Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles

Definitions

• Sydnocarb is conventionally produced by cyanometh- ylation of amphetamine followed by nitrosation and ring closure with a mineral acid yielding sydnophen as an acid halide salt which is reacted with phenylisocyanate under mildly basic conditions to introduce the N-phen- ylcarbamoyl group.
• amphet ⁇ amine may be employed as the initial reactant as the racemic ⁇ ,.l-mixture or as the pure d.- or _l-isomer to yield racemic or optically active sydnophen and ultim- ately sydnocarb.
• Sydnocarb The metabolites of Sydnocarb have been studied by several groups. L.E. Kholodov and E.T. Lilin, Mater. Resp. Rasshir. Konf. Farmacol. Gruz. 2nd 1977, 84-5 report finding hydroxylation of Sydnocarb at the beta carbon of the phenylisopropyl substituent and at the phenyl ring of the phenylcarbamoyl group, hydrolytic cleavage of the phenylcarbamoyl group and ring opening of the heterocyclic nucleus. They report that the psycho- stimulating activity of Sydnocarb is a property of that compound and not its metabolites. Polgar et al. Acta. Pharm. Hung. , 48, Suppl. 23-24 (1978) and Xenobiotica , No. 8, 511-520 (1979) report several hydroxylated metabolites and conjugates of hydroxylated Sydnocarb.
• central nervous system (CNS) stimulants which are 3-(2-amino-2-phenylethyl)-N-[(phenylamino)carbonyl]- sydnonimines optionally substituted in either or both -
• R 1 and R2 are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of l ' to 6 carbon atoms, halo, perfluoroalkyl of 1 to
• R is hydrogen, halo, nitro or alkanoyl of 2 to carbon atoms;
• R 4 is hydrogen, halo, nitro or perfluoroalkyl of
• R and R are, independently, hydrogen or methyl
• R and R are, independently, alkyl of 1 to 4 car ⁇ bon atoms, or when taken with the nitrogen atom to which they are attached, form a pip ⁇ eridinyl, pyrrolidinyl, morpholinyl, N-alkyl piperazinyl in which the alkyl group contain from 1 to 6 carbon atoms or N-phenylpipera- zinyl group; or a non-toxic acid addition salt thereof.
• oxadiazolium salts of this invention are rep ⁇ resented by the following structural formula:
• R- 1 and R are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, perfluoroalkyl of 1 to 3 carbon atoms, nitro, alkanoyl of 2 to 4 carbon atoms, or alkoxyearbonyl of 2 to 4 carbon atoms; . ⁇ fi
• R and R are, independently, hydrogen or methyl;
• R 7 and R8 are, independently, alkyl of 1 to 4 car ⁇ bon atoms, or when taken with the nitrogen atom to which they are attached, form a piper- idinyl, pyrrolidinyl, morpholinyl, N-alkyl piperazinyl in which the alkyl group contains from 1 to 6 carbon atoms or N-phenylpiper- azinyl group; and
• X is the anion of a strong acid having a pKa below 2.
• the oxadiazolium salts of this invention revert to the corresponding nitroso-nitrile precursor via a pH dependent ring opening. Ring opening occurs rapidly un ⁇ der basic conditions and slower in mild acid, in essence demonstrating the reverse of the ring closing accom ⁇ plished with strong acids.
• the nitroso-nitriles are,
• R 1 and R2 are,, independently, hydrogen, alkyl of 1 to ' 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, perfluoroalkyl of 1 to 3 carbon atoms, nitro, alkanoyl of 2 to 4 carbon atoms, or alkoxycarbonyl of 2 to 4 carbon atoms;
• R and R are, independently, hydrogen or methyl
• R are, independently, alkyl of 1 to 4 car ⁇ bon atoms, or when taken with the nitrogen atom to which they are attached, form a pip ⁇ eridinyl, pyrolidinyl, morpholinyl, N-alkyl piperazinyl in which the alkyl group contains from 1 to 6 carbon atoms or N-phenylpipera- zinyl group; or a pharmaceutically acceptable salt thereof.
• halo substituent be chlorine, bromine or fluorine although iodine is acceptable.
• the alkyl and alkoxy sub ⁇ stituents be relatively small, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy and isopropoxy groups being preferred.
• the pharmaceutically acceptable acid addition salts of the compounds of formulae II and II are convention ⁇ ally produced by the method and from any of the acids disclosed in U.S. 3,277,108, which exhibit a pKa below 2.
• the salt is preferably that formed during cycliza- tion of the nitrosonitrile, such as with hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, p_- toluene sulfonic acid, and the like.
• the anion can subsequently be replaced with a desired anion of ion ex- change chromatography following conventional procedures.
• the salts of the compounds of formulae I may be produced with milder acids such as acetic, propionic, oxalic, succinic, maleic, fumeric acid, and the like, as well as with the strong acids previously mentioned in connection with the compounds of formulae II and III.
• the salts formed with the aminic bases of this invention are gen ⁇ erally water soluble, dissociating sufficiently to dis ⁇ solve in aqueous medium to provide a homogeneous solu ⁇ tion.
