US3562286A - Nitrofuryl isoxazole derivatives - Google Patents

Nitrofuryl isoxazole derivatives Download PDF

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US3562286A
US3562286A US704570A US3562286DA US3562286A US 3562286 A US3562286 A US 3562286A US 704570 A US704570 A US 704570A US 3562286D A US3562286D A US 3562286DA US 3562286 A US3562286 A US 3562286A
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furyl
nitro
isoxazole
compound
amino
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William Hoyle
Graham Arton Howarth
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Novartis Corp
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Geigy Chemical Corp
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles

Definitions

  • the compounds are of the class of nitrofuryl isoxazole derivatives, and more particularly 3-(5-nitro-2-furyl)-5- amino isoxazole further substituted in 4-position.
  • the compounds are useful as antimicrobial, anthelmintic and growth-promoting agents.
  • Illustrative embodiments are 3-(5-nitro-2-furyl) 4 chlorocarbonyl-S-amino isoxazole and 3-(5-nitro 2 furyl)-4-dimethylcarbamoyl-S-arnino isoxazole.
  • the present invention relates to substituted heterocyclic compounds, and in particular to nitrofuryl derivatives of isoxazoles.
  • a 5-nitro-2-furyl-isoxazole having the Formula I i L ozNlo CON ⁇ O NH2 methods and compositions containing a compound of the above-mentioned Formula I for effecting antimicrobial, particularly, antibacterial, antifungal, antiviral and coccidiostatic, and anthelmintic and growth-promoting activities in warm-blooded animals, especially mammals. More particularly, the method of effecting antimicrobial, especially antibacterial, antifungal, antiviral and coccidiostatic, anthelmintic and growth-promoting activities in mammals is concerned with administering a compound as defined in Formula I in therapeutic doses. Moreover the present invention relates to intermediates of Formula 1.
  • lower alkyl as used herein alone or in lower alkenyl, cycloalkyl, and lower alkoxycarbonyl means straight or branchedlalkyl chains of the general formula C H wherein m represents an integer of 6 or less. These terms may be further illustrated as follows:
  • each of these groups may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.
  • the halogen may .be fluorine or iodine but is preferably chlorine or bromine.
  • the alkyl group contains one or two halogen, alkoxy or hydroxy substituents.
  • alkenyl this may be, for example, allyl, 2-methallyl, Z-butenyl (crotyl) or 3-butenyl.
  • R and R is cycloalkyl, this may be cyclopentyl but is preferably cyclohexyl.
  • R or R is an alkoxycarbonyl group
  • the alkyl portion of the carbalkoxy group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tertiary butyl.
  • Particularly preferred compounds of the invention have the Formula I wherein R and R are the same and especially when each is alkyl containing from 1 to 4 carbon atoms, or alkyl substituted by hydroxy or lower alkoxy.
  • the 5-nitro-2-furyl-isoxazole of Formula I may be prepared by reacting a reactive functional derivative of a carboxylic acid of a S-nitro-furyl-isoxazole compound of Formula II O2N CO-OH 0 Lu j:
  • the reactive functional derivative of an acid of a substituted S-nitro-furyl-isoxazole compound of Formula II is a compound capable of reacting with the reactant of Formula III to produce the desired S-nitro-furyl-isoxazole of Formula I.
  • the compound of Formula II may be, for instance, a 5-nitro-2-furyl-isoxazole acid halide having the Formula Ila NHz the halogen being preferably chlorine or bromine.
  • the reaction with the acid halide is conveniently carried out in the presence of an organic solvent which is substantially inert under the conditions of the reaction.
  • the reaction may .be carried out at a temperature in the range of from 10 C. to the boiling point of the mixture under reflux.
  • a conventional hydrogen halide binding agent may advantageously be present in the reaction mixture; and, if desired, instead of employing an added base as binding agent, the process may be effected using an excess of the reactant of Formula III over the stoichiometric equivalent of the acid halide of Formula 1141.
  • Suitable reactive functional derivatives of the compound of Formula II which may be used in the process of the invention comprise anhydrides and mixed anhydrides in the presence of an acid binding agent, free acids in the presence of agents combining with water, and azides and activated esters, for example cyanomethyl esters and p-nitrophenyl esters.
