US3352912A - Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes - Google Patents

Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes Download PDF

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US3352912A
US3352912A US376259A US37625964A US3352912A US 3352912 A US3352912 A US 3352912A US 376259 A US376259 A US 376259A US 37625964 A US37625964 A US 37625964A US 3352912 A US3352912 A US 3352912A
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undecane
tricycle
adamantane
tricyclo
ether
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US376259A
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William W Prichard
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EIDP Inc
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EI Du Pont de Nemours and Co
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Priority to DE19641793208 priority patent/DE1793208A1/en
Priority to DE19641793207 priority patent/DE1793207A1/en
Priority to DE19641468769 priority patent/DE1468769C/en
Priority to DE19641792295 priority patent/DE1792295B1/en
Priority to BR160975/64A priority patent/BR6460975D0/en
Priority to CH1457468A priority patent/CH479535A/en
Priority to CH946964A priority patent/CH476673A/en
Priority to AT1064566A priority patent/AT269835B/en
Priority to AT1064666A priority patent/AT269836B/en
Priority to FI1584/64A priority patent/FI42322B/fi
Priority to IL21753A priority patent/IL21753A/en
Priority to DK367964AA priority patent/DK112027B/en
Priority to SE09751/67A priority patent/SE330693B/xx
Priority to ES0302369A priority patent/ES302369A1/en
Priority to SE9752/67A priority patent/SE320363B/xx
Priority to BE650919D priority patent/BE650919A/xx
Priority to SE8987/64A priority patent/SE321924B/xx
Priority to NL6408505A priority patent/NL6408505A/xx
Priority to FR1572956D priority patent/FR1572956A/fr
Priority to GB30940/64A priority patent/GB1069563A/en
Priority to AT06819/68A priority patent/AT279581B/en
Priority to DK353365AA priority patent/DK114199B/en
Priority to DK353265AA priority patent/DK114769B/en
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Priority to FI0198/69A priority patent/FI42211B/fi
Priority to NL7102097A priority patent/NL7102097A/xx
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/29—Saturated compounds containing keto groups bound to rings
    • C07C49/313—Saturated compounds containing keto groups bound to rings polycyclic
    • C07C49/323—Saturated compounds containing keto groups bound to rings polycyclic having keto groups bound to condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the com-pounds of this invention are adamantanes of the formula and tricyclo[4.3.l.l ]undecanes of the formula 3,352,912 Patented Nov. 14, 1967 where X and Y can be the same or different and are hydrogen,
  • n 2, 3, 4, 5, or 6; NR R or N CHR wherein 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 different and each is an alkyl radical 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; for-myl; CH COOH or CH COOC H with the proviso that when R is alkenyl or alkynyl having the unsaturated bond in the 1-position, R is alkyl or mono-substituted alkyl as above defined;
  • substituent is aromatic or heterocyclic; aromatic; or heterocyclic containing not more than 12 carbon atoms.
  • compounds of the invention are preferred Where the amine on the adamantane or undecane moiety is substituted with dialkyl (N,N-dialkylated compounds) because they provide a very favorable balance of antiviral activity with reduced stimulant activity.
  • dialkyl N,N-dialkylated compounds
  • the lower alkyl substituents such as the dimethyl and diethyl derivatives are most preferred from considerations of higher anti-viral activity.
  • Compounds of the invention where the amine on the adamantane or undecane moiety is monoalkylated also demonstrate reduced stimulant acanti-viral activity than the dialkylated amine derivatives.
  • R is aliphatic; mono-substituted aliphatic where the zit-substituted compounds exhibit higher anti-viral activity but less favorable drug dynamics in comparison to the :,oL-Sllb5iil1lll6d compounds.
  • the compounds of this invention can be prepared by a variety of methods.
  • l-adamantane carboxylic acid and 3-tricyclo[4.3.1.1 undecane carboxylic acid can be converted to the corresponding acid chlorides with thionyl chloride.
  • the unsubstituted amides and a variety of N-alkyland N,N-dialkylsubstituted amides can be prepared from the acidchlorides by reaction with the appropriately substituted amines and ammonia. These amides are then reduced with lithium aluminum hydride to the corresponding amino-, N-alkylaminoand N,N-dialkylaminomethyl-adamantanes .and tricycloundecanes.
  • Thea-alkyl-l-adamantanemethylamines and a-alkyl-3- tricyclo[4.3.1.1 ]undecanemethylamines are prepared by reduction of adamantyl-(l) alkyl ketone oximes and tricyclo[4.3.1.1 ]undecyl-(3) alkyl ketone oximes with lithium aluminum hydride.
  • the ketones from which these oximes are derived are conveniently made by the reaction of the appropriate dialkyl cadmium with l-adamantoyl chloride or 3-tricyclo[4.3.1.1 ]undecoy1 chloride.
  • the u,a-dialkyl-l-adamantanemethylamines and .ot,oL- dialkyl 3 tricyclo[4.3.1.1 ]undecanemethylamines are made by the reaction of acetonitrile and sulfuric acid (Ritter reaction) with the corresponding a,a-dialkyl-1-adamantanemethanol or (1,0: dialkyl 3 tricycl0[4.3.1.l ]undecanemethanol, which gives the N acetyl a,ot dialkyll adamantanemethylamine or N acetyl 04,0: dialkyl 3 tricyclo[4.3.l.1 ]undecanemethylamine.
  • the amine is obtained by alkaline hydrolysis.
  • the starting alcohols for these reactions are made by the reaction of 1 adamantoyl chloride or 3-tricyclo[4.3.1.1 ]undecoyl chloride with alkyl Grignard reagents.
  • reactions of the acid chlorides with allylamine and diallylamine give the N-allyl and N,N-diallyl compounds after reduction.
  • Reactions of the acid chlorides with propargylamine and dipropargylamine give the N-propargyl and N,N-dipropargy1 compounds after reduction.
  • Some substituted alkyl amino compounds are more easily made by other routes. Hydroxyethyland bis-hydroxyethyl compounds are made by reaction of the amine with ethylene oxide. N-carbalkoxymethylamino compounds are made by alkylation with alkyl chloroacetate and base.
  • Aminoalkyl-, alkylaminoalkyl-, and dialkylaminoalkyl compounds are made by alkylation with appropriate aminoalkyl halides and base, although they can be made by treating the corresponding hydroxyalkyl compound with a thionyl halide to replace the hydroxyl group with a halogen and then replacing the halogen with the amino, alkylamino, or dialkylamino group by reaction with ammonia or a primary or secondary amine.
  • N-alkyland N,N-dialkyl-compounds are easily made by alkylation of l-(aminomethyl)adamantane and 3-(aminomethyl)tricyclo[4.3.1.l ]undecane with alkylating agents (such as alkyl halides), without resorting to reduction of N-alkyland N,N-dialkyl-amides.
  • the monoalkylamino compound When the reagents are used in molar amounts, 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 clean-cut as reduction of the amides 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 alkoxyalkyl-substitutions. For the reasons just given, these reactions are less preferable than other methods but. may be preferred in certain instances, and they illustrate an alternate route to substituted alkylaminomethyltricyclo[4.3.1.1 ]undecanes and adamantanes by ordinary alkylation with a substituted alkylating reagent.
  • Reactions of l-(aminomethyl)adamantane and 3- (aminomethyl)tricyclo[4.3.1.1 ]undecane with aldehydes give the corresponding alkylidene, arylidene or heterocyclicylidene aminomethyladamantanes and aminomethyltricycloundecancs.
  • reaction of l-(aminomethyl)adamantane with formaldehyde gives N-(l-adamantylmethyl)azomethine.
  • Reaction of 3-(aminomethyl) tricyclo[4.3.l.l ]undecane with benzaldehyde gives 3- (benzylideneaminomethyl)tricyclo [4.3.1.1 ]undecane.
  • undecane 3- [N- 2-rnethylamineethyl) aminemethyl] tricycle [4.3 .1.1 ]undecane 3 [N- 3-dirnethylamineprepyl aminemethyl] tricycle [4.3 .1 1 undecane 3 [N- (2-dimethylarnineethyl -N-methylaminomethyl] tricycle [4.3.
  • undecane 3- (N-chlere-Nhexylarninemethyl) tricycle [4.3 1 1 undecane 3- (N-bremeaminernethyl) tricycle [4.3.1. 1 ]undecane 3- (N-brome-N-methylaminemethyl tricycle [4.3 .1. 1
  • undecane 3- (N-brerno-N-hexylaminemethyl) tricycle [4.3 1 1 undecane 3-(fermamidernethyl) tricycle [4.3.1.1 undecane 3- (N rnethylfermarnidemethyl) tricycle [4.3 1 1 undecane 3 -(N-hexylfermamidernethyl)tricycle[4.3.l.1
  • Example 1 A solution of 6 parts of I-adamantane carbexamide in 200 parts of tetrahydrefuran is added slowly to a wellstirred suspension of 6.15 parts of lithium aluminum hydride in 200 parts of dry diethyl ether. After completion of addition, the mixture is refluxed for one hour and the solvent distilled 01f. The residue is subjected to steam distillation. The waxy l-aminomethyl adamantane is extracted from the steam distillate with ether and the ethereal solution dried with solid potassium hydroxide. Dry hydrogen chloride is then passed into the ether solution to precipitate the amine hydrochloride. The yield is 5.25 parts of l-(aminomethyl)adamantane hydrochloride which melts at 337-340 C. after recrystallization from chloroform-benzene.
  • the free l-aminomethyl adamantane melts at 128.5 C. and can be converted to an acetyl derivative by treatment with acetic anhydride which, after recrystallization from n-hexane, melts at 123-124".
  • Example 2 A solution of 17 parts of l-adamantoyl chloride in 150 parts of acetone is treated with 15 parts of a 40% aqueous solution of methylarnine at C. After complete addition, the mixture is warmed gently and diluted with Water. The crystalline l-N-methyl adamantane carboxamide is isolated by filtration as 11.27 parts of material melting at 137138 C. In an alternative synthesis of this compound, dry methylamine, 2 equivalents, is distilled into an ethereal solution of adamantoyl chloride, 1 equivalent, and the resulting solution evaporated to dryness.
  • Example 3 A solution of 19.85 parts of l-adamantoyl chloride in 100 parts of dry diethyl ether is stirred at 0 C. and an ethereal solution of 9 parts of dimethylamine added slowly. The mixture is then stirred at room temperature for 30 minutes and evaporated to dryness. The residual solid is triturated with water and extracted with ether. The ethereal solution is dried over anhydrous sodium sulfate and the ether removed. This gives 19.5 parts (94.2%) of 1-N,N-dimethyl adamantane carboxamide which melts at 76-78 C. The 19.5 parts of amide is dissolved in 100 parts of ether and added slowly to a well stirred suspension of 4.5 parts of LiAlH in 300 parts of ether.
  • Example 4 A solution of 19.85 parts of l-adamantoyl chloride is treated with 9 parts of ethylamine under the condi- 10 tions outlined in the previous example to give 19.56 parts, 94.5%, of l-N-ethyl adamantane carboxamide melting at 138 C.
  • Example 5 A solution of 19.85 parts of l-adamantoyl chloride in other is reacted with an ethereal solution of 12 parts of propylamine by the procedure of Example 3 to give 21.38 parts of l-(N-propyl)adamantane carboxamide melting at 140141 C. Twenty-one parts of this amide is reduced with LiAlH as shown in the previous example to give 19.4 parts of l-(N-propylamino-rnethyl)adamantane hydrochloride. After recrystallization from methanol, this melts at 342 C.
