------------------------------------------------------------------------------- N-alkyl-4,4-Diphenylpiperidines as CNS stimulants found by Fuchem ------------------------------------------------------------------------------- I was just farting-around on the net, when I ran into something interesting: "4,4-Diarylpiperidines Abstract 4,4-Diarylpiperidine compounds, preferably 4,4-diphenylpiperidine which are substituted or unsubstituted in the 1-position of the piperidine nucleus, such as 1-(lower alkyl)-4,4-diphenylpiperidines, 1-(lower alkyl)-4-phenyl-4-tolyl- piperidines, and their substantially non-toxic, pharmaceutically-acceptable acid addition salts, are highly effective central nervous system (CNS) stimulants which are superior to known amphetamine-type stimulants. A novel and highly advantageous process of making such 4,4-diarylpiperidine compounds comprises reacting a 4-aryl-4-hydroxypiperidine compound which may be substituted in its 3-position by an aroyl group, with an aromatic hydrocarbon, in particular with benzene, in the presence of a Friedel-Crafts-type catalyst." Source --> http://water-cooler.com/WC/patentviewer/patent-4022786.html ------------------------------------------------------------------------------- From same page: REACTION EXAMPLE 1 1-Methyl-4,4-diphenylpiperidine 20 g. of 1-methyl-4-hydroxy-4-phenylpiperidine are suspended in 150 ml. of anhydrous benzene. 61.5 g. of finely pulverized anhydrous aluminum chloride are added in portions thereto within 25 minutes while stirring. The reaction temperature increases on starting addition of aluminum chloride to about 45.degree. C. After about 20 minutes the temperature is increased to and maintained at about 50.degree. to 55.degree. C. for about one hour. The resulting reaction solution is cooled to about 20.degree. C. and is poured into a mixture of ice and concentrated hydrochloric acid. After warming the mixture to room temperature, the hydrochloric acid layer together with the dark oil formed on decomposition is separated from the benzene layer and is washed with benzene. Water is added to said hydrochloric acid-oil phase, while stirring, in portions and in an amount sufficient to produce an almost clear solution. Said acid solution is rendered alkaline by the addition of 40% sodium hydroxide solution whereby the mixture is well cooled. The alkalized mixture is repeatedly extracted with ether. The combined ether extracts are dried over anhydrous potassium carbonate and are concentrated by evaporation of the ether. 24 g. of the crude base are obtained as residue in the form of yellowish oil. A water clear oil boiling at 98.degree. to 103.degree. C./0.01 mm. Hg is recovered by distillation of said crude oil in a high vacuum. The oil solidifies to crystals on standing for a short period of time. After recrystallization from aqueous dimethylformamide, the resulting 1-methyl-4,4-diphenylpiperidine has a melting point of 71.degree. to 73.degree. C. Its hydrochloride is produced by dissolving the base in acetic acid ethyl ester and adding an ethereal hydrochloric acid solution thereto. After recrystallization from acetic acid ethyl ester, the melting point of the hydrochloride is 220.degree. to 223.degree. C. EXAMPLE 2 1-Methyl-4,4-diphenylpiperidine 100 g. of 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine are suspended in 600 ml. of anhydrous benzene while stirring. 200 g. of finely pulverized, anhydrous aluminum chloride are added in portions thereto within 25 minutes. The reaction temperature increases to about 45.degree. C. when adding the first portion of aluminum chloride. After about 20 minutes the reaction temperature of the reaction mixture is maintained at 50.degree. to 55.degree. C. for about 1 hour. The reaction mixture is then cooled to room temperