Classifications

• • 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 invention relates to nitrofuryl derivatives having valuable pharmacological properties and in particular to S-nitro-Z-furyl-Z isoxazolines exhibiting antimicrobial activity. It further relates to pharmaceutical compositions containing these compounds as well as to methods for the treatment of mammals sufiering from microbial infections, particularly urinary tract infections, by administering to said mammals an effective amount of a compound according to the invention.
• the invention also provides methods for protecting organic material susceptible to microbial attack by treating said material with an eiiective amount of a compound according to the invention.
• R represents chlorine or bromine; cyano, amino, 2,3- epoxypropoxy, morpholino, piperidino or pyrrolidino; the grouping -SR -OR --O.CO.R CH .CO.R or N(R ).R wherein R represents alkyl having from 1 to 3 carbon atoms; the grouping NH.CO.R wherein R represents alkoxy having from 1 to 3 carbon atoms, cycloalkyl having from 5 to 7 carbon atoms in the carbocyclic ring, alkyl having from 1 to 6 carbon atoms or alkyl having from 1 to 6 carbon atoms substituted by one or two chlorine atoms, bromine atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups having from 2 to 7 carbon atoms, or cyano groups; ureido or ureido N-substituted by one to three al
• R represents hydrogen or alkyl having from 1 to 3 carbon atoms have not been known up to now.
• Representative compounds of this scope which have been found to possess antimicrobial properties, especially antibacterial properties to a favourable degree are:
• the subject S-nitro-2-furyl-2-isoxazolines of the Formula I, given above may be prepared by reacting a 5-nitro-2-furyl nitrile oxide having the Formula II with an ethene derivative having the Formula III RzCHzR (III)
• the reaction is conveniently effected by generating the nitrile oxide of Formula II as required during the course of the reaction from the corresponding 5-nitro-2-furohydroxamoyl halide having the Formula IV wherein X represents halogen.
• the 5-nitro-2-furohydroxamoyl halide of Formula IV and the ethene derivative of Formula III are preferably contacted in the presence of a basic condensation promotor, for example sodium methoxide.
• the compound of Formula IV may be directly reacted with the compound of 'Formula III, preferably by heating together in the presence of toluene or other inert solvent.
• the S-nitro-2-furohydroxamoyl halide of Formula IV is preferably the chloride or bromide.
• the halides may be prepared by conventional methods: the chloride may be obtained, for instance, by the method described by Doyle, Hanson, Long and Nayler in the Journal of the Chemical Society (1963) at page 5845 or by that described in Helvetica Chimica Acta (1963) volume 46 at page 1067.
• the halide used as starting material in the process of the invention may be a purified product or it may be the crude product as prepared, if desired after partial purification.
• the compounds of the invention have useful pharmacological and, in particular, antimicrobial properties, being valuable antibacterial, antifungal, antiviral, antihelminthic and coccidiostatic agents.
• the compounds are thus suitable for internal or external veterinary and medicinal use and are particularly valuable in the treatment of infections of the intestinal and, more especially, the urinary tract.
• the present invention further provides a method for the treatment of a mammal suffering from a microbial infection, which method comprises administering to said mammal a therapeutically effective amount of a compound of the Formula I as hereinbefore defined, and in a particular aspect the invention provides a method for the treatment of a mammal suffering from a urinary tract, microbial infection, which method comprises administering to said mammal a therapeutically etfective amount of a compound of the Formula I as hereinbefore defined.
• the specific compounds listed above are of special interest.
• 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 paraifin, 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 contain at least one active ingredient of the Formula I in aqueous ethanol, in particular 45% to 75% by weight ethanol, to which to 20% by weight of glycerol may be added, if desired. Solutions prepared from polyethyleue 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% by weight.
• 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% by weight of active substance to which glycerol or fiavourings 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 fiavourings.
• Solid dosage units in particular tablets, drages (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 90% by weight of the comp of the general Formula I to enable the administration of daily doses of from 0.1 to 2.5 grams to adult mammals, or of suitably reduced doses to children, to be made.
• Tablets and drage 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.