  • Example 6 Under the conditions of the previous example, 19.85 parts of l-adamantoyl chloride and 14.67 parts of diethylamine give 22.8 parts of 1-N,N-diethyladamantane carboxamide, M.P. 6263 C.
  • Example 7 A solution of 5.8 parts of 3-carboxytricyclo[4.3.1.1 undecane in 10 parts of thionyl chloride is refluxed until hydrogen chloride evolution ceases.
  • the crude acid halide thus prepared is isolated by distilling off the excess thionyl chloride under reduced pressure, adding a small amount of benzene and removing this under reduced pressure.
  • the acid chloride is then dissolved in 200 parts of ether and an excess of dry methylamine passed into the stirred solution at 0 C.
  • the reaction is then stirred for 30 minutes and diluted with water.
  • the layers are separated, the ether layer washed with water and dried over calcium chloride. Removal of the solvent gives 3.7 parts of white leaflets, melting at 133 C., of N-methyltricyclo [4.3. l.1 ]undecyl-3 -carboxamide.
  • Example 8 The amine hydrochloride of Example 2, 5.4 parts, is dissolved in 20 parts of pyridine and 5 parts of acetic anhydride is added. The mixture is warmed gently until a clear solution is obtained, then heated on a steam bath for 30 minutes and diluted with cold water.
  • the solid Example 9 A sample of B-carboxamidotricyclo [4.3.l.1 ]undecane is prepared by convertin the 3-carboxytricyclo[4.3.1. 1 ]undecane of Stetter, Ber., 92, 1629-1635 (1959), to
  • Example 10 A solution of 19.85 grams (0.10 mole) of l-adamantoyl chloride in 100 milliliters of dry diethyl ether is stirred at C. and an ethereal solution of 12.7 grams (0.15 mole) of piperidine is added slowly. The mixture is stirred at room temperature for 30 minutes and evaporated to dryness. The residual solid is triturated with water and extracted with ether. The ethereal solution is dried over anhydrous sodium sulfate and the ether removed to leave 1-adamantoylpiperidide.
  • Example 11 A mixture of 3.6 g. of magnesium turnings, a small crystal of iodine,,1l ml. of anhydrous benzene and 1 ml. of absolute ethanol is heated until a reaction begins. Then heating is discontinued and a mixture of 24.0 g. of diethyl malonate, 7.0 g. of absolute ethanol and 30 ml. of benzene is added dropwise at a rate which causes the reactionmixture to reflux. After addition is completed, the mixture is heated at reflux until the magnesium has dissolved. The excess ethanol is removed by azeotropic distillation with some of the benzene. To the resultant solution of ethoxymagnesiumdiethylmalonate is added a solution of 19.8 g.
  • a mixture of 14 g. of hydroxylamine hydrochloride, 65 ml. of anhydrous pyridine and 65 ml. of anhydrous ethanol is heated on a steam bath until a clear solution is obtained.
  • 13.4 g. of adamantyl-(l) methyl ketone is added to this is added 13.4 g. of adamantyl-(l) methyl ketone, and the mixture is heated at reflux for 2 hours, then cooled. It is concentrated to dryness in a vacuum at 70, and the residue is suspended in 150 ml. of water and stirred well.
  • the solids are filtered and dried to yield 14.2 g. of adamantyl-( 1) methyl ketone oxime, a white, crystalline compound melting at 180.5 182 C. This can be recrystallized from a dioxane-water mixture without affecting the melting point.
  • oxime is added to a mixture of 3.3 g. of lithium aluminum hydride in 150 ml. of anhydrous tetrahydrofuran, and the mixture is stirred and heated at reflux for 3 hours. It is cooled in an ice bath and the excess of lithium aluminum hydride is destroyed with a water-tetrahydrofuran mixture. Several ml. of 10% sodium hydroxide solution is added to aid in the coagulation of the solids, which are removed by filtration, washed with 50 ml. of chloroform, and discarded. The filtrate, which includes the tetrahydrofuran solution and the chloroform solution, is saturated with dry hydrogen chloride and then concentrated to dryness in a vacuum at 50 C.
  • Example 12 Substitution of 21.3 g. of 3-tricyclo[4.3.1.1 ]-undecoyl chloride for the 19.8 g. of l-adamantoyl chloride in Example 11 and repetition of the procedure of that example leads to tricyclo[4.3.l.1 ]undecyl-(3) methyl ketone, then to tricyclo[4.3.1.1 ]undecyl-(3) methyl ketone oxime, and, after the reduction, to u-methyl-3- tricyclo [4.3 1. 1 -undecanemethylamine hydrochloride.
  • Example 13 To a solution of 31.5 g. of l-adamantoyl chloride in 500 ml. of anhydrous ether under a nitrogen atmosphere is added, dropwise, ml. of commercial 3 M methyl magnesium bromide at a rate which maintains a gentle reflux. The reaction mixture is heated for 1 hour after the addition, then cooled. To decompose the metal complex, 300 ml. of saturated ammonium chloride is added. The ether layer is separated and the aqueous layer is extracted with 100 ml. of chloroform. This extract is combined with the ether layer, and the mixture is dried with anhydrous magnesium sulfate and vacuum-concentrated to dryness at 35 C.
  • Example 14 Substitution of 33.7 g. of 3-tricyclo[4.3.1.1 ]undecoyl chloride for the 31.5 g. of l-adamantoyl chloride in Example 13 and repetition of the procedure of that example leads to a,a-dimethyl-3-tricyclo[4.3.1.l ]undecanemethanol, then to N-acetyl-u,ot-din1ethyl-3-tricyclo[4.3.1.1 undecanemethylamine, and, after hydrolysis, to aux-(limethyl-3-tricyclo[4.3.l.1 Jundecane methylamine hydrochloride.
  • Example 15 To a mixture of 1.5 g. of lithium aluminum hydride in 100 ml. of anhydrous diethylene glycol, dimethyl ether is added 4.1 g. of N-acetyl-a,a-dimethyl-1-adamantanemethylamine, prepared in Example 13. The reaction mixture is stirred and heated at reflux for 3 hours, then cooled in an ice bath. The excess lithium aluminum hydride is decomposed by adding wet diethylene glycol, dimethyl ether. Several ml. of 10% sodium hydroxide is added to coagulate the precipitate, which is then filtered and washed with 50 ml. of ether. The filtrate is treated with dry hydrogen chloride until no additional precipitate forms. This is filtered, dissolved in 100 ml.
  • Example 17 A solution of diethyl cadmium in benzene is prepared by adding 19.6 g. of powdered anhydrous cadmium chloride over a 5-minute period to 0.2 mole of ethyl magnesium bromide in ml. of anhydrous ether at ice bath temperature. The mixture is heated at reflux with vigorous stirring for 30 minutes. Then, the ether is removed by distillation on a steam bath, and 65 ml. of benzene is added to the nearly dry, brown, pasty residue. Distillation is continued until the vapor temperature of the distillate reaches 61 C. An additional 100 ml. of benzene is added to the diethyl cadmium solution, and the solution is again heated to reflux.
  • a mixture of 75 ml. of anhydrous ethanol, 75 ml. of anhydrous pyridine, 16 g. of hydroxylamine hydrochloride and 16.0 g. of adamantyl-(l) ethyl ketone is heated at reflux for 2 hours and then vacuum concentrated to semi-dryness .at 80 C.
  • a ZOO-ml. amount of water is added, and the mixture is again concentrated to semidryness.
  • the residue is suspended in 300 ml. of water, and the solids are filtered.
  • the melting point of this crude material is -177 C. Recrystallization from a mixture of dioxane and acetonitrile gives 10.3 g. of white, crystalline adamantyl-(l) ethyl ketone oxime, M.P. 177- 179 C.
  • a 7.7-g. quantity of adamantyl-(l) ethyl ketone oxime is added to a mixture of 3.0 g. of lithium aluminum hydride and 150 ml. of anhydrous diethylene glycol dimethyl ether, and the mixture is stirred and heated at reflux for three hours. It is cooled to 10 C. with an ice bath and the excess lithium aluminum hydride is destroyed with wet diethylene glycol dimethyl ether. Five ml. of 10% sodium hydroxide is added to coagulate the solids, which are then filtered, washed with 50 m1. of ether and discarded. The filtrate is saturated with dry hydrogen chloride and vacuum concentrated until precipitation is complete.
  • the concentrated filtrate is cooled and the solids are filtered, washed with ether and dried.
  • the dried salt is dissolved in 150 ml. of Water and the solution is treated with excess 50% sodium hydroxide and extracted with two 50-ml. portions of ether.
  • the ether extracts are combined, dried with potassium hydroxide pellets, and treated with dry hydrogen chloride until precipitation is complete.
  • the precipitate is filtered and dried to give 5.2 g. of white, crystalline a-ethyl-ladamantanemethylamine hydrochloride, M.P. 278-282" C. (sealed tube).
  • Example 18 Substitution of 21.3 g. of 3-tricyclo[4.3.l.l ]undecoyl chloride for the 19.8 g. of l-adamantoyl chloride in Example 17, and repetition of the procedure of that example leads to tricyclo[4.3.l.l ]undecyl-(3) ethyl ketone, then to tricyclo [4.3.1.1 ]undecyl-( 3) ethyl ketone oxime, and, after the reduction, to a-ethyl-3-tricyclo [4.3.1.1 ]undecanemethylamine hydrochloride.
  • Example 19 Use of 0.10 mole of 3-tricyclo[4.3.1.l ]undecoylchlo-
  • Example 21 Use of 0.10 mole of 3-tricyclo[4.3.1.1 ]undecoylchloride (see Example 7) and 0.15 mole of diallylamine instead of the l-adamantoyl chloride and piperidine in the procedure of Example 10 gives 3-(N,N-di-allylaminomethyl)tricyclo [4.3.1.1 ]undecane hydrochloride.
  • Example 22 Use of 0.15 mole of propargylamine instead of the 0.15 mole of piperidine in Example 10 gives l-(N-propargylaminomethyhadamantane hydrochloride.
  • Example 23 Use of 0.15 mole of cyclopropylmethylamine instead of the 0.15 mole of piperidine in Example 10 gives l-(N- cyclopropyl-methylaminomethyl)adamantane hydrochloride.
  • Example 24 Use of 0.10 mole of 3-tricyclo[4.3.1.1 ]undecoylchloride (See Example 7) and 0.15 mole of cyclobutylamine instead of the l-adamantoyl chloride and piperidine in the procedure of Example 10 gives 3-(N-cyclobutylaminoethyl) -tricycl [4.3. 1 1 undecane hydrochloride.
  • Example 25 A milliliter flask with magnetic stirrer and reflux condenser is charged with 0.050 mole of l-(aminomethyl) adamantane, 6.13 grams (0.050 mole) of ethyl chloroacetate, 5.00 grams (0.060 mole) of sodium bicarbonate and 20 milliliters of methanol. The insoluble material is filtered and the filtrate is evaporated to dryness. The residue is dissolved in 60 millilitersof 1N hydrochloric acid, and 10 milliliters of, 70% perchloric acid is added. The precipitated perchlorate salt is filtered, Washed with cold water, and dried. The free base is regenerated with 10% sodium hydroxide and distilled to remove unchanged starting material. The higher boiling fraction is N( l-adamantylmethyl) glycine, ethyl ester.
  • Example 26 fate, and concentrated in vacuo to give l-[N-Z-diethylaminoethyl) -N-methylaminomethyl] adamantane.
