US3838151A - Cycloalkyllactamimides - Google Patents

Cycloalkyllactamimides Download PDF

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Publication number
US3838151A
US3838151A US00280049A US28004972A US3838151A US 3838151 A US3838151 A US 3838151A US 00280049 A US00280049 A US 00280049A US 28004972 A US28004972 A US 28004972A US 3838151 A US3838151 A US 3838151A
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US
United States
Prior art keywords
hydrochloride
adamantanylimino
compounds
mixture
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US00280049A
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English (en)
Inventor
J Grisar
G Claxton
T Blohm
E Roberts
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richardson Vicks Inc
Original Assignee
Richardson Merrell Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richardson Merrell Inc filed Critical Richardson Merrell Inc
Priority to US00280049A priority Critical patent/US3838151A/en
Priority to ZA732927A priority patent/ZA732927B/xx
Priority to GB2091673A priority patent/GB1401735A/en
Priority to AU55179/73A priority patent/AU466344B2/en
Priority to IL42202A priority patent/IL42202A/xx
Priority to CA170,730A priority patent/CA962268A/en
Priority to DE2324634A priority patent/DE2324634A1/de
Priority to JP48054179A priority patent/JPS4945063A/ja
Priority to DK344973AA priority patent/DK134014B/da
Priority to NL7308929A priority patent/NL7308929A/xx
Priority to CH1086173A priority patent/CH587814A5/xx
Priority to FR7329217A priority patent/FR2195446B1/fr
Priority to BE134468A priority patent/BE803484A/xx
Application granted granted Critical
Publication of US3838151A publication Critical patent/US3838151A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Computer Networks & Wireless Communication (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
US00280049A 1972-08-11 1972-08-11 Cycloalkyllactamimides Expired - Lifetime US3838151A (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
US00280049A US3838151A (en) 1972-08-11 1972-08-11 Cycloalkyllactamimides
ZA732927A ZA732927B (en) 1972-08-11 1973-04-30 Cycloalkyllactamimides
GB2091673A GB1401735A (en) 1972-08-11 1973-05-02 Imino-lactams
AU55179/73A AU466344B2 (en) 1972-08-11 1973-05-03 Cycloalkyllactamimides
IL42202A IL42202A (en) 1972-08-11 1973-05-04 Norbornyl or adamantyl lactaminides
CA170,730A CA962268A (en) 1972-08-11 1973-05-08 Cycloalkyllactamimides
DE2324634A DE2324634A1 (de) 1972-08-11 1973-05-16 Cycloalkyllactamimide, verfahren zu ihrer herstellung und diese verbindungen enthaltende therapeutische zubereitungen
JP48054179A JPS4945063A (enrdf_load_stackoverflow) 1972-08-11 1973-05-17
DK344973AA DK134014B (da) 1972-08-11 1973-06-21 Analogifremgangsmåde til fremstilling af cycloalkyllactamimider eller syreadditionssalte deraf.
NL7308929A NL7308929A (enrdf_load_stackoverflow) 1972-08-11 1973-06-27
CH1086173A CH587814A5 (enrdf_load_stackoverflow) 1972-08-11 1973-07-25
FR7329217A FR2195446B1 (enrdf_load_stackoverflow) 1972-08-11 1973-08-09
BE134468A BE803484A (fr) 1972-08-11 1973-08-10 Cycloalkyl-lactamimides

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US00280049A US3838151A (en) 1972-08-11 1972-08-11 Cycloalkyllactamimides

Publications (1)

Publication Number Publication Date
US3838151A true US3838151A (en) 1974-09-24

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US00280049A Expired - Lifetime US3838151A (en) 1972-08-11 1972-08-11 Cycloalkyllactamimides

Country Status (13)

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US (1) US3838151A (enrdf_load_stackoverflow)
JP (1) JPS4945063A (enrdf_load_stackoverflow)
AU (1) AU466344B2 (enrdf_load_stackoverflow)
BE (1) BE803484A (enrdf_load_stackoverflow)
CA (1) CA962268A (enrdf_load_stackoverflow)
CH (1) CH587814A5 (enrdf_load_stackoverflow)
DE (1) DE2324634A1 (enrdf_load_stackoverflow)
DK (1) DK134014B (enrdf_load_stackoverflow)
FR (1) FR2195446B1 (enrdf_load_stackoverflow)
GB (1) GB1401735A (enrdf_load_stackoverflow)
IL (1) IL42202A (enrdf_load_stackoverflow)
NL (1) NL7308929A (enrdf_load_stackoverflow)
ZA (1) ZA732927B (enrdf_load_stackoverflow)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007181A (en) * 1974-02-11 1977-02-08 The Upjohn Company Adamantyl containing guanidines
US4254128A (en) * 1977-11-22 1981-03-03 Teva Pharmaceutical Industries Ltd. 2-Adamantyl hydrazines and biocidal compositions thereof
EP0348891A3 (en) * 1988-06-28 1991-05-15 Merrell Dow Pharmaceuticals Inc. Lactamimides as calcium antagonists
CN103664639A (zh) * 2013-11-19 2014-03-26 中国科学院广州生物医药与健康研究院 胺类化合物及其制备方法和在制备抗流感病毒药物中的应用
CN104844532A (zh) * 2014-02-19 2015-08-19 周敬业 抗病毒化合物、其制备方法和用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3121093A (en) * 1962-08-31 1964-02-11 Rohm & Haas Substituted iminopyrrolidines
BE758363A (fr) * 1969-11-03 1971-05-03 Bayer Ag Nouvelles compositions a base de 2-arylimino-1-alkyl-lactames destineesa combattre des ectoparasites animaux

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007181A (en) * 1974-02-11 1977-02-08 The Upjohn Company Adamantyl containing guanidines
US4254128A (en) * 1977-11-22 1981-03-03 Teva Pharmaceutical Industries Ltd. 2-Adamantyl hydrazines and biocidal compositions thereof
EP0348891A3 (en) * 1988-06-28 1991-05-15 Merrell Dow Pharmaceuticals Inc. Lactamimides as calcium antagonists
CN103664639A (zh) * 2013-11-19 2014-03-26 中国科学院广州生物医药与健康研究院 胺类化合物及其制备方法和在制备抗流感病毒药物中的应用
CN103664639B (zh) * 2013-11-19 2015-05-20 中国科学院广州生物医药与健康研究院 胺类化合物及其制备方法和在制备抗流感病毒药物中的应用
CN104844532A (zh) * 2014-02-19 2015-08-19 周敬业 抗病毒化合物、其制备方法和用途

Also Published As

Publication number Publication date
BE803484A (fr) 1973-12-03
DK134014B (da) 1976-08-30
AU466344B2 (en) 1975-10-23
JPS4945063A (enrdf_load_stackoverflow) 1974-04-27
IL42202A (en) 1975-11-25
NL7308929A (enrdf_load_stackoverflow) 1974-02-13
FR2195446A1 (enrdf_load_stackoverflow) 1974-03-08
ZA732927B (en) 1974-03-27
CA962268A (en) 1975-02-04
CH587814A5 (enrdf_load_stackoverflow) 1977-05-13
DE2324634A1 (de) 1974-02-28
FR2195446B1 (enrdf_load_stackoverflow) 1976-12-31
AU5517973A (en) 1974-11-07
IL42202A0 (en) 1973-07-30
DK344973A (enrdf_load_stackoverflow) 1975-02-10
GB1401735A (en) 1975-07-30
DK134014C (enrdf_load_stackoverflow) 1977-01-31

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