US3397233A - 3-aminotricyclo [4.3.1.13.8] undecanes - Google Patents

3-aminotricyclo [4.3.1.13.8] undecanes Download PDF

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US3397233A
US3397233A US375338A US37533864A US3397233A US 3397233 A US3397233 A US 3397233A US 375338 A US375338 A US 375338A US 37533864 A US37533864 A US 37533864A US 3397233 A US3397233 A US 3397233A
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undecane
mole
aminotricyclo
acid
tricyclo
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Theodore L Cairns
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EIDP Inc
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EI Du Pont de Nemours and Co
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Priority to GB1054275D priority Critical patent/GB1054275A/en
Priority to FI0834/64A priority patent/FI41550B/fi
Priority to DE19641468758 priority patent/DE1468758B1/de
Priority to CH523664A priority patent/CH468966A/de
Priority to CH642467A priority patent/CH485655A/de
Priority to AT08046/67A priority patent/AT277202B/de
Priority to LU45979D priority patent/LU45979A1/xx
Priority to SE15198/66A priority patent/SE307943B/xx
Priority to SE15199/66A priority patent/SE307944B/xx
Priority to NL646404755A priority patent/NL143813B/xx
Priority to SE5362/64A priority patent/SE307942B/xx
Priority to BE647418D priority patent/BE647418A/xx
Priority to FR1561907D priority patent/FR1561907A/fr
Priority to US375338A priority patent/US3397233A/en
Application filed by EI Du Pont de Nemours and Co filed Critical EI Du Pont de Nemours and Co
Priority to DK367565AA priority patent/DK111889B/da
Priority to DK367665AA priority patent/DK119155B/da
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Publication of US3397233A publication Critical patent/US3397233A/en
Priority to MY196841A priority patent/MY6800041A/xx
Priority to FI2079/69A priority patent/FI42550B/fi
Priority to FI2078/69A priority patent/FI42549B/fi
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    • 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
    • A61K31/13—Amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems

