US3711495A - Isoxazalin-3-yl-substituted-5-nitroimidazoles - Google Patents

Isoxazalin-3-yl-substituted-5-nitroimidazoles Download PDF

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US3711495A
US3711495A US00001307A US3711495DA US3711495A US 3711495 A US3711495 A US 3711495A US 00001307 A US00001307 A US 00001307A US 3711495D A US3711495D A US 3711495DA US 3711495 A US3711495 A US 3711495A
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nitroimidazole
methyl
prepared
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isoxazol
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P Kulsa
C Rooney
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/95—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by nitrogen atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • ABSTRACT Substituted nitroimidazoles having a l-alkyl or hydroxyalkyl substituent; a S-nitro substituent; and a .2-substituent, the latter being a A -4,5-disubstitutedisoxazoline.
  • the 4,5-substitution on the isoxazolinemoiety is a saturated alkyl ring structure.
  • This invention relates to isoxazol-3-yl-, A isoxazolin-3 -yl-, or
  • R is hydrogen, loweralkyl having l-6 carbon atoms, or -CH CH OH
  • Y is loweralkyl having l-6 carbon atoms, benzyl, or hydrogen
  • R, and R are the same or different and are each hydrogen, loweralkyl having 'l-6 carbon atoms, carboxyalkyl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, amino, phenyl, aminoalkyl, aminodialkyl, or R and R are a ring structure having the following structure:
  • n an integer 3-10
  • C (CHz);C 2)m m equals an integer from 1-3; 1?. equals an integer from 1-2;
  • z Z equals hydrogen or benz'oyl
  • n equals an integer from 1-4;
  • tiltand R and R are the same or different and are each hydrogen, loweralkyl havingl-6 carbon atoms, carboxylalkyl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, amino, phenyl, aminoalkyl, or aminodialkyl; or R and R are a ring structure of -C H,+,,, n equals an integer from 3'l0; except that when only one of R, and R or R and R are derivative
  • the novel compounds disclosed in this invention are prepared following three different processes.
  • the isoxazolyl derivatives are prepared by reacting an acetylene with I a hydroxamoyl chloride.
  • the A -isoxazolinyl derivatives are prepared by reacting an olefin with a l-loweralkyl-5-nitroimidazol-2 '-hydroxamoyl chloride.
  • the isoxazolidinyl derivatives are prepared by reacting an olefin with an a-( l-methyl-5-nitroimidazol-'2- yl)-N-alkylnitrone. These processes are separately discussed in greater detail hereinafter.
  • the reactive olefin used to prepare both the A -isox- ,azolinyl and the isoxazolidinyl derivatives can be amidodialkyl, phenyl, or R and R are a ring structure having the following structure:
  • v 1 m equals an integer from 1-3;
  • Z hydrogen or benzoyl
  • the acetylene compound used to prepare the isoxazolyl derivative can be defined as R -C C---R wherein R and R are the same or different and are each hydrogen, loweralkyl having l-6 carbon atoms, carboxyalkyl, carboxamido, carboxamidoalkyl, carboxamidodialkyl, or phenyl.
  • R is hydrogen, loweralkyl having l-6 carbon atoms, or CH CH OH, to prepare the isoxazolyl derivative.
  • the hydroxamoyl chloride is prepared from the 2- formyll -'substituted-5 -nitroimidazole following 1-loweralkyl-S-nitroimidazol-Z- procedures known in the art. For example, reaction with hydroxylamine is followed by chlorination with nitrosyl chloride. Preparation of the 2-formyl starting material is described in Belgium Pat. No. 661,162 issued Sept. 17, 1965.
  • the acetylene and the hydroxamoyl chloride are reacted in an inert solvent such as tetrahydrofuran, benzene, or chloroform.
  • an inert solvent such as tetrahydrofuran, benzene, or chloroform.
  • the molar ratio of the hydroxamoyl chloride to the acetylene is approximately 1:1,
  • the reaction takes place in the presence of an organic base, such as an alk'ylamin'e, for example, triethylamine, N-methyl piperidine, or any suitable tertiary amine.
  • the temperature of the reaction is preferably -25C. Lower temperatures, may be used, to 20C., and the operable upper temperature limit is such that substantially no acetylene polymerization occurs.
  • the reaction takes place in from onehalf to' hours.
  • This nitroimidazole is then hydrolyzed in acidic or basic aqueous solution to remove either the carboxyalkyl group or the carboxamido group, thereby producing the free carboxylic acid functionality at positions R R R or R of the corresponding ring.
  • the acid chloride is, prepared by reacting withthionyl chloride or oxalyl chloride.
  • the acid chloride is then reacted with an alkali metal azide, such as sodium, potassium, or lithium azide to prepare the acid azide of the nitroimidazole.
  • This latter acid azide can be rearranged to the corresponding isocyanate by heating to reflux in an inert organic solvent such as benzene, xylene, or the like.
