|Publication number||US3397233 A|
|Publication date||Aug 13, 1968|
|Filing date||Jun 15, 1964|
|Priority date||May 1, 1963|
|Also published as||DE1468758B1|
|Publication number||US 3397233 A, US 3397233A, US-A-3397233, US3397233 A, US3397233A|
|Inventors||Theodore L Cairns|
|Original Assignee||Du Pont|
|Export Citation||BiBTeX, EndNote, RefMan|
|Non-Patent Citations (1), Referenced by (8), Classifications (18)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent Office 3,397,233 Patented Aug. 13, 1968 ABSTRACT OF THE DISCLOSURE 3-aminotricyclo[4.3.l.1 ]undecanes have the formula where R is an amine radical which may be substituted by a carboXyl or a carboxylate. The compounds have the ability to inhibit and deter the incidence and growth of harmful viruses.
Background of the invention This invention relates to tricycloundecanes. More particularly, this invention refers to novel tricyclo[220.127.116.11 undecanes having an amino or substituted amino group attached to a 3-position tertiary or bridgehead nuclear carbon.
The need continues for effective antiviral agents useful for the treatment of virus infections. I have now discovcred a novel class of 3-amino and 3-substituted aminotricyclo[18.104.22.168 ]undecanes which show outstanding properties in their ability to inhibit and deter incidence and growth of a variety of harmful viruses.
Within the class of compounds of this invention an outstanding combination of properties exists, as evidenced by standard tests in both tissue culture and animals. Antiviral activity within this invention has been observed against influenza A (strains WSN and swine), influenza A-2 (strains Michigan A/AA and JPC) and parainfluenza (Sendai).
Summary of the invention The compounds of this invention have the formula:
where R1 R is N where n is 2, 3, 4, 5 or 6;
H N=G 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 diiferent and are alkyl radicals of 1 through 4 carbon atoms; alkenyl of 2 through 6 carbon atoms; alkynyl of 2 through 6 carbon atoms; cyclopropyl; cyclobutyl; cyclopropylmethyl; cyclobutylmethyl; R is R chlorine; bromine; formyl; CH;'COOH; -CH COOCH CH -COOC H with the proviso that when R, is an alkenyl or 'alkynyl having the unsaturated bond in the l-position, R is alkyl or mono-substituted alkyl as defined above; and R is aliphatic; mono-substituted aliphatic where the substituent is aromatic or heterocyclic; aromatic; or heterocyclic containing not more than 12 carbon atoms.
Detailed description of the invention Compounds hydrolyzable to the compounds of formula 1 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 Formula 1 having a basic amino group, form salts, and such salts having a nontoxic anion are also included within the scope .of the present invention. Representative of such salts are the hydrochlorides, hydrobromides, sulfates, phosphates, acetates, succinates, adipates, propionates, tartrates, citrates, bicarbonates, pamoates, cyclohexylsulfamates and acetylsalicylates. Of these the hydrochlorides and acetates and cyclohexylsulfamates are preferred, The cyclohexylsulfamates have a pleasant taste and thus are particularly useful in preparing syrups for oral administration. Additionally, the cyclohexylsulfarnates have usefulness in making uncoated tablets for oral administration which have no objectionable bitter taste. Other salts include those with caprochlorone and with penicillin.
The salts described above enhance the usefulness of the relatively insoluble amines in pharmaceutical applications.
Compounds of the above Formula 1 are preferred where the amine on the undecane moiety is substituted with dialkyl because of their outstanding combination of unusual properties. While unsubstituted dialkyl is most preferred, some formulating advantages can be obtained using particular substituted products such as the hydroxy or alkoxy substituted compounds as will be appreciated.
Lower alkyl substitutents such as the dimethyl and diethyl are most preferred. However, the monomethyl and monoethyl derivatives, as well as the unsubstituted amino compounds, are preferred by comparison with most of the substituted alkylamino derivatives.
Particularly preferred are the hydrochlorides of the following compounds:
3-aminotricyclo[4.3.1.l ]undecane 3-N-methylamin0tricyclo[22.214.171.124 ]undecane 3N-ethylaminotricyclo[126.96.36.199 ]undecane 3-N,N-dimethylaminotricyclo[4.3.l.l ]undecane 3- (N-ethyl-N-methylamino tricyclo [4.3 .1 1 undecane 3-N,N-diethylaminotricyclo[4.3.1 1 undecane The above compounds can be prepared by a variety of methods.
The 3-aminotn'cyclo[4.3.l.1 ]undecane is readily prepared from the known compound 3-carboxytricyclo[4.3. 1.1 ]undecane by conversion of the acid to the acid chloride with thionyl chloride, followed by ammoniation to the corresponding amide. The amide in turn is reacted with metallic sodium and bromine in methanol to give S-carbomethoxyaminotricyclo[4.3.1.l ]undecane which is hydrolyzed under basic conditions to obtain the desired 3-aminotricyclo[188.8.131.52 ]undecane.
This is basically the Hofmann procedure for converting a carboxylic acid to the corresponding amine. The acid can be reacted with methyl chlorocarbonate and sodium azide, and the resulting acyl azide decomposed by heating, to give the isocyanate which can be reacted with methanol to give the methyl urethane, which is hydrolyzed to the amine with alkali. This is an adaption of the Curtius reaction. These two methods of obtaining 3-aminotricyclo[184.108.40.206 ]undecane are illustrated in Examples 1 and 2.