• Drage cores may then be coated, for example with concentrated sugar solutions which can also contain gum arabic, talcum and/0r titanium dioxide, or they may be coated with a lacquer dissolved in volatile organic solvents or mixture of solvents.
• Dyestuffs 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 contain, for example mixtures of a compound of Formula I with polyethylene glycol.
• Hard gelatine capsules contain, for example, granulates of an active substance with solid pulverulent carriers, for instance lactose, saccharose, sorbitol, mannitol, starches (such as potato starch, maize starch or amylopectin), cellulose derivatives of gelatine, and magnesium stearate or stearic acid.
• compounds of the General Formula I can be present as sole active ingredients or they can also be combined with other known pharmacologically active, and especially antibacterial and/ or antimycotically or other antimicrobially active substances, for example, to broaden the range of application.
• Daily dosages for example for the treatment of urinary tract infections, are preferably of the order of from about 1 to 100, or more preferably from about 1 to 40 mg./kg. administered orally.
• the compounds of the invention have been shown to exhibit valuable antimicrobial and notably anti-bacterial properties in vitro and are thus suitable for use in the protection of organic materials susceptible to microbial attack.
• organic material include synthetic polymeric materails, proteinaceous or carbohydrate substances or natural or synthetic fibres or textile materials produced therefrom.
• the present invention further provides a method for protecting organic material susceptible to microbial attack, which process comprises treating said material with an effective amount of a compound of the Formula I as hereinbefore defined.
• a compound of the Formula I as hereinbefore defined.
• EXAMPLE 1 A solution of 2.3 grams of metallic sodium dissolved in 50 millilitres of anhydrous methanol was added slowly to a mixture of 19.1 grams of 5-nitro-2-furohydroxamoyl chloride and 6.7 grams of allyl cyanide dissolved in 150 millilitres of anhydrous methanol at to After allowing to stand, the crystalline precipitate which formed was collected, washed with water and recrystallised from a mixture of water and ethanol.
• the product was 5-cyanomethyl-3-(5-nitro-2-furyl)-2- isoxazoline, having melting point 165.
• the product was 5-methyhnercaptomethyl-3-(S-nitro- 2-furyl)-2-isoxazoline, having melting point 130".
• the product was 5-(2,3-epoxy-1-propoxymethyl)-3- (S-nitro-Z-furyl)-2-isoxazo1ine, having melting point 81.
• the product was 5-acetoxymethyl-3-(5-nitro-2-furyl)- 2-isoxazoline, having melting point 136.
• the product was 5 acetamidomethyl 3 (5-nitro-2- furyl)-2-isoxazoline, having melting point 164.
• the product was 5-(but-3-one-l-yl)-3-(5-nitro-2-furyl)- 2-isoxazoline, having melting point 110".
• the product was 5-cyanoacetamidomethyl-3-(5-nitro-2- furyl)-2-isoxazoline, having melting point 156.
• the product was 3 (5 nitro 2 furyl) 5 ureidomethyl-2-isoxazoline, having melting point 218 with decomposition.
• Example 10 The procedure described in Example 1 was carried out using the molecular equivalent of N-allylmorpholine as starting material instead of allyl cyanide, the reaction conditions being otherwise essentially the same.
• Example 11 The procedure described in Example 1 was carried out using the molecular equivalent of allyl bromide as starting material instead of allyl cyanide, the reaction conditions being otherwise essentially the same.
• the product was 5-bromomethyl-3-(5-nitro-2-furyl)-2- isoxazoline having melting point 105.
• the product was 5-chloromethyl-5-methyl-3-(5-nitro-2- furyl)-2-isoxazoline, having melting point 113.
• EXAMPLE 13 A solution of 2.3 grams of metallic sodium dissolved in 50 millilitres of anhydrous methanol was added slowly to a solution of 19.1 grams of 5-nitro-2-furohydroxamoyl chloride dissolved in millilitres of anhydrous methanol through which was passed a continuous stream of propylene gas and which was maintained at 10 to 15. After allowing to stand the crystalline precipitate which formed was collected, Washed with water and recrystallised from a mixture of water and ethanol.
