Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis

Definitions

• Novel compounds useful as hypoglycemic agents are represented by the formula wherein X represents oxygen or sulfur; A represents a bond, or a straight or branched alkylene chain of from 1 to 3 carbon atoms; R represents hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, a straight or branched lower alkenyl group of from 3 to 6 carbon atoms, a cycloalkyl group of from 3 t 6 carbon atoms or phenyl; R represents hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms; n is an integer of from 3 to 11; and pharmaceutically acceptable acid addition salts and individual optical isomers of the compounds where applicable.
• This invention relates to novel lactamimide derivatives useful as hypoglycemic agents and to methods of using the compounds either alone or in the form of pharmaceutical preparations.
• Lactamimide derivatives of the following Formula I and pharmaceutically acceptable acid addition salts and individual optical isomers where applicable are useful as hypoglycemic agents.
• X represents oxygen or sulfur
• A represents a bond or a straight or branched alkylene chain of from 1 to 3 carbon atoms
• R represents hydrogen, or a straight or branched lower alkyl group from 1 to 4 carbon atoms, a straight or branched lower alkenyl group of from 3 to 6 carbon atoms, cycloalkyl of from 3 to 6 carbon atoms or phenyl
• R represents hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms
• n is an integer of from 3 to 11.
• Pharmaceutically acceptable acid addition salts and individual optical isomers of the compounds where applicable are also included within the scope of this invention.
• R and R may represent in the above Formulas I to I11 there may be mentioned methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, and the like.
• alkenyl groups of from 3 to 6 carbon bon atoms which R may represent in the above Formulas I to HI there may be mentioned cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• alkenyl groups of from 3 to 6 carbon atoms which R may represent in the above Formulas I to III there may be mentioned allyl, Z-butenyl, 3-butenyl, 3-pentenyl, and the like.
• Pharmaceutically acceptable acid addition salts of the base compounds of this invention are those of any suitable inorganic or organic acids.
• 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, rnalonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, and the like, or sulfonic acids such as methane sulfonic, Z-hydroxyethane sulfonic acid and the like.
• the compounds of this invention are useful as hypoglycemic agents and may be used to control hyperglycemic conditions, such as occur for example in diabetic patients, by inducing a hypoglycemic response in the patient.
• hypoglycemic agents male rats of the Charles River C.D. strain each weighing from 120 to 140 grams were fastened for 15 hours then injected subcutaneously with 1 g./kg. of body weight of glucose in 0.5 ml. of 0.9% sodium chloride solution. Immediately following the glucose injection the animals were administered by oral intubation a compound of this invention in 0.5 ml. of carboxymethyl cellulose.
• novel compounds can be administered to animals, warm blooded animals and particularly mammals, 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 administration.
• the quantity of compound administered can vary over a wide range to provide from about 0.1 mg./kg. (milligram per kilogram) to about 100 mg./kg. of body weight of the patient per day to achieve the desired efiect.
• Unit doses of these compounds can contain from about to 500 mg. of the compound and may be administered, for example, from 1 to 4 times daily. Specific Examples 25 to 28 are illustrative of pharmaceutical preparations containing as active ingredients compounds of this invention.
• the compounds of this invention may be prepared by reacting an excess of a lactim ether of the formula N lower alkyl 0- 0 (CH R Formula IV with a primary amine of the following formula II X/ A CH NH: Formula V in a manner similar to that reported by R. E. Benson and T. L. Cairns in J. Am. Chem. Soc. 70, 2115-8 (1948).
• the various symbols X, A, R, R and n have the meanings defined hereinbefore.
• This reaction may be carried out with or without a solvent.
• a solvent that preferred is a lower alcohol, such as methanol, ethanol, isopropyl alcohol, butanol and the like.
• solvents such as, aromatic hydrocarbons, for example, benzene and toluene may also be used as suitable solvents for this reaction.
• a basic or an acidic catalyst such as a tertiary amine or hydrogen chloride may be added to the reaction mixture.
• the hydrochloride salt of the amine be used in the reaction.
• the temperature of the reaction varies from 40 C. to C., and the preferred temperature is about 1525 C.
• the reaction time varies from 1 hour to about 60 days being dependent upon the temperature of the reaction, the reactant primary amine, and more particularly on the degree of steric hindrance of the amine since highly sterically hindered amines react very slowly.
• lactim others as represented by Formula IV 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 an appropriate lactam with dirnethyl sulfate in a solvent such as benzene, toluene, xylene or the like at the reflux temperature of the solvent for 2-24 hours the corresponding o-methyl lactim ether is obtained.
• a solvent such as benzene, toluene, xylene or the like
• the amines as represented by Formula V which find use in this reaction may be prepared by several methods known to the art.
• a nitrile of the formula H HA-CN X Formula VI may be reacted with an alkylor phenylmagnesium halide compound followed by reduction of the resulting ketimine complex in situ with lithium aluminum hydride.
