Classifications

• • H—ELECTRICITY
  • H04—ELECTRIC COMMUNICATION TECHNIQUE
  • H04Q—SELECTING
  • H04Q11/00—Selecting arrangements for multiplex systems
  • H04Q11/04—Selecting arrangements for multiplex systems for time-division multiplexing
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

• This invention relates to novel cycloalkyllactamimides which are useful as hypoglycemic and antiviral agents.
• H anion 1 Formula III This invention relates to compounds represented or named in either tautomeric form as illustrated by general Formulas I and II.
• R and n have the meanings defined hereinbefore.
• Pharmaceutically acceptable acid addition salts of the base compounds of this invention are those of any suitable inorganic or organic acid.
• Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric, or phosphoric acids and the like.
• Suitable organic acids are, for example, carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetie, cinnamic, salicylic, 2-phen0xybenzoic and the like, or sulfonic acids such as methane sulfonic, 2-hydroxyethane sulfonic acid and the like.
• novel compounds of this invention and pharmaceutically acceptable acid addition salts thereof are useful as hypoglycemic and antiviral agents.
• the compounds of this invention can be administered to animals, mammals and humans either alone or in the form of pharmaceutical preparations which contain the novel compounds suitable for oral or parenteral administration.
• Pharmaceutical preparations containing novel compounds of this invention and conventional pharmaceutical carriers can be employed in unit dosage forms such as solids, for example, tablets and capsules, or liquid solutions, suspensions or elixirs for oral administration or liquid solutions suspensions, emulsions and the like for parenteral use.
• the quantity of compound administered can vary over a wide range to provide from about 1.0 mg./kg. (milligram per kilogram) to about mg./kg. of body weight of the patient per day to achieve the desired effect.
• Unit doses of these compounds can contain, for example, from about 25 to 500 mg. of the compound and may be administered, for example, from 1 to 4 times daily.
• compounds of this invention may be used to control hyperglycemic conditions, for example, as occurs in diabetic patients.
• hypoglycemic activity of compounds of this invention when each of 2-(2-norbornylimino)hexahydroazepine hydrochloride and Z-(Z-adamantanylimino)pyrrolidine hydrochloride were administered to glucose primed rats at 100 mg./kg. of body weight, the plasma glucose was reduced respectively to 78% and 77% of control.
• tail lesions were produced in mice by subcutaneous inoculation of vaccinia -(IDH) virus after which hexahydro-Z-(Z- adamantanylimino] azepine hydrochloride was administered at a dosage level of 20 mg./kg. in one test and at 5 tug/kg. in another test. In each test the number of lesions was decreased by 33% and by 43% respectively as compared to control.
• the compounds of this invention are prepared by reacting an excess of a lactim ether of the formula wherein n and R have the meanings defined hereinbefore and lower alkyl may be methyl, ethyl, and the like in a manner similar to that reported by R. E. Benson and T. L. Cairns, J. Am. Chem. Soc. 70, 2115-8 (1943).
• This reaction may be carried out in the presence or absence of a solvent.
• Suitable solvents for this reaction include lower alcohols such as methanol or ethanol, benzene, toluene, and the like.
• Preferred solvents are lower alcohols.
• a basic or acidic catalyst such as a tertiary amine or hydrogen chloride may be added to the reaction mixture.
• the hydrochloride salt of the reactant primary amine be used in the reaction.
• the temperature of the reaction may vary from 40 C. to 180 C., and preferably the temperature is from about 15 to 25 C.
• the reaction time may vary from 1 hour to about 60 days depending upon the temperature of the reaction, the reactant primary amine, and more particularly the degree of steric hindrance of the amine since highly sterically hindered amines react very slowly.
• lactim ethers which find use in this reaction may be prepared from commercially available corresponding lactams by methods known in the art. For example, by reaction of the appropriate lactam with dimethyl sulfate in a solvent such as benzene, toluene, xylene or the like at the reflux temperature of the solvent for 224 hours the corresponding O-methyllactim ether is obtained.