• the product was S-methyl-S-(5-nitro-2-furyl)-2-isoxazoline, having melting point 137.
• the product was 3-(5-nitro-2-furyl)-5-pyrrolidin-1-ylmethyl-Z-isoxazoline.
• Example 17 The procedure described in Example 1 was carried out using the molecular equivalent of N,N-diethylallylamine as starting material instead of allyl cyanide, the reaction conditions being otherwise essentially the same.
• the product was 5-(N,N-diethylaminomethyl)-3-(5- nitro-2-furyl)-2-isoxazoline.
• the molecular equivalent of any of the following reactants instead of N,N-diethylallylamine, N,N-dimethylallylamine, N,N-di-propylallylamine, the following products are obtained, respectively: 5-(N,N dimethylaminomethyl) -3-(5-nitro-2-furyl)-2-isoxazoline, 5 (N,N-di-npropylaminomethyl)-3-(5-nitro-2-furyl)-2-isoxazoline.
• Example 1 The procedure described in Example 1 was carried out using the molecular equivalent of N-allylisobutyramide as starting material instead of allyl cyanide, the reaction conditions being otherwise essentially the same.
• the product was 5-(isobutyramidomethyl)-3-(5-nitro- 2-furyl)-2-isoxazoline, having melting point 161.
• the product was S-(hexanamidomethyl)-3-(5-nitro-2- furyl)-2-isoxazoline.
• the product was 5-chloroacetamidomethyl-3-(S-nitro- 2-furyl)-2-isoxazoline, having melting point 148.
• the product was 5-dichloroacetamidomethyl3-(5-nitro- 2-furyl)-2-isoxazo1ine, having melting point 187.
• the product was 5-bromoacetamidomethyl-3-(5-nitro- 2-furyl)-2-isoxazoline.
• the product was 5-methoxyacetamidomethyl-3-(5- nitro-2-furyl)-2-isoxazoline, having melting point 144.
• EXAM'PLE 24 A solution of grams of 5-cyanoacetamidomethyl-3- (5-nitro-2-furyl)-2-isoxazoline dissolved in 200 millilitres of anhydrous ethanol was saturated with anhydrous hydrogen chloride gas at 20 to 30. After allowing to stand, 100 millilitres of water was added and the mixture was heated to 60 and then cooled. The crystalline precipitate which formed was collected, washed with water and recrystallised from a mixture of water and ethanol.
• the product was 5-(ethoxycarbonyl-acetamidomethyl)- 3-(5-nitro-2-furyl)-2-isoxazoline.
• EXAMPLE 25 The procedure described in Example 1 was carried out using the molecular equivalent of N-allyl-cyclohexanecarboxamide as starting material instead of allyl cyanide, the reaction conditions being otherwise essentially the same.
• the product was 5-(N-cyclohexanecarbox-amidomethyl)-3-(5-nitro-2-furyl)-2-isoxazoline, having melting point 158.
• Example 8 The procedure described in Example 1 was carried out using the molecular equivalent of 1-allyl-3-methylurea as starting material instead of allyl cyanide, the reaction conditions being otherwise essentially the same.
• the product was 5-(3-methylureidomethyD-3-(S-nitro- 2-furyl)-2-isoxazoline, having melting point 216.
• the product was 5-isopropoxymethyl-3-(S-nitro-Z- furyl)-2-isoxazolir1e, having melting point 79.
• EXAMPLE 28 The procedure described in Example 1 was carried out using the molecular equivalent of allyl-chloride as starting material instead of allyl cyanide, the reaction conditions being otherwise essentially the same.
• the product was 5-chloromethyl-3-(5-nitro-2-furyl)-2- isoxazoline having melting point 102.
• EXAMPLE 29 Preparation of tablets g. of active substance, e.g., of S-cyanoacetamidomethyl-3-(5-nitro-2-furyl)-2-isoxazoline are mixed with 60.0 g. of maize starch and 35.0 g. of lactose, the mixture is moistened with a solution of 5.0 g. of gelatin and 3.0 g. of glycerol in 70.0 g. of Water and granulated through a sieve. The granulate is mixed with a' mixture of 15.0 g. of talcum, 10.0 g. of maize starch and 2.0 g. of magnesium stearate. The resulting mixture is pressed into 1,000 tablets each containing 100 mg. of active substance. If desired the tablets can be grooved for better adaptation of the dosage.