Definitions

  • This invention relates to tricycloundecanes. More particularly, this invention refers to novel tricyclo[4.3.1.1 undecanes having an amino or substituted amino group attached to a 3-position tertiary or bridgehead nuclear carbon.
  • R1 R is N where n is 2, 3, 4, 5 or 6;
  • R is hydrogen; alkyl of 1 through 6 carbon atoms; mono-substituted alkyl of 1 through 6 carbon atoms where the substituent is hydroxy, alkoxy of 1 through 2 carbon atoms, --NH NHR or NR R where R; and R can be the same or diiferent and are alkyl radicals of 1 through 4 carbon atoms; alkenyl of 2 through 6 carbon atoms; alkynyl of 2 through 6 carbon atoms; cyclopropyl; cyclobutyl; cyclopropylmethyl; cyclobutylmethyl; R is R chlorine; bromine; formyl; CH;'COOH; -CH COOCH CH -COOC H with the proviso that when R, is an alkenyl or 'alkynyl having the unsaturated bond in the l-position, R is alkyl or mono-substituted alkyl as defined above; and R is aliphatic; mono-substituted alkyl as
  • salts and such salts having a nontoxic anion are also included within the scope .of the present invention.
  • Representative of such salts are the hydrochlorides, hydrobromides, sulfates, phosphates, acetates, succinates, adipates, propionates, tartrates, citrates, bicarbonates, pamoates, cyclohexylsulfamates and acetylsalicylates.
  • hydrochlorides and acetates and cyclohexylsulfamates are preferred,
  • the cyclohexylsulfamates have a pleasant taste and thus are particularly useful in preparing syrups for oral administration.
  • the cyclohexylsulfarnates have usefulness in making uncoated tablets for oral administration which have no objectionable bitter taste.
  • Other salts include those with caprochlorone and with penicillin.
  • Lower alkyl substitutents such as the dimethyl and diethyl are most preferred.
  • the monomethyl and monoethyl derivatives, as well as the unsubstituted amino compounds, are preferred by comparison with most of the substituted alkylamino derivatives.
  • hydrochlorides of the following compounds are particularly preferred.
  • the 3-aminotn'cyclo[4.3.l.1 ]undecane is readily prepared from the known compound 3-carboxytricyclo[4.3. 1.1 ]undecane by conversion of the acid to the acid chloride with thionyl chloride, followed by ammoniation to the corresponding amide.
  • the amide in turn is reacted with metallic sodium and bromine in methanol to give S-carbomethoxyaminotricyclo[4.3.1.l ]undecane which is hydrolyzed under basic conditions to obtain the desired 3-aminotricyclo[4.3.1.1 ]undecane.
  • One or both of the hydrogens of the 3-amino nitrogen of 3-aminotricyclo[4.3.1.1 ]undecane can be replaced by alkyl. This is most conveniently done by acylation, for instance with an acyl halide, to give a 3-acylaminotricyclo[4.3.1.1 ]undecane, (which is then reduced to 3-N-alkylaminotricyclo[4.3.1.1 ]undeoane. Lithium aluminum hydride is excellent for this, although catalytic hydrogenation or any one of a number of means of reduction can be used.
  • the 3-N-alkylaminotricyclo[4.3.1.1 ]undecanes can be acylated again and reduced to give the 3-N,N-dialkylamintricyclo[4.3.1.1 ]undecanes. .Difrerent alkyl groups can be attached by this means. For instance, reduction of 3-acetamidotricyclo[4.3.1.1 ]undecane, followed by reaction of the product with butyryl chloride, followed by reduction gives the 3-(N-butyl-N-ethylamino) compound. Of course, if acetyl chloride is used, the product is 3 (N,N diethylamino)t1icyclo[4.3.1.1 ]undecane, where the alkyl groups are alike.
  • N-methylamino compound Although formylation of the amino compound followed by reduction is a practical means of obtaining the N-methylamino compound, it may if desired also be obtained by reducing tricyclo[4.3.1.1 ]undecane-3-methyl urethane, described in Example 3. Reduction of the 3-ethyl urethane gives the N-methylamino compound also.
  • the method of acylation and reduction is applicable to making compounds in which the alkyl substituents are substituted.
  • Acylation of B-N-methylaminotricyclo [4.3.1.l ]undecane with 3-methoxypropionyl chloride followed by reduction gives 3-[N-(3-methoxypropyD-N- methylaminoJtricyclo[4.3.l.1 ]undecane.
  • Reaction of the amine or monoalkyl amine with a dicarboxylic acid anhydride to give the N-substituted alkanamic acid, followed by reduction introduces the hydroxyalkyl grouping.
  • the reduction of N-[tricyclo [4.3.1.1 undecyl-(3)]-succinamic acid yields 3-N-(4-hydroxybutyl)aminotricyclo[4.3.1.l ]undec ane.
  • Some substituted alkyl amino compounds are more easily made by other routes. Hydroxyethyland bishydroxyethyl compounds are made by reaction of the amine with ethylene oxide. N-carb-alkoxymethylamino compounds are made by alkylation with alkyl chloroacetate and base. Aminoalkyl-, alkylaminoalkyl-, and dialkylaminoalkyl compounds are made by alkylation with approproiate aminoalkyl halides and base.
  • 3-N-alkylamino and dialkylaminotricyclo[4.3.1.1 ]undecanes are easily made by alkylation with alkylating reagents (such as alkyl halides), without resorting to the method of acylation and reduction.
  • alkylating reagents such as alkyl halides
  • the monoalkylamino compound is generally formed as the major product, whereas greater amounts of the reagents give the dialkylamino compound.
  • This method is not as clearcut as the method of acylation and reduction, which is why it is less preferred. However, it sometimes becomes the method of choice because it involves fewer steps.
  • Ethylene chloroand bromo-hydrin, and alkoxyalkyl halides can be used to alkylate the amino nitrogen, to give the hydroxyethyland *alkoxyalkylsubstitutions. For the reason just given, these reactions are less preferable than the method of acylation and reduction, but may be preferred in certain instances, and they illustrate an alternate route to substituted-alkylaminotricyclo[4.3.1. 1 ]undecanes by ordinary alkylation with a substituted alkylating reagent.
