Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• v I v I R is lower alkyl or cycloalkyl
• R is hydrogen, fluorine, chlorine, bromine, lower alkyl or lower alkoxy
• the present invention relates to furanone derivatives.
• the invention provides compounds of formula I,
• a compound of formula I may be obtained by a process comprising reacting a compound of formula II, r R2 wherein R is as defined above, 7 i
• R,--N o;o f wherein R is as definedabove.
• the process of the invention is preferably effected in an inert solvent, e.g. an aromatic hydrocarbon such as benzene, toluene or xylene.
• the reaction temperature is preferably from about to 180 0., preferably to C. Conveniently an excess of an isocyanate of formula III is used.
• the reaction is preferably effected in a sealed vessel, e.g., an autoclave, especially when low-boiling compounds of formula III or low-boiling solvents are used.
• the compounds of formula I may be isolated from the reaction mixture and purified in known manner.
• the free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa.
• the compounds of formula I are useful because they possess pharmacological activity in animals.
• the compounds of formula I are useful as analgesic agents, as indicated in standard tests, for example, the hot plate test in mice on p.o. administration of 10 to 50 mg./kg. animal body weight of the compounds, and, as further indicated, by an inhibition of the phenylbenzoquinone syndrome in mice on p.o. administration of 10 to 50 mg./kg. animal body weight of the compounds.
• the total daily dosage is in the range from about 50 to about 500 mg.
• dosage forms suitable for oral administration comprise from about 12 mg. to about 250 mg. of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
• the compounds of formula I are furthermore useful as central nervous system depressants, as indicated in standard tests, for example, the climbing test and the rotating rod test on i.p. administration of 1 to 10 mg./kg. animal body weight, of the compounds, and, as further indicated, by a depression of the rectal temperature in mice on i.p. administration of from 15 to 30 mg./kg. animal body weight of the compounds.
• the dosage will, of course, vary depending on the compound employed, mode of administration and treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 1 mg. to about 30 mg. per kg. animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form.
• the total daily dosage is in the range from about 50 to about 500 mg.
• dosage forms suitable for oral administration comprise from about 12 mg. to about 250 mg. of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
• the compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
• Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner.
• Representative acid addition salt forms include organic acid salt forms such as the hydrogen maleate, fumarate, tartrate and methane sulphonate and mineral acid salt forms such as the hydrochloride, hydrobromide and sulphate.
• a pharmaceutical composition may comprise a compound of formula I, in free base form or in pharmaceutically acceptable acid additionsalt form, in association with a pharmaceutical carrier or diluent.
• Such compositions may be prepared by conventional techniques to be in the form of, for example, capsules, tablets, suppositories, suspensions or solutions, for enteral or parenteral administration.
• these pharmaceutical compositions may contain suitable preserving, stabilizing, wetting, solubilizing, sweetening, flavouring or colouring agents.
• the contents of the autoclave are evaporated to dryness, the resulting title compound is dissolved in ethanol and converted into the hydrochloride form by the addition of hydrochloroic acid in ethanol.
• the crude product is crystallized from methanol for purposes of purification.
• the hydrochloride form of the title compound has a M.P. of 216-218 (decomp.).
• Example 2 3- [4-ethylcarbamoyloxy-l- (4-oxo-4-phenylbutyl -4-piperidyl] -dihydro-2 (3H) -furanone 12 g. of dihydro-3-[4-hydroxy-1-(4-oxo-4-phenylbutyl 4-piperidyl]-2(3H)furanone and 30 cc. of ethyl isocyanat-e are heated in 120 cc. of benzene at 140 in an autoclave for 48 hours, and the reaction mixture is worked up as described in Example 1.
• the hydrochlorideform of the title compound has a M.P. of 205-208 (decomp) from methanol.
• EXAMPLE 4 3-[1-(4-pfluoropheny1-4-oxobuty1)-4-isopropylcarbamoyloxy 4 piperidyl]-dihydro-2(3H)- furanone 7.5 g. of dihydro-3-[4-hydroxy-l-(4-p-fluorophenyl-4- oxobutyl)-4-piperidyl]-2(3H)-furanone and 11.5 cc. of isopropyl isocyanate are heated in 400 cc. of benzene at 160 in'an autoclave for 21 hours, and the reaction mitxure is worked up as described in Example 1.
• the hydrochloride form of the title compound has a M.P. of 220-221.5 (decomp.) from methanol.
• EXAMPLE 5 Dihydr'o-3- [4-methylcarbamoyloxy-l-(4- oxo-4-phenylbutyl)-4 piperidyl]-2(3H)-furanone 8.5 g. of dihydro-3-[4-hydroxy-l- (4-oxo-4-phenylbutyl)-4-piperidyl]-2(3H)-furanone and 7.3 g. of methyl isocyanate are heatedin 1-00 cc'.'of benzene at 120 in an autoclave for 15 hours, and the crude title compound is converted into'its hydrogen maleate form. M.P. 181- 182 from methanol.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Hydrogenated Pyridines (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=4346960

Family Applications (1)

Country Status (10)

Family Cites Families (1)

• 1973
  • 1973-06-08 DE DE2329338A patent/DE2329338A1/de active Pending
  • 1973-06-08 NL NL7308006A patent/NL7308006A/xx unknown
  • 1973-06-11 US US00368863A patent/US3845061A/en not_active Expired - Lifetime
  • 1973-06-12 JP JP48065460A patent/JPS4949970A/ja active Pending
  • 1973-06-12 FR FR7321234A patent/FR2189031B1/fr not_active Expired
  • 1973-06-12 DD DD171560A patent/DD105234A5/xx unknown
  • 1973-06-13 HU HUSA2499A patent/HU165843B/hu unknown
  • 1973-06-13 BE BE132221A patent/BE800858A/xx unknown
  • 1973-06-15 SU SU1933762A patent/SU468415A3/ru active
  • 1973-06-15 AU AU57005/73A patent/AU5700573A/en not_active Expired

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