  • Example Product of Example 16 Example 27 A flask equipped with a Dean-Stark water separator is charged with 0.10 mole. of 3-(aminomethyl)tricyclo- [4.3.1.l ]undecane (see Example 9), 15.4 grams (0.10 mole) of freshly distilled benzaldehyde, and 50 milliliters of toluene. The solution is allowed to reflux for 45 hours. The toluene is evaporated and the residue is recrystallized to give N-(3-tricyclo[4.3.1.1 ]undecylmethyl)benzaldimine.
  • Example 28 A solution of 0.5 mole of l-(aminomethyl)adamantane in 120 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 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 l-(aminomethyl)adamantane. The residue from the sublimation is distilled under vacuum to yield 1-[N-(2-hydroxyethyl)aminomethyl]adamantane.
  • Example 29 A solution of 0.10 mole of 1-(aminomethyl)adamantane in milliliters of 98% formic acid is allowed to stand 48 hours at room temperature. The formic acid is removed by concentration in vacuo to leave the residue, l-(formamidomethyl)adamantane.
  • this compound is prepared by refluxing 0.05 mole of l-(aminomethyl)adamantane for 19 hours in 25 ml. of butyl formate. The excess butyl formate is removed by vacuum concentration to leave a residue of l-(formamidomethyl)adamantane.
  • Example 30 A suspension of 0.1 mole of 3-(aminomethyl)tricyclo- [4.3.1.1 ]undecane in 100 milliliters of ice water is placed in a 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 Chl0rox) is added at such a rate that the temperature does not exceed 10 C.
  • sodium hypochlorite solution commercial Chl0rox
  • Example 31 A mixture of 0.10 mole of 1-(aminomethyl)adaman tame 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, l-(aminomethyl)adamantane hydrochloride, is dried in vacuo at 60 C.
  • Example 18 is repeated, substituting the following indicated reactants for those of that example, .to obtain the indicated product.
  • Acid Product 1 (free base) 2 (free base) 0.10 mole). 3 (free base) (0.10 mole) 4 (free base) (0.10 mole). 5 (free base) (0.10 mole). 6 (tree base) (0.10 mole).
  • Lactic acid (0.10 mole) 1 7
  • Example 41 A solution of 0.20 mole of l-(aminoethyl)adamantane hydrochloride in 100 milliliters of water is added to a solution of 0.10 mole of pamoic acid, disodium salt [44'- methylene bis(3-hydroxy-2naphthoic acid), disodium salt] in 500 milliliters of water. The resulting precipitate is filtered, washed well with water, and dried in vacuo to give l-(aminomethyl)adamantane, pamoate.
  • Example 42 Carbon dioxide is passed into a solution of 0.10 mole of l-(aminomethyl)adamantane in 100 milliliters of ethyl ether until precipitation is complete. The precipitate is filtered and dried in vacuo to give l-(aminoethyl) adamantane, bicarbonate.
  • the compounds of this invention 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, intraveneously, intramuscularly, or intraperitoneally. Alternatively or concurrently, administration can be by the oral route.
  • 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. Ordinarily, from 1 to 20 and preferably 1 to 10 milligrams per kilogram per day, in one or more applications per day is effective to obtain the desired result.
  • the active ingredient of this invention 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 active ingredient will ordinarily always be present in an amount of at least 0.5% by weight based on the total weight of the composition and not more than 90% by weight.
  • the antiviral composition will contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.
  • the solid carrier is a capsule which can be of the ordinary gelatin type.
  • the capsule will be from about 30-60% by weight of a compound of Formulas 1 and 2 and 70-40% 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 95% 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, he 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, sesame 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, sesame oil, and the like.
  • water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carries, particularly for injectible solutions.
  • Sterile 18 injectible solutions such as saline 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 composition can be a Watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.
  • Suitable pharmaceutical carriers are described in Rem ingtons Practice of Pharmacy by E. W. Martin and E. F. Cook, a well known reference text in this field.
  • Example 43 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 1- (aminoethyl)adamantane, hydrochloride, 125 milligrams of lactose and 1 milligram of Cab-o-sil.
  • Example 44 Example 43 is repeated except that soft gelatin capsules are used and powdered l-(aminomethyl)adamantane is first dissolved in mineral oil.
  • Example 45 Example 43 is repeated except that the dosage unit is 50 milligrams of active ingredient, 5 milligrams of gelatin, 1.5 milligrams of magnesium stearate and milligrams of lactose, mixed and formed into a tablet by a conventional tableting machine. Slow release pills or tablets can also be used, .by applying appropriate coatings. A sugar coating may be applied to increase palatability.
  • Example 46 A parenteral composition suitable for administration by injection is prepared by stirring 5% by weight of the active ingredient of Example 43 in sterile aqueous 0.9% saline.
  • compositions according to this invention can thus readily be made by substituting other compounds of thisinvention, 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. f
  • Compounds within the scope of Formulae 1 and 2 of the invention are anti-viral agents in domestic animals and livestock.
  • compounds within the'scope of Formulae 1 and 2 are effective against swine influenza and an embodiment of the intlention, therefore, is a 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 compounds 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.
  • 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.
  • a compound selected from the group consisting of those of the formula 20 and A is hydrogen
  • X and Y are each hydrogen, methyl, or ethyl; and R is m -N H2).
  • R is alkenyl or alkynyl having the unsaturated bond in the l-position, R is alkyl of 1 through 6 carbon atoms or 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 and R is hydrogen, alkyl of 1 through 5 carbon atoms,

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Description

United States Patent 3,352,912 ADAMANTANES AND TRICYCL0[4.3.1.1
UNDECANES William W. Prichard, Hockessin, Del., assignor to E. I. du Pont de Nemours and Company, Wilmington, Del., a corporation of Delaware No Drawing. Filed June 18, 1964, Ser. No. 376,259 19 Claims. (Cl. 260-563) ABSTRACT OF THE DESCLOSURE Cross-reference This application is a continuation-in-part of my copendin application S.N. 297,23 3, filed July 24, 1963, now abandoned.
According to the present invention, I have discovered a class of novel compounds having pharmaceutical ap plication and useful as antiviral agents. They have the ability to inhibit and deter incidence and growth of harmful viruses. Additionally, compounds of this class of compounds exhibit significant stimulant activity.
The com-pounds of this invention are adamantanes of the formula and tricyclo[4.3.l.l ]undecanes of the formula 3,352,912 Patented Nov. 14, 1967 where X and Y can be the same or different and are hydrogen,
methyl or ethyl; and
where n is 2, 3, 4, 5, or 6; NR R or N CHR wherein 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 different and each is an alkyl radical 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; for-myl; CH COOH or CH COOC H with the proviso that when R is alkenyl or alkynyl having the unsaturated bond in the 1-position, R is alkyl or mono-substituted alkyl as above defined; and
substituent is aromatic or heterocyclic; aromatic; or heterocyclic containing not more than 12 carbon atoms.
Compounds hydrolyzable to the compounds of Formulas l and 2 are for most purposes equivalent to those compounds and are of course contemplated as within the present invention.
It also will be understood that the compounds within the scope of Formulas 1 and 2 having a basic amino group, readily form salts and such salts having a non-toxic anion are also included within the scope of the present invention. Representative of such salts are hydrochlorides, hydrobromides, sulfates, phosphates, acetates, succinates, adipates, propionates, tartrates, citrates, bicarbonates,
pamoates, cyclohexylsulfamates and acetylsalicylates. Of
For example, by proper selection of compounds, it is found that it is possible to attain different desired balances of stimulant and anti-viral activities as well as different desired balances of drug dynamics and anti-viral activities depending upon the type of disease and patient being treated.
Accordingly, compounds of the invention are preferred Where the amine on the adamantane or undecane moiety is substituted with dialkyl (N,N-dialkylated compounds) because they provide a very favorable balance of antiviral activity with reduced stimulant activity. Of these, the lower alkyl substituents such as the dimethyl and diethyl derivatives are most preferred from considerations of higher anti-viral activity. Compounds of the invention where the amine on the adamantane or undecane moiety is monoalkylated also demonstrate reduced stimulant acanti-viral activity than the dialkylated amine derivatives.
R is aliphatic; mono-substituted aliphatic where the zit-substituted compounds exhibit higher anti-viral activity but less favorable drug dynamics in comparison to the :,oL-Sllb5iil1lll6d compounds.
In view of. the foregoing considerations, the most preferred compounds of the invention for pharmaceutical application'are the following compounds and their hydrochloride salts:
1- (N,N-dimethylaminomethyl) adamantane 1- N-methylaminomethyl) adamantane 1- N-ethyl-N-methylaminomethyl) adamantane 1-( aminomethyl adamantane 1- (MN-diethylaminomethyl) adamantane 1- N-ethylaminomethyl adamantane 3 -(N,N-dimethylaminomethyl)tricyclo [4.3 .1.1
undecane 3 -(N-methylaminomethyl)tricyclo[4.3.1.1 ]undecane 3-(N-ethyl-N-methylaminomethyl)tricyclo[4.3.1.1
undecane 3 aminomethyl tricyclo [4.3 .1 l ]undecane 3 N,N-diethylarninomethyl tricyclo [4.3 1.1 undecane 3 -(N-ethylaminomethyl)tricyclo [4.3.1.1 ]undecane a-methyl- 1 -adamantanemethylamine a-methyl-3 -tricyclo [4.3 l .1 undecanernethylamine a,a-dimethyl-l -adamantanemethylamine a,u-dimethyl-3-tricyclo[4.3 l 1 undecanemethylamine The compounds of this invention can be prepared by a variety of methods.
l-adamantane carboxylic acid and 3-tricyclo[4.3.1.1 undecane carboxylic acid can be converted to the corresponding acid chlorides with thionyl chloride. The unsubstituted amides and a variety of N-alkyland N,N-dialkylsubstituted amides can be prepared from the acidchlorides by reaction with the appropriately substituted amines and ammonia. These amides are then reduced with lithium aluminum hydride to the corresponding amino-, N-alkylaminoand N,N-dialkylaminomethyl-adamantanes .and tricycloundecanes.
Thea-alkyl-l-adamantanemethylamines and a-alkyl-3- tricyclo[4.3.1.1 ]undecanemethylamines are prepared by reduction of adamantyl-(l) alkyl ketone oximes and tricyclo[4.3.1.1 ]undecyl-(3) alkyl ketone oximes with lithium aluminum hydride. The ketones from which these oximes are derived are conveniently made by the reaction of the appropriate dialkyl cadmium with l-adamantoyl chloride or 3-tricyclo[4.3.1.1 ]undecoy1 chloride.
The u,a-dialkyl-l-adamantanemethylamines and .ot,oL- dialkyl 3 tricyclo[4.3.1.1 ]undecanemethylamines are made by the reaction of acetonitrile and sulfuric acid (Ritter reaction) with the corresponding a,a-dialkyl-1-adamantanemethanol or (1,0: dialkyl 3 tricycl0[4.3.1.l ]undecanemethanol, which gives the N acetyl a,ot dialkyll adamantanemethylamine or N acetyl 04,0: dialkyl 3 tricyclo[4.3.l.1 ]undecanemethylamine. The amine is obtained by alkaline hydrolysis. The starting alcohols for these reactions are made by the reaction of 1 adamantoyl chloride or 3-tricyclo[4.3.1.1 ]undecoyl chloride with alkyl Grignard reagents.