  • N-alkenyl, N,N-dialkenyl, N-alkynyl, and N,N dialkynyl 3 aminotricyclo[4.3.1.1 ]undecanes use of the appropriate alkenyl or alkynyl halide with an acid acceptor such as sodium bicarbonate in a solvent such as ethanol is the method of choice.
  • an acid acceptor such as sodium bicarbonate
  • a solvent such as ethanol
  • N-cyclopropyl and N-cyclobutyl compounds the known 3-hydroxytricyclo[4.3.1.1 ]undecane is converted to 3 (p toluenesulfonyloxy)tricyclo- [4.3.1.l ]undecane, for example with p-toluenesulfonyl chloride in pyridine, and this compound is heated in the presence of cyclopropylamine or cyclobutylamine to yield 3 N cyclopropylor 3 N cyclobutylaminotricyclo- [4.3.1.1 ]undecane by aminolysis.
  • This method is also applicable to making N-[tricyclo[4.3.1.1 ]undecyl- (3)]alkyleneimines. Substitution of pyrrolidine for the cyclopropylamine yields N-[tricyclo[4.3.1.1 ]undecyl- (3) ]pyrrolidine.
  • EXAMPLE 1 3-carboxytricyclo[4.3.1.1 ]undecane is prepared according to Stetter, Schwarz, and Hirschhorn, Ben, 92, 1634 (1959), from l-hydroxymethyl adamantane.
  • the acid is converted to the acid chloride by refluxing with excess thionyl chloride.
  • the excess reagent is removed, under reduced pressure, and the crude acid chloride is dropped slowly into concentrated ammonia at 5 C.
  • the resultant amide is recrystallized from acetone-water to give a white crystalline solid, M.P. 180-181 C., in 90% yield.
  • the amide, 8 parts is added to a solution of 2.1 parts of metallic sodium in 175 parts of methanol, the solution is cooled to 0 C., and 8 parts of liquid bromine is dropped into the well-stirred solution. Stirring is continued for minutes at 0, then for 15 minutes at 55, and finally for 30 minutes at the boiling point.
  • the methanol is removed by distillation and the residue is recrystallized from dilute acetone.
  • the product is a white crystalline solid, 10 parts or 97% yield, of 3-carbomethoxyaminotricyclo[4.3.1.1 ]undecane. This is hydrolyzed by refluxing with excess powdered sodium hydroxide in diethylene glycol for 16 hours.
  • reaction mixture is stirred for 16 hours at room temperature, diluted with 4 volumes of water and extracted with toluene.
  • the toluene extract is washed with water, 1% solution hydroxide, 1% hydrochloric acid and then with water.
  • the toluene solution is then dried with calcium chloride and heated at C. until no more nitrogen is evolved from the acyl azide.
  • the toluene is removed under reduced pressure and the residue is refluxed for 16 hours with methanol. Removal of the methanol leaves a solid residue, 26.16 grams, 76% conversion to tricyclo[4.3.l.l ]undecane-3-methyl urethane. After recrystallization from acetone-water, this melts at 104- 106 C. Alkaline hydrolysis gives 3 aminotricyclo- [4.3.1.1 ]undecane.
  • EXAMPLE 3 A solution of 20.5 grams (0.092 mole) of tricyclo- [4.3.1.1 ]undecane-3-methyl urethane, prepared as in Example 2, in 100 milliliters of dry diethyl ether is added slowly to a suspension of 5.65 grams of lithium aluminum hydride in 100 milliliters of dry ether. After complete addition, the reaction mixture is refluxed for one hour, the ether is removed by distillation, the residue is made strongly alkaline with sodium hydroxide and the product is isolated by steam distillation. The steam distillate is extracted with ether, the extract is dried with solid KOI-I, filtered, and dry HCl is passed into the solution.
  • EXAMPLE 4 A 10.35 gram sample (0.05 mole) of 3-acetamidotr1cyclo[4.3.l.1 ]undecane prepared by acetylation of the corresponding amine with acetic anhydride containing a drop of sulfuric acid is dissolved in 200 milliliters of dry tetrahydrofuran and added to a suspension of 3.0 grams of lithium aluminum hydride in 350 milliliters of dry ether. After complete addition, the mixture is refluxed for one hour and the solvent is distilled from the reaction vessel. Steam is then passed in until a clear distillate results. The distillate is then extracted with ether and the extract is dried with solid sodium hydroxide. Dry hydrogen chloride is then passed into the filtered solution and the precipitated amine hydrochloride is removed by filtration and recrystallized to yield 3-N-ethylaminotricyclo[4.3.1.1 ]undecane hydrochloride.
  • EXAMPLE 6 A 50-milliliter round-bottom flask is charged with 6.90 grams (0.15 mole) of 98% formic acid and 12.1 grams (0.15 mole) of 37% formalin solution. Then 8.26 grams (0.05 mole) of 3-aminotricyclo[4.3.l.1 ]undecane is charged, a condenser is attached, and the mixture is heated at 95 C. on the steam bath for 16 hours. Gas is evolved during the heat-up period and for some time thereafter. After cooling, the mixture is transferred to a separatory funnel with 50 milliliters of water, 25 milliliters of 50% sodium hydroxide is added, and the mixture is extracted with three ZS-milliliter portions of ether.
  • EXAMPLE 7 The 3 -N-methylaminotricyclo [4. 3 1 1 undecane prepared in Example 3 is converted to the acetyl derivative by gently warming the compound with a slight excess of acetic anhydride containing a drop of sulfuric acid. The resulting solution is poured on ice and extracted with chloroform. Removal of the chloroform yields 3-N- methylacetaminotricyclo[4.3.1.l ]undecane which is purified by distillation. A solution of the amide in tetrahydrofuran is added slowly to a suspension of one molar equivalent of lithium aluminum hydride in diethyl ether.
  • reaction mixture is refluxed for 4 hours, the solvent removed and the amine isolated by steam distillation.
