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

Definitions

• the present invention relates to substituted heterocyclic compounds, and in particular to nitrofuryl derivatives of isoxazoles and to processes for the production of these compounds.
• a 5-nitro-2-furyl-isoxazole having the Formula I wherein R is a CN, --CO.OR or grouping, the group R being a straightor branched-chain alkyl group containing from 1 to 6 carbon atoms, the alkyl group being unsubstituted or hydroxyl-, alkoxyor halogen-substituted, a straightor branched-chain alkenyl group containing 3 or 4 carbon atoms; or a cycloalkyl group; the group R being hydrogen and the group R being hydrogen, a straightor branched-chain alkyl group containing from 1 to 12 carbon atoms, the alkyl group being unsubstituted or hydroxyl, alkoxyor halogen-substituted, a straightor branched-chain alkenyl group containing 3 or 4 carbon atoms, cycloalkyl, carbalkoxy the alkyl portion of which is a straightor
• R or the group R is alkyl
• each of these groups may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-amyl, isoamyl or n-hexyl.
• Alkyl groups having from 1 to 4 carbon atoms are particularly preferred. If either R or R is an alkyl group subsittuted by a halogen substituent, the halogen may be fluorine or iodine but is preferably chlorine or bromine.
• R or R is an alkyl group which is hydroxyl-, alkoxyor halogen-substituted, preferably the alkyl group contains 1 or 2 halogen, alkoxy or hydroxyl substituents.
• R or R is an alkenyl group, this may be, for example, allyl, Z-methallyl, 2-butenyl (crotyl) or 3-butenyl.
• R or R is a cyclo alkyl 3,562,267 Patented Feb. 9, 1971 group, this may be, for example, cyclohexyl.
• the alkyl portion of the carbalkoxy group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl or n-amyl.
• this chain may be, for example, ethylene, trimethylene, propylene, tetramethylene, methyl-substituted trimethylene, dimethyl-substituted ethylene, pentamethylene, hexamethylene, heptamethylene or dimethyl-substituted pentamethylene.
• the grouping R thus formed may be, for example, morpholinocarbonyl; if the alkylene chain formed by R and R together is interrupted by a nitrogen atom (preferably in the form of a grouping NQ- where Q is hydrogen or an alkyl group having from 1 to 3 carbon atoms) or by a sulphur atom, the grouping R thus formed may be, for example, a l-piperazinylcarbonylor a thiomorpholino-carbonyl grouping, respectively.
• Particularly preferred compounds of the invention have the Formula I wherein R is a CN group or is a 7 Formula II OzN 04: 0 a
• X represents a halogen atom
• the reaction between the 5nitro-2-furohydroxamoyl halide and the reactive methylene compound of Formula III is conveniently carried out in the presence of a basic condensation promotor, preferably sodium methoxide.
• the reactive methylene compound of Formula III used in the reaction may be the compound having the formula NCCH -R or a corresponding reactive alkali metal derivative, preferably the sodium derivative, having the formula NCCH(M)R wherein M is an alkali metal.
• the 5nitro-2-furohydroxa-moyl halide of Formula II 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 so prepared, if desired, after partial purification.
• the reactive methylene compound of Formula III may be, for instance, malononitrile, cyanoacetamide or an N- substituted cyanoacetamide; or an ester of cyanoacetic acid. Examples of preferred reactive methylene compounds are given in the following table in which the appropriate R substituents of Formula III are stated.
• the dehydration may be carried out, for example, by heating at an elevated temperature, preferably at a temperature in the range of from 50 C. to the boiling point of the reaction mixture under reflux.
• the process is preferably carried out in the presence of a conventional agent for dehydrating carbamoyl compounds to the corresponding nitriles, for instance phosphorus oxychloride.
• the compounds of the invention have useful pharmacological and, in particular, antimicrobial properties, being valuable antibacterial, antifungal, antiviral, anthelmintic, coccidiostatic or growth-promoting agents for external or internal pharmaceutical uses.
• novel compounds according to the invention have been found to exhibit outstanding antimicrobial activities, in particular antibacterial activity. In living organisms they are active, for example, against general Staphylococcal infections and infections due to Salmonella and Escherichia coli species.
• 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 4 deterioration by contacting with, impregnation in or otherwise treating the material with the compounds.
• the invention also provides a composition comprising an antimicrobially effective proportion of a S- nitro-Z-furyl-isoxazole of Formula I and a pharmacologically 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 paraffin, or they can consist of aqueous emulsion 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% 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 flavourings 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, 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 compounds of the general Formula I to enable the administration of daily doses of from 0.1 to 2.5 grams to adults, or of suitable 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.
• 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
• Drage 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 volative 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 the 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 gelatines, and magnesium stearate or stearic acid.
• solid pulverulent carriers for instance lactose, saccharose, sorbitol, mannitol, starches (such as potato starch, maize starch or amylopectin), cellulose derivatives of gelatines, 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. They can be combined for example, with 5,7-dichloro-2- methyl-S-quinolinol or other derivatives of 8-quinolinol, with sulfamerazine or sulfafurazole or other derivatives of.