A variety of aminescan be used for the preparation of l-adamantanecarboxamides and 3 tricyclo[4.3.1.1 ]undecanecarboxamides, to give a variety of substituent groups on the nitrogen of l-(aminomethyl)adamantane and 3-(aminomethyl)tricyclo[4.3.1.1 ]undecane. For example, reactions of the acid chlorides with allylamine and diallylamine give the N-allyl and N,N-diallyl compounds after reduction. Reactions of the acid chlorides with propargylamine and dipropargylamine give the N-propargyl and N,N-dipropargy1 compounds after reduction. Reactions with cyclopropylarnine cyclopropylrnethylamine and pyrrolidine give the N-cyclopropyl, N-cyclopropylmethyl and pyrrolidino compounds after reduction. Reactions with alkoxyalkylamines give the N-alkoxyalkyl compounds after reduction. Of course, reactions of the acid chlorides with amines having difierent N-substituents give corresponding N,N-disubstituted amino compounds. For instance, reactions of the acid chlorides with N-allyl-N- methylamine give 1-(N-allyl-N-methylaminomethyl)adamantane and 3-(N-allyl-Nrmethylaminomethyl)tricyclo- [4.3.1.1 ]undecane.
Some substituted alkyl amino compounds are more easily made by other routes. Hydroxyethyland bis-hydroxyethyl compounds are made by reaction of the amine with ethylene oxide. N-carbalkoxymethylamino compounds are made by alkylation with alkyl chloroacetate and base.
Aminoalkyl-, alkylaminoalkyl-, and dialkylaminoalkyl compounds are made by alkylation with appropriate aminoalkyl halides and base, although they can be made by treating the corresponding hydroxyalkyl compound with a thionyl halide to replace the hydroxyl group with a halogen and then replacing the halogen with the amino, alkylamino, or dialkylamino group by reaction with ammonia or a primary or secondary amine.
In some cases, N-alkyland N,N-dialkyl-compounds are easily made by alkylation of l-(aminomethyl)adamantane and 3-(aminomethyl)tricyclo[4.3.1.l ]undecane with alkylating agents (such as alkyl halides), without resorting to reduction of N-alkyland N,N-dialkyl-amides.
When the reagents are used in molar amounts, 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 clean-cut as reduction of the amides 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 alkoxyalkyl-substitutions. For the reasons just given, these reactions are less preferable than other methods but. may be preferred in certain instances, and they illustrate an alternate route to substituted alkylaminomethyltricyclo[4.3.1.1 ]undecanes and adamantanes by ordinary alkylation with a substituted alkylating reagent.
Reactions of l-(aminomethyl)adamantane and 3- (aminomethyl)tricyclo[4.3.1.1 ]undecane with aldehydes give the corresponding alkylidene, arylidene or heterocyclicylidene aminomethyladamantanes and aminomethyltricycloundecancs. For instance, reaction of l-(aminomethyl)adamantane with formaldehyde gives N-(l-adamantylmethyl)azomethine. Reaction of 3-(aminomethyl) tricyclo[4.3.l.l ]undecane with benzaldehyde gives 3- (benzylideneaminomethyl)tricyclo [4.3.1.1 ]undecane.
Reactions of l-(aminomethyl)adamantane. or 3-(aminomethyl)tricyclo [4.3.1.l. ]undecane or the corresponding l-(N-alkylaminomethyl) compounds with butyl formate give the formamido-compounds.
Representative of the compounds of this invention are the following compounds and their salts:
1- aminomethyl) adamantane 1- (N-methylaminomethyl) adamantane l- (N,N-dirnethylaminomethyl) adamantane 1- (N-ethyl-N-methylaminomethyl adamantane 1- (N,N-diethylaminomethyl) adamantane l-(N-propylaminomethyl) adamantane 1- (N-methyl-N-propylaminomethyl) adamantane 1- (N-isopropylaminomethyl adamantane 1-( N-methyl-N-isopropylaminomethyl) adamantane l-(N,N-diisopropylaminomethyl) adamantane 1-(N-sec-butylarninomethyl) adamantane 1-(N-isobutylaminomethyl) adamantane 1- (N-tert-butylaminomethyl adamantane 1- N-hexylaminomethyl adamantane 1- (N-isoa-mylaminomethyl) adamantane 3 (N-allyl-N-methylaminemethyl) tricycle [4. 3 1 1 undecane 3- (N,N-di-allylaminemethyl tricycle [4.3 1 1 undecane 3-. [N- (heXen-3 -yl) aminemethyl] tricycle [4.3. 1. 1 undecane 3 (N-ethynyl-N-methylaminemethyl) tricycle [4.3 1 1 undecane 3- (N-prepargylaminemethyl tricycle [4.3 1 1 undecane 3 -(N,N-di-prepargylaminemethyl) tricycle[4.3.1.1
undecane 3- (N-hydrexyrnethylaminemethyl) tricycle [4. 3 1 .1
undecane 3 -(N-methexymethylaminemethyl)tricyclo[4.3.1.1
undecane 3- (N-ethexymethylarninemethyl tricycle [4.3 1 1 1 undecane 3- [N-(Z-methexyethyl) aminemethyl] tricycle [4.3 1. 1
undecane 3 [N- (Z-hydrexyethyl) anlinemethyl] tricycle [4.3 l 1 3 undecane 3- [N- Z-hydrexyethyl) -N-methylaminernethyl] tricycle [4.3.1.1 ]undecane 3- [N,N-di 2-hydrexyethyl) aminemethyl] tricycle [4.3.1.1 ]undecane 3- (N-aminemethylarninornethyl) tricycl-e[4.3 1 1 undecane 3- N-aminernethyLN-methylaminemethyl) tricycle [4.3.1.1 ]undecane 3 [N- methylarninemethyl) aminemethyl] tricycle [4.3.1.1 ]undecane 3- [N- butylarninernethyl) aminemethyl] tricycle [4.3 .1.1 undecane 3- [N- (isebutylarninemethyl aminemethyl tricycle [4.3.1.1 ]undecane 3- [N- (sec-butylaminernethyl) aminernethyl] tricycle [4.3.1 1 undecane 3 [N-(tert-butylaminernethyl arninomethyl] tricycle [4.3.1.1 ]undecane 3- [N- (dirncthylaminemethyl) aminernethyl tricycle [4.3.1.1 ]undecane 3- [N- (N-butyl-N'-methylarninernethyl) aminemethyl] tricycle[4.3.1.1 ]undecane 3- [N-dibutylaminernethyl) aminernethyl] tricycle [4.3 .1.1 ]undecane 3 [N-diisebutylarninernethyl) aminernethyl} tricycle [4.3 .1 1 undecane 3 -N- [di( l-methylpentyl) aminernethyl] aminemethyl tricycle [4.3 .1.1 ]undecane 3- [N-(di-tert-butylaminemethyl) aminemethyl] tricycle [4.3 .1.1 ]undecane 3 [N-(6-hydrexyhcxyl) aminemethyl] tricycle [4.3 1 .1
undecane 3 -[N-(3-hydrexyhexyl) aminomethyl]tricycle[4.3.1.1
undecane 3 [N- 6-methexyhexyl) aminemethyl] tricycle [4.3 1.1
undecane 3 [N- (3 -rnethexyhexyl)aminernethyl]tricyclo[4.3.1.1
undecane 3 [N- 6-ethexyhexyl) aminemethyl] tricycle [4.3 1 1 undecane 3 [N-( 3 -ethexy-2-rnethylpentyl) aminemethyl] tricycle- [4.3.1.1 ]undecane 3- [N- Z-amineethyl aminemethyl tricycle [4.3 1.1]
undecane 3- [N- 2-rnethylamineethyl) aminemethyl] tricycle [4.3 .1.1 ]undecane 3 [N- 3-dirnethylamineprepyl aminemethyl] tricycle [4.3 .1 1 undecane 3 [N- (2-dimethylarnineethyl -N-methylaminomethyl] tricycle [4.3. 1 .1 undecane 3 [N-(6-amiuehexyl) aminemethyl] tricycle [4.3 l 1 undecane 3- N-( l-amine- 1 -ethylbutyl aminomethyl] tricycle- [4.3.1.1 ]undecane 3- [N- 6-methylaminehexyl) aminemethyl] tricycle- [4.3.1.1 ]undecane 3- [N- (4-butylaminohexyl) aminemethyl] tricycle- [4.3.1.1 ]undecane.
3- [N- 6-isebutylarninehexyl) aminerncthyl] tricycle- [4.3.1. l ]undecane 3-N- 6-( l-rnethylpentyl) aminohexyl] aminemethyl tricycle [4.3 .1. 1 ]undecane 3-[N- (6-tert-butylarninehexyl) aminornethyl] tricycle- [4.3.1.1 ]undecane 3- [N,N-di- Z-diethylamineethyl) aminernethyl] tricycle- [4.3.1. l ]undecane 3- [N- 6-dirnethylaminehexyl) aminemethyl] tricycle- [4.3.1 1 ]undecane 3- N- 3-dimethylarninehexyl)aminemethyl1 tricycle- [4.3.1. l ]undecane 3- N-( 6-dibutylaminehexyl) aminernethyl] tricycle- [4.3.1.1 ]undecane 3- [N- 6-diisebutylarninehexyl) aminemethyl] tricycle- [4.3.1.1 ]undecane 3- [N- 6-di-tertbutylaminehexyl aminemethyl1tricycle- [4.3 l 1 undecane 3- (N-chlereaminernethyl) tricycle [4.3 .l.1 undecane 3- (N-chlere-N-methylaminemethyl) tricycle [4.3 11
undecane 3- (N-chlere-Nhexylarninemethyl) tricycle [4.3 1 1 undecane 3- (N-bremeaminernethyl) tricycle [4.3.1. 1 ]undecane 3- (N-brome-N-methylaminemethyl tricycle [4.3 .1. 1
undecane 3- (N-brerno-N-hexylaminemethyl) tricycle [4.3 1 1 undecane 3-(fermamidernethyl) tricycle [4.3.1.1 undecane 3- (N rnethylfermarnidemethyl) tricycle [4.3 1 1 undecane 3 -(N-hexylfermamidernethyl)tricycle[4.3.l.1
undecane N- (Fr-tricycle [4.3.1. 1 undecylmethyl) glycine N-(3-tricycle [4.3.1.1 ]undecylmethyl) sarcesine N-(3-tricycle [4.3 1. 1 undecylmethyl -N-hexylglycine N-(3-tricycle [4.3.1. 1 undecylmethyl) sarcesine, methyl ester N-(3-tricycle[4.3.1.1 ]undccylmethyl)-N-hexylglycine,
methyl ester N- 3 -tricycle [4.3. 1.1 ]undecyln1ethyl) glycine, ethyl ester N-(3-tricycle[4.3.1.1 ]undecylmethyhsarcesine, ethyl ester N- (3-tricycle [4.3 .1 .1 undecylmethyl) -N-hexylglycine,
ethyl ester 3-(benzylideneaminernethyl) tricycle [4.3 .1 1 undecane 3- (ethylideneaminemethyl) tricycle [4.3 1 1 ]undecane 3- isehexylideneaminemethyl) tricycle [4.3 1 1 undecane 3- (naphthylidenearninernethyl) tricycle [4.3. 1 1
undecane 3- (furfurylideneaminemcthyl) tricycle [4.3 .1. 1
undecane N-( 3-tricycle [4.3.1.1 ]undecylrnethyl) aziridine N- 3-tricycle [4.3 .1 .1 ]undecylrnethyl) azetidine N- 3 -tricycle[4.3.1.1 undecylmethyl)pyrrelidine N-(B-tricycle[4.3.1.1 3 ]undecylmethybpiperidine N- 3-tricycle [4.3 1.1 undecylmethyl) hexamethyleneimine This invention will be more fully understood by reference to the fellewng illustrative examples in which parts and percentages are by weight unless otherwise indicated.