  • the steam distillate is extracted with ether and the extract is dried with solid sodium hydroxide.
  • the dry ethereal solution is saturated with hydrogen chloride and after removal of the ether, the hydrochloride of 3-(N-methyl N ethylamino)tricyclo- [4.3.1.1 ]undecane is obtained.
  • Example 5 is repeated, substituting equivalent amounts of cyclopropanecarboxylic acid chloride for the caproyl chloride, to obtain 3 N cyclopropylcarbonylaminotricyclo[4.3.1.l ]undecane which is then reduced with lithium aluminum hydride to 3 N cyclopropylmethylaminotricyclo[4.3.1.1 ]undecane.
  • EXAMPLE 9 A 100 milliliter flask with a stirrer and reflux condenser is charged with 0.1 mole of 3-aminotricyclo[4.3.1.1 undecane, 0.1 mole of ethyl chloroacetate, 0.11 mole of sodium bicarbonate and 40 milliliters of methanol. The mixture is refluxed overnight, the insoluble material is removed by filtration and the solution is evaporated to dryness. The residue is dissolved in 1 Normal hydrochloric acid, regenerated by 5% sodium hydroxide, and extracted with ether. The ether solution is dried over anhydrous sodium sulfate and the solvent is removed. The residue is subjected to vacuum distillation at 0.1 mm. and divided into a lower boiling fraction, which is recovered starting material, and a higher boiling fraction, which is N-[tricyclo[4.3.1.l ]undecyl-(3)] glycine ethyl ester.
  • EXAMPLE 1 l A 2-liter 4-necked round-bottom flask is equipped with thermometer, dropping funnel, reflux condenser, paddle stirrer and a connection to a gas meter, and charged with 500 ml. of absolute ethanol, 50.4 g. (0.60 mole) of sodium bicarbonate and 40.3 g. (0.20 mole of 3-aminotricyclo[4.3.1.1 ]undecane hydrochloride. Then, 24.2 g. (0.20 mole) of allyl bromide is added from the dropping funnel. There is no appreciable evolution of carbon dioxide. The mixture is gradually warmed to 65 C., whereupon gas evolution begins. The reaction is allowed to proceed until no more gas is evolved (about 11.5 liters).
  • EXAMPLE 12 A Z-liter 4-necked round-bottom flask is equipped with thermometer, dropping funnel, reflux condenser, paddle stirrer and a connection to a gas meter. It is charged with 500 ml. of abs. ethanol, 50.4 g. (0.60 mole) of sodium bicarbonate and 43.0 g. (0.20 mole) of 3-N-methylaminotricyclo[4.3.l.1 ]undecane hydrochloride. Then, 24.2 g. (0.20 mole) of allyl bromide is added from the dropping funnel. The mixture is gradually warmed to 65 (3., when gas evolution begins. The reaction is allowed to proceed until no more gas is evolved (ca. 11.5 lite-rs).
  • EXAMPLE 13 A reaction is run as described in Example 12, using 40.3 g. (0.20 mole) of S-aminotricyclo[4.3.1.l ]undecane, 16.4 g. (0.20 mole) of propargyl chloride, 50.4 g. (0.60 mole) of sodium bicarbonate and 500 ml. of absolute ethanol. The cooled mixture is filtered and the filtrate is evaporated. The residue is distributed between 10% sodium hydroxide and ether. The ether layer is dried with anhydrous potassium carbonate and evaporated. The residue is distilled at reduced pressure to yield two main fractions. The lower-boiling fraction is 3-N-propargylaminotricyclo[4.3.1.1 ]undecane and the higher is 3-N,N- dipropargylaminotricyclo [4.3.1.1 ]undecane.
  • EXAMPLE 14 A flask equipped with a Dean-Stark water separator is charged with 0.1 mole of 3-aminotricyclo[4.3.1.l ]undecane and 0.1 mole of freshly distilled benzaldehyde in 50 milliliters of toluene. The reaction mixture is refluxed for 45 hours, the toluene evaporated and the residue recrystallized to give 3 -benzaldiminotricyclo [4.3.l.1 ]undecane.
  • EXAMPLE 15 The organic layer of 3-N-hydroxymethylaminotricyclo [4.3.1.l ]undecane or obtained in accordance with Example 19 hereinafter, is distilled at reduced pressure to yield N-[tricyclo[4.3.l.l ]undecyl-(3)] azomethine.
  • EXAMPLE 16 A 3-neck l-liter flask fitted with a stirrer and a thermometer is charged with 250 milliliters of 98% sulfuric acid which is then cooled to C. A mixture of grams of solid 1-hydroxymethyladamantane and 9 grams of sodium cyanide (3 molar equivalents) is added in small portions, with good stirring, to the acid, controlling the temperature of the reaction mixture between 20 C. by ice-bath cooling. When addition is complete, the reaction is allowed to warm slowly to room temperature. An exothermic reaction occurs but is controlled by the ice bath so that the temperature of the reaction mass does not exceed 50 C. The reaction mixture is stirred for 2 hours and poured on ice.
  • the acidic solution is neutralized with ammonium hydroxide and the organic material isolated by extraction with chloroform. Evaporation of the chloroform yields 3-formamidotricyclo[4.3.l.1 ]undecane mixed with l-formamidomethyladamantane.
  • the desired product, 3-formamid0tricyclo [4.3 1 l lundecane, can if desired be separated from the by-product by extraction of the mixture with cold excess cyclohexane in which it is insoluble.
  • the melting point is l58l60 C. after crystallization from ethyl acetate.
  • This compound can also be made as follows:
  • EXAMPLE 17 A solution of 0.1 mole of 3-aminotricyclo[4.3.1.1 undecane in 50 milliliters of benzene is added slowly to a solution of 0.1 mole of succinic anhydride in 100 milliliters of benzene. The mixture is then heated under reflux for one hour and the benzene removed by distillation. An
  • reaction mixture is refluxed for 2 hours, the solvent removed by distillation, and the amine isolated by steam distillation.
  • the steam distillate is extracted with ether, the solution dried with sodium hydroxide, and dry hydrogen passed into the filtered solution until no more is absorbed. Evaporation of the ether yields N-[tricyclo[4.3.l.1 ]undecyl- (3) ]pyrrolidine hydrochloride.