• a solvent such as benzene, toluene, xylene or the like
• the reactant primary amines as represented by Formula V are commercially available or may be prepared, for example, by reduction of the oxime of the corresponding ketone.
• the above described reaction may also be carried out using known thiolactim ethers, such as, S-methylthiocaprolactim [I-I. Behringer and H. Meier, Ann. 607, 67- 91 (1957)], or by using thiolactams wherein it may be advantageous to employ a catalyst such as mercury or silver oxide or cyanide [J A. Gautier and J. Renault, C. R. Acad. Sci. 234, 2081 (1952)].
• thiolactim ethers such as, S-methylthiocaprolactim [I-I. Behringer and H. Meier, Ann. 607, 67- 91 (1957)]
• thiolactams wherein it may be advantageous to employ a catalyst such as mercury or silver oxide or cyanide [J A. Gautier and J. Renault, C. R. Acad. Sci. 234, 2081 (1952)].
• the compounds of this invention may also be prepared using a complex of an appropriate lactam with phosphorus oxychloride, phosgene, borontrifiuoride etherate, dimethyl sulfate, hydrogen halide or a combination of two or more such reagents.
• This reaction has been studied by H. Bredereck in a series of articles in Chem. Ber., 1953-1968, particularly in volume 94, 2278 (1969) and volume 97, 1403 (1964).
• the complex formed is reacted with an appropriate primary amine described hereinabove in an aromatic hydrocarbon solvent such as benzene, toluene, or xylene or an alkyl polyhalide solvent such as carbon tetrachloride, chloroform, methylene chloride, tetrachloroethylene or the like.
• aromatic hydrocarbon solvent such as benzene, toluene, or xylene
• alkyl polyhalide solvent such as carbon tetrachloride, chloroform, methylene chloride, tetrachloroethylene or the like.
• the reaction temperature is limited by the boiling point of the solvent, however, in some cases it is advantageous to carry out the reaction at room temperature or with cooling at to -40 C. depending on the reactants.
• EXAMPLE 7 2- (Z-Norbornylimino) azacyclotridecane hydrochloride To 21.7 g. (0.11 mole) of 2-azacyclotridecanone in 200 ml. of dry benzene is added dropwise 16.9 g. (0.11 mole) of phosphorus oxychloride. The mixture is stirred at room temperature for 4 hours after which is added 14.7 g. (0.10 mole) of 2-aminonorbornane. Stirring is continued for 5 hours, then the mixture is refluxed for 12 hours. The mixture is acidified with 2N HCl and allowed to stand at room temperature for 4 weeks. Crystals form and are separated, and dissolved in chloroform.
• a compound of Claim 2 which is 2-(2-norb0rnylimino)hexahydroazepine and pharmaceutically acceptable acid addition salts thereof.
• a compound of Claim 4 which is Z-(Z-adamantanylimino)pyrrolidine and pharmaceutically acceptable acid addition salts thereof.
• a compound of Claim 4 which is 2-( l-adamantanylimino)piperidine and pharmaceutically acceptable acid addition salts thereof.
• a compound of Claim 4 which is heXahydro-2-(1- adamantanylimino)azepine and pharmaceutically acceptable acid addition salts thereof.

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Cited By (5)

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• 1972
  • 1972-08-11 US US00280049A patent/US3838151A/en not_active Expired - Lifetime
• 1973
  • 1973-04-30 ZA ZA732927A patent/ZA732927B/xx unknown
  • 1973-05-02 GB GB2091673A patent/GB1401735A/en not_active Expired
  • 1973-05-03 AU AU55179/73A patent/AU466344B2/en not_active Expired
  • 1973-05-04 IL IL42202A patent/IL42202A/xx unknown
  • 1973-05-08 CA CA170,730A patent/CA962268A/en not_active Expired
  • 1973-05-16 DE DE2324634A patent/DE2324634A1/de active Pending
  • 1973-05-17 JP JP48054179A patent/JPS4945063A/ja active Pending
  • 1973-06-21 DK DK344973AA patent/DK134014B/da unknown
  • 1973-06-27 NL NL7308929A patent/NL7308929A/xx not_active Application Discontinuation
  • 1973-07-25 CH CH1086173A patent/CH587814A5/xx not_active IP Right Cessation
  • 1973-08-09 FR FR7329217A patent/FR2195446B1/fr not_active Expired
  • 1973-08-10 BE BE134468A patent/BE803484A/xx unknown

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