  • the acid binding agent used in the process may be, for example, sodium or potassium carbonate or bicarbonate dispersed in an aqueous-organic or organic medium or triethylamine, pyridine or other tertiary organic base dispersed in dioxan, tetrahydrofuran, acetone, chloroform or other organic media.
  • the agent combining with water may be, for example, dicyclohexyl carbodiimide.
  • mixed anhydrides signifies firstly anhydrides mixed with anhydrides of lower alkanoic acids, especially acetic acid, and secondly anhydrides which are carbonic acid semi-esters, produced for instance by reacting the monocarboxylic acid of Formula II with the benzyl, p-nitrobenzyl, isobutyl, ethyl or methallyl esters of chloroformic acid.
  • the present invention also comprises the -nitro-2- furyl-isoxazole acid halides of Formula 11a in which the halogen is chlorine or bromine, these compounds being novel substances.
  • the starting materials of Formula IIa may themselves be produced by reacting the corresponding carboxylic acid derivative having the Formula II with a halogenating agent containing the corresponding halogen.
  • a halogenating agent containing the corresponding halogen.
  • preferred halogenating agents include thionyl chloride and thionyl bromide. If a thionyl halide is used, it may, if desired be in the form of a complex with dimethyl formamide.
  • the carboxylic acid derivative of Formula II is also a novel compound and is comprised within the present invention.
  • the compound may be conveniently produced by hydrolysing a tertiary alkyl ester having the Formula IV O2N J1 00.0114
  • R is a tertiary alkyl group containing from four to twelve carbon atoms, with an acid hydrolysing agent.
  • the tertiary ester of Formula IV is preferably the tertiary butyl ester, but may also be the tertiary octyl or tertiary dodecyl ester.
  • the hydrolysis is carried out in the presence of an acid hydrolysing agent, for example an aqueous formic acid solution containing a major proportion of formic acid.
  • the product of the hydrolysis may be purified, if desired, but conveniently the crude product containing the compound of Formula II is reacted with the halogenating agent.
  • the compounds of the invention have useful pharmacological and, in particular, antimicrobial properties, being valuable antibacterial, antifungal, antiviral, anthelminthic, coccidiostatic or growth-promoting agents for external or internal use in warm-blooded animals, particularly mammals.
  • the compounds are particularly valuable in the treatment of infections of the intestinal or urinary tract.
  • the compounds may also be used to protect an organic material susceptible to bacterial, fungal or other microbial deterioration by contacting with, impregnation in or other- Wise treating the material with the compounds.
  • compositions comprising an antimicrobially effective proportion of a 5-nitro-2-furyl-isoxazole of Formula I and a pharmaceutically acceptable solid carrier or liquid diluent.
  • compositions according to the invention contain at least one compound of general Formula I as active substance together with a conventional pharmaceutical carrier.
  • a conventional pharmaceutical carrier for external use, for example in disinfecting healthy skin, disinfecting wounds and in treating dermatoses and affections of the mucous membranes caused by bacteria; ointments, powders and tinctures are used in particular.
  • the ointment bases may be anhydrous, for instance they can consist of mixtures of wool fat and soft paraflin, or they can consist of aqueous emulsions in which the active substance is suspended.
  • Suitable carriers for powders are, for instance, rice starch and other starches; the bulk weight of the carriers may be made lighter, if desired, for example by adding highly dispersed silicic acid, or may be made heavier by adding talcum.
  • the tinctures may con tain at least one active compound of the Formula I in aqueous ethanol, in particular 45% to ethanol, to which 10% to 20% of glycerol may be added, if desired. Solutions prepared from polyethylene glycol and other conventional solubility promoters, and also optionally, from emulsifying agents, may be used with particular advantage in disinfecting healthy skin.
  • the content of active ingredient in pharmaceutical compositions for external application is preferably in the range of from 0.1% to 5%.
