Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
  • C07D487/18—Bridged systems

Definitions

• This invention relates to compounds and compositions effective in controlling pathogenic microorganisms, and particularly to derivatives of methenamine.
• the preferred known chemotherapeutic agents against many infections of the intestinal tract are 5-chloro-7- iodo-8-quinolinol and sulfaguanidine.
• the first mentioned compound is not well tolerated by persons allergic to iodine. The latter is relatively weak in its antimicrobial elfects.
• Methenamine, mandelic acid, and the salt of methenamine with mandelic acid have been used as disinfectants for the urinary tract.
• quaternary ammonium salts of the formula in which R is lower alkoxy, preferably methoxy, or hydroxy, and X- is the anion of an acid at least as strong as phosphoric acid have much stronger bacteriostatic efiects in vitro against a wide variety of microorganisms including those which are not readily controlled by tolerable doses of the known chemotherapeutic agents, and that the quaternary ammonium salts are relatively nontoxic.
• discs of filter paper having a diameter of 9 millimeters were sterilized in an autoclave and placed on cultures of the microorganisms on agar plates. 10% solutions or suspensions of each tested compound containing 2.5 mg. of the compound were applied to the discs, and the cultures carrying the discs were incubated at 37 C.
• Table 1 lists the diameters of the zones in which the compounds were elfective in inhibiting microbial growth. A diameter of 9 mm. indicates no practical bacteriostatic action, and a large diameter value is indicative of high bacteriostatic potency.
• the compounds of the invention are prepared by reacting methenamine with an equimolecular amount of a 2-hydroxyor 2-alkoxy-5-nitrobenzyl ester of the formula wherein R is hydroxy or lower alkoxy, and X is the anionic radical of a physiologically tolerated acid, at least as strong as phosphoric acid.
• the 2-hydroxyand 2-methoxy-S-nitrobenzyl halides are most readily available and are preferred.
• the reaction occurs readily in a liquid medium, such as an inert solvent, at any temperature at which the reaction mixture is liquid, a reaction temperature of 20 to 50 C. being most convenient.
• the several compounds of the invention can also be converted into each other by a double reaction of the type.
• R is hydroxy or lower alkoxy
• X and X- are anions of an acid at least as strong as phosphoric acid
• Y is a cation whose salt with X is much less soluble than the desired, antimicrobial compound in any convenient solvent.
• EXAMPLE 1 9.38 g. 2-hydroxy-5-nitrobenzyl chloride (0.05 mole) of high purity were dissolved in 250 ml. chloroform, and the solution was added in a thin stream with stirring to a solution of 7.01 g. pure methenamine (0.05 mole) in ml. chloroform. A slightly exothermic reaction started at once, and yellow methenamine 2-hydroxy-5- nitrobenzyl chloride started precipitating at once. The reaction mixture was further stirred for 18 hours at ambient temperature whereupon the precipitate was filtered off with suction and dried in a vacuum at room temperature. It weighed 16.4 g. (100% yield) and melted with decomposition at C.
• Methenamine 2-hydroxy-5-nitrobenzyl chloride is only sparingly soluble in cold water and practically insoluble in the usual organic solvents. Methanol or ethanol may therefore be used instead of chloroform in the aforedescribed procedure.
• EXAMPLE 2 70 g. 2-methoxy-5-nitrobenzyl chloride (0.348 mole) of high purity were dissolved in 400 ml. chloroform, and 48.7 g. pure methenamine (0.348 mole) were gradually added with stirring and dissolved almost completely. Methenamine 2-methoxy-5-nitrobenzyl chloride started precipitating after about two hours at ambient temperature, and stirring was continued for three days.
• the precipitate was then recovered by suction filtration and dried in a vacuum. It weighed 102.7 g. (86.3% yield) and melted with decomposition at 184 C. The compound was identified as C H ClN O by elementary microanalysis and by its equivalent weight which was determined as in Example 1.
• the compound dissolves very readily in water and methanol, is soluble in glacial acetic acid, slightly soluble in ethanol, and only sparingly soluble in other common organic solvents.
• EXAMPLE 4 5 g. methenamine 2-methoxy-5-nitrobenzyl chloride (0.0146 mole) were reacted in 30 ml. water with 2.3 g. powdered silver sulfate (0.0073 mole). The mixture was shaken at ambient temperature for two hours. The silver chloride formed was removed by filtration, and the filtrate was evaporated to dryness in a vacuum at ambient temperature.
• Salts of methenamine 2-hydroxy-5-nitrobenzyl hydroxide and of its lower alkyl ethers with all strong acids are readily prepared from methenamine and the corresponding 2-hydroxy-5-nitrobenzy1 esters or 2-lower-alkoxy-5-nitrobenzyl esters, as illustrated in Examples 1 to 3 or by double reaction of salts as illustrated in Examples 4 and 5.
• the salts with acids weaker than phosphoric acid are not stable enough and have not been isolated successfully.
• the quaternary ammonium salts of the invention are compounded with suitable carriers, excipients, and compatible other physiologically active agents in the usual manner to convert them to dosage units, as illustrated in the following example.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=4354107

Family Applications (1)

Country Status (9)

Cited By (2)

Family Cites Families (1)

• 1968
  • 1968-06-27 CH CH964168A patent/CH505121A/de not_active IP Right Cessation
• 1969
  • 1969-05-08 BR BR208634/69A patent/BR6908634D0/pt unknown
  • 1969-05-12 GB GB24160/69A patent/GB1199268A/en not_active Expired
  • 1969-05-21 SE SE07165/69A patent/SE340100B/xx unknown
  • 1969-05-26 US US827950A patent/US3574209A/en not_active Expired - Lifetime
  • 1969-06-10 FR FR6919046A patent/FR2011711A1/fr not_active Withdrawn
  • 1969-06-19 ES ES368557A patent/ES368557A1/es not_active Expired
  • 1969-06-25 AT AT604069A patent/AT291223B/de not_active IP Right Cessation
  • 1969-06-27 BE BE735338D patent/BE735338A/xx unknown

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