  • Example 5 is repeated, substituting equivalent amounts of 3-methoxypropionyl chloride for the caproyl chloride, to obtain 3-(N-methyl-3-methoxypropionamido)tricyclo 12 [4.3.l.1 ]undecane which is then reduced with lithium aluminum hydride to 3-N-(3-methoxypropyl)-N-methylaminotricyclo[4.3.1.l ]undecane.
  • EXAMPLE 19 A suitable flask equipped with stirrer, thermometer, reflux condenser, dropping funnel and cooling bath is charged with 2.0 moles of 3-aminotricyclo[4.3.1.1 undecane. A 37% aqueous solution of formaldehyde (2.05 moles) is added slowly with stirring, maintaining the temperature below 40 C. After addition is complete, the reaction is cooled to room temperature, and powdered potassium hydroxide (10 g.) is added to aid in separation of the water. The organic layer is separated and dried over potassium hydroxide to yield 3-N-hydroxymethylaminotricyclo[4.3.1.l ]undecane.
  • Example 19 is repeated using 2.0 moles of 3-N- methylaminotricyclo[4.3.1.l ]undecane is place of the 2.0 moles of 3-aminotricyclo[4.3.1.l ]undecane.
  • the product is 3 -N-hydroxymethyl N-methylaminotricyclo [4.3.1.1 ]undecane.
  • EXAMPLE 21 A 0.1 mole amount of 3-N-hydroxymethyl-N-methylaminotricyclo[4.3.l.1 ]undecane (Example 20) is refluxed at 55 C. in a mixture of ml. of anhydrous diethylamine and 10 g. of potassium hydroxide pellets for 4 hours. The mixture is cooled and the liquid is decanted from the residual pellets and the small layer of concentrated potassium hydroxide solution. It is distilled at reduced pressure to yield 3N-diethyaminomethyl-N-methylaminotricyclo[4.3.l.1 ]undecane.
  • EXAMPLE 22 A solution of 0.5 mole of 3-aminotricyclo[4.3.1.1 undecane in milliliters of tetrahydrofuran and 30 milliliters of water is charged into a 400 milliliter stainless steel autoclave, and 5.0 grams (0.11 mole) of ethylene oxide is injected. The autoclave is heated to 70 C. for 24 hours after which time it is cooled and cautiously vented. Solvent is removed at reduced pressure, and the residue is extracted with ether. The ether extract is dried With anhydrous potassium carbonate. Solvent is removed at reduced pressure and the residue is subjected to sublimation at 100 C./20 mm. in order to remove unreacted 3-aminotricyclo[4.3.l.l ]undecane.
  • EXAMPLE 23 A suspension of 0.1 mole of 3-aminotricyclo[4.3.1.1 undecane in 100 milliliters of ice water is placed in 500- milliliter flask equipped with mechanical stirrer and thermometer. The flask is cooled in an ice bath and 142 grams of 5.25% sodium hypochlorite solution (commercial Clorox) is added at such a rate that the temperature does not exceed 10 C.
  • sodium hypochlorite solution commercial Clorox
  • EXAMPLE 24 A mixture of 0.10 mole of 3-aminotricyclo[4.3.1.1 undecane and 9.87 grams (0.10 mole of 38% hydrochloric acid in 100 milliliters of water is concentrated in vacuo at 60 C. The resulting salt, 3-aminotricyclo- [4.3.l.l ]undecane hydrochloride, is dried in vacuo at 60 C.
  • the antiviral composition will contain a solid or liquid nontoxic EXAMPLES 25-37 Example 24 is repeated substituting the following indicated reactants for those of that example to obtain the indicated product:
  • Citric acld (0.10 mole) 3-N-(2-(1iethylaminoethyl)-N- methylarnino-tricyclo[4.3.1.1 undecane, dihydrogen citrate.
  • EXAMPLE 38 In one embodiment of a pharmaceutical composition of A solution of 0.20 mole of 3-aminotricyclo[4.3.1.1 undecane hydrochloride in 100 milliliters of water is added to a solution of 0.10 mole of pamoic acid disodium salt [4,4-methylenebis(3-hydroxy-2-naphthoic acid) disodium salt] in 500 milliliters of water. The resulting precipitate is filtered, washed well with water, and dried in vacuo to give 3-aminotricyclo[4.3.1.1 ]undecane pamoate.
  • the compounds of Formula 1 above can be administered in the antiviral treatment according to this invention by any means that effects contact of the active ingredient compound with the site of virus infection in the body. It will be understood that this includes the site prior to infection setting in as well as after.
  • administration can be parenterally, that is subcutaneously, intravenously, intramuscularly, or intraperitoneally.
  • the compounds are effective on administration by the oral route. Since particularly effective against respiratory infections such as viral pneumonia, administration can be by vapor or spray through the mouth or nasal passages.
  • the compounds within the scope of this invention are valuable for viral prophylaxis, as well as for therapeutic treatment.
  • the dosage administered will be dependent upon the virus being treated, the age, health and weight of the recipient, the extent of infection, kind of concurrent treatment if any, frequency of treatment and the nature of the effect desired.
  • a daily dosage of active ingredient compound will be from about 1 to 50 milligrams per kilogram of body weight, although lower, such as 0.5 milligram per kilogram, or higher amounts can be used.
  • the active ingredient of Formula 1 can be employed in useful compositions according to the present invention in such dosage forms as tablets, capsules, powder packets or liquid solutions, suspensions, or elixirs, for oral administration, or liquid solutions for parenteral use, and in certain cases, suspensions for parenteral use (except intravenous).
  • the solid carrier is a capsule which can be of the ordinary gelatin type. In the capsule will be from about 30-60% by weight of a compound of Formula 1 or 2 and 7040% of a carrier.
  • the active ingredient is tableted with or without adjuvants.
  • the active ingredient is put into powder packets and employed.