• active substance e.g., of S-cyanoacetamidomethyl-3-(5-nitro-2-furyl)-2-isoxazoline are mixed with 60.0 g
• Active substance e.g. 5-chloracetamidomethyl- 3-(5-nitro-2-furyl)-2-isoxazoline 100.0 Maize starch 27.0 Gelatin 8.0
• Composition I is granulated in the heat with composition (II) through a sieve of 1.2 mm. mesh diameter. The dried granulate is mixed with composition (HI) and the resulting mixture is pressed into 1,000 dragee cores. These are then coated with composition (IV) and dried. The dragees obtained weigh 255.0 mg. and contain 100 mg. of active substance.
• Active substance e.g. S-methoxyacetamido-
• the active substance and the colloidal silicon dioxide are passed through a sieve of 1.2 mm. mesh diameter (I).
• the p-hydroxybenzoic acid esters, the citric acid and the sodium cyclamate are dissolved in the given amount of boiling distilled water; the glycerol is then added to this solution (II).
• the sodium carboxymethyl cellulose and the sugar are thoroughly mixed (III).
• composition (III) is then added at 75 C. to Solution (II) under stirring until complete dissolution of (III).
• the viscous, slightly turbid liquid is cooled to room temperature, filtered, if necessary, and mixed with composition (I). Water is added to the resulting mixture up to the prescribed weight of 1,155.0 g. and the syrup obtained is homogenised.
• R represents the grouping NH.CO.R wherein R represents alkoxy having from 1 to 3 carbon atoms, the group alkyl having from 1 to 6 carbon atoms or alkyl having from 1 to 6 carbon atoms substituted by 1 or 2 chlorine atoms, bromine atoms, alkoxy groups having from 1 to 6 carbon atoms, alkoxycarbonyl groups having from 2 to 7 carbon atoms, or cyano groups, ureido or ureido N-substituted by one to three alkyl groups, which alkyl groups may be the same or different and may each have from 1 to 3 carbon atoms; and R represents hydrogen or methyl.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• 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)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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Cited By (14)

• 0
  • NL NL137326D patent/NL137326C/xx active
• 1967
  • 1967-08-26 GB GB3935167A patent/GB1234213A/en not_active Expired
• 1968
  • 1968-08-09 FI FI682252A patent/FI48930C/fi active
  • 1968-08-14 US US00752479A patent/US3769295A/en not_active Expired - Lifetime
  • 1968-08-16 DK DK397368AA patent/DK118820B/da unknown
  • 1968-08-16 NL NL6811722A patent/NL6811722A/xx unknown
  • 1968-08-16 NO NO3235/68A patent/NO125931B/no unknown
  • 1968-08-16 SE SE11046/68A patent/SE330540B/xx unknown
  • 1968-08-22 CH CH1259968A patent/CH502372A/de not_active IP Right Cessation
  • 1968-08-23 AT AT824568A patent/AT277221B/de not_active IP Right Cessation
  • 1968-08-23 IE IE1030/68A patent/IE32300B1/xx unknown
  • 1968-08-23 BE BE719891A patent/BE719891A/xx unknown
  • 1968-08-23 FR FR1589115D patent/FR1589115A/fr not_active Expired
  • 1968-08-23 CS CS605368A patent/CS157037B2/cs unknown
  • 1968-08-23 ES ES357511A patent/ES357511A1/es not_active Expired
  • 1968-08-23 YU YU01990/68A patent/YU199068A/xx unknown
  • 1968-08-23 DE DE19681795208 patent/DE1795208A1/de active Pending
  • 1968-08-23 JP JP43059998A patent/JPS4827310B1/ja active Pending
  • 1968-08-23 CA CA028264A patent/CA933926A/en not_active Expired
  • 1968-11-22 FR FR174905A patent/FR8102M/fr not_active Expired

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