• sulfanilamide with chloramphenicol or tetracycline or other antibiotics, with 3,4,5-tribromosalicylanilide or other halogenated salicylanilides, with halogenated carbanilides, with halogenated benzoxazoles or benzoxazolones, with polychlorohydroxy-diphenylmethanes, with halogen-dihydroxy-diphenyl sulphides, with 4,4-dichloro- 2-hydroxy-diphenylether or 2',4,4'-trichloro-2-hydroxydiphenylether or other polyhalogen-hydroxydiphenylethers, or with bactericidal quaternary compounds or with certain dithiocarbamic acid derivatives such as tetramethylthiuram disulphide.
• carriers which themselves have favourable pharmacological properties may be used, for instance sulphur as powder base or zinc stearate as a component of ointment bases.
• 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 -nitro-2-furyl-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.
• EXAMPLE 1 A solution of 1.15 g. of metallic sodium dissolved in 20 ml. of anhydrous methanol was added slowly to a mixture of 9.5 g. of 5-nitro-2-furohydroxamoylchloride and 3.3 g. of malononitrile dissolved in 80 ml. of anhydrous methanol at 20 to 25.
• the product was 3-(5nitrofuryl-2')-4-carbamoyl-5- amino-isoxazole, having melting point 212 with decomposition.
• EXAMPLE 3 A solution of 1.15 g. of metallic sodium dissolved in 20 ml. of anhydrous methanol was added slowly to a mixture of 9.5 g. of 5-nitro-2-furohydroxamoylchloride and 7.6 g. of l-cyanoacetylpyrrolidine dissolved in 120 ml. of anhydrous methanol at 20 to 25.
• the product was 3-(5-nitrofuryl-2)-4-pyrrolidinocarbonyl-S-amino-isoxazole, having melting point 186.
• the 1-cyanoacetylpyrrolidine used as reactant in the process of Example 3 was prepared by the following method:
• Example 4 The procedure described in Example 3 was carried out using the molecular equivalent of l-cyanoacetylpiperidine as starting material instead of the l-cyanoacetylpyrrolidine, the reaction conditions being otherwise essentially the same.
• the product was 3-(5'-nitrofuryl-2')-4-piperidinocarbonyl-5-amino-isoxazole, having melting point 188 with decomposition.
• the product was 3-(5-nitrofuryl-2)-4-ethoxycarbonylcarbamoyl-S-amino-isoxazole, having melting point 218 with decomposition.
• EXAMPLE 6 A solution of 2.3 g. of metallic sodium dissolved in 40 ml. of anhydrous ethanol was added slowly to a mixture of 19.1 g. of 5 nitro-2-furohydr0xamoyl chloride and 11.3 g. of ethyl cyanoacetate dissolved in ml. of anhydrous ethanol at 20 to 25.
• the product was 3-(5-nitrofuryl-2)-4-ethoxycarbonyl- S-amino-isoxazole, having melting point 200.
• EXAMPLE 7 The procedure described in Example 3 was carried out using the molecular equivalent of N-cyanoacetylmorpho line as starting material instead of the 1-cyanoacetylpyrrolidine, the reaction conditions being otherwise essentially the same.
• the product was 3-(5'-nitrofuryl-2')-4-morpholinocarbonyl 5 amino-isoxazole, having melting point 245 with decomposition.
• EXAMPLE 8 The procedure described in Example 3 was carried out using the molecular equivalent of cyanoacetyl urea as starting material instead of 1-cyanoacetylpyrrolidine, the reaction conditions being otherwise essentially the same.
• the product was 3-(5'-nitrofuryl-2')-4-ureidocarbonyl-S-amino-isoxazole having melting point 208 with decomposition.
• the product was 3-(5'-nitrofuryl-2')-4-(fl-hydroxyethyl-carbamoyl)-5-amino-isoxazole, having melting point 209 with decomposititon.
• EXAMPLE 10 A solution of 2.3 g. of metallic sodium dissolved in 40 ml. of anhydrous methanol was added slowly to a mixture of 19.1 g. of S-nitro-Z-furohydroxamoyl chloride and 9.9 g. of methyl cyanoacetate dissolved in 120 m1. of anhydrous methanol at to After allowing to stand, the crystalline precipitate was collected, washed with water and recrystallised from a mixture of water and dimethylformamide.
• the product was 3-(5-nitrofuryl-2)-4-methoxycarbonyl-S-amino-isoxazole having melting point 240 with decomposition.
• EXAMPLE 12 The procedure described in Example 11 was carried out using the molecular equivalent of isopropylcyanoacetate as starting material instead of the methyl cyanoacetate, the reaction condititons being otherwise essentially the same.
• the product was 3-(5'-nitrofuryl-2)-4-isopropoxycarbonyl-S-amino-isoxazole having melting point 174.
• the product was 3-(5-nitrofuryl-2')-4-allyloxycarbonyl-5-amino-isoxazole having melting point 124.
• the product was 3-(S-nitrofuryl-2)-4-cyclohexyloxycarbonyl-5-amino-isoxazole having melting point 170.