  • Gargles or concentrates for their preparation, and tablets for slow dissolution in the mouth are suitable for the disinfection of the mouth and throat.
  • the former are preferably prepared from alcoholic solutions containing 1% to 5% of active substance to which glycerol or flavorings may be added.
  • Lozenges that is solid dosage units, preferably have a relatively high content of sugar or similar substances and a relatively low content of active substance, for instance 0.2% to 20% by weight, as well as the usual conventional additives such as binding agents and flavorings.
  • Solid dosage units in particular tablets, dragees (sugar coated tablets) and capsules, are convenient for use in intestinal disinfection and for the oral treatment of urinary tract infections. These units preferably contain from 10% to of the compound of the general Formula I. Tablets and dragee cores are produced by combining the compounds of the general Formula I with solid, pulverulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivatives or gelatines, preferably with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weight.
  • solid, pulverulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivatives or gelatines, preferably with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weight.
  • Dragee cores may then be coated, for example with concentrated sugar solutions which can also contain gum arabic, talcum and/or titanium dioxide, or they may be coated with a lacquer dissolved in volatile organic solvents or mixture of solvents.
  • Dyestulfs can be added to these coatings, for instance to differentiate between varying dosages.
  • Soft gelatine capsules and other closed capsules consist, for example, of a mixture of gelatines and glycerol and may con- Muench: Am. J. Hyg. 27, 493 (1938)] for 3-(5-nitro-2- furyl)-4-dimethylcarbamoyl-S-amino isoxazole was about 40 mg./kg.
  • the antimicrobial activity was also determined by ascertaining the diameter of zones in which the growth of bacteria was inhibited in agar medium.
  • the agar medium was pretreated with a suspension of Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, or Staphylococcus aureus.
  • the invention also provides a method of protecting an organic material susceptible to bacterial, fungal or other microbial attack which comprises treating the material with a 5-nitro-2-fury1-isoxazole of Formula I.
  • the organic material may be, for instance, a natural or synthetic polymeric material, a proteinaceous or carbohydrate substance, or a natural or synthetic fibre or textile material formed therefrom.
  • the toxicity of the compounds of the present invention is low: for instance, subchronical toxicity tests proved that amounts of more than 300 mg./ kg. of 3-(5-nitro-2-furyl)- 4-dimethylcarbamoyl-S-amino isoxazole were tolerated by mice on oral administration without causing undesirable side effects. Also the oral administration of 3-(5-nitr0-2- furyl -4-di ,B-hydroxyethyl carbamoyl-S-amino isoxazole to mice were tolerated up to doses higher than 300 mg./ kg. in subchronic tests.
  • the antimicrobial activity was studied on the following bacteria and fungi by determining the inhibiting concentration in p.p.m. in in vitro experiments:
  • the compounds of the invention may be used in warmblooded animals, particularly mammals, in form of pharmaceutical compositions containing the compounds in admixture or conjunction with a pharmaceutical organic or inorganic, solid or liquid carrier for oral, rectal, parenteral, or topical administration.
  • the preferred routes of administration are the oral and topical routes.
  • the total daily doses for mammals can vary from about 0.5 mg./ kg. to about 300 mg./kg., preferably about 1 mg./ kg. to about 100 mg./kg., depending on the mammal and condition.
  • EXAMPLE 1 A mixture of 30 g. of 3-(5-nitro-2-furyl)-4-amino-5- tert-butoxycarbonyl-isoxazolev and 300 ml. of aqueous formic acid was heated at 70 for 10 minutes. After cooling, the crystalline precipitate was collected, washed with water and recrystallised from a mixture of acetone and water.
  • the product was 3 (5 nitro 2 furyl)-4-carboxy-S- amino-isoxazole, having melting point 237, with decomposition.
  • the product was 3-(5-nitro-2-furyl)-4-chlorocarbonyl- S-amino-isoxazole, having melting point 199.
  • EXAMPLE 4 The procedure described in Example 3 was carried out using the molecular equivalent of dimethylamine gas dissolved in 25 ml. of ethyl acetate as starting material instead of diethylamine, the reaction conditions being otherwise essentially the same.