One or both of the hydrogens of the 3-amino nitrogen of 3-aminotricyclo[220.127.116.11 ]undecane can be replaced by alkyl. This is most conveniently done by acylation, for instance with an acyl halide, to give a 3-acylaminotricyclo[18.104.22.168 ]undecane, (which is then reduced to 3-N-alkylaminotricyclo[22.214.171.124 ]undeoane. Lithium aluminum hydride is excellent for this, although catalytic hydrogenation or any one of a number of means of reduction can be used.
The 3-N-alkylaminotricyclo[126.96.36.199 ]undecanes can be acylated again and reduced to give the 3-N,N-dialkylamintricyclo[188.8.131.52 ]undecanes. .Difrerent alkyl groups can be attached by this means. For instance, reduction of 3-acetamidotricyclo[184.108.40.206 ]undecane, followed by reaction of the product with butyryl chloride, followed by reduction gives the 3-(N-butyl-N-ethylamino) compound. Of course, if acetyl chloride is used, the product is 3 (N,N diethylamino)t1icyclo[220.127.116.11 ]undecane, where the alkyl groups are alike.
Although formylation of the amino compound followed by reduction is a practical means of obtaining the N-methylamino compound, it may if desired also be obtained by reducing tricyclo[18.104.22.168 ]undecane-3-methyl urethane, described in Example 3. Reduction of the 3-ethyl urethane gives the N-methylamino compound also.
The method of acylation and reduction is applicable to making compounds in which the alkyl substituents are substituted. Acylation of B-N-methylaminotricyclo [4.3.1.l ]undecane with 3-methoxypropionyl chloride followed by reduction gives 3-[N-(3-methoxypropyD-N- methylaminoJtricyclo[4.3.l.1 ]undecane. Reaction of the amine or monoalkyl amine with a dicarboxylic acid anhydride to give the N-substituted alkanamic acid, followed by reduction, introduces the hydroxyalkyl grouping. For instance, the reduction of N-[tricyclo [22.214.171.124 undecyl-(3)]-succinamic acid yields 3-N-(4-hydroxybutyl)aminotricyclo[4.3.1.l ]undec ane.
Some substituted alkyl amino compounds are more easily made by other routes. Hydroxyethyland bishydroxyethyl compounds are made by reaction of the amine with ethylene oxide. N-carb-alkoxymethylamino compounds are made by alkylation with alkyl chloroacetate and base. Aminoalkyl-, alkylaminoalkyl-, and dialkylaminoalkyl compounds are made by alkylation with approproiate aminoalkyl halides and base.
In some cases, 3-N-alkylamino and dialkylaminotricyclo[126.96.36.199 ]undecanes are easily made by alkylation with alkylating reagents (such as alkyl halides), without resorting to the method of acylation and reduction. 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 clearcut as the method of acylation and reduction, which is why it is less preferred. However, it sometimes becomes the method of choice because it involves fewer steps.
Ethylene chloroand bromo-hydrin, and alkoxyalkyl halides can be used to alkylate the amino nitrogen, to give the hydroxyethyland *alkoxyalkylsubstitutions. For the reason just given, these reactions are less preferable than the method of acylation and reduction, but may be preferred in certain instances, and they illustrate an alternate route to substituted-alkylaminotricyclo[4.3.1. 1 ]undecanes by ordinary alkylation with a substituted alkylating reagent.
In preparing N-alkenyl, N,N-dialkenyl, N-alkynyl, and N,N dialkynyl 3 aminotricyclo[188.8.131.52 ]undecanes, use of the appropriate alkenyl or alkynyl halide with an acid acceptor such as sodium bicarbonate in a solvent such as ethanol is the method of choice. Mixtures of the mono and di-alkenylated and -alkynylated compounds are produced, but the amount of the nudesired component can be minimized by varying the amount of the halide. With equimolar amounts of the amine and the halide the mono substituted compounds predominate. With an excess of halide, the disubstituted compounds predominate. In any event, the mono and disubstituted compounds are relatively easy to separate, for example by distillation. Of course, if the halide is present in huge excess, some quaternization will occur.
The method of acylation and reduction is quite applicable to preparing N-cyclopropylmethyl and N-cyclobutylmethyl compounds. Acylation of 3-aminotricyclo [4.3.1.l ]undecane with cyclopropanecarboxylic acid chloride gives 3-(N-cyclopropylcarbonyl)aminotricyclo [184.108.40.206 ]undecane, which gives 3-N-cyclopropylmethylaminotricyclo[4.3. l.1 ]undecane on reduction.
To prepare N-cyclopropyl and N-cyclobutyl compounds, the known 3-hydroxytricyclo[220.127.116.11 ]undecane is converted to 3 (p toluenesulfonyloxy)tricyclo- [4.3.1.l ]undecane, for example with p-toluenesulfonyl chloride in pyridine, and this compound is heated in the presence of cyclopropylamine or cyclobutylamine to yield 3 N cyclopropylor 3 N cyclobutylaminotricyclo- [18.104.22.168 ]undecane by aminolysis. This method is also applicable to making N-[tricyclo[22.214.171.124 ]undecyl- (3)]alkyleneimines. Substitution of pyrrolidine for the cyclopropylamine yields N-[tricyclo[126.96.36.199 ]undecyl- (3) ]pyrrolidine.
Reaction of 3-aminotricyclo[188.8.131.52. ]undecane with aldehydes gives the corresponding alkylidene, arylidene or heterocyclicylidene tricycloundecane. For instance, reaction of S-aminotricyclo[4.3.l.1. ]undecane with formaledhyde gives N [tricyclo[4.3.l.1. ]undecyl- (3)]azomethine. Reaction of 3-aminotricyclo[184.108.40.206 undecane with benzaldehyde gives 3-benzylideneaminotricyclo [4.3.1. 1 ]undecane.