• the product obtained is 3-(5'-nitrofuryl-Z -4- (n-hexyloxycarbonyl -5 -amino-isoxazole, having melting point 185 to 187.
• the product was 3-(5'-nitrofuryl-2)-4-methyl-carbamoyl-5-amino-isoxazole having melting point 238 with decomposition.
• EXAMPLE 16 The procedure described in Example 3 was carried out using the molecular equivalent of N-ethylcyanoaceta mide as starting material instead of the l-cyanoacetylpyrrolidine, the reaction conditions being otherwise essentially the same.
• the product was 3-(5-nitrofuryl-2')-4-ethylcarbamoyl- S-amino-isoxazole having melting point 206 with decomposition.
• N-cyanoacetylamino-n-propanol N'cyanoacetyl-fl-bromo-ethylamine 8 the reaction conditions being otherwise the same, the following products are obtained respectively: 3-(5'-nitrofuryl-Z) 4 'y hydroxypropylcarbamoyl-S-amino-isoxazole, 3-(5'-nitrofuryl-2') 4 B brornoethylcarbamoyl- S-amino-isoxazole.
• the product was 3-(5-nitrofuryl-2')-4-(tertiarybutoxycarbonyl)-5-amino-isoxazole having melting point 171.
• EXAMPLE 22 The procedure described in Example 11 was carried out using the molecular equivalent of fi-chloroethyl cyanoacetate as starting material instead of the methyl cyanoacetate, the reaction conditions being otherwise essentially the same.
• the product was 3-(5'-nitrofuryl-2')-4-(l3-chloroethoxycarbonyl)-5-amino-isoxazole, having melting point initially at 152 following by resetting with subsequent melting at 158.
• R is -CN, -COOR or R2 CON in which R is alkyl of 1 to 6 carbon atoms which is unsubstituted or substituted by hydroxy, halo or alkoxy of from 1 to 4 carbon atoms; alkenyl of 3 or 4 carbon atoms; or cycloalkyl of from 5 to 7 carbon atoms; and
• R is hydrogen
• R is hydrogen; alkyl of from 1 to 12 carbon atoms which is unsubstituted or substituted by hydroxy, halo or alkoxy of from 1 to 4 carbon atoms; alkenyl of 3 or 4 carbon atoms; alkoxycarbonyl on which the alkoxy group has from 1 to 5 carbon atoms; or carbamoyl; or
• R and R taken together, together with the nitrogen atom to which they are attached are pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or 4-lower i alkylpiperazino.
• a compound according to claim 1 wherein R is 3.
• R is hydrogen and R is alkyl of 1 to 5 carbon atoms which is unsubstituted or substituted by hydroxy.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-2)-4-cyano-5-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5' nitrofuryl-2 -4-carbamoyl-5-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z -4-pyrrolidinocarbonyl-S-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5- nitrofuryl-Z')-'4-piperidinocarbonyl-5-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z')-4-(ethoxycarbonyl-carbamoyl) 5 aminoisoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z' -4-ethoXycarbonyl-S-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-2' -4-morpholinocarbonyl-S-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-2' -4-ureidocarbonyl-5-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5- nitrofuryl-Z')-4-(B-hydroxyethyl-carbamoyl) 5 aminoisoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-2' -4-methoxycarbonyl-S-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z' -4-isopropoxycarbonyl-S-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z' -allyloxycarbony1-S-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z) 4 cyclohexyloxycarbonyl 5 aminoisoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-2' -4-methylcarbamoyl-S-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z -4-ethylcarbamoyl-S-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z' -4-allylcarbamoyl-S-amino-isoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-2') 4 tertiarybutoxycarbonyl 5 aminoisoxazole.
• a compound as defined in claim 1 which is 3-(5'- nitrofuryl-Z) 4 (fi-chloroethoxycarbonyl) 5 aminoisoxazole.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Cited By (3)

• 1965
  • 1965-08-18 GB GB35448/65A patent/GB1108397A/en not_active Expired
• 1966
  • 1966-08-10 US US571412A patent/US3562267A/en not_active Expired - Lifetime
  • 1966-08-15 FI FI662125A patent/FI45045C/fi active
  • 1966-08-17 NO NO164335A patent/NO121097B/no unknown
  • 1966-08-17 DK DK421866AA patent/DK118132B/da unknown
  • 1966-08-17 NL NL6611584A patent/NL6611584A/xx unknown
  • 1966-08-17 IL IL26353A patent/IL26353A/xx unknown
  • 1966-08-17 BE BE685636D patent/BE685636A/xx unknown
  • 1966-08-17 SE SE11132/66A patent/SE310679B/xx unknown
  • 1966-08-17 DE DE19661695085 patent/DE1695085A1/de active Pending
  • 1966-08-17 BR BR182173/66A patent/BR6682173D0/pt unknown
  • 1966-08-17 CH CH1188766A patent/CH475270A/de not_active IP Right Cessation
  • 1966-11-15 FR FR83599A patent/FR5947M/fr not_active Expired

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