  • These capsules, tablets and powders will generally constitute from about 5% to about and preferably from 25% to 90% by weight.
  • These dosage forms preferably contain from about 5 to about 500 milligrams of active ingredient, with from about 25 to about 250 most preferred.
  • the pharmaceutical carrier can, as previously indicated, be a sterile liquid such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, for example peanut oil, soybean oil, mineral oil, seasame oil and the like.
  • a sterile liquid such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, for example peanut oil, soybean oil, mineral oil, seasame oil and the like.
  • Water, saline and aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectible solutions.
  • Sterile injectible solutions will ordinarily contain from about 0.5 to 25%, and preferably about 1 to 10% by weight of the active ingredient.
  • oral administration can be in a suitable suspension or syrup, in which the active ingredient ordinarily will constitute from about 0.5 to 10%, and preferably about 2 to 5%, by weight.
  • the pharmaceutical carrier in such compositions can be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.
  • Suitable pharmaceutical carriers are described in Remingtons Practice of Pharmacy by E. W. Martin and E. F. Cook, a well known reference text in this field.
  • EXAMPLE 39 A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules weighing about 50 milligrams each with 50 milligrams of powdered 3- aminotricyclo[4.3.1.l ]undecane hydrochloride; milligrams of lactose and 1 milligram of Cab-O-Sil.
  • Example 39 is repeated except that soft gelatin capsules are used and the powdered 3-aminotricyclo[4.3.1.1 un decane hydrochloride is first dissolved in mineral oil.
  • Example 39 is repeated except that the dosage unit is 50 milligrams of active ingredient, 5 milligrams of gelatin, 1.5 milligrams of magnesium stearate and 100 milligrams of lactose, mixed and for-med into a tablet by a conventional ta'bleting machine.
  • Slow release pills or tablets can also be used, by applying appropriate coatings such as sugar-base coatings well known to the art.
  • EXAMPLE 42 A parenteral composition suitable for administration by injection is prepared by stirring 5% by weight of the active ingredient of Example 39 in sterile aqueous 0.9% saline.
  • compositions according to this invention can thus readily be made by substituting other compounds of this invention, and including specifically but not limited to compounds of this invention that have specifically been named hereinbefore.
  • the compounds will be used in the amounts indicated in accordance with procedures well known and described in the Martin and Cook text mentioned above.
  • the compounds of this invention are particularly effective against swine influenza.
  • An important embodiment of this invention therefore is the control of this infection by incorporating an active ingredient compound in the diet of the affected animal.
  • an amount of active compound will be used to provide from about 0.0001 to 0.1% by weight of the active compound based on the total weight of feed intake. Preferably, from 0.001% to 0.02% by weight will be used.
  • compositions which comprise at least one active ingredient compound within the scope of this invention in admixture with an animal feed.
  • suitable feeds can be found in the book Feeds and Feeding by Frank B. Morrison, published by the Morrison Publishing Company of Ithaca, N.Y., 1948, 21st edition. The selection of the particular feed is within the knowledge of the art and will depend of course on the animal, the economics, natural materials available, the surrounding circumstances and the nature of the effect desired, as will be readily understood.
  • composition according to this feature of the invention is a concentrate, suitable for preparation and sale to a farmer or livestock grower for addition to the animals feedstufls in appropriate proportion.
  • These concentrates ordinarily comprise about 0.5% to about 95% by weight of the active ingredient compound together with a finely divided solid, preferably flours, such as wheat, corn, soya bean and cottonseed.
  • the solid adjuvant can be ground cereal, charcoal, fullers earth, oyster shell and the like. Finely divided attapulgite and bentonite can be used, these latter materials also acting as solid dispersing agents.
  • the feed compositions can additionally contain other components of feed concentrates or animal feeds, as will be readily understood.
  • Other particularly important additives include proteins, carbohydrates, fats, vitamins, minerals, antibiotics, etc.
  • R is selected from the group consisting of /Rt -N and where n is an integer of 2 through 6; wherein:
  • R is selected from the group consisting of hydrogen; alkyl of 1 through 6 carbon atoms; mono-substituted alkyl of 1 through 6 carbon atoms where the substituent is hydroxy, alkoxy of 1 through 2 carbon atoms, NH -NHR and NR R where R and R are each alkyl of 1 to 4 carbon atoms; alkenyl of 2 through 6 carbon atoms; alkynyl of 2 through 6 carbon atoms; cyclopropyl; cyclobutyl; cyclopropylmethyl; and cyclobutylmethyl; and
  • R is selected from the group consisting of R chlorine and bromine; with the proviso that when R is selected from the group consisting of alkenyl or alkynyl having the unsaturated bond in the l-position, R is selected from the group consisting of alkyl of 1 through 6 carbon atoms and mono-substituted alkyl of 1 through 6 carbon atoms where the substituent is selected from the group consisting of hydroxy, alkoxy of 1 through 2 carbon atoms, NH NHR and -NR R where R; and R are each alkyl radicals of 1 through 4 carbon atoms;