Representative of the compounds of this invention are the following compounds and their salts:
3 -aminotricyclo[220.127.116.11 ]undecane 3 -N-methylaminotricyclo [18.104.22.168 ]undecane 3-N,N-dimethylaminotricyclo[4.3.l.1 ]undecane 3-N-ethyl-N-methylaminotricyclo [4.3. l l undecane 3-N,N-diethylaminotricyclo[22.214.171.124 ]undecane 7 N-chloro-N-methyl-3-aminotricyclo[126.96.36.199
undecane N-bromo-3 -aminotricyclo [4.3. 1.1 ]undecane N-bromo-N-methyl-3-aminotricyclo[188.8.131.52
undecane 3 -formamidotricyclo[184.108.40.206 ]undecane 3-N-methylformamidotricyclo[220.127.116.11 ]undecane 3-N-hexylformamidotricyclo[18.104.22.168 ]undecane N- [tricyclo [4.3. 1 1 undecyl-(3 glycine N-[tricyclo [22.214.171.124 sarcosine N- [tricyclo [4.3 l 1 undecyl-( 3 ]-N-hexyl glycine N- [tricyclo [4.3 .1 1 undecyl- 3 -Nhexylglycine,
;methyl ester N-[tricyclo[126.96.36.199 ]undecy1-(3 ]sarcosine, ethyl ester N-[tricyclo [188.8.131.52 ]undecyl-(3 glycine, ethyl ester N- [tricyclo [4.3. l 1 undecyl- 3 N-hexylglycine,
ethyl ester N-[tricyclo[184.108.40.206 ]undecyl-(3) ]azomethine 3-benzylideneaminotricyclo[220.127.116.11 ]undecane 3-ethylideneaminotricyclo [4.3 1.1 undecane 3-isohexylideneaminotricyclo [4.3.1. l ]undecane 3 -naphthylideneaminotricyclo [4.3 1 1 1 undecane 3-furfurylideneaminotricyclo[4.3 .1.1 ]undecane N-[tricyclo [4.3. 1.1 undecyl-( 3 Jaziridine N- [tricyclo[4.3.1. 1 undecyl- (3 azetidine N-[tricyclo[18.104.22.168 undecyl-(3 lpyrrolidine N-[tricyclo[22.214.171.124 ]undecyl-(3) ]piperidine N- [tricyclo [4.3 1 1 undecyl- (3 )-l hexamethyleneimine This invention will be better understood by reference to the following illustrative examples, which are given in addition to those above. Parts and percentages are by weight unless otherwise indicated.
EXAMPLE 1 3-carboxytricyclo[126.96.36.199 ]undecane is prepared according to Stetter, Schwarz, and Hirschhorn, Ben, 92, 1634 (1959), from l-hydroxymethyl adamantane. The acid is converted to the acid chloride by refluxing with excess thionyl chloride. The excess reagent is removed, under reduced pressure, and the crude acid chloride is dropped slowly into concentrated ammonia at 5 C. The resultant amide is recrystallized from acetone-water to give a white crystalline solid, M.P. 180-181 C., in 90% yield. The amide, 8 parts, is added to a solution of 2.1 parts of metallic sodium in 175 parts of methanol, the solution is cooled to 0 C., and 8 parts of liquid bromine is dropped into the well-stirred solution. Stirring is continued for minutes at 0, then for 15 minutes at 55, and finally for 30 minutes at the boiling point. The methanol is removed by distillation and the residue is recrystallized from dilute acetone. The product is a white crystalline solid, 10 parts or 97% yield, of 3-carbomethoxyaminotricyclo[188.8.131.52 ]undecane. This is hydrolyzed by refluxing with excess powdered sodium hydroxide in diethylene glycol for 16 hours. A large excess of water is added and the 3-aminotricyclo[184.108.40.206 ]undecane is extracted from the reaction mixture with chloroform. This solvent is removed, replaced by cyclohexane and dry hydrogen chloride is passed into the solution. The precipitated amine hydrochloride is removed by filtration, dissolved in water, and the free amine is regenerated by making the solution strongly alkaline. This is taken up in chloroform, the solvent is removed, and the free amine is sublimed at 0.2 mm. pressure. The sublimate is pure S-aminotricyclo [220.127.116.11 ]undecane, M.P. 206206.5 C., in a sealed capillary.
Analysis.Calcd. for C H N: C, 79.94; H, 11.59; N, 8.48. Found: C, 81.68; H, 11.72; N, 8.59. N.E. Calcd.: 165.27. Found: 176.
The infrared spectrum and the NMR spectrum are consistent with those expected for this compound.
EXAMPLE 2 3 carboxytricyclo[18.104.22.168 ]undercane, 30 grams (0.1545 mole) is dissolved in 200 milliliters of acetone and a solution of 12.7 grams (0.16 mole) of pyridine in 25 milliliters of acetone is added slowly. The reaction mixture is cooled at 3 C. and a solution of 16 grams (0.17 mole) of methyl chlorocarbonate in 25 milliliters of acetone is added slowly while holding the temperature below 5 C. The mixture is stirred for one hour and a solution of 11.8 grams (0.18 mole) of sodium azide in 30 milliliters of water is added slowly. After complete addition the reaction mixture is stirred for 16 hours at room temperature, diluted with 4 volumes of water and extracted with toluene. The toluene extract is washed with water, 1% solution hydroxide, 1% hydrochloric acid and then with water. The toluene solution is then dried with calcium chloride and heated at C. until no more nitrogen is evolved from the acyl azide. The toluene is removed under reduced pressure and the residue is refluxed for 16 hours with methanol. Removal of the methanol leaves a solid residue, 26.16 grams, 76% conversion to tricyclo[4.3.l.l ]undecane-3-methyl urethane. After recrystallization from acetone-water, this melts at 104- 106 C. Alkaline hydrolysis gives 3 aminotricyclo- [22.214.171.124 ]undecane.