  • the isocyanate can be treated with mineral acid such as HCl, H 80 or the like to'prepare the free amino substituent. Alternately, the isocyanate can be reacted at elevated temperatures with methanol in an inert organic solvent as above to prepare the carbamate, and the latter removed by acid or base hydrolysis to yield the final amine.
  • mineral acid such as HCl, H 80 or the like
  • the isocyanate can be reacted at elevated temperatures with methanol in an inert organic solvent as above to prepare the carbamate, and the latter removed by acid or base hydrolysis to yield the final amine.
  • the nitroimidazole can be treatedwith a loweralkyl halide, loweralkyl having 1-6 carbon atoms, for instance, methyl iodide, ethyl chloride, n-butyl iodide, hexyl bromide, or the like.
  • a loweralkyl halide loweralkyl having 1-6 carbon atoms
  • An inert organic solvent such as ethanol, methanol, dimetl'iyl formamide, and an elevated temperature between 60l C. can be used.
  • the amino group at R, R, R, or'R is then alkylated within 1 3 hours. If a luoioeulur equivalent! is used. the secondary amine is produced, or an uminoalkyl group at R R R or'R If an excess of reagent is used, the tertiary amine, the aminodialkyl group,;is produced at R R R or R, if an unsymmetrical tertiary amine is desired, the reaction can be conducted in two stages, with a molecular equivalent of each desired alkyl halide being used in each step.
  • This latter compound can be isolated, and treated with a strong mineral acid to remove the element of morpholine thereby preparing the desired compound:
  • the A -isoxazolinyl derivatives are also prepared from the l-loweralkyl-S-nitroimidazol-2-hydroxamoyl chloride by reaction of the latter with the olefin defined above.
  • the olefin and the ,hydroxamoyl chloride are reacted in an inert solvent at reflux.
  • the solvent is chosen so that the reflux temperature is preferably l00-l50C., and can be- -200C.
  • the ratio of hydroxamoyl chloride to olefin is approximately lzl. although l:l-l 5 can be used.
  • the reaction takes place inabout 18 to 24 hours.
  • the other route used to prepare the A -isoxazolinyl derivative utilizes the presence of an organic base, such as alkylamine, for example, triethylamine, N-methyl piperidine or any other suitable tertiary amine.
  • an organic base such as alkylamine, for example, triethylamine, N-methyl piperidine or any other suitable tertiary amine.
  • the reaction takes place in a solvent such as tetrahydrofuran atlow temperatures, preferably from O-25C.
  • the reaction takes place in from one-half to 10 hours.
  • Y is hydrogen, a benzyl radical or an alkyl radical having 1-6 carbon atoms.
  • the hydroxylamine can preferably be employed in the salt form, such as the hydrochloride, acetate, carbonate and others, or in the free base form.
  • the two reactants are mixed together and allowed to react at room temperature to 60C. for 2-12 hours in a solvent such as methanol, ethanol, or water.
  • the desired product can be isolated after the solution is made alkaline with an inorganic base.
  • the chosen nitrone is then reacted with an olefin chosen from the group described above.
  • the reactants are reacted in an inert solvent at reflux, and operably at a temperature of about 80-200C., and preferably ll50C.
  • the ratio of nitrone to olefin is approximately lzl, although l:l-l can be used.
  • the reaction takes place in about 1-1 2 hours.
  • novel compounds of this invention have antibacterial and antiprotozoal activity especially against human and animal trypanosomiasis, including Chagas disease, and trichomoniasis.
  • Trypanosomiasis is a term used to describe a group of allied protozoal diseases,each of which is due to infection with a species of the genus Trypanosoma. They reach their greatest importance in Africa where their presence in enz ootic form precludes the keeping of domestic animals throughout the largest part of the continent between l5N and S latitude.
  • the pathogenic trypanosomes of Africa are considered to be primarily associated with the tsetse flies (glossina) which feed on vertebrate blood. Wherever tsetse are present, trypanosomiasis will also be found in some part of the mammalian population.
  • the clinical findings are typically those of a wasting disease with intermittent fever.
  • Anemia, edema, and cachexia are parts of the syndrome. r
  • the important trypanosomes pathogenic to domestic animals are T. congolense, T. simiae, T. vivax, and T. brucei.
  • the latter trypanosome is morphologically identical to T. gambiense, responsible for human sleeping sickness of Africa.
  • a trypanosome found in the Western Hemisphere is T. cruzi, which affects both domestic animals and man.
  • Acute Chagas" disease occurs predominantly in young children.
  • the chronic form may be mild and asymptomatic, but complications from myocarditis and C.N.S. involvement may result with fatal outcome.
  • Trichomoniasis is a protozoan disease affecting cattle, poultry, and humans
  • the causative protozoan is Trichohiona s fetus which produces a contagious venereal disease characterized by sterility, pyometra and abortion.