Example 1 A solution of 6 parts of I-adamantane carbexamide in 200 parts of tetrahydrefuran is added slowly to a wellstirred suspension of 6.15 parts of lithium aluminum hydride in 200 parts of dry diethyl ether. After completion of addition, the mixture is refluxed for one hour and the solvent distilled 01f. The residue is subjected to steam distillation. The waxy l-aminomethyl adamantane is extracted from the steam distillate with ether and the ethereal solution dried with solid potassium hydroxide. Dry hydrogen chloride is then passed into the ether solution to precipitate the amine hydrochloride. The yield is 5.25 parts of l-(aminomethyl)adamantane hydrochloride which melts at 337-340 C. after recrystallization from chloroform-benzene.
Analysis.Calcd. for C H NCI: C, 65.6; H, 9.93; N, 6.96. Found: C, 65.16; H, 10.06; N, 6.94.
The free l-aminomethyl adamantane melts at 128.5 C. and can be converted to an acetyl derivative by treatment with acetic anhydride which, after recrystallization from n-hexane, melts at 123-124".
Analysis.Calcd. for C H ON: C, 75.31; H, 10.20; N, 6.76. Found: C, 75.45; H, 9.97; N, 7.08.
Example 2 A solution of 17 parts of l-adamantoyl chloride in 150 parts of acetone is treated with 15 parts of a 40% aqueous solution of methylarnine at C. After complete addition, the mixture is warmed gently and diluted with Water. The crystalline l-N-methyl adamantane carboxamide is isolated by filtration as 11.27 parts of material melting at 137138 C. In an alternative synthesis of this compound, dry methylamine, 2 equivalents, is distilled into an ethereal solution of adamantoyl chloride, 1 equivalent, and the resulting solution evaporated to dryness. The product is washed thoroughly with water to remove the rnethylammonium chloride formed and dried in vacuum to give a 96% yield of l-N-methyl adaznantane carboxamide. A solution of 11 parts of the crude amide in 100 parts of tetrahydrofuran is added slowly to a suspension of 2.4 parts of lithium aluminum hydride in 100 parts of ether. After complete addition, the mixture is refluxed for one hour, the solvent distilled ofl, and the residue subjected to steam distillation. The steam distillate is extracted with cyclohexane, the cyclohexane solution dried with solid sodium hydroxide and dry hydrogen chloride passed into the solution. The solid l-(N- methylaminomethyl)adamantane hydrochloride is recrystallized from ethanol to give crystals melting at 324.5- 325 C. in a sealed capillary.
Analysis.Calcd. for C H NCl: N, 6.51. Found: N, 6.11.
Example 3 A solution of 19.85 parts of l-adamantoyl chloride in 100 parts of dry diethyl ether is stirred at 0 C. and an ethereal solution of 9 parts of dimethylamine added slowly. The mixture is then stirred at room temperature for 30 minutes and evaporated to dryness. The residual solid is triturated with water and extracted with ether. The ethereal solution is dried over anhydrous sodium sulfate and the ether removed. This gives 19.5 parts (94.2%) of 1-N,N-dimethyl adamantane carboxamide which melts at 76-78 C. The 19.5 parts of amide is dissolved in 100 parts of ether and added slowly to a well stirred suspension of 4.5 parts of LiAlH in 300 parts of ether. After complete addition the reaction is refluxed for 1 hour and the solvent removed. The residue is steam distilled to give 1-(N,N-dimethylaminomethyl)adamantane in the distillate. The steam distillate is extracted with cyclohexane, the extract dried with sodium hydroxide and dry hydrogen chloride passed into the solution. The yield of 1-(N,N-dimethylaminomethyl)adamantane hydrochloride is 17 parts or 84%. The crystals melt at 254 in a sealed capillary after crystallization from methanol-ethyl acetate.
Analysis.--Calcd. for C H NCl: C, 68.20; H, 10.51; N, 6.1. Found: C, 66.94; H, 10.57; N, 5.94.
Example 4 A solution of 19.85 parts of l-adamantoyl chloride is treated with 9 parts of ethylamine under the condi- 10 tions outlined in the previous example to give 19.56 parts, 94.5%, of l-N-ethyl adamantane carboxamide melting at 138 C.
A tetrahydrofuran solution of this amide is reduced with LiA1H as described in the previous example. After removal of the organic solvent the residue is refluxed with water for 10 minutes to facilitate filtration and filtered. Both the filtrate and the solid are extracted thoroughly with ether. The combined extracts are dried with sodium hydroxide and hydrogen chloride passed into the solution. This gives 19.68 parts (86% overall yield) of l-(N-ethylaminomethyl)adamantane hydrochloride. The melting point, after recrystallization from methanol is 356 C.
Analysis.Calcd. for C H NCI: C, 68.2; H, 10.51; N, 6.1. Found: C, 67.83; H, 10.43; N, 5.97.
Example 5 A solution of 19.85 parts of l-adamantoyl chloride in other is reacted with an ethereal solution of 12 parts of propylamine by the procedure of Example 3 to give 21.38 parts of l-(N-propyl)adamantane carboxamide melting at 140141 C. Twenty-one parts of this amide is reduced with LiAlH as shown in the previous example to give 19.4 parts of l-(N-propylamino-rnethyl)adamantane hydrochloride. After recrystallization from methanol, this melts at 342 C.
Analysis.-Calcd for C H NCl: C, 69.1; H, 10.78; N, 5.76. Found: C, 68.86; H, 10.93; N, 5.80.
Example 6 Under the conditions of the previous example, 19.85 parts of l-adamantoyl chloride and 14.67 parts of diethylamine give 22.8 parts of 1-N,N-diethyladamantane carboxamide, M.P. 6263 C.
This amide when reduced with LiAlH gives 22.7 parts of 1-(N,N-diethylaminomethyl)adamantane hydrochloride. This, after recrystallization from ethyl acetatemethanol, melts at 240241 C.
Example 7 A solution of 5.8 parts of 3-carboxytricyclo[4.3.1.1 undecane in 10 parts of thionyl chloride is refluxed until hydrogen chloride evolution ceases. The crude acid halide thus prepared is isolated by distilling off the excess thionyl chloride under reduced pressure, adding a small amount of benzene and removing this under reduced pressure. The acid chloride is then dissolved in 200 parts of ether and an excess of dry methylamine passed into the stirred solution at 0 C. The reaction is then stirred for 30 minutes and diluted with water. The layers are separated, the ether layer washed with water and dried over calcium chloride. Removal of the solvent gives 3.7 parts of white leaflets, melting at 133 C., of N-methyltricyclo [4.3. l.1 ]undecyl-3 -carboxamide.
A solution of this amide in parts of tetrahydrofuran is added to a suspension of 2 parts of LiAlH in 100 parts of diethyl ether. After complete addition, the mixture is refluxed for one hour and the solvent removed by distillation. Water is added slowly to the dry residue and the mixture then refluxed for ten minutes and filtered. Both the cooled filtrate and the solid filter cake are extracted thoroughly with ether, the ethereal solution dried with sodium hydroxide and excess dry hydrogen chloride passed into the solution. The amine hydrochloride which precipitates is isolated by filtration and recrystallized from methanolethyl acetate. A yield of 2.1 parts of 3 N methylaminomethyl)tricyclo[4.3.l.1 ]undecane HCl melting at 338 C., is obtained.
Example 8 The amine hydrochloride of Example 2, 5.4 parts, is dissolved in 20 parts of pyridine and 5 parts of acetic anhydride is added. The mixture is warmed gently until a clear solution is obtained, then heated on a steam bath for 30 minutes and diluted with cold water. The solid Example 9 A sample of B-carboxamidotricyclo [4.3.l.1 ]undecane is prepared by convertin the 3-carboxytricyclo[4.3.1. 1 ]undecane of Stetter, Ber., 92, 1629-1635 (1959), to
the acid chloride by treatment with thionyl chloride fol-- lowed by treatment of the crude acid chloride with ammonia. The amide melts at 180-181 C. after recrystallization from acetone.,The amide, 9.75 parts, is added in tetra hydrofuran solution, to 3 parts of lithium aluminum hydride suspended in 100 parts of ether. The mixture is refluxed one hour and the resulting amine is isolated as in Example 4. The product is 6.5 parts of 3-(aminomethyl)tricyclo[4.3.1.1 ]undecane hydrochloride, M.P. 352- 352.5 C.
Example 10 A solution of 19.85 grams (0.10 mole) of l-adamantoyl chloride in 100 milliliters of dry diethyl ether is stirred at C. and an ethereal solution of 12.7 grams (0.15 mole) of piperidine is added slowly. The mixture is stirred at room temperature for 30 minutes and evaporated to dryness. The residual solid is triturated with water and extracted with ether. The ethereal solution is dried over anhydrous sodium sulfate and the ether removed to leave 1-adamantoylpiperidide. A solution of 0.10 mole of l-adamantoylpiperidide in 100 milliliters of ether and added slowly to a well-stirred suspension of 4.5 grams of lithium aluminum hydride in 300 milliliters of ether. After complete addition, the reaction is refluxed for 1 hour and the solvent removed. Then, the residue is refluxed with 250 milliliters of water for minutes, cooled, filtered, and both the filtrate and the solids are extracted thoroughly with ether. The combined extracts are dried with potassium hydroxide, and then hydrogen chloride is passed into the solution. The precipitate is filtered and dried to give N-(LadamantylmethyDpiperidine hydrochloride.
Example 11 A mixture of 3.6 g. of magnesium turnings, a small crystal of iodine,,1l ml. of anhydrous benzene and 1 ml. of absolute ethanol is heated until a reaction begins. Then heating is discontinued and a mixture of 24.0 g. of diethyl malonate, 7.0 g. of absolute ethanol and 30 ml. of benzene is added dropwise at a rate which causes the reactionmixture to reflux. After addition is completed, the mixture is heated at reflux until the magnesium has dissolved. The excess ethanol is removed by azeotropic distillation with some of the benzene. To the resultant solution of ethoxymagnesiumdiethylmalonate is added a solution of 19.8 g. of l-adamantoyl chloride in 30 ml. of anhydrous benzene, dropwise, over a 50-minute period. The reaction mixture is refluxed for an additional hour, and then cooled in an ice bath. To the cold mixture is added 50 g. of ice followed by suflicient 10% sulfuric acid to cause two clear layers to appear. The layers are separated and the aqueous layer is extracted with two 25-ml. portions of benzene. The extracts are combined with the organic layer, washed with 30 ml. of water, and dried with anhydrous sodium sulfate. The benzene is removed by vacuum concentration at 40. A solution of 64 ml. of glacial acetic acid, 39 ml. of water and 7 ml. of concentrated sulfuric acid is added to the residue (32 g.), and the mixture is heated at reflux for 7 hours. Then it is cooled and poured into 350 ml. of water. The solid which separates is filtered and dried, and then recrystallized from methanol-water mixture to give 13.4 g. of White, crystalline adamantyl-(l) methyl ketone, M.P. 53.5-55" C.
A mixture of 14 g. of hydroxylamine hydrochloride, 65 ml. of anhydrous pyridine and 65 ml. of anhydrous ethanol is heated on a steam bath until a clear solution is obtained. To this is added 13.4 g. of adamantyl-(l) methyl ketone, and the mixture is heated at reflux for 2 hours, then cooled. It is concentrated to dryness in a vacuum at 70, and the residue is suspended in 150 ml. of water and stirred well. The solids are filtered and dried to yield 14.2 g. of adamantyl-( 1) methyl ketone oxime, a white, crystalline compound melting at 180.5 182 C. This can be recrystallized from a dioxane-water mixture without affecting the melting point.