EXAMPLE 3 A solution of 20.5 grams (0.092 mole) of tricyclo- [126.96.36.199 ]undecane-3-methyl urethane, prepared as in Example 2, in 100 milliliters of dry diethyl ether is added slowly to a suspension of 5.65 grams of lithium aluminum hydride in 100 milliliters of dry ether. After complete addition, the reaction mixture is refluxed for one hour, the ether is removed by distillation, the residue is made strongly alkaline with sodium hydroxide and the product is isolated by steam distillation. The steam distillate is extracted with ether, the extract is dried with solid KOI-I, filtered, and dry HCl is passed into the solution. The amine hydrochloride which forms crystallizes out of the ethereal solution and is removed by filtration. After recrystallization from ethyl acetate, the melting point is 225-226 C. The yield is 6.8 grams, 34% of theory, of 3 N methylaminotricyclo[188.8.131.52 ]undecane hydrochloride.
Analysis.Calcd. for C H NCl: N, 6.52; C], 16.45. Found: N, 6.41; Cl, 15.98.
EXAMPLE 4 A 10.35 gram sample (0.05 mole) of 3-acetamidotr1cyclo[4.3.l.1 ]undecane prepared by acetylation of the corresponding amine with acetic anhydride containing a drop of sulfuric acid is dissolved in 200 milliliters of dry tetrahydrofuran and added to a suspension of 3.0 grams of lithium aluminum hydride in 350 milliliters of dry ether. After complete addition, the mixture is refluxed for one hour and the solvent is distilled from the reaction vessel. Steam is then passed in until a clear distillate results. The distillate is then extracted with ether and the extract is dried with solid sodium hydroxide. Dry hydrogen chloride is then passed into the filtered solution and the precipitated amine hydrochloride is removed by filtration and recrystallized to yield 3-N-ethylaminotricyclo[184.108.40.206 ]undecane hydrochloride.
EXAMPLE 5 Molar equivalents of 3-aminotricyclo[220.127.116.11 ]undecane and caproyl chloride are reacted in pyridine solution to give 3 N caproylaminotricyclo[18.104.22.168 ]undecane, which is isolated by pouring the reaction mixture into water and removing the crystalline amide by filtration. After careful drying of the product, a tetrahydrofuran solution is added slowly to a suspension of one molar equivalent (25% excess) of lithium aluminum hydride in diethyl ether. After complete addition, the reaction mixture is refluxed for 2 hours, the solvent is distilled and the amine is steam distilled until the distillate is clear. The product is extracted with ether and the ethereal solution is dried over solid sodium hydroxide. Dry hydrogen chloride is passed into the ethereal solution. Evaporation of the ether gives 3-N-hexylaminotricyclo[22.214.171.124 undecane, hydrochloride.
EXAMPLE 6 A 50-milliliter round-bottom flask is charged with 6.90 grams (0.15 mole) of 98% formic acid and 12.1 grams (0.15 mole) of 37% formalin solution. Then 8.26 grams (0.05 mole) of 3-aminotricyclo[4.3.l.1 ]undecane is charged, a condenser is attached, and the mixture is heated at 95 C. on the steam bath for 16 hours. Gas is evolved during the heat-up period and for some time thereafter. After cooling, the mixture is transferred to a separatory funnel with 50 milliliters of water, 25 milliliters of 50% sodium hydroxide is added, and the mixture is extracted with three ZS-milliliter portions of ether. The ether extracts are combined, washed with 50 milliliters of 12.5% sodium hydroxide, dried with potassium hydroxide pellets, and concentrated in a vacuum to yield 3-N,N-dimethylarninotricyclo [4.3. 1.1 undecane.
EXAMPLE 7 The 3 -N-methylaminotricyclo [4. 3 1 1 undecane prepared in Example 3 is converted to the acetyl derivative by gently warming the compound with a slight excess of acetic anhydride containing a drop of sulfuric acid. The resulting solution is poured on ice and extracted with chloroform. Removal of the chloroform yields 3-N- methylacetaminotricyclo[4.3.1.l ]undecane which is purified by distillation. A solution of the amide in tetrahydrofuran is added slowly to a suspension of one molar equivalent of lithium aluminum hydride in diethyl ether. After complete addition, the reaction mixture is refluxed for 4 hours, the solvent removed and the amine isolated by steam distillation. The steam distillate is extracted with ether and the extract is dried with solid sodium hydroxide. The dry ethereal solution is saturated with hydrogen chloride and after removal of the ether, the hydrochloride of 3-(N-methyl N ethylamino)tricyclo- [126.96.36.199 ]undecane is obtained.
EXAMPLE 8 Example 5 is repeated, substituting equivalent amounts of cyclopropanecarboxylic acid chloride for the caproyl chloride, to obtain 3 N cyclopropylcarbonylaminotricyclo[4.3.1.l ]undecane which is then reduced with lithium aluminum hydride to 3 N cyclopropylmethylaminotricyclo[188.8.131.52 ]undecane.