  • Trichomonas gallinarum invades the lower intestine of domestic birds and causes diarrhea'an'd lesions in the intestinal wall.
  • the infective protozoa are Trichomonas vaginalis, infecting the vagina and prostrate, and Trichomonas hominis, found in the intestine.
  • the compounds of this invention have particular value in the control of trypanosomiasis and trichomoniasis in domesticated animals, particularly cattle.
  • they may be administered orally with an ingest'ible carrier as a component of the animal feedstuff, in the drinking water, in salt blocks and in unit dosage forms such as boluses and drenches.
  • the amount of active ingredient required for optimum control of trypanosomiasis varies in accordance with such factors as the particular compound employed, the species of animal to be treated, the species of infecting parasite, the severity of infection, and whether the compound is employed therapeutically or prophylactically.
  • the compounds defined by Formula I when administered orally to domestic animals in daily doses of from about 0.1 mg. to about 500 mg.
  • Administration may be in a single dose or divided into a plurality of smaller doses over a period of 24 hours. Where prophylactic treatment is desired and the compounds are fed continuously, satisfactory results are obtained when the animals ingest daily dosages of about 0.1 mg. to lOO mg. per kilogram of body weight.
  • the unit dosage'forms may be'readily prepared by conventional formulating techniques and are particularly useful when administration is to be made in a single dose. or divided doses over a period of 24 hours.
  • compositions may vary provided that a sufficient amount is ingested to give the required dosage.
  • tablets, boluses and drenches containing from about 5 to percent weight of active ingredient may be satisfactorily employed to supply the desired dosage.
  • the substituted imidazoles defined by Formula 1 above may be administered, dispersed in or admixed with the normal elements of animal sustenance, i. e., the feed, drinking water or other liquids normally partaken by the animals.
  • This method is preferred when it is desired to administer the active compounds continuously, either as a therapeutic or prophylactic agent, for a period of several days or more.
  • the present invention also contemplates the employment of compositions containing the active compounds intimately dispersed in or admixed with any other carrier or diluent which is inert with respect to the active ingredient, orally administrable and is tolerated by the animals.
  • .solid edible carrier such as corn meal, wheat shorts, a1-
  • feed supplements containing from about percent to about 50 percent by weight of active ingredient may be satisfactorily employed to supply the desired .dosage in the finished feed.
  • the active ingredient is added to the carrier and the whole mixed to give substantially uniform dispersion of the antitrypanosomiasis agent in the carrier.
  • the substituted nitroimidazoles of this invention' are used in the prevention and treatment of Chagas disease and human sleeping sickness
  • the compounds can be administered .as intravenous, intramuscular, or interperitoneal injections.
  • the compounds are suspended or dissolved in an inert non-toxic pharmaceutically acceptable carrier and administered.
  • 2-12 mg./l g. of body weight are injected every 1-8 months.
  • the compounds can also be used orally against Chagas disease or human sleeping sickness.
  • the oral dosage is 3 -20 mg. per kg. twice a day for 5-10 days. This therapy can be given alone or in addition to other drugs useful against trypanosomiasis, such as sodium s'uramin, melarsoprol, tryparsamide, or pentamidine.
  • the compounds of the present invention are also useful as topical trichomonacides.
  • one or more of the active agents are uniformly distributed in a suitable chemotherapeutic vehicle that is chemically compatible with the particular compound selected, non-inhibiting with respect to the action of the effective agent upon the parasite and essentially non-injurious to body tissue under the conditions of use.
  • the vehicle is preferably a semi 1iquid or semi-solid type and the final preparation may be in the form of a suppository if desired.
  • Oil and water types of emulsions or creams as well as aqueous jellies such as those prepared with the aid of EXAMPLE 1
  • 1-Methyl-5-nitroimidazole 24.2 0., (0.214 moles) of 4(5)-nitroimidazole is heated with 24.0 g. (0.1 1 mole) of methyl tosylate for 1 hour at l80190C. and cooled to give a hard solid.
  • the mixture is shaken with 175 ml. of 2.5 N aqueous sodium hydroxide until it is dissolved and diluted with 175 ml. of water to give an oily precipitate.
  • the mixture is extracted with ether; the ether extract washed with 2.5 N aqueous hydrochloric acid and water.
  • aqueous acid wash is treated with excess aqueous sodium hydroxide and extracted with ether. This latter ether extract is evaporated to dryness and recrystallized from petroleum ether to yield l-methyl-S- nitroimidazole, m.p. 154155C.
  • l-ethyl- 2-hydroxymethyl-5-nitroimidazole 1-propyl-2-hydroxany of a number of commercially used j'elling agents including acacia, tragacanth, bentonite, alginic acid and the like are suitable vehicles.
  • the vehicle may also be a viscous aqueous gel containing one or more cellulose derivatives such as methyl cellulose, hydroxyethyl cel-' lulose, and sodium carboxym'ethyl cellulose.