An 8.3-g. amount of adamantyl-(1)methyl ketone.
oxime is added to a mixture of 3.3 g. of lithium aluminum hydride in 150 ml. of anhydrous tetrahydrofuran, and the mixture is stirred and heated at reflux for 3 hours. It is cooled in an ice bath and the excess of lithium aluminum hydride is destroyed with a water-tetrahydrofuran mixture. Several ml. of 10% sodium hydroxide solution is added to aid in the coagulation of the solids, which are removed by filtration, washed with 50 ml. of chloroform, and discarded. The filtrate, which includes the tetrahydrofuran solution and the chloroform solution, is saturated with dry hydrogen chloride and then concentrated to dryness in a vacuum at 50 C. The residue is placed in a separatory funnel and shaken with a mixture of ml. of 10% sodium hydroxide and 300 ml. of ether. The aqueous layer is discarded and the ether solution is dried over potassium hydroxide pellets. Dry hydrogen chloride is passed into the ether solution until precipitation is complete, and the resultant amine hydrochloride is filtered and dried. This crude salt is dissolved in water, treated with excess 50% sodium hydroxide solution, and the free amine is extracted with ether. The ether extract is dried over potassium hydroxide pellets, decanted, and hydrogen chloride is passed in until precipitation is complete. The precipitate is filtered and dried to yield 5.6 g. of white, crystalline u-methyl-ladamantanemethylamine hydrochloride, M.P. 373375 C. (sealed tube).
Analysis.--Calcd. for C l-I NCl: C, 66.82; H, 10.20;
N, 6.49. Found: C, 66.52; H, 10.13; N, 6.38.
Example 12 Substitution of 21.3 g. of 3-tricyclo[4.3.1.1 ]-undecoyl chloride for the 19.8 g. of l-adamantoyl chloride in Example 11 and repetition of the procedure of that example leads to tricyclo[4.3.l.1 ]undecyl-(3) methyl ketone, then to tricyclo[4.3.1.1 ]undecyl-(3) methyl ketone oxime, and, after the reduction, to u-methyl-3- tricyclo [4.3 1. 1 -undecanemethylamine hydrochloride.
Example 13 To a solution of 31.5 g. of l-adamantoyl chloride in 500 ml. of anhydrous ether under a nitrogen atmosphere is added, dropwise, ml. of commercial 3 M methyl magnesium bromide at a rate which maintains a gentle reflux. The reaction mixture is heated for 1 hour after the addition, then cooled. To decompose the metal complex, 300 ml. of saturated ammonium chloride is added. The ether layer is separated and the aqueous layer is extracted with 100 ml. of chloroform. This extract is combined with the ether layer, and the mixture is dried with anhydrous magnesium sulfate and vacuum-concentrated to dryness at 35 C. The residue is steam-distilled until the distillate is no longer milky, about 3 liters of distillate being collected. On cooling, the steam distillate crystallizes. The solids are filtered and dried to yield 26.9 g. of a,a-dimethyl-l-adamantanemethanol, M.P. 77- 80 C.
A 35-m1. amount of concentrated sulfuric acid is added dropwise with cooling to hold the temperature below C. to 160 ml. of acetonitrile. Then, 21 g. of (1,0:- dimethyl-l-adamantanemethanol is added. The temperature is raised to 48 C. and maintained at 48 C. for 45 minutes. The reaction mixture is allowed to cool to room temperature and is then slowly poured into 1000 ml. of ice water. The solidswhich separate are filtered and dried to yield 24.2 g. of crude product. This is taken up in 500 ml. of ether and dry hydrogen chloride is bubbled into the ether solution until no further precipitation occurs. The solids are filtered, dried, and placed in a separatory funnel containing 200 ml. of water and 500 ml. of ether. This is shaken until the solids dissolve, and the aqueous layer is separated and discarded. The ether solution is dried with anhydrous sodium sulfate and concentrated to dryness to give white crystals of N-acetyl-a,a-dimethyll-adamantanernethylamine.
A mixture of 2.0 g. of N-acetyl-a,a-dimethyl-ladamantane methylamine, 10 g. of potassium hydroxide and 40 m1. of methanol is heated at 225 C. in a sealed tube for 18 hours, then cooled. The tube contents are added to 100 ml. of water, and the mixture is extracted with two 50-ml. portions of ether. The extracts are combined, dried with potassium hydroxide pellets, and dry hydrogen chloride is bubbled in until precipitation is complete. The precipitate is filtered and dried to give 1.8 g. of crude salt. This is dissolved in 80 ml. of water and treated with an excess of 50% sodium hydroxide. The amine precipitates, and is filtered and dried, M.P. 103- 105 C. This is taken up in ether and precipitated with hydrogen chloride. The hydrochloride is filtered and dried. The melting point of a,or-dimethyl-1 adamantanemethylamine hydrochloride is 340-345 C. (sealed tube).
Analysis.-Calcd. for C H NCl: C, 67.98; H, 10.45; N, 6.10. Found: C, 67.75; H, 10.35; N, 6.17.
Example 14 Substitution of 33.7 g. of 3-tricyclo[4.3.1.1 ]undecoyl chloride for the 31.5 g. of l-adamantoyl chloride in Example 13 and repetition of the procedure of that example leads to a,a-dimethyl-3-tricyclo[4.3.1.l ]undecanemethanol, then to N-acetyl-u,ot-din1ethyl-3-tricyclo[4.3.1.1 undecanemethylamine, and, after hydrolysis, to aux-(limethyl-3-tricyclo[4.3.l.1 Jundecane methylamine hydrochloride.
Example 15 To a mixture of 1.5 g. of lithium aluminum hydride in 100 ml. of anhydrous diethylene glycol, dimethyl ether is added 4.1 g. of N-acetyl-a,a-dimethyl-1-adamantanemethylamine, prepared in Example 13. The reaction mixture is stirred and heated at reflux for 3 hours, then cooled in an ice bath. The excess lithium aluminum hydride is decomposed by adding wet diethylene glycol, dimethyl ether. Several ml. of 10% sodium hydroxide is added to coagulate the precipitate, which is then filtered and washed with 50 ml. of ether. The filtrate is treated with dry hydrogen chloride until no additional precipitate forms. This is filtered, dissolved in 100 ml. of water, and an excess of 50% sodium hydroxide is added. The mixture is extracted with three -ml. portions .of ether, and the ether extracts are combined, dried with potassium hydroxide pellets, and treated With hydrogen chloride until precipitation is complete. This precipitate is filtered and dried to yield 3.2 g. of N-ethyl-a,a-dimethyll-adamantanemethylamine hydrochloride, M.P. 276-279 C. (sealed tube).
Analysis.Calcd. for C H NCl: C, 69.91; H, 10.87; N, 5.44. Found: C, 69.33; H, 11.00; N, 5.67.
Ex mple 16 Substitution of 4.5 g. of N-acetyl-a,a-dimethyl-3- tricyclo[4.3.l.1 ]undecanemethylamine, prepared in Example 14, for the 4.1 g. of N-acetyl-u,u-dimethyl-1- adamantanemethylamine and repetition of the procedure of Example 15, leads to N-ethyl-a,u-dimethyl-3-tricyclo- [4.3.1.1 ]undecanemethylamine hydrochloride.
Example 17 A solution of diethyl cadmium in benzene is prepared by adding 19.6 g. of powdered anhydrous cadmium chloride over a 5-minute period to 0.2 mole of ethyl magnesium bromide in ml. of anhydrous ether at ice bath temperature. The mixture is heated at reflux with vigorous stirring for 30 minutes. Then, the ether is removed by distillation on a steam bath, and 65 ml. of benzene is added to the nearly dry, brown, pasty residue. Distillation is continued until the vapor temperature of the distillate reaches 61 C. An additional 100 ml. of benzene is added to the diethyl cadmium solution, and the solution is again heated to reflux. Heating is discontinued, vigorous stirring is begun, and a solution of 19.8 g. of l-adamantoyl chloride is added as rapidly as the exothermic reaction will allow. Refluxing and stirring is continued for an additional 45 minutes. The reaction mixture is cooled in an ice bath and 200 g. of water and ice is added, followed by ml. of 20% sulfuric acid. The benzene layer is separated and the aqueous layer is extracted with 75 ml. of benzene. The benzene solutions are combined, dried With anhydrous sodium carbonate, and the benzene is removed by vacuum concent-ration at 50 to yield a liquid residue. This crystallizes on cooling, giving 21.6 g. of adamantyl-(l) ethyl ketone, M.P. 30.5-32.5 C.
A mixture of 75 ml. of anhydrous ethanol, 75 ml. of anhydrous pyridine, 16 g. of hydroxylamine hydrochloride and 16.0 g. of adamantyl-(l) ethyl ketone is heated at reflux for 2 hours and then vacuum concentrated to semi-dryness .at 80 C. A ZOO-ml. amount of water is added, and the mixture is again concentrated to semidryness. The residue is suspended in 300 ml. of water, and the solids are filtered. The melting point of this crude material is -177 C. Recrystallization from a mixture of dioxane and acetonitrile gives 10.3 g. of white, crystalline adamantyl-(l) ethyl ketone oxime, M.P. 177- 179 C.
A 7.7-g. quantity of adamantyl-(l) ethyl ketone oxime is added to a mixture of 3.0 g. of lithium aluminum hydride and 150 ml. of anhydrous diethylene glycol dimethyl ether, and the mixture is stirred and heated at reflux for three hours. It is cooled to 10 C. with an ice bath and the excess lithium aluminum hydride is destroyed with wet diethylene glycol dimethyl ether. Five ml. of 10% sodium hydroxide is added to coagulate the solids, which are then filtered, washed with 50 m1. of ether and discarded. The filtrate is saturated with dry hydrogen chloride and vacuum concentrated until precipitation is complete. The concentrated filtrate is cooled and the solids are filtered, washed with ether and dried. The dried salt is dissolved in 150 ml. of Water and the solution is treated with excess 50% sodium hydroxide and extracted with two 50-ml. portions of ether. The ether extracts are combined, dried with potassium hydroxide pellets, and treated with dry hydrogen chloride until precipitation is complete. The precipitate is filtered and dried to give 5.2 g. of white, crystalline a-ethyl-ladamantanemethylamine hydrochloride, M.P. 278-282" C. (sealed tube).
Analysis.-Calcd. for C H NCl: C, 67.99; H, 10.45; N, 6.10. Found: C, 68.55; H, 10.48; N, 6.14.
Example 18 Substitution of 21.3 g. of 3-tricyclo[4.3.l.l ]undecoyl chloride for the 19.8 g. of l-adamantoyl chloride in Example 17, and repetition of the procedure of that example leads to tricyclo[4.3.l.l ]undecyl-(3) ethyl ketone, then to tricyclo [4.3.1.1 ]undecyl-( 3) ethyl ketone oxime, and, after the reduction, to a-ethyl-3-tricyclo [4.3.1.1 ]undecanemethylamine hydrochloride.
Example 19 Use of 0.10 mole of 3-tricyclo[4.3.1.l ]undecoylchlo- Example 21 Use of 0.10 mole of 3-tricyclo[4.3.1.1 ]undecoylchloride (see Example 7) and 0.15 mole of diallylamine instead of the l-adamantoyl chloride and piperidine in the procedure of Example 10 gives 3-(N,N-di-allylaminomethyl)tricyclo [4.3.1.1 ]undecane hydrochloride.
Example 22 Use of 0.15 mole of propargylamine instead of the 0.15 mole of piperidine in Example 10 gives l-(N-propargylaminomethyhadamantane hydrochloride.