EXAMPLE 9 A 100 milliliter flask with a stirrer and reflux condenser is charged with 0.1 mole of 3-aminotricyclo[184.108.40.206 undecane, 0.1 mole of ethyl chloroacetate, 0.11 mole of sodium bicarbonate and 40 milliliters of methanol. The mixture is refluxed overnight, the insoluble material is removed by filtration and the solution is evaporated to dryness. The residue is dissolved in 1 Normal hydrochloric acid, regenerated by 5% sodium hydroxide, and extracted with ether. The ether solution is dried over anhydrous sodium sulfate and the solvent is removed. The residue is subjected to vacuum distillation at 0.1 mm. and divided into a lower boiling fraction, which is recovered starting material, and a higher boiling fraction, which is N-[tricyclo[4.3.1.l ]undecyl-(3)] glycine ethyl ester.
EXAMPLE 10 Equimolar quantities of freshly prepared Z-diethylaminoethyl chloride and 3 N methylamin0tricyclo- [220.127.116.11 ]undecane and 10% excess of sodium bicarbonate are refluxed in methyl alcoholic solution for 16 hours. The reaction mixture is poured into Water and extracted with ether. The ether extract is dried with solid sodium hydroxide and the solvent is removed. The residue is 3-N-(Z-diethylaminoethyl) N methylaminotricyclo- [4.3.1.l ]undecane.
EXAMPLE 1 l A 2-liter 4-necked round-bottom flask is equipped with thermometer, dropping funnel, reflux condenser, paddle stirrer and a connection to a gas meter, and charged with 500 ml. of absolute ethanol, 50.4 g. (0.60 mole) of sodium bicarbonate and 40.3 g. (0.20 mole of 3-aminotricyclo[18.104.22.168 ]undecane hydrochloride. Then, 24.2 g. (0.20 mole) of allyl bromide is added from the dropping funnel. There is no appreciable evolution of carbon dioxide. The mixture is gradually warmed to 65 C., whereupon gas evolution begins. The reaction is allowed to proceed until no more gas is evolved (about 11.5 liters). The mixture is cooled, the solids are filtered, and the filtrate is evaporated. The residue is distributed between ether and 10% sodium hydroxide solution. The ether layer is dried with anhydrous potassium carbonate and evaporated to give an oil. This is distilled at reduced pressure to give two main fractions. The lower-boiling fraction is 3 N allylaminotricyclo[4.3.l.1 ]undecane. The higher is 3-N,N-diallylaminotricyclo[4.3.l.1 ]undecane.
EXAMPLE 12 A Z-liter 4-necked round-bottom flask is equipped with thermometer, dropping funnel, reflux condenser, paddle stirrer and a connection to a gas meter. It is charged with 500 ml. of abs. ethanol, 50.4 g. (0.60 mole) of sodium bicarbonate and 43.0 g. (0.20 mole) of 3-N-methylaminotricyclo[4.3.l.1 ]undecane hydrochloride. Then, 24.2 g. (0.20 mole) of allyl bromide is added from the dropping funnel. The mixture is gradually warmed to 65 (3., when gas evolution begins. The reaction is allowed to proceed until no more gas is evolved (ca. 11.5 lite-rs). It is cooled, the solids are filtered, and the filtrate is evaporated. The residue is distributed between ether and 10% sodium hydroxide solution. The ether layer is dried with anhydrous potassium carbonate and evaporated to give a residue of 3 N allyl N methylaminotricyclo- [22.214.171.124 ]undecane.
EXAMPLE 13 A reaction is run as described in Example 12, using 40.3 g. (0.20 mole) of S-aminotricyclo[4.3.1.l ]undecane, 16.4 g. (0.20 mole) of propargyl chloride, 50.4 g. (0.60 mole) of sodium bicarbonate and 500 ml. of absolute ethanol. The cooled mixture is filtered and the filtrate is evaporated. The residue is distributed between 10% sodium hydroxide and ether. The ether layer is dried with anhydrous potassium carbonate and evaporated. The residue is distilled at reduced pressure to yield two main fractions. The lower-boiling fraction is 3-N-propargylaminotricyclo[126.96.36.199 ]undecane and the higher is 3-N,N- dipropargylaminotricyclo [188.8.131.52 ]undecane.
EXAMPLE 14 A flask equipped with a Dean-Stark water separator is charged with 0.1 mole of 3-aminotricyclo[4.3.1.l ]undecane and 0.1 mole of freshly distilled benzaldehyde in 50 milliliters of toluene. The reaction mixture is refluxed for 45 hours, the toluene evaporated and the residue recrystallized to give 3 -benzaldiminotricyclo [4.3.l.1 ]undecane.
EXAMPLE 15 The organic layer of 3-N-hydroxymethylaminotricyclo [4.3.1.l ]undecane or obtained in accordance with Example 19 hereinafter, is distilled at reduced pressure to yield N-[tricyclo[4.3.l.l ]undecyl-(3)] azomethine.
EXAMPLE 16 A 3-neck l-liter flask fitted with a stirrer and a thermometer is charged with 250 milliliters of 98% sulfuric acid which is then cooled to C. A mixture of grams of solid 1-hydroxymethyladamantane and 9 grams of sodium cyanide (3 molar equivalents) is added in small portions, with good stirring, to the acid, controlling the temperature of the reaction mixture between 20 C. by ice-bath cooling. When addition is complete, the reaction is allowed to warm slowly to room temperature. An exothermic reaction occurs but is controlled by the ice bath so that the temperature of the reaction mass does not exceed 50 C. The reaction mixture is stirred for 2 hours and poured on ice. The acidic solution is neutralized with ammonium hydroxide and the organic material isolated by extraction with chloroform. Evaporation of the chloroform yields 3-formamidotricyclo[4.3.l.1 ]undecane mixed with l-formamidomethyladamantane. The desired product, 3-formamid0tricyclo [4.3 1 l lundecane, can if desired be separated from the by-product by extraction of the mixture with cold excess cyclohexane in which it is insoluble. The melting point is l58l60 C. after crystallization from ethyl acetate.