  • Gelling agents such as pectin, gum tragacanth, sodium alginate and other vegetable gelling agents are also useful vehicles in this regard.
  • the lead diacetate then removed by filtration and washed ,with 2 X mlof benzene.
  • the combined benzene filtrate and washes are extracted with 1 ,500 m1. of water and then with two 1 liter portions of saturated aqueous potassium bicarbonate.
  • EXAMPLE 4 l-( 2-Acetoxyethyl )-5-nitroimidazole 4.0 g. of 4(5)-nitroimidazole and 4.7 ml. of B-ethoxyethyl tosylate are heated together in a l70l75C. oil bath for 1 hour with occasional stirring until the mixture becomes homogeneous. The mixture is cooled to near room temperature and dissolved by agitating with amixture of about 50 ml. of chloroform and 50 ml. 4N ammonium hydroxide. The chloroform phase is extracted twice with 2N ammonium hydroxide and dried over sodium sulfate. Evaporation to dryness in vacuo gives a black syru'p which is filtered through 30 g. of basic alumina eluting with l,2-dichloroethanezether.
  • EXAMPLE 5 l-(2-Acetoxyethyl)-2-formyl-5-nitroimidazole A mixture of 24.25 g. of l-(2-acetoxyethyl)'-5- nitroimidazole prepared as in Example 4, g. of paraformaldehyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube overnight at l0O-l50C. The dimethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and thesolution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields l-(2'-acetoxyethyl)-2-hydroxymethyl-S-nitroimidazole, m.p. l38l45C.
  • Example 6 shows the preparation of the nitrone of Formula Ill.
  • Example 7 is the preparation of the hydroxyamoyl chloride of Formulall.
  • EXAMPLE 6 a-( lMethyl-5-nitroimidazolc-2-yl)-N-methylnitrone I -To a solution of l-methyl-2-formyl-5-nitroimidazole I prepared as in Example 3, (4.65 g., 0.03 mole) in ml. of methanol is added 2.5 g. (0.03 mole) of N- methylhydroxylamine hydrochloride CH NHOH'HCL.
  • a-(l-methyl-S- nitroimidazol-Z-yl)-N-benzylnitrone can also be prepared using N-benzylhydroxylamine hydrochloride in the above reaction with l-methyl-2formyl-5- nitroimidazole.
  • hydroxamoylchloride, l-n-butyl-5-nitroimidazole-2- hydroxamoylchloride, and 5-nitroimid-azoIe-Z-hydroxamoylchloride are prepared respectively from l-(2- acetoxyethyl)-2-formyl-5-nitroimidazole, l -ethyl-2- formyl-S-nitroimidazole, l-n-butyl-Z-formyl-S- nitroimidazole, and 2-formyl-5snitroimidazole prepared as in Examples 3. and 5.
  • EXAMPLE 8 l-Methyl2-(2-methyl-5carboxymethyl-'isoxazolidinyl- 3-yl)-5-nitroimidazole
  • EXAMPLE 9 l-Methyl-2-( 2-methyl-4,5-hexamethyleneisoxazolidinyl-3-yl)-5-nitroimidazole hydrochloride (Illa-CH2 CH2 I $112 oar-0H1 1.87 g. of the compound prepared in Example 6, a- (l-methyl--nitroimidaZol-2-yl)-N-methylnitrone, and 1.1 g. of cyclooctene are added in 30 ml. of'toluene. The mixture is refluxed for about 16 hours.
  • the nitrone is dissolved.
  • the reaction mixture after filtering, is evaporated to a yellow oil.
  • This'oil is purified by chromatographic techniques on silica gel with a benzenezchloroform-eluent. 2.5 g. of a clear yellow oil is, obtained.
  • This oil is then mixed with ether containing dry hydrochloric acid to obtain 2.4 g.
  • EXAMPLE 13 1-Methyl-2-(5-carboxamido-isoxazol-3-yl)-5- nitroimidazole C ONHz 3 g. of the compound prepared in Example 12 is dissolved inhot methanol. The solution is saturated with ammonia. A precipitate is formed and the mixture is cooled by placing in the refrigerator. After filtration and purification, the pure product having-a melting point of 235238C. is recovered. This productis l-methyl-2-( 5-carboxamido-isoxazol-3- yl)-5-nitroimidazole.
  • EXAMPLE 14 l-Methyl-2r(5-aminoisoxazol-3-yl)-5-nitroimidazole nitroimidazole. are dissolved in 30 ml. of a 10% HCl solution, and the mixture heated to reflux. After 30 minutes, the reaction is terminated and the product, 1- methyl-2-(5-carboxylic acid-isoxazol-3-yl)-5- nitroimidazole, is obtained.
