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

• compositions in the treatment of trichomoniasis. More specifically, it relates to the provision of esters of 3-(or )-(5'-nitrofur-2'-yl)- 5-(or 3)-(lower)alkyl-isoxazol-4-yl carboxylates characterized by trichomonocidal activity.
• Trichomoniasis is a disease caused by trichomonads in both humans and animals.
• the disease in the human female is characterized by a persistent vaginal discharge.
• the trichomonad also sometimes invades the male urethra and bladder.
• trichomoniasis is a venereal disease accompanied by abortion, sterility and pyometra. Because of the seriousness of the disease, various attempts have been made to develop effective trichomonocidal agents.
• the present invention is based upon the discovery of new compounds and of good trichomonocidal activity therein.
• These compounds are (lower) alkyl esters of 3-(or 5 (5 '-nitrofur-2-yl) -5- or 3 (lower) alkyl-isoxazol-4-y1 carboxylates which may be characterized by the following general formula I:
• R and R is 5-nitro-2-furyl and the other is a (lower)alkyl;
• R is a (lower)alkylene or (lower)alkylidene;
• R and R may be each a (lower)alkyl or together may form a ring system of up to ten atoms which may contain an additional heteroatom, such as oxygen or 3,465,000 Batented Sept. 2, 1969
• I OzN 0 F71- dlO-CHz-CHz-N(OH)3)2 N2 sir 1 CH 0 3 n and is named, for example, di-N-methylaminoethyl 5- methyl-3-(5'-nitro-2-furyl)isoxazol-4-carboxylate.
• the 5-methyl-3-(5'-nitro-2'-furyl)isoxazol-4-carboxylate esters are prepared from S-nitrofur-Z-aldoxime according to the following scheme in which R R and R have the meaning set forth above.
• Compound IV was condensed with a tort.- butyl alkanoylacetate (e.g., the acetoacctate) in the presence of an alkali metal alkoxide in an alkanol (e.g., sodium methoxide in methanol [following the procedure of Doyle et al., J. Chem. Soc. 5845 (1963)] to give tert.- butyl 5-lower alkyl-3-(5'-nitro-2-furyl)isoxazol 4 carboxylate (V). Hydrolysis of the latter with concentrated sulfuric acid for two hours at 60 gives 5-lower alkyl-3- (5-nitro-2'-furyl)isoxazol-4-carboxylic acid (VI).
• a tort.- butyl alkanoylacetate e.g., the acetoacctate
• an alkali metal alkoxide in an alkanol e.g., sodium methoxide in methanol [following the procedure of Doyle
• the 3- lower alkyl-5- (5 '-nitro2'-furyl isoxazol-4-carboxylate esters are prepared from 2-furoyl chloride (X) by condensation with an alkali metal salt of an alkyl alkanoylacetate (e.g. sodio ethyl acetoacetate) in the presence of an inert solvent (e.g. benzene) to give Compound XII which is treated with hydroxylamine hydrochloride, giving Compound XIII, ethyl 3-R -5-(2-furyl)-isoxazol- 4-carboxylate.
• an alkali metal salt of an alkyl alkanoylacetate e.g. sodio ethyl acetoacetate
• an inert solvent e.g. benzene
• Compound XIV is hydrolyzed with an alcoholic base or acid to Compound XIV, 3R -5-(2'-furyl)-isox azol-4-carboxylic acid.
• the acid is nitrated with concentrated nitric acid in acetic anhydride to give Compound XV, 3-R -5-(5-nitro-2'-furyl)isoxazol-4-carboxylic acid.
• Compound XV may be converted to the 4-carbonyl chloride (Compound XVI) by heating under reflux for about two-three hours with thionyl chloride. Condensation of Compound XVI with an aminoalcohol of Formula VIII as described above, gives the desired compounds of Formula XVII.
• aminoalcohols of Formula VIII which are useful for the abovedescribed reactions with Compounds VII or XVI are di-N-methylethanolamine, di-N-methyl-yaminopropanol, di N cyclohexylethanolamine, 3-azabicyclo[3.2.2]nonane-3-ethanol, N-methylol pyrrolidone, N-methylol-morpholine, N-methylol-thiamorpholine, and the like.
• Trichomonocidal compositions can be formulated with the compounds of the present invention as the active component so as to be administered in the form of tablets, dragees, capsules, suppositories, injectable liquids or liquids to be administered in drops, emulsions, suspensions, syrups and the like.
• the formulation should contain the active trichomonocidal component and conventional pharmaceutical excipients.
• the trichomonocidal compositions should contain at least 0.1% of the active trichomonocidal component.
• the actual percentage of the active component in the composition may be varied and should conveniently be between about 2% and 60%, or more, of the weight of each dosage unit.
• the amount of active ingredient in a therapeutically useful composition or preparation should be such that a suitable dosage unit will be obtained.
• the trichomonocidal compositions of the present invention should contain an amount of active ingredient such that the dosage schedule will result in the daily administration of between 10 and 500 mg./kg. of body weight of animal being treated.
• the reaction mixture was left at room temperature overnight the acetone removed under reduced pressure, and the residue shaken with water (50 ml.) and extracted with ethyl acetate (2 50 ml.).
• the combined ethyl acetate extracts were washed with water (2 75 ml.), dried over magnesium sulfate, filtered, and the ethyl acetate removed under reduced pressure, when a white solid was obtained.
• the solid was washed with cold hexane (50 ml.), filtered and dried. It had a MP. of 125130 and weight of 1.7 g. (51%).
• the infrared and n.m.r. spectra were in agreement with the assigned structure.
• R and R are 5'-nitro-2-furyl and the other is (lower) alkyl; R is a (lower) alkylene and each of R and R is individually a (lower) alkyl 2.
• R is (lower)- alkyl and R is 5-nitro-2-furyl.
• the compound having the formula N I h ⁇ 0 10.
• the compound having the formula CH CH3 ⁇ 0 3 11.
• the compound having the formula 10 References Cited UNITED STATES PATENTS 1,889,678 11/1932 Mannich 260--477 2,421,129 5/1947 Reasenberg et a1. 260-477 ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Plural Heterocyclic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Cosmetics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

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Country Status (14)

Cited By (1)

Citations (2)

• 1966
  • 1966-12-28 US US605155A patent/US3465000A/en not_active Expired - Lifetime
• 1967
  • 1967-12-21 IL IL29189A patent/IL29189A/en unknown
  • 1967-12-22 DK DK647167AA patent/DK123359B/da unknown
  • 1967-12-22 GR GR670134949A patent/GR34949B/el unknown
  • 1967-12-27 NO NO00171162A patent/NO126181B/no unknown
  • 1967-12-27 SE SE17784/67A patent/SE338048B/xx unknown
  • 1967-12-27 ES ES348709A patent/ES348709A1/es not_active Expired
  • 1967-12-27 DE DE19671695534 patent/DE1695534A1/de active Pending
  • 1967-12-28 GB GB58763/67A patent/GB1212698A/en not_active Expired
  • 1967-12-28 FR FR1560394D patent/FR1560394A/fr not_active Expired
  • 1967-12-28 AT AT1175167A patent/AT271474B/de active
  • 1967-12-28 CH CH1826867A patent/CH484936A/de not_active IP Right Cessation
  • 1967-12-28 BE BE708636D patent/BE708636A/xx unknown
  • 1967-12-28 NL NL6717736A patent/NL6717736A/xx unknown
• 1968
  • 1968-03-27 FR FR145698A patent/FR7385M/fr not_active Expired

Patent Citations (2)

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