This compound can also be made as follows:
An 0.05 mole amount of 3-aminotricyclo[4.3.l.1 undecane is refluxed 19 hours in 25 ml. of butyl formate. The excess butyl formate is removed by vacuum concentration, and the residue is recrystallized to yield 3-formamidotricyclo[184.108.40.206 ]undecane.
EXAMPLE 17 A solution of 0.1 mole of 3-aminotricyclo[220.127.116.11 undecane in 50 milliliters of benzene is added slowly to a solution of 0.1 mole of succinic anhydride in 100 milliliters of benzene. The mixture is then heated under reflux for one hour and the benzene removed by distillation. An
.excess of acetyl chloride, 0.15 mole, is added to the residue and the mixture heated under reflux on a steam bath for one hour. The excess acetyl chloride is distilled off at atmospheric pressure and the acetic acid formed by dehydration of the initially formed succinamic acid is removed at 100 C. under 15 mm. pressure. The residue is nearly pure 3-N-tricyclo[4.3.1.l ]undecylsuccinimide. The crude product, after drying in a vacuum desiccator over solid sodium hydroxide pellets, is dissolved in dry tetrahydrofurane and added slowly to a suspension of 0.15 mole, an excess of lithium aluminum hydride in diethyl ether. After complete addition, the reaction mixture is refluxed for 2 hours, the solvent removed by distillation, and the amine isolated by steam distillation. The steam distillate is extracted with ether, the solution dried with sodium hydroxide, and dry hydrogen passed into the filtered solution until no more is absorbed. Evaporation of the ether yields N-[tricyclo[4.3.l.1 ]undecyl- (3) ]pyrrolidine hydrochloride.
EXAMPLE 18 Example 5 is repeated, substituting equivalent amounts of 3-methoxypropionyl chloride for the caproyl chloride, to obtain 3-(N-methyl-3-methoxypropionamido)tricyclo 12 [4.3.l.1 ]undecane which is then reduced with lithium aluminum hydride to 3-N-(3-methoxypropyl)-N-methylaminotricyclo[4.3.1.l ]undecane.
EXAMPLE 19 A suitable flask equipped with stirrer, thermometer, reflux condenser, dropping funnel and cooling bath is charged with 2.0 moles of 3-aminotricyclo[18.104.22.168 undecane. A 37% aqueous solution of formaldehyde (2.05 moles) is added slowly with stirring, maintaining the temperature below 40 C. After addition is complete, the reaction is cooled to room temperature, and powdered potassium hydroxide (10 g.) is added to aid in separation of the water. The organic layer is separated and dried over potassium hydroxide to yield 3-N-hydroxymethylaminotricyclo[4.3.1.l ]undecane.
EXAMPLE 20 Example 19 is repeated using 2.0 moles of 3-N- methylaminotricyclo[4.3.1.l ]undecane is place of the 2.0 moles of 3-aminotricyclo[4.3.1.l ]undecane. The product is 3 -N-hydroxymethyl N-methylaminotricyclo [22.214.171.124 ]undecane.
EXAMPLE 21 A 0.1 mole amount of 3-N-hydroxymethyl-N-methylaminotricyclo[4.3.l.1 ]undecane (Example 20) is refluxed at 55 C. in a mixture of ml. of anhydrous diethylamine and 10 g. of potassium hydroxide pellets for 4 hours. The mixture is cooled and the liquid is decanted from the residual pellets and the small layer of concentrated potassium hydroxide solution. It is distilled at reduced pressure to yield 3N-diethyaminomethyl-N-methylaminotricyclo[4.3.l.1 ]undecane.
EXAMPLE 22 A solution of 0.5 mole of 3-aminotricyclo[126.96.36.199 undecane in milliliters of tetrahydrofuran and 30 milliliters of water is charged into a 400 milliliter stainless steel autoclave, and 5.0 grams (0.11 mole) of ethylene oxide is injected. The autoclave is heated to 70 C. for 24 hours after which time it is cooled and cautiously vented. Solvent is removed at reduced pressure, and the residue is extracted with ether. The ether extract is dried With anhydrous potassium carbonate. Solvent is removed at reduced pressure and the residue is subjected to sublimation at 100 C./20 mm. in order to remove unreacted 3-aminotricyclo[4.3.l.l ]undecane. The residue from the sublimation is distilled under vacuum to yield 3 N (2-hydroxymethyl)aminotricyclo[188.8.131.52 undecane. Continuation of the distillation gives 3-N,N-di(2-hydroxyethyl)aminotricyclo [184.108.40.206 undecane as a higherboiling fraction.
EXAMPLE 23 A suspension of 0.1 mole of 3-aminotricyclo[220.127.116.11 undecane in 100 milliliters of ice water is placed in 500- milliliter flask equipped with mechanical stirrer and thermometer. The flask is cooled in an ice bath and 142 grams of 5.25% sodium hypochlorite solution (commercial Clorox) is added at such a rate that the temperature does not exceed 10 C.
After the addition is complete the ice bath is removed and the mixture is stirred for 30 minutes. It is then extracted with three SO-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 chloroaminotricyclo [18.104.22.168 undecane.
EXAMPLE 24 A mixture of 0.10 mole of 3-aminotricyclo[22.214.171.124 undecane and 9.87 grams (0.10 mole of 38% hydrochloric acid in 100 milliliters of water is concentrated in vacuo at 60 C. The resulting salt, 3-aminotricyclo- [4.3.l.l ]undecane hydrochloride, is dried in vacuo at 60 C.