• the compounds of. this invention- may be formulated for administration in aqueous vehicle for- practical dosing to reduce blood pressure in patients unable to receive treatment orally.
• the compounds of this invention contain one chiral center when R is hydrogen and two chiral centers when R is methyl. Thus, depending upon the identity of the substituent R , there is obtained either one or two racemic mixtures of product.
• the epimers and optical isomers are readily separable by standard techniques well known to the chemist. By selection of the desired starting material, the product can be limited to a single racemic mixture of isomers.
• oxadiazolium salts and the nitroso-nitriles of this invention are prepared by conventional techniques employed in the preparation of sydnonimines.
• the starting materials are either known of pre- parable by routine synthetic methods.
• a properly substituted 2-tertiary amino-2-phenylethyl amine is cyanomethylated with a reactant XCH 2 CN where X may be
• the compounds of formula I are produced from either the nitroso-nitrile of formula III or the oxadiazolium salt of formula II by reaction with an isocyanate-
• the base selected must be suf- ficiently alkaline to neutralize the oxadiazolium salt (including the aminic salt) which permits ring opening and reformation of the nitroso-nitrile which in turn undergoes nucleophilic addition of the isocyanate.
• the antihypertensive activity of c, L-5-amino-3- (2-(dimethylamino)-2-phenylethyl)-l,2,3-oxadiazolium chloride, hydrochloride, which compound is representa- tive in its activity of the compounds of formulae II and III, was established by orally administering the compound to a group of unanesthetized, spontaneously hypertensive rats while indirectly measuring their sys ⁇ tolic blood pressure employing a Decker Caudal Plethys- mograph. A decrease of 51 mmHg blood pressure was found at 1.5 hours after oral administration of 50 mg/ kg of compound and a decrease of 40 mmHg at 1.5 and 4 hours at 25 mg/kg was demonstrated.
• the antihypertensive agents of formulae II and III are useful in treatment of hypertension and as such they may be administered to a patient suffering from hypertension, orally or parenterally, in an amount of from about 25 to 50 mg/kg or more, based upon the test results, in single or divided doses.
• the dosage regimen and route of administration may be varied by the attending physician to achieve the desired response de- pending upon the condition of the pateitn relative to age, severity of hypertensive state, etc.
• mice weighing 17 to 25 gms. are injected orally with drug solubilized or suspended in 1% Tweefl ⁇ 80.
• Control animals are injected with 1% Tween® 80.
• Six Columbus Instrument Company activity cham ⁇ bers are employed.
• Three mice given identical treat ⁇ ment are placed in each chamber for all tests. During each run, control animals (1% Tween® only) occupy 3 chambers; the other 3 chambers measure activity of drug treated animals.
• mice are used in the drug group and 18 mice in the control group.
• Activity counts are recorded every ten minutes for a period of 2 hours.
• the data are analyzed using Stu ⁇ dents "t" test comparing the means of the control and drug groups for each 10 minute period.
• the drug treat ⁇ ed group is compared graphically with the control group in regard to duration of action and dose response at peak drug activity.
• the compounds of formula I are use ⁇ ful in the treatment of anergic disorders (such as sleepiness and fatigue) including related types of depression and narcolepsy.
• anergic disorders such as sleepiness and fatigue
• the dose con- templated for use in the 70 kilogram human would vary from about 35-700 milligrams administered orally once or twice per day under the guidance of a physician.
• the dosage regimen as well as the route of ad ⁇ ministration, oral or parenteral will vary with the condition of the patient relative to age, severity of depression, etc.

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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)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Hydrogenated Pyridines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1981
  • 1981-05-18 US US06/264,892 patent/US4324897A/en not_active Expired - Fee Related
  • 1981-09-08 JP JP56503096A patent/JPS57501479A/ja active Pending
  • 1981-09-08 WO PCT/US1981/001205 patent/WO1982001184A1/en not_active Ceased
  • 1981-09-09 GR GR65999A patent/GR75816B/el unknown
  • 1981-09-10 EP EP81304143A patent/EP0050916A3/en not_active Ceased
  • 1981-09-10 GB GB8127410A patent/GB2100266A/en not_active Withdrawn
• 1982
  • 1982-06-01 DK DK246782A patent/DK246782A/da not_active Application Discontinuation

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