS) -1IMIDAZOLES AND PROCESS FOR THEIR PREPARATION
DE19732345521 DE2345521A1 (en) 1972-09-11 1973-09-10 2-METHYL-5-NITRO-1 SQUARE BRACKET ON 2- (HETEROARYLOXY) -AETHYL SQUARE BRACKET FOR -IMIDAZOLE
NL7312458A NL7312458A (en) 1972-09-11 1973-09-10
CA180,630A CA1006873A (en) 1972-09-11 1973-09-10 2-methyl-5-nitro-1-(2-(heteroaryloxy)ethyl)imidazole
ZA737188A ZA737188B (en) 1972-09-11 1973-09-10 2-methyl-5-nitro-1-2-(heteroaryloxy)ethyl imidazole
DK496673AA DK135166B (en) 1972-09-11 1973-09-10 Analogous process for the preparation of 2-methyl-5-nitro-imidazoles.
GB4256273A GB1386210A (en) 1972-09-11 1973-09-11 2-methyl-5 nitro-1- 2-heteroaryloxy-ethyl imidazoles
AR250031A AR197526A1 (en) 1972-09-11 1973-09-11 PROCEDURE FOR THE PREPARATION OF 2-METHYL-5-NITRO-1 <2- (HETEROARYLOXY) ETHYL> IMIDAZOLES
FR7332655A FR2208657B1 (en) 1972-09-11 1973-09-11
JP48102571A JPS4962480A (en) 1972-09-11 1973-09-11
ES418666A ES418666A1 (en) 1972-09-11 1973-09-11 (2-(2-methyl-5-nitro-1-imidazolyl)ethyl)heteroaryloxy ethers
CH1299173A CH582694A5 (en) 1972-09-11 1973-09-11
US473145A US3910925A (en) 1972-09-11 1974-05-24 {8 2-(2-Methyl-5-nitro-1-imidazolyl)ethyl{9 benzo(b)pyridyloxy ethers

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4046896A (en) * 1975-05-17 1977-09-06 Hoechst Aktiengesellschaft 1-Methyl-2-(pyridyl-oxymethyl)-5-nitro-imidazoles
US6509471B2 (en) 1998-07-21 2003-01-21 Syngenta Participations Ag 3-substituted pyridine compounds and related synthesis
WO2020063824A1 (en) * 2018-09-29 2020-04-02 江苏亚虹医药科技有限公司 Nitroxoline prodrug and use thereof

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JP2002521366A (en) * 1998-07-21 2002-07-16 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト Trisubstituted pyridine compounds and related syntheses
AU2018205811B2 (en) * 2017-01-06 2022-02-17 Rivus Pharmaceuticals, Inc. Novel phenyl derivatives

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FR1479120A (en) * 1965-05-10 1967-04-28 Ward Blenkinsop & Co Ltd Imidazole compounds and their preparation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4046896A (en) * 1975-05-17 1977-09-06 Hoechst Aktiengesellschaft 1-Methyl-2-(pyridyl-oxymethyl)-5-nitro-imidazoles
US6509471B2 (en) 1998-07-21 2003-01-21 Syngenta Participations Ag 3-substituted pyridine compounds and related synthesis
US20030100766A1 (en) * 1998-07-21 2003-05-29 Hoglen Dean Kent 3-substituted pyridine compounds and related synthesis
US6710180B2 (en) 1998-07-21 2004-03-23 Syngenta Participations Ag Diazonium salts which are intermediates for 3-substituted pyridines
WO2020063824A1 (en) * 2018-09-29 2020-04-02 江苏亚虹医药科技有限公司 Nitroxoline prodrug and use thereof
CN111295372A (en) * 2018-09-29 2020-06-16 江苏亚虹医药科技有限公司 Nitroxoline prodrugs and uses thereof
CN111295372B (en) * 2018-09-29 2021-03-09 江苏亚虹医药科技股份有限公司 Nitroxoline prodrugs and uses thereof

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