14 0.5% by weight based on the total weight of the composition and not more than 90% by weight.
Besides the active ingredient of Formula 1 the antiviral composition will contain a solid or liquid nontoxic EXAMPLES 25-37 Example 24 is repeated substituting the following indicated reactants for those of that example to obtain the indicated product:
pharmaceutical carrier for the active ingredient.
Ex. Product of Example Acid Product as 1, 0.10 mole 48% hydrobromic acid (0.10 mole) 3-aminotricyclo[126.96.36.199 undecane,
26 3, Free Amine, 0.10 mole 85% phosphoric acid (0.33 mole) 3-N-methylaminotricyc1o[43.1.1 1-
27 5, Free Amine, 0.10 mole Sulfuric acid (0.050 mole) 3-N-hoxylaminotricyclo[188.8.131.52 1-
undecane, sulfate. 28 7, Free Amine, 0.10 mole Tartaric acid (0.10 mole) 3-N-methyl-N-ethylaminotricyclo- [4.3.1.l ]undecane, bitartrate.
29 4, Free Amine, 0.10 mole Tartaric acid (0.050 mole) 3-N-ethylaminotricyelo[184.108.40.206
3, Free Amine, 0.10 mole Maleic acid (0.050 mole) 3-N-rnethylaminotrieyclo[220.127.116.11
31 18, 0.10 mole Perchloric acid (0.10 mole) 3N-(8methoxypropyl)-N-methylaminotricyc1o[18.104.22.168 ]undecane, perchlorate.
32 17, Free Amine, 0.10 mole"--- Acetic acid (0.10 mole) N-[tricyclo[22.214.171.124 ]undecyl-(3)lpyrrolidine, acetate. 33 9, 0.10 mole Citric acid (0.033 mole) 3-(N-carboethoxyrnethylamino)tricyclo[126.96.36.199 Hundecane, citrate.
34 10, 0.10 mole Citric acld (0.10 mole) 3-N-(2-(1iethylaminoethyl)-N- methylarnino-tricyclo[188.8.131.52 undecane, dihydrogen citrate.
35 22, 0.10 mole Succinic acid (0.050 mole) 3-N-(2-hydroxyethyl)aminotricyclo- [184.108.40.206 ]undecane, succinate.
36 2, 0.10 mole Mandelic acid (0.10 mole) 3aminotricyclo[220.127.116.11 ]undecane,
37 1, 0.10 mole Lactic acid, 0.10 mole 3-aminotricyclo[4.3.1.l ]undecane,
EXAMPLE 38 In one embodiment of a pharmaceutical composition of A solution of 0.20 mole of 3-aminotricyclo[18.104.22.168 undecane hydrochloride in 100 milliliters of water is added to a solution of 0.10 mole of pamoic acid disodium salt [4,4-methylenebis(3-hydroxy-2-naphthoic acid) disodium salt] in 500 milliliters of water. The resulting precipitate is filtered, washed well with water, and dried in vacuo to give 3-aminotricyclo[22.214.171.124 ]undecane pamoate.
The preceding examples can be repeated substituting equivalent amounts of appropriate starting materials to obtain other compounds of this invention including those listed hereinbefore.
The compounds of Formula 1 above can be administered in the antiviral treatment according to this invention by any means that effects contact of the active ingredient compound with the site of virus infection in the body. It will be understood that this includes the site prior to infection setting in as well as after. For example, administration can be parenterally, that is subcutaneously, intravenously, intramuscularly, or intraperitoneally. Alternatively or concurrently, the compounds are effective on administration by the oral route. Since particularly effective against respiratory infections such as viral pneumonia, administration can be by vapor or spray through the mouth or nasal passages.
The compounds within the scope of this invention are valuable for viral prophylaxis, as well as for therapeutic treatment.
The dosage administered will be dependent upon the virus being treated, the age, health and weight of the recipient, the extent of infection, kind of concurrent treatment if any, frequency of treatment and the nature of the effect desired. 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 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 Formula 1 can be employed in useful compositions according to the present invention in such dosage forms as tablets, capsules, powder packets or liquid solutions, suspensions, or elixirs, for oral administration, or liquid solutions for parenteral use, and in certain cases, suspensions for parenteral use (except intravenous). In such compositions the active ingredient will ordinarily always be present in an amount of at least 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 Formula 1 or 2 and 7040% 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 and preferably from 25% to 90% by weight. These dosage forms preferably contain from about 5 to about 500 milligrams of active ingredient, with from about 25 to about 250 most preferred.
The pharmaceutical carrier can, as previously indicated, be a sterile liquid such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, for example peanut oil, soybean oil, mineral oil, seasame oil and the like. In general, Water, saline and aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectible solutions. Sterile injectible solutions will ordinarily contain from about 0.5 to 25%, and preferably about 1 to 10% by weight of the active ingredient.
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 compositions can be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.
Suitable pharmaceutical carriers are described in Remingtons Practice of Pharmacy by E. W. Martin and E. F. Cook, a well known reference text in this field.
In addition to the exemplary illustrations above, the following examples further explain the present invention:
EXAMPLE 39 A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules weighing about 50 milligrams each with 50 milligrams of powdered 3- aminotricyclo[4.3.1.l ]undecane hydrochloride; milligrams of lactose and 1 milligram of Cab-O-Sil.
15 EXAMPLE 40 Example 39 is repeated except that soft gelatin capsules are used and the powdered 3-aminotricyclo[126.96.36.199 un decane hydrochloride is first dissolved in mineral oil.