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US375338A 1963-05-01 1964-06-15 3-aminotricyclo [4.3.1.13.8] undecanes Expired - Lifetime US3397233A (en)

Priority Applications (19)

Application Number Priority Date Filing Date Title
GB1054275D GB1054275A (enrdf_load_stackoverflow) 1963-05-01
FI0834/64A FI41550B (enrdf_load_stackoverflow) 1963-05-01 1964-04-20
DE19641468758 DE1468758B1 (de) 1963-05-01 1964-04-21 3-Amino-tricyclo[4,3,1,1?]-undekan-Derivate und Verfahren zu ihrer Herstellung
CH642467A CH485655A (de) 1963-05-01 1964-04-22 Verfahren zur Herstellung von Tricyclo(4,3,1,1 3,8)undecanen
AT08046/67A AT277202B (de) 1963-05-01 1964-04-22 Verfahren zur herstellung von neuen 3-alkylaminotricyclo<4,3,1,1,3,8,> undecanen und ihren salzen
CH523664A CH468966A (de) 1963-05-01 1964-04-22 Verfahren zur Herstellung von 3-Aminotricyclo-(4,3,1,1,3,8)-undecan
LU45979D LU45979A1 (enrdf_load_stackoverflow) 1963-05-01 1964-04-27
SE15199/66A SE307944B (enrdf_load_stackoverflow) 1963-05-01 1964-04-29
NL646404755A NL143813B (nl) 1963-05-01 1964-04-29 Werkwijze ter bereiding van tegen viri werkzame farmaceutische preparaten.
SE5362/64A SE307942B (enrdf_load_stackoverflow) 1963-05-01 1964-04-29
SE15198/66A SE307943B (enrdf_load_stackoverflow) 1963-05-01 1964-04-29
BE647418D BE647418A (enrdf_load_stackoverflow) 1963-05-01 1964-04-30
FR1561907D FR1561907A (enrdf_load_stackoverflow) 1963-05-01 1964-04-30
US375338A US3397233A (en) 1963-05-01 1964-06-15 3-aminotricyclo [4.3.1.13.8] undecanes
DK367565AA DK111889B (da) 1963-05-01 1965-07-16 Fremgangsmåde til fremstilling af 3-N-substituerede tricycloundecaner.
DK367665AA DK119155B (da) 1963-05-01 1965-07-16 Fremgangsmåde til fremstilling af 3-amino-tricyclo[4,3,1,1<3,8>]undecan eller salte deraf.
MY196841A MY6800041A (en) 1963-05-01 1968-12-31 Tricycloundecane derivatives
FI2079/69A FI42550B (enrdf_load_stackoverflow) 1963-05-01 1969-07-11
FI2078/69A FI42549B (enrdf_load_stackoverflow) 1963-05-01 1969-07-11

Applications Claiming Priority (2)

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US27713463A 1963-05-01 1963-05-01
US375338A US3397233A (en) 1963-05-01 1964-06-15 3-aminotricyclo [4.3.1.13.8] undecanes

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US375338A Expired - Lifetime US3397233A (en) 1963-05-01 1964-06-15 3-aminotricyclo [4.3.1.13.8] undecanes