  • the product is l-methyl-2-(5-carboxylic acid azideisoxazol-3-yl)-5-nitroimidazole. 1.4 g. of the latter is dissolved in 60 ml. of benzene and refluxed for 3 hours. 10 ml. of concentrated HCl are (25 added and refluxing continued for one-half hour. The reaction is diluted with chloroform and made basic. The dried organic phase yielded 0.5 g. of the product, l-methyl-2-(5- aminoisoxazol-3-yl)-5-nitroimidazole, m.p. l80-l85 C.
  • This latter morpholino compound l g. is dissolved in concentrated sulfuric acid (I00 ml.) and heated on a steam bath for Bi hours. The yellow reaction mixture is poured onto ice to quench. After filtration, a crude product isobtained. lt is recrystallized from methanol and yields 4.5 g. of a product identified as l-methyl-2- (4,5,6,7-tetrahydrocyclohex[d]isoxazol-3-yl)-5- nitroimidazole,'having a melting point of l61-l62C.
  • Examples 16 through 36 relate to the preparation of the A -isoxazoline. It will be clear to one skilled in the art that, although the l-vmethyl derivatives are prepared, the other loweralkyl, acetoxyethyl, and unsubstituted derivatives can be prepared from'the corresponding hydroxamoyl chloride compounds in Example 7. 1
  • EXAMPLE l6 l-Methyl-2-(S-carboxymethyl-A -isoxazolin-3-yl)-5- v nitroimidazole ganic layer is evaporated and the residual yellow oil is crystallized.
  • the product is identified as l-methyl-2-(5- carboxymethyl-A -isoxazolin 3 -yl )-5 -nit'roimidazole, and has a melting point of l09-l 10C.
  • EXAMPLE l8 1-Methyl-2-(5-phenyl-A -isoxazolin-B-yl)-5- nitroimidazole 2.04 g. of the hydroxamoylchloride prepared in Example 7 are dissolved in 40 ml. of tetrahydrofuran. One gram of styrene is added and the solution is kept at 0C. while a solution of triethylamine tetrahydrofuran (1.01 g. in 10 ml.) is added. The mixture is stirred 15 minutes at 0C. and l hour at room temperature.
  • Example 16 After filtering and removing the solvent, the residue is treated with chloroform and washed with sodium bicarbonate v
  • the compound preparedin Example 16 is dissolved in methanol (119mg. in l0 ml.). Ammonia is bubbled through the solution until a precipitate formed. The mixture is filtered after 1 hour and purification and recrystallization yield 95 mg. of the product, l-methyl- 2-(5-carboxarnido-A isoxazolin-3-yl) 5- nitroimidazole, having a melting point-of 238239 C. v
  • the product after recrystallization, is identified as lmethyl-2-( 3a,5 ,6,7a-tetrahydro-4H-pyrano[ 3 ,2-d l- 5 isoxazol-3-yl)-5-nitroimidazole having a melting point TUA l -M'ethyl-2-( i,5-cis-dimethyl-A -is0xazolin-3-yl)-5- nitroimidazole of l40-l42C.
  • the product, NI after recrystallization, is identified as l-methyl-(4,5- N NH cis-dimethyl-A -isoxazolin-3-yl-5-nitroimidazole, hav- C ing a melting point of 8384C.
  • EXAMPLE 23 Following the same general procedure of Examples 16 through 19, the hydroxamoylchloride prepared as in Example 7 is reacted with norbornene. The product, after recrystallization, is identified as exo-2- (321,4,5,6,7,7a-hexahydro-4,7-methano-l,Z-benz-isoxazol-3-yl)- l -methyl-5-nitroimidazole, having -a melting l J point of l24-l25C.
  • the product after NI recrystallization, is identified as l-methyl-2-(A -isoxazolin-3-yl)-5-nitroimidazole, having a melting point of N
  • the hydroxamoylchloride prepared as in Example 7 is reacted with N-benzoyl-2,5-dihydropyriole. identified tetrahydro-4H-pyrrolo[ 3 ,4-d]-isoxazol-3 -yl nitroimidazole, having a melting point of l53-l 55C.
  • fractions containing the product are A reduced to yield a yellow crystalline material.
  • This product is recrystallized from hexane, yielding the product, l-met hyl-2-( 3a,4,5,6,7,8,9,9a-0ctahydrocyclooct[d]-isoxazol-3 -yl)-5-nitroimidazole, having a melting point of 1 to 115C.
  • hydroxamoylchloride is reacted with 6-amino-2-hexl-Methyl-2-( trans-4,5-dipropyl-A -isoxazolin-3-yl )-5- enoic acid lacmm:
  • hydroxamoylchloride is reacted with trans-3-hexene.
  • L The product, 1-methyl-2-(trans-4,5-diethyl-A -isoxazolin-S-yl)-5-nitroimidazole, has a melting point of 6667C.
  • EXAMPLE 40 where in equals an integer of from l-3; and where n equals an integer of from 1-2. 2.