EXAMPLE 41 Example 39 is repeated except that the dosage unit is 50 milligrams of active ingredient, 5 milligrams of gelatin, 1.5 milligrams of magnesium stearate and 100 milligrams of lactose, mixed and for-med into a tablet by a conventional ta'bleting machine. Slow release pills or tablets can also be used, by applying appropriate coatings such as sugar-base coatings well known to the art.
EXAMPLE 42 A parenteral composition suitable for administration by injection is prepared by stirring 5% by weight of the active ingredient of Example 39 in sterile aqueous 0.9% saline.
A large variety of compositions according to this invention can thus readily be made by substituting other compounds of this invention, and including specifically but not limited to compounds of this invention that have specifically been named hereinbefore. The compounds will be used in the amounts indicated in accordance with procedures well known and described in the Martin and Cook text mentioned above.
The compounds of this invention are particularly effective against swine influenza. An important embodiment of this invention therefore is the control of this infection by incorporating an active ingredient compound in the diet of the affected animal. 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 compound based on the total weight of feed intake. Preferably, from 0.001% to 0.02% by weight will be used.
In a related aspect, novel and useful compositions are provided 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.
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 feedstufls in appropriate proportion. These concentrates ordinarily comprise about 0.5% to about 95% by weight of the active ingredient compound together with a finely divided solid, preferably flours, such as wheat, corn, soya bean and cottonseed. 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 following example will further illustrate this aspect of this invention,
16 EXAMPLE 43 A feed for pigs is prepared as follows:
Pounds Oat groats 350 Yellow corn, ground 1000 Molasses Soybean meal 450 Dried skim milk 100 Ground limestone 20 Dicalcium phosphate 20 Salt plus trace mineral mix 10 Standard vitamin premix 1 According to this invention there is added to the pigs diet a concentrate of 50% of 3-N-methylaminotricyclo [188.8.131.52 ]undecane hydrochloride as the active ingredient and 50% by weight corn flour, in an amount that pro vides 0.015% by weight of the active ingredient based on the total diet.
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.
1. A compound selected from the group consisting of those of the formula:
where R is selected from the group consisting of /Rt -N and where n is an integer of 2 through 6; wherein:
R is selected from the group consisting of hydrogen; alkyl of 1 through 6 carbon atoms; mono-substituted alkyl of 1 through 6 carbon atoms where the substituent is hydroxy, alkoxy of 1 through 2 carbon atoms, NH -NHR and NR R where R and R are each alkyl of 1 to 4 carbon atoms; alkenyl of 2 through 6 carbon atoms; alkynyl of 2 through 6 carbon atoms; cyclopropyl; cyclobutyl; cyclopropylmethyl; and cyclobutylmethyl; and
R is selected from the group consisting of R chlorine and bromine; with the proviso that when R is selected from the group consisting of alkenyl or alkynyl having the unsaturated bond in the l-position, R is selected from the group consisting of alkyl of 1 through 6 carbon atoms and mono-substituted alkyl of 1 through 6 carbon atoms where the substituent is selected from the group consisting of hydroxy, alkoxy of 1 through 2 carbon atoms, NH NHR and -NR R where R; and R are each alkyl radicals of 1 through 4 carbon atoms;
and nontoxic salts of said compound.
2. A compound of the formula NR 1R2 17 18 wherein R and R are each an alkyl group of from 8. 3-N,N-diethy1aminotricyclo[184.108.40.206 ]undecane. 1 to 6 carbon atoms.
3. 3-aminotricyclo[220.127.116.11 ]undecane. N0 feferencfis 4. 3-N-methy1a1ninotricyc1o[18.104.22.168 ]undecane. 5. 3-N-ethy1aminotricyclo[22.214.171.124 ]undecane. 5 CHARLES PARKER: Pnmmy Examme 6. 3-N,N-dimethy1aminotricyclo[126.96.36.199 ]undecane. P, C, IVES Assistant Examiner.
7. 3 (N-ethy1 N methylamino)tricycl0[188.8.131.52 undecane.
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3532748 *||May 11, 1967||Oct 6, 1970||Du Pont||2-adamantanamines|
|US4078085 *||Jun 28, 1976||Mar 7, 1978||Kao Soap Co., Ltd.||3-Aminomethyl-4-homoisotwistane and its salt and process for producing same|
|US4101580 *||Jun 14, 1976||Jul 18, 1978||Kao Soap Co., Ltd.||3-Amino-4-homoisotwistane and an acid addition salt thereof and a process for producing the same|
|US4174407 *||Jan 13, 1978||Nov 13, 1979||Sumitomo Chemical Company, Limited||Antiviral agent|
|US4229375 *||Feb 28, 1979||Oct 21, 1980||Kao Soap Company, Limited||1-Aminomethyltricyclo[184.108.40.206,5 ]undecane and acid-addition salts thereof|
|US4230725 *||Sep 5, 1978||Oct 28, 1980||Sumitomo Chemical Company, Limited||Antiviral agent|
|US4254128 *||Nov 22, 1978||Mar 3, 1981||Teva Pharmaceutical Industries Ltd.||2-Adamantyl hydrazines and biocidal compositions thereof|
|US8691808||May 18, 2012||Apr 8, 2014||Influmedix, Inc.||Antiviral compounds and their methods of use|
|U.S. Classification||564/459, 564/217, 548/529, 546/203, 564/117, 562/499, 564/248, 564/456, 564/270, 564/453, 549/491, 560/117|
|International Classification||C07C211/38, A61K31/13|
|Cooperative Classification||A61K31/13, C07C211/38|
|European Classification||C07C211/38, A61K31/13|