Example 23 Use of 0.15 mole of cyclopropylmethylamine instead of the 0.15 mole of piperidine in Example 10 gives l-(N- cyclopropyl-methylaminomethyl)adamantane hydrochloride.
Example 24 Use of 0.10 mole of 3-tricyclo[4.3.1.1 ]undecoylchloride (See Example 7) and 0.15 mole of cyclobutylamine instead of the l-adamantoyl chloride and piperidine in the procedure of Example 10 gives 3-(N-cyclobutylaminoethyl) -tricycl [4.3. 1 1 undecane hydrochloride.
Example 25 A milliliter flask with magnetic stirrer and reflux condenser is charged with 0.050 mole of l-(aminomethyl) adamantane, 6.13 grams (0.050 mole) of ethyl chloroacetate, 5.00 grams (0.060 mole) of sodium bicarbonate and 20 milliliters of methanol. The insoluble material is filtered and the filtrate is evaporated to dryness. The residue is dissolved in 60 millilitersof 1N hydrochloric acid, and 10 milliliters of, 70% perchloric acid is added. The precipitated perchlorate salt is filtered, Washed with cold water, and dried. The free base is regenerated with 10% sodium hydroxide and distilled to remove unchanged starting material. The higher boiling fraction is N( l-adamantylmethyl) glycine, ethyl ester.
Example 26 fate, and concentrated in vacuo to give l-[N-Z-diethylaminoethyl) -N-methylaminomethyl] adamantane.
Example Product of Example 16 Example 27 A flask equipped with a Dean-Stark water separator is charged with 0.10 mole. of 3-(aminomethyl)tricyclo- [4.3.1.l ]undecane (see Example 9), 15.4 grams (0.10 mole) of freshly distilled benzaldehyde, and 50 milliliters of toluene. The solution is allowed to reflux for 45 hours. The toluene is evaporated and the residue is recrystallized to give N-(3-tricyclo[4.3.1.1 ]undecylmethyl)benzaldimine.
Example 28 A solution of 0.5 mole of l-(aminomethyl)adamantane in 120 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 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 l-(aminomethyl)adamantane. The residue from the sublimation is distilled under vacuum to yield 1-[N-(2-hydroxyethyl)aminomethyl]adamantane.
Example 29 A solution of 0.10 mole of 1-(aminomethyl)adamantane in milliliters of 98% formic acid is allowed to stand 48 hours at room temperature. The formic acid is removed by concentration in vacuo to leave the residue, l-(formamidomethyl)adamantane.
Alternatively, this compound is prepared by refluxing 0.05 mole of l-(aminomethyl)adamantane for 19 hours in 25 ml. of butyl formate. The excess butyl formate is removed by vacuum concentration to leave a residue of l-(formamidomethyl)adamantane.
Example 30 A suspension of 0.1 mole of 3-(aminomethyl)tricyclo- [4.3.1.1 ]undecane in 100 milliliters of ice water is placed in a 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 Chl0rox) is added at such a rate that the temperature does not exceed 10 C.
After the addition is complete the ice bath is removed and the mixture is stirred for 30 minutes. It is then extracted with three 50 milliliter portions of ether. The combined ether extracts are dried over calcium chloride. The solution is filtered and solvent is removed under vacuum to yield 3-(N-chloroaminomethyl)tricyclo[4.3.1.1 undecane.
Example 31 A mixture of 0.10 mole of 1-(aminomethyl)adaman tame 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, l-(aminomethyl)adamantane hydrochloride, is dried in vacuo at 60 C.
Examples 32 through 40 Example 18 is repeated, substituting the following indicated reactants for those of that example, .to obtain the indicated product.
Acid Product 1 (free base) 2 (free base) 0.10 mole). 3 (free base) (0.10 mole) 4 (free base) (0.10 mole). 5 (free base) (0.10 mole). 6 (tree base) (0.10 mole).
7 (0.10 mole) 8 (0.10 mole) 9 (0.10 mole) phosphoric acid (0.10 mole) Sulfuric acid (0.050 mole) Tartan'c acid (0.10 mole) Tartaric acid (0.050 mole) Maleic acid (0.10 mole) Acetic acid (0.10 mole) Succinic acid (0.050 mole) Mandelic acid. (0.10 mole) Lactic acid (0.10 mole) 1 7 Example 41 A solution of 0.20 mole of l-(aminoethyl)adamantane hydrochloride in 100 milliliters of water is added to a solution of 0.10 mole of pamoic acid, disodium salt [44'- methylene bis(3-hydroxy-2naphthoic acid), disodium salt] in 500 milliliters of water. The resulting precipitate is filtered, washed well with water, and dried in vacuo to give l-(aminomethyl)adamantane, pamoate.
Example 42 Carbon dioxide is passed into a solution of 0.10 mole of l-(aminomethyl)adamantane in 100 milliliters of ethyl ether until precipitation is complete. The precipitate is filtered and dried in vacuo to give l-(aminoethyl) adamantane, bicarbonate.
The preceding examples can be repeated substituting equivalent amounts of appropriate starting materials toobtain other compounds of this invention including those listed hereinbefore.
The compounds of this invention 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. For example, administration can be parenterally, that is subcutaneously, intraveneously, intramuscularly, or intraperitoneally. Alternatively or concurrently, administration can be by the oral route.
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. Generally, 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. Ordinarily, from 1 to 20 and preferably 1 to 10 milligrams per kilogram per day, in one or more applications per day is effective to obtain the desired result.
The active ingredient of this invention 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). In such compositions the active ingredient will ordinarily always be present in an amount of at least 0.5% by weight based on the total weight of the composition and not more than 90% by weight.
Besides the active ingredient of this invention the antiviral composition will contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.
In one embodiment of a pharmaceutical composition of this invention, 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 Formulas 1 and 2 and 70-40% of a carrier. In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is put into powder packets and employed. These capsules, tablets and powders will generally constitute from about 5% to about 95% 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, he 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, sesame oil, and the like. In general, water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carries, particularly for injectible solutions. Sterile 18 injectible solutions such as saline will ordinarily contain from about 0.5% to 25%, and preferably about 1 to 10% by weight of the active ingredient.
As mentioned above, 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 composition can be a Watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.
Suitable pharmaceutical carriers are described in Rem ingtons Practice of Pharmacy by E. W. Martin and E. F. Cook, a well known reference text in this field.
In addition to the exemplary illustrations above, the following examples further explain the present invention:
Example 43 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 1- (aminoethyl)adamantane, hydrochloride, 125 milligrams of lactose and 1 milligram of Cab-o-sil.
Example 44 Example 43 is repeated except that soft gelatin capsules are used and powdered l-(aminomethyl)adamantane is first dissolved in mineral oil.
Example 45 Example 43 is repeated except that the dosage unit is 50 milligrams of active ingredient, 5 milligrams of gelatin, 1.5 milligrams of magnesium stearate and milligrams of lactose, mixed and formed into a tablet by a conventional tableting machine. Slow release pills or tablets can also be used, .by applying appropriate coatings. A sugar coating may be applied to increase palatability.
Example 46 A parenteral composition suitable for administration by injection is prepared by stirring 5% by weight of the active ingredient of Example 43 in sterile aqueous 0.9% saline.
A large variety of compositions according to this invention can thus readily be made by substituting other compounds of thisinvention, 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. f
Compounds within the scope of Formulae 1 and 2 of the invention are anti-viral agents in domestic animals and livestock. As an illustration, compounds within the'scope of Formulae 1 and 2 are effective against swine influenza and an embodiment of the intlention, therefore, is a control of this infection by incorporating an active ingredient compound in the diet of the affected animal. For most purposes, an amount of active compound will be used to provide from about 0.0001% to 0.1% by weight of the active compounds based on the total weight of feed intake. Preferably, from 0.001% to 0.02% by weight will be used.
In like manner novel and useful compositions are pro vided by this invention which comprise at least one active ingredient compound within the scope of this invention in admixture with an animal feed. Descriptions of 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.
A particularly important 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 feedstuffs 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. Depending on the recipient animal, 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, as well as the just-described concentrates, 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.
The disclosure herein should not be taken as a recommendation to use the disclosed invention in any Way without full compliance with US. Food and Drug laws and other laws and governmental regulations which may be applicable.
The above and similar examples can be carried out in accordance with the teachings of this invention, as will be readily understood by persons skilled in the art, by substitution of components and amounts in place of those specified. Thus, the foregoing detailed description has been given for clearness of understanding only and no unnecessary limitations are to be understood therefrom.
The invention claimed is:
1. A compound selected from the group consisting of those of the formula 20 and A is hydrogen, and
wherein X and Y are each hydrogen, methyl, or ethyl; and R is m -N H2).
where n is an integer of from 2 through 6; NR R or --N=CHR wherein 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 are each alkyl of 1 through 4 carbon atoms; alkenyl of 2 through 6 carbon atoms; alkynyl of 2 through 6 carbon atoms; cyclopropyl; cyclobutyl; cyclopropylmethyl; or cyclobutylmethyl; R is R chlorine; bromine; formyl; -CH COOH;
CH COOCH or -CH COOC H with the proviso that when R is alkenyl or alkynyl having the unsaturated bond in the l-position, R is alkyl of 1 through 6 carbon atoms or 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 and R is hydrogen, alkyl of 1 through 5 carbon atoms,
phenyl, naphthyl or furyl; and non-toxic, acid-addition salts of the compounds of said formula. 2. l-(N,N dimethylarninomethyl)adamantane hydrochloride.
References Cited Stetter et al., Ber. Deut. Chem, vol. 96, pp. 550-55, February 1963.
CLLARLES B. PARKER, Primary Examiner.
N. WIC ZER P. C. IVES, Assistant Examiners.

Claims (1)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULA
US376259A 1963-07-24 1964-06-18 Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes Expired - Lifetime US3352912A (en)

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US376259A US3352912A (en) 1963-07-24 1964-06-18 Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes
DE19641793208 DE1793208A1 (en) 1963-07-24 1964-07-18 New cyclic hydrocarbon compounds
DE19641793207 DE1793207A1 (en) 1963-07-24 1964-07-18 Non-toxic acid addition salts of 1- (aminomethyl) adamantane
DE19641468769 DE1468769C (en) 1963-07-24 1964-07-18 Alkylamino adamantand derivatives and their salts
DE19641792295 DE1792295B1 (en) 1963-07-24 1964-07-18 Pharmaceutical preparation containing 1-aminomethyladamantane
BR160975/64A BR6460975D0 (en) 1963-07-24 1964-07-20 PROCESS FOR THE PREPARATION OF TRICYCLIC COMPOUNDS
CH1457468A CH479535A (en) 1963-07-24 1964-07-20 Process for the preparation of α-alkyl-1-adamantane methylamines and α-alkyl-3-tricyclo (4,3,1,1 3,8) undecane methylamines
CH946964A CH476673A (en) 1963-07-24 1964-07-20 Process for the preparation of salts of adamantane and tricyclo (4,3,1,13,8) undecane compounds
AT1064666A AT269836B (en) 1964-06-18 1964-07-22 Process for the preparation of new basic, tricyclic compounds and their salts
AT1064566A AT269835B (en) 1964-06-18 1964-07-22 Process for the preparation of new basic, tricyclic compounds and their salts
ES0302369A ES302369A1 (en) 1963-07-24 1964-07-23 Method of preparation of triciclic compounds. (Machine-translation by Google Translate, not legally binding)
IL21753A IL21753A (en) 1963-07-24 1964-07-23 Adamantanes and tricycloundecanes
DK367964AA DK112027B (en) 1963-07-24 1964-07-23 Process for the preparation of basic tricyclic compounds or their salts, formamides or N-halogenamines.