  • the compound of claim 1 which is exo-2- (3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benz-isoxazol-3-yl)- l -methyl-5-nitroimidazole.

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  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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US3915978A (en) * 1970-01-07 1975-10-28 Merck & Co Inc Nitroimidazoles
US3954789A (en) * 1971-07-30 1976-05-04 Gruppo Lepetit S.P.A. 2-Nitroimidazole derivatives
US4010176A (en) * 1972-10-27 1977-03-01 Merck & Co., Inc. Isoxazole substituted nitroimidazoles
US4080340A (en) * 1975-07-30 1978-03-21 Merck & Co., Inc. Nitroimidazoles
US4144345A (en) * 1977-11-30 1979-03-13 Merck & Co., Inc. Dihydroxybenzisoxazolin-3-yl-substituted-5-nitroimidazoles as antibacterials and antiprotozoals
US4268674A (en) * 1977-11-14 1981-05-19 The Dow Chemical Company Preparation of substituted oxatriazoles
US4269830A (en) * 1979-05-17 1981-05-26 Merck & Co., Inc. Compositions and methods for the treatment of chronic trypanosomiasis infections
FR2508314A1 (fr) * 1981-05-22 1982-12-31 Merck & Co Inc Compositions et procedes pour le traitement des infections chroniques de trypanosomiase
US4719306A (en) * 1986-08-27 1988-01-12 Pennwalt Corporation Substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4723021A (en) * 1986-08-27 1988-02-02 Pennwalt Corporation Substituted 5-(phenoxyalkyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4727157A (en) * 1986-08-27 1988-02-23 Pennwalt Corporation 3-(Substituted phenyl)-3-(1H-1,2,4-triazol-1-yl)methyl-2-methyl-5-[(substituted phenoxy)methyl]isoxazolidine derivatives
US4727156A (en) * 1986-08-27 1988-02-23 Pennwalt Corporation 3-(Substituted phenyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-5-{[(substituted phenyl)thio]me}isoxazolidine derivatives
US4749793A (en) * 1987-10-02 1988-06-07 Pennwalt Corporation 5-substituted-3-phenyl-3-[1H-imidazol-1-ylmethyl) or (1H-1,2,4-triazol-1-ylmethyl]-2-benzylisoxazolidines (ir 3011)
US4754042A (en) * 1987-10-02 1988-06-28 Pennwalt Corporation 5-{[naphthyl(or 2-oxo-1,3-benzoxathiol-6-yl)oxy]methyl}-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4767867A (en) * 1987-04-10 1988-08-30 Pennwalt Corporation 5-(alkoxyalkyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4767866A (en) * 1987-04-10 1988-08-30 Pennwalt Corporation 3-Phenyl-3-(1H-1,2,4-triazol-1-ylmethyl)-2-methyl-5-alkylisoxazolidines
US4767868A (en) * 1987-04-10 1988-08-30 Pennwalt Corporation 3-Phenyl-3-(1H-imidazol-1-ylmethyl)-2-methyl-5-[(phenylamino)methyl]isoxazolidines
US4769469A (en) * 1987-04-10 1988-09-06 Pennwalt Corporation 5-(phenyl or phenoxyalkyl)-3-(2-furanyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4769470A (en) * 1987-10-02 1988-09-06 Pennwalt Corporation 5-(phenyl or phenoxyalkyl)-3-(2-thienyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4769468A (en) * 1987-04-10 1988-09-06 Penwalt Corporation 5-(acyloxyalkyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4769471A (en) * 1987-04-10 1988-09-06 Pennwalt Corporation Substituted 3,5-diphenyl-3-(1H-1,2,4-triazol-1-yl-methyl)-2-methylisoxazolidines
US4777264A (en) * 1987-10-02 1988-10-11 Pennwalt Corporation 5-carbonyl derivatives of 3-phenyl-3-(1H-imadazol-1-ylmethyl)-2-methylisoxazolidines and related compounds thereof
US4777263A (en) * 1987-10-02 1988-10-11 Pennwalt Corporation 5-substituted-3-(2-naphthalenyl)-3-((1H-imidazol-1-ylmethyl) or (1H-1,2,4-triazol-1-ylmethyl))-2-methylisoxazolidines
US4777262A (en) * 1987-10-02 1988-10-11 Pennwalt Corporation 5-(substituted thiomethyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine derivatives
US4785117A (en) * 1987-10-02 1988-11-15 Pennwalt Corporation 5,5-disubstituted-3-phenyl-3-phenyl-3-[(1H-imidazol-1-ylmethyl) or (1H-1,2,4-triazol-1-ylmethyl)]-2-methylisoxazolidine derivatives (IR 3012)