• nitriles of the formula RCN Formula VII via Hoffman or Curtius degradation, such as described by F. J. McCarty et al., J. Med. Chem. 11, 534 (1968), or as described by Van Zoeren in U.S. 2,367,702.
• the compounds of this invention may also be prepared using a complex of an appropriate lactam of the formula Formula VIII R Formula IX wherein n and R have the meaning defined above, with phosphorus oxychloride, phosgene, borontrifluoride etherate, dimethylsulfate, hydrogenjhalide or a combination of two or more such reagents.
• phosphorus oxychloride, phosgene, borontrifluoride etherate, dimethylsulfate, hydrogenjhalide or a combination of two or more such reagents Several attempts have been made to formulate the structure of these complexes, and one formulation includes the imino halide, that is, 2- chloro-4,5,6,7-tetrahydro-3g-azepine. However, none of the formulations have been unambiguously established. This reaction has been studied by H. Bredereck in a series of articles in Chem. Ber., 1953-1968, particularly in vol.
• the complex formed is reacted with an appropriate primary amine describedhereinabove in an aromatic hydrocarbon solvent such as benzene, toluene or xylene or an alkyl polyhalide solvent such as carbon tetrachloride, chloroform, methylene chloride, dichloroethane, tetrachloroethylene or the like.
• aromatic hydrocarbon solvent such as benzene, toluene or xylene
• an alkyl polyhalide solvent such as carbon tetrachloride, chloroform, methylene chloride, dichloroethane, 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 0 to'40 C. depending on the reactants.
• the above reaction may be carried out by using known thiolactim ethers such as S-methylthiocaprolactim [H. Behringer and H. Meier, Ann. 607, 73-91 (1957)], or by using thiolactams'wherein the latter case it may be advantageous to employ a catalyst such as mercury or silver oxide or cyanide [1. Gautier and J. Renault, C. 'R. Acad. Sci. 234, (1952)].
• thiolactim ethers such as S-methylthiocaprolactim [H. Behringer and H. Meier, Ann. 607, 73-91 (1957)]
• thiolactams'wherein the latter case it may be advantageous to employ a catalyst such as mercury or silver oxide or cyanide [1. Gautier and J. Renault, C. 'R. Acad. Sci. 234, (1952)].
• a-(Z-thienyDbenZylamine hydrochloride is added. Stirring is continued at room temperature for 1 hour then at reflux temperature for 4 hours. The resulting solution is allowed to cool to room temperature and stand over night after which it is washed with 2 N h ydrochloric acid. The organiclayer is separated and. washed with a saturated sodium chloride solution and dried over sodium sulfate.
• EXAMPLE 25 An illustrative composition for tablets is as follows:
• a granulation obtained upon mixing lactose with the starch and granulated starch paste is dried, screened and mixed with the active ingredient (a) and magnesium stearate. The mixture is compressed in tablets weighing 150 mg. each.
• EXAMPLE 26 An illustrative composition for hard gelatin capsules is as follows:
• EXAMPLE 27 An illustrative composition for pills is as follows:
• composition is prepared by dissolving the active ingredient and suflicient sodium chloride in water for injection to render the solution isotonic.
• the composition may be dispensed in a single ampule containing 100 mg. of the active ingredient for multiple dosage or in 10 ampules for a single dosage.
• a compound selected from a base of the formula H R N K A-( 3H-N C (CH1) wherein X is selected from oxygen or sulfur; A is selected from the group representing a bond or a straight or branched alkylene chain of from 1 to 3 carbon atoms; R is selected from the group consisting of hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms, a straight or branched lower alkenyl group of from 3 to 6 carbon atoms, a cycloalkyl group of from 3 to 6 carbon atoms and phenyl; R is selected from the group consisting of hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms; 11 is an integer of from 3 to 11; and pharmaceutically acceptable acid addition salts thereof.
• a compound of claim 2 which is 2-[(a-[2-furyl] benzyl)imino]hexahydroazepine and pharmaceutically acceptable acid addition salts thereof.
• a compound of claim 2 which is 2[[a-(2furyl)- benzyl1imino]octahydroazocine and pharmaceutically acceptable acid addition salts thereof.
• a compound of claim 5 which is octahydro-Z-[l-(Z- thienyl) 2 butylimino]azonine and pharmaceutically acceptable acid addition salts thereof.
• a compound of claim 5 which is hexahydro-2-[2-(1- [2-thienyl1pent 4 enyl)imino1azepine and pharmaceutically acceptable acid addition salts thereof.
• a compound of claim 5 which is heXahydro-Z-Ha- (2- thienyl)benzyl]imino]azepine and pharmaceutically acceptable acid addition salts thereof.
• a compound of claim 5 which is 2-[a-cyclopropyl- 2-thenyl)imino]hexahydroazepine and pharmaceutically acceptable acid addition salts thereof.

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• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Diabetes (AREA)
• Epidemiology (AREA)
• Hematology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Obesity (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Furan Compounds (AREA)

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• 1973
  • 1973-01-05 US US00321160A patent/US3816457A/en not_active Expired - Lifetime
  • 1973-11-13 ZA ZA738704A patent/ZA738704B/xx unknown
  • 1973-11-15 AU AU62509/73A patent/AU469726B2/en not_active Expired
  • 1973-11-22 CA CA186,439A patent/CA1018170A/en not_active Expired
  • 1973-11-26 IL IL43704A patent/IL43704A/en unknown
  • 1973-11-28 GB GB5521173A patent/GB1417030A/en not_active Expired
  • 1973-12-28 JP JP14481073A patent/JPS5647186B2/ja not_active Expired
  • 1973-12-28 DE DE2365006A patent/DE2365006A1/de active Pending
• 1974
  • 1974-01-04 FR FR7400315A patent/FR2213063B1/fr not_active Expired

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