SE09751/67A SE330693B (en) 1963-07-24 1964-07-23
FI1584/64A FI42322B (en) 1963-07-24 1964-07-23
SE9752/67A SE320363B (en) 1963-07-24 1964-07-23
BE650919D BE650919A (en) 1963-07-24 1964-07-23
SE8987/64A SE321924B (en) 1963-07-24 1964-07-23
FR1572956D FR1572956A (en) 1963-07-24 1964-07-24
NL6408505A NL6408505A (en) 1963-07-24 1964-07-24
GB30940/64A GB1069563A (en) 1963-07-24 1964-08-04 Adamantane and tricyclo[4,3,1,1]undecane derivatives
AT06819/68A AT279581B (en) 1963-07-24 1964-08-07 PROCESS FOR THE PRODUCTION OF NEW, BASIC, TRICYCLIC COMPOUNDS AND THEIR SALTS
DK353365AA DK114199B (en) 1963-07-24 1965-07-09 Process for the preparation of basic tricyclic compounds or salts thereof.
DK353265AA DK114769B (en) 1963-07-24 1965-07-09 Process for the preparation of basic tricyclic compounds or salts thereof.
FI0197/69A FI42548B (en) 1963-07-24 1969-01-22
FI0198/69A FI42211B (en) 1963-07-24 1969-01-22
NL7102097A NL7102097A (en) 1963-07-24 1971-02-17

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DE (3) DE1793208A1 (en)
DK (3) DK112027B (en)
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US3449422A (en) * 1966-02-09 1969-06-10 Smithkline Corp Pentacycloundecane amines
US3624086A (en) * 1969-11-10 1971-11-30 Searle & Co Adamantanecarboxamidoalkanoic acid amides
US3682922A (en) * 1969-01-16 1972-08-08 Searle & Co N-acyl-n-{8 (n{40 ,n{40 -disubstituted amino)-alkyl{9 -1-adamantylmethylamines
US3852339A (en) * 1970-06-15 1974-12-03 Squibb & Sons Inc Aminoalkoxyphenylurea derivatives
US3870759A (en) * 1969-07-19 1975-03-11 Yoshiaki Inamoto 1-Adamantyl alkyl ketones and their preparation
US3879400A (en) * 1973-11-16 1975-04-22 Upjohn Co 1-Lower alkyl-(1-adamantylmethyl)piperidines and process for their preparation
US4111990A (en) * 1976-10-12 1978-09-05 Kao Soap Co., Ltd. 1-Acetylaminotricyclo [4.3.1.12,5 ] undecane and process for the preparation thereof
US4351847A (en) * 1981-06-26 1982-09-28 Pennwalt Corporation Antiviral alpha, alpha-dialkyl adamantylethylamines
US4551552A (en) * 1984-05-23 1985-11-05 E. I. Du Pont De Nemours And Company Process for preparing rimantadine
US4751245A (en) * 1986-06-25 1988-06-14 E. R. Squibb & Sons, Inc. Antifungal derivatives of N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine and method of using same
US5576355A (en) * 1993-06-04 1996-11-19 Mobil Oil Corp. Diamondoid derivatives for pharmaceutical use
US5684024A (en) * 1996-01-25 1997-11-04 Viropharma Incorporated Pyrazole dimers compositions and methods for treating influenza
US5821243A (en) * 1996-07-22 1998-10-13 Viropharma Incorporated Compounds compositions and methods for treating influenza
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US20060287317A1 (en) * 2005-06-17 2006-12-21 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
WO2007062272A1 (en) 2005-11-28 2007-05-31 Omega-Biopharma (H.K.) Limited Materials and methods for treating viral infections with a cysteamine compound
CN100450994C (en) * 2002-12-23 2009-01-14 詹森药业有限公司 Adamantyl acetamides as 11-beta hydroxysteroid dehydrogenase inhibitors
WO2015086428A1 (en) * 2013-12-09 2015-06-18 Unilever Plc Process of making adamantanamides
US9227990B2 (en) 2012-10-29 2016-01-05 Cipla Limited Antiviral phosphonate analogues and process for preparation thereof
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WO2019018185A1 (en) * 2017-07-15 2019-01-24 Arisan Therapeutics Inc. Enantiomerically pure adamantane derivatives for the treatment of filovirus infection

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DE1294371B (en) * 1966-12-21 1969-05-08 Penicillin Ges Dauelsberg & Co Process for the preparation of 1-aminoadamantane and its N-alkyl or N-cyclohexyl derivatives
US3489802A (en) * 1967-01-23 1970-01-13 Du Pont Preparation of alpha-methyl-1-adamantane-methylamine and alpha,4 - dimethyl - 1 - bicyclo(2,2,2)octane methylamine
NL6900004A (en) * 1969-01-02 1970-07-06
DK0870757T3 (en) * 1997-04-10 2002-07-15 Pfizer Fluorine-substituted adamantane derivatives
GB0013737D0 (en) 2000-06-07 2000-07-26 Astrazeneca Ab Novel compounds
SE0103836D0 (en) * 2001-11-16 2001-11-16 Astrazeneca Ab Novel compounds
AU2003217676B2 (en) 2002-02-22 2009-06-11 Takeda Pharmaceutical Company Limited Active agent delivery systems and methods for protecting and administering active agents
SE0300480D0 (en) 2003-02-21 2003-02-21 Astrazeneca Ab Novel compounds
GB0312609D0 (en) 2003-06-02 2003-07-09 Astrazeneca Ab Novel compounds
CA2680761A1 (en) 2007-03-22 2008-09-25 Astrazeneca Ab Quinoline derivatives for the treatment of inflammatory diseases
US8106073B2 (en) 2007-11-30 2012-01-31 Astrazeneca Ab Quinoline derivatives 057

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US3449422A (en) * 1966-02-09 1969-06-10 Smithkline Corp Pentacycloundecane amines
US3682922A (en) * 1969-01-16 1972-08-08 Searle & Co N-acyl-n-{8 (n{40 ,n{40 -disubstituted amino)-alkyl{9 -1-adamantylmethylamines
US3870759A (en) * 1969-07-19 1975-03-11 Yoshiaki Inamoto 1-Adamantyl alkyl ketones and their preparation
US3624086A (en) * 1969-11-10 1971-11-30 Searle & Co Adamantanecarboxamidoalkanoic acid amides
US3852339A (en) * 1970-06-15 1974-12-03 Squibb & Sons Inc Aminoalkoxyphenylurea derivatives
US3879400A (en) * 1973-11-16 1975-04-22 Upjohn Co 1-Lower alkyl-(1-adamantylmethyl)piperidines and process for their preparation
US4111990A (en) * 1976-10-12 1978-09-05 Kao Soap Co., Ltd. 1-Acetylaminotricyclo [4.3.1.12,5 ] undecane and process for the preparation thereof
US4351847A (en) * 1981-06-26 1982-09-28 Pennwalt Corporation Antiviral alpha, alpha-dialkyl adamantylethylamines
US4551552A (en) * 1984-05-23 1985-11-05 E. I. Du Pont De Nemours And Company Process for preparing rimantadine
US4751245A (en) * 1986-06-25 1988-06-14 E. R. Squibb & Sons, Inc. Antifungal derivatives of N-(6,6-dimethyl-2-hepten-4-ynyl)-1-naphthalenemethanamine and method of using same
US5576355A (en) * 1993-06-04 1996-11-19 Mobil Oil Corp. Diamondoid derivatives for pharmaceutical use
US5684024A (en) * 1996-01-25 1997-11-04 Viropharma Incorporated Pyrazole dimers compositions and methods for treating influenza
US5821243A (en) * 1996-07-22 1998-10-13 Viropharma Incorporated Compounds compositions and methods for treating influenza
US5935957A (en) * 1996-07-22 1999-08-10 Viropharma Incorporated Compounds, compositions and methods for treating influenza
US6180628B1 (en) 1996-07-22 2001-01-30 Viropharma Incorporated Compounds, compositions and methods for treating influenza
US6271373B1 (en) 1996-07-22 2001-08-07 Viropharma Incorporated Compounds, compositions and methods for treating influenza
WO2003004461A1 (en) * 2001-07-02 2003-01-16 Schering Corporation Drugs for treating viral infections
CN100450994C (en) * 2002-12-23 2009-01-14 詹森药业有限公司 Adamantyl acetamides as 11-beta hydroxysteroid dehydrogenase inhibitors
US20060287317A1 (en) * 2005-06-17 2006-12-21 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
US7338961B2 (en) * 2005-06-17 2008-03-04 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
US20080167352A1 (en) * 2005-06-17 2008-07-10 Apogee Biotechnology Corporation Sphingosine Kinase Inhibitors
US8063248B2 (en) 2005-06-17 2011-11-22 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
US8557800B2 (en) 2005-06-17 2013-10-15 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
USRE49811E1 (en) * 2005-06-17 2024-01-23 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
WO2007062272A1 (en) 2005-11-28 2007-05-31 Omega-Biopharma (H.K.) Limited Materials and methods for treating viral infections with a cysteamine compound
US9227990B2 (en) 2012-10-29 2016-01-05 Cipla Limited Antiviral phosphonate analogues and process for preparation thereof
CN105829284A (en) * 2013-12-09 2016-08-03 荷兰联合利华有限公司 Process of making adamantanamides
JP2016540774A (en) * 2013-12-09 2016-12-28 ユニリーバー・ナームローゼ・ベンノートシヤープ Method for producing adamantane amide
US9840466B2 (en) 2013-12-09 2017-12-12 Conopco, Inc. Process of making adamantanamides
CN105829284B (en) * 2013-12-09 2019-01-22 荷兰联合利华有限公司 The method for preparing adamantane Carbox amide
EA031458B1 (en) * 2013-12-09 2019-01-31 Юнилевер Н.В. Process of making adamantanamides
WO2015086428A1 (en) * 2013-12-09 2015-06-18 Unilever Plc Process of making adamantanamides
WO2017093354A1 (en) 2015-11-30 2017-06-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Nmdar antagonists for the treatment of diseases associated with angiogenesis
WO2019018185A1 (en) * 2017-07-15 2019-01-24 Arisan Therapeutics Inc. Enantiomerically pure adamantane derivatives for the treatment of filovirus infection
US11548893B2 (en) 2017-07-15 2023-01-10 Arisan Therapeutics Inc. Enantiomerically pure adamantane carboxamides for the treatment of filovirus infection

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DK114769B (en) 1969-08-04
SE330693B (en) 1970-11-30
CH476673A (en) 1969-08-15
DE1468769B1 (en) 1972-06-29
FR1572956A (en) 1969-07-04
NL6408505A (en) 1965-01-25
FI42548B (en) 1970-06-01
NL7102097A (en) 1971-05-25
DK112027B (en) 1968-11-04
DE1792295B1 (en) 1971-05-27
FI42211B (en) 1970-03-02
DE1793207A1 (en) 1972-03-30
BR6460975D0 (en) 1973-08-09
SE320363B (en) 1970-02-09
BE650919A (en) 1964-11-16
FI42322B (en) 1970-03-31
SE321924B (en) 1970-03-23
ES302369A1 (en) 1965-03-16
CH479535A (en) 1969-10-15
IL21753A (en) 1968-01-25
GB1069563A (en) 1967-05-17
AT279581B (en) 1970-03-10
DK114199B (en) 1969-06-09
DE1793208A1 (en) 1972-04-06

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