US4831154A (en) * 1987-04-10 1989-05-16 Pennwalt Corporation 5-alkyl(or alkenyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4835283A (en) * 1988-03-07 1989-05-30 Pennwalt Corporation 3,5-diphenyl-3-[(1H-imidazol-1-ylmethyl) or (1H-1,2,4-triazol-1-ylmethyl)]-2
US5208251A (en) * 1986-05-09 1993-05-04 Warner-Lambert Company Styryl pyrazoles, isoxazoles and analogs thereof having activity as 5-lipoxygenase inhibitors, pharmaceutical compositions and methods of use therefor
US6072057A (en) * 1996-06-06 2000-06-06 Gliatech Inc. 1H-4(5)-cyclo-substituted imidazole derivatives as histamine H3 receptor agents
US6329342B1 (en) 1997-08-19 2001-12-11 Eli Lilly And Company Treatment of congestive heart failure with growth hormone secretagogues
US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
US20040058971A1 (en) * 2001-10-09 2004-03-25 Dodge Jeffrey Alan Substituted dipeptides as growth hormone secretagogues
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
US20050240001A1 (en) * 2002-04-09 2005-10-27 Eli Lilly And Company Growth hormone secretagogues
US20060167268A1 (en) * 2002-04-09 2006-07-27 Eli Lilly And Company, Patent Division, Growth hormone secretagogues

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2613167A1 (de) * 1976-03-27 1977-10-06 Bayer Ag Oximcarbamate, verfahren zu ihrer herstellung und ihre verwendung als insektizide, akarizide und nematozide
DE2862035D1 (en) * 1977-11-30 1982-11-04 Merck & Co Inc Substituted nitroimidazoles, process for their preparation and compositions containing them
JP2002504550A (ja) * 1998-02-25 2002-02-12 ファルマシア・アンド・アップジョン・カンパニー 抗微生物剤として有用な置換アミノメチルイソオキサゾリン誘導体

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3472857A (en) * 1966-02-03 1969-10-14 Ciba Ltd N-(3-pyrazolyl-propyl)-n'-phenyl piperazines

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1162257A (en) * 1965-09-22 1969-08-20 Danippon Pharmaceutical Co Ltd 3-(5-Nitro-2-Furyl) Isoxazole Derivatives and methods of preparation thereof
US3452035A (en) * 1966-12-23 1969-06-24 American Cyanamid Co 2 - amino - 5 - (5 - nitro - 1 - substituted-2 - imidazolyl) - 1,3,4 - thiadiazoles and oxadiazoles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3472857A (en) * 1966-02-03 1969-10-14 Ciba Ltd N-(3-pyrazolyl-propyl)-n'-phenyl piperazines

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3915978A (en) * 1970-01-07 1975-10-28 Merck & Co Inc Nitroimidazoles
US3954789A (en) * 1971-07-30 1976-05-04 Gruppo Lepetit S.P.A. 2-Nitroimidazole derivatives
US4010176A (en) * 1972-10-27 1977-03-01 Merck & Co., Inc. Isoxazole substituted nitroimidazoles
US4080340A (en) * 1975-07-30 1978-03-21 Merck & Co., Inc. Nitroimidazoles
US4268674A (en) * 1977-11-14 1981-05-19 The Dow Chemical Company Preparation of substituted oxatriazoles
US4144345A (en) * 1977-11-30 1979-03-13 Merck & Co., Inc. Dihydroxybenzisoxazolin-3-yl-substituted-5-nitroimidazoles as antibacterials and antiprotozoals
US4269830A (en) * 1979-05-17 1981-05-26 Merck & Co., Inc. Compositions and methods for the treatment of chronic trypanosomiasis infections
FR2508314A1 (fr) * 1981-05-22 1982-12-31 Merck & Co Inc Compositions et procedes pour le traitement des infections chroniques de trypanosomiase
US5208251A (en) * 1986-05-09 1993-05-04 Warner-Lambert Company Styryl pyrazoles, isoxazoles and analogs thereof having activity as 5-lipoxygenase inhibitors, pharmaceutical compositions and methods of use therefor
US4719306A (en) * 1986-08-27 1988-01-12 Pennwalt Corporation Substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4723021A (en) * 1986-08-27 1988-02-02 Pennwalt Corporation Substituted 5-(phenoxyalkyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4727157A (en) * 1986-08-27 1988-02-23 Pennwalt Corporation 3-(Substituted phenyl)-3-(1H-1,2,4-triazol-1-yl)methyl-2-methyl-5-[(substituted phenoxy)methyl]isoxazolidine derivatives
US4727156A (en) * 1986-08-27 1988-02-23 Pennwalt Corporation 3-(Substituted phenyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-5-{[(substituted phenyl)thio]me}isoxazolidine derivatives