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US (1) US3397233A (enrdf_load_stackoverflow)
AT (1) AT277202B (enrdf_load_stackoverflow)
BE (1) BE647418A (enrdf_load_stackoverflow)
CH (1) CH468966A (enrdf_load_stackoverflow)
DE (1) DE1468758B1 (enrdf_load_stackoverflow)
DK (2) DK111889B (enrdf_load_stackoverflow)
FI (3) FI41550B (enrdf_load_stackoverflow)
FR (1) FR1561907A (enrdf_load_stackoverflow)
GB (1) GB1054275A (enrdf_load_stackoverflow)
LU (1) LU45979A1 (enrdf_load_stackoverflow)
MY (1) MY6800041A (enrdf_load_stackoverflow)
NL (1) NL143813B (enrdf_load_stackoverflow)
SE (3) SE307943B (enrdf_load_stackoverflow)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3532748A (en) * 1966-10-20 1970-10-06 Du Pont 2-adamantanamines
US4078085A (en) * 1975-08-06 1978-03-07 Kao Soap Co., Ltd. 3-Aminomethyl-4-homoisotwistane and its salt and process for producing same
US4101580A (en) * 1975-06-27 1978-07-18 Kao Soap Co., Ltd. 3-Amino-4-homoisotwistane and an acid addition salt thereof and a process for producing the same
US4174407A (en) * 1978-01-13 1979-11-13 Sumitomo Chemical Company, Limited Antiviral agent
US4229375A (en) * 1977-07-04 1980-10-21 Kao Soap Company, Limited 1-Aminomethyltricyclo[4.3.1.12,5 ]undecane and acid-addition salts thereof
US4230725A (en) * 1977-03-10 1980-10-28 Sumitomo Chemical Company, Limited Antiviral agent
US4254128A (en) * 1977-11-22 1981-03-03 Teva Pharmaceutical Industries Ltd. 2-Adamantyl hydrazines and biocidal compositions thereof
RU2147573C1 (ru) * 1998-08-24 2000-04-20 Волгоградский государственный технический университет Способ получения адамант-1-иламина и его производных
US8691808B2 (en) 2011-05-20 2014-04-08 Influmedix, Inc. Antiviral compounds and their methods of use

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH435243A (de) * 1964-03-26 1967-05-15 Geigy Ag J R Verfahren zur Herstellung von neuen N'-substituierten N-Arylsulfonyl-harnstoffen
CH529083A (de) * 1968-09-09 1972-10-15 Du Pont Verfahren zur Herstellung von Tricyclo-(4,3,1,13,8)-undecan-4-on

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3532748A (en) * 1966-10-20 1970-10-06 Du Pont 2-adamantanamines
US4101580A (en) * 1975-06-27 1978-07-18 Kao Soap Co., Ltd. 3-Amino-4-homoisotwistane and an acid addition salt thereof and a process for producing the same
US4078085A (en) * 1975-08-06 1978-03-07 Kao Soap Co., Ltd. 3-Aminomethyl-4-homoisotwistane and its salt and process for producing same
US4230725A (en) * 1977-03-10 1980-10-28 Sumitomo Chemical Company, Limited Antiviral agent
US4229375A (en) * 1977-07-04 1980-10-21 Kao Soap Company, Limited 1-Aminomethyltricyclo[4.3.1.12,5 ]undecane and acid-addition salts thereof
US4254128A (en) * 1977-11-22 1981-03-03 Teva Pharmaceutical Industries Ltd. 2-Adamantyl hydrazines and biocidal compositions thereof
US4174407A (en) * 1978-01-13 1979-11-13 Sumitomo Chemical Company, Limited Antiviral agent
RU2147573C1 (ru) * 1998-08-24 2000-04-20 Волгоградский государственный технический университет Способ получения адамант-1-иламина и его производных
US8691808B2 (en) 2011-05-20 2014-04-08 Influmedix, Inc. Antiviral compounds and their methods of use

Also Published As

Publication number Publication date
NL6404755A (enrdf_load_stackoverflow) 1964-11-02
LU45979A1 (enrdf_load_stackoverflow) 1964-06-27
DK111889B (da) 1968-10-21
SE307942B (enrdf_load_stackoverflow) 1969-01-27
DE1468758B1 (de) 1970-05-27
DK119155B (da) 1970-11-23
BE647418A (enrdf_load_stackoverflow) 1964-10-30
SE307944B (enrdf_load_stackoverflow) 1969-01-27
FI42550B (enrdf_load_stackoverflow) 1970-06-01
CH468966A (de) 1969-02-28
GB1054275A (enrdf_load_stackoverflow)
NL143813B (nl) 1974-11-15
FR1561907A (enrdf_load_stackoverflow) 1969-04-04
FI42549B (enrdf_load_stackoverflow) 1970-06-01
SE307943B (enrdf_load_stackoverflow) 1969-01-27
MY6800041A (en) 1968-12-31
FI41550B (enrdf_load_stackoverflow) 1969-09-01
AT277202B (de) 1969-12-10

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