  • the product was 3-(5-nitro 2 furyl) 4 dimethylcarbamoyl-S-amino-isoxazole, having melting point 208 with decomposition.
  • the product was 3 (5 nitro 2 furyl)-4-diallyl-carbamoyl-S-arnino-isoxazole, having melting point 178.
  • the product was 3-(5-nitro 2 furyl)-4-di-isopropylcarbamoyl-S-amino-isoxazole, having melting point 181.
  • the product was 3 (5 nitro-2-furyl)-4-(N-methyl-N- ethoxy-carbonyl-carbamoyl)-5-amino-isoxazo1e.
  • the product was 3-(5-nitro-2-furyl)-4-ally1carbamoyl- 5-amino-isoxazole, having melting point 164.
  • the product was 5-amino-4-[bis (2 methoxyethyl)]- carbamoyl-3-(5-nitro 2-furyl)-isoxazole, having melting point 134.
  • EXAMPLE 12 250 g. of 3-(5-nitro-2-furyl)-4-dimethylcarbamoyl-5- amino isoxazole, 175.8 g. of lactose, and 169.7 g. of potato starch are mixed, the mixture is moistened with an alcoholic solution of g. of stearic acid and granulated through a sieve. After drying, 160 g. of potato starch,
  • talcum 200 g. of talcum, 2.5 g. of magnesium stearate and 32 g. of colloidal silicon dioxide are mixed in and the mixture is pressed into 10,000 tablets each weighing mg. and containing 25 mg. of 3 (5 nitro 2 furyl)-4-dimethylcarbamoyl-S-amino isoxazole. If desired, the tablets can be grooved to enable better adaptation of the dosage instructions.
  • EXAMPLE 13 A granulate is produced from 250 g. of 3-(5-nitro-2- furyl)-4-di(fi-hydroxyethyl)carbamoyl-S-amino isoxazole, 175.9 g. of lactose and the alcoholic solution of 10 g. of stearic acid. After drying, the granulate is mixed with 56.6 g. of colloidal silicon dioxide, 165 g. of talcum, 20 g. of potato starch, and 2.5 g. of magnesium stearate and 10,000 dragee cores are pressed from the mixture. These are first coated with an alcoholic solution of 6 g. of shellac, then with a concentrated syrup made from 502.28 g.
  • EXAMPLE 14 10 mg. to 50 mg. of 3-(5-nitro-2-furyl)-4-dimethylcarbamoyl-S-amino isoxazole are introduced into a twopiece gelatine No. 1 capsule.
  • R and R each independently are lower alkyl of from 1 to 4 carbon atoms; lower alkyl of from 1 to 4 carbon atoms substituted by hydroxy, lower alkoxy or halogen; lower alkenyl of from 3 or 4 carbon atoms; cycloalkyl with 5 or 6 carbon atoms; or lower alkoxycarbonyl wherein the alkyl contains from 1 to 4 carbon atoms; or
  • R is hydrogen
  • R and R each independently are lower alkyl with 1 to 4 carbon atoms or lower alkyl with 1 to 4 carbon atoms substituted by hydroxy.
  • R and R each independently are lower alkyl with 1 to 4 carbon atoms substituted by lower alkoxy.
  • a compound as defined in claim 1 wherein said compound is 3-(5-nitro-2-furyl)-4-diethylcarbamoyl-S-aminoisoxazole.
  • a compound as defined in claim 1 wherein said compound is 3 (5 nitro 2 furyl)-4-dimethylcarbamoyl-5- amino isoxazole.
  • a compound as defined in claim 1 wherein said compound is 3-(5-nitro-2-furyl)-4-diallylcarbamoyl-5-amino isoxazole.
  • a compound as defined in claim 1 wherein said compound is 3 (5-nitro-2-furyl)-4-(N-methyl-N-ethoxycarbonyl-carbamoyl)-5-amino isoxazole.
  • a compound as defined in claim 1 wherein said a gg ai c em arm u v0 pp compound is 3-fi5-nifro-2-furyn-4-[b1$(2-methXYethY1)1 Morrison et 211., Organic Chemistry (Allyn and Bacon, carbamoyl-5 ammo lsoxazole. D 5 Inc. Boston, 1961),

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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
US704570A 1967-02-15 1968-02-12 Nitrofuryl isoxazole derivatives Expired - Lifetime US3562286A (en)

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GB7288/67A GB1203039A (en) 1967-02-15 1967-02-15 Process for the production of nitrofuryl derivatives
GB7289/67A GB1203040A (en) 1967-02-15 1967-02-15 5-nitro-2-furyl-isoxazoles and compositions thereof

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005113519A1 (en) * 2004-05-14 2005-12-01 Irm Llc Compounds and compositions as ppar modulators

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005113519A1 (en) * 2004-05-14 2005-12-01 Irm Llc Compounds and compositions as ppar modulators
US20080114044A1 (en) * 2004-05-14 2008-05-15 Robert Epple Compounds And Compositions As Ppar Modulators
US7820705B2 (en) 2004-05-14 2010-10-26 Irm Llc Compounds and compositions as PPAR modulators

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FR1584727A (is") 1970-01-02
GB1203039A (en) 1970-08-26
CH494769A (de) 1970-08-15
NL6802101A (is") 1968-08-16
GB1203040A (en) 1970-08-26
BE710795A (is") 1968-08-14

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