US4769471A (en) * 1987-04-10 1988-09-06 Pennwalt Corporation Substituted 3,5-diphenyl-3-(1H-1,2,4-triazol-1-yl-methyl)-2-methylisoxazolidines
US4831154A (en) * 1987-04-10 1989-05-16 Pennwalt Corporation 5-alkyl(or alkenyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4767866A (en) * 1987-04-10 1988-08-30 Pennwalt Corporation 3-Phenyl-3-(1H-1,2,4-triazol-1-ylmethyl)-2-methyl-5-alkylisoxazolidines
US4767868A (en) * 1987-04-10 1988-08-30 Pennwalt Corporation 3-Phenyl-3-(1H-imidazol-1-ylmethyl)-2-methyl-5-[(phenylamino)methyl]isoxazolidines
US4769469A (en) * 1987-04-10 1988-09-06 Pennwalt Corporation 5-(phenyl or phenoxyalkyl)-3-(2-furanyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4767867A (en) * 1987-04-10 1988-08-30 Pennwalt Corporation 5-(alkoxyalkyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4769468A (en) * 1987-04-10 1988-09-06 Penwalt Corporation 5-(acyloxyalkyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4754042A (en) * 1987-10-02 1988-06-28 Pennwalt Corporation 5-{[naphthyl(or 2-oxo-1,3-benzoxathiol-6-yl)oxy]methyl}-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4777264A (en) * 1987-10-02 1988-10-11 Pennwalt Corporation 5-carbonyl derivatives of 3-phenyl-3-(1H-imadazol-1-ylmethyl)-2-methylisoxazolidines and related compounds thereof
US4777263A (en) * 1987-10-02 1988-10-11 Pennwalt Corporation 5-substituted-3-(2-naphthalenyl)-3-((1H-imidazol-1-ylmethyl) or (1H-1,2,4-triazol-1-ylmethyl))-2-methylisoxazolidines
US4777262A (en) * 1987-10-02 1988-10-11 Pennwalt Corporation 5-(substituted thiomethyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine derivatives
US4785117A (en) * 1987-10-02 1988-11-15 Pennwalt Corporation 5,5-disubstituted-3-phenyl-3-phenyl-3-[(1H-imidazol-1-ylmethyl) or (1H-1,2,4-triazol-1-ylmethyl)]-2-methylisoxazolidine derivatives (IR 3012)
US4749793A (en) * 1987-10-02 1988-06-07 Pennwalt Corporation 5-substituted-3-phenyl-3-[1H-imidazol-1-ylmethyl) or (1H-1,2,4-triazol-1-ylmethyl]-2-benzylisoxazolidines (ir 3011)
US4769470A (en) * 1987-10-02 1988-09-06 Pennwalt Corporation 5-(phenyl or phenoxyalkyl)-3-(2-thienyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines
US4835283A (en) * 1988-03-07 1989-05-30 Pennwalt Corporation 3,5-diphenyl-3-[(1H-imidazol-1-ylmethyl) or (1H-1,2,4-triazol-1-ylmethyl)]-2
US6072057A (en) * 1996-06-06 2000-06-06 Gliatech Inc. 1H-4(5)-cyclo-substituted imidazole derivatives as histamine H3 receptor agents
US6329342B1 (en) 1997-08-19 2001-12-11 Eli Lilly And Company Treatment of congestive heart failure with growth hormone secretagogues
US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
US20040122234A1 (en) * 1998-08-18 2004-06-24 Hauser Kenneth Lee Growth Hormone secretagogues
US6992097B2 (en) 1998-08-18 2006-01-31 Eli Lilly And Company Growth hormone secretagogues
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
US20050143318A1 (en) * 1999-02-19 2005-06-30 Dodge Jeffrey A. Growth hormone secretagogues
US20040058971A1 (en) * 2001-10-09 2004-03-25 Dodge Jeffrey Alan Substituted dipeptides as growth hormone secretagogues
US7125840B2 (en) 2001-10-09 2006-10-24 Eli Lilly And Company Substituted dipeptides as growth hormone secretagogues
US20050240001A1 (en) * 2002-04-09 2005-10-27 Eli Lilly And Company Growth hormone secretagogues
US20060167268A1 (en) * 2002-04-09 2006-07-27 Eli Lilly And Company, Patent Division, Growth hormone secretagogues
US7396846B2 (en) 2002-04-09 2008-07-08 Eli Lilly And Company Growth hormone secretagogues

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FR2081416B1 (enrdf_load_stackoverflow) 1974-09-27
ZA707997B (en) 1972-07-26
GB1316221A (en) 1973-05-09
OA03554A (fr) 1971-03-30
FR2081416A1 (enrdf_load_stackoverflow) 1971-12-03
CH555852A (de) 1974-11-15
DE2100242C2 (de) 1984-07-19
NL7018072A (enrdf_load_stackoverflow) 1971-07-09
ZM14570A1 (en) 1972-08-21
CA988089A (en) 1976-04-27
JPS511717B1 (enrdf_load_stackoverflow) 1976-01-20
DE2100242A1 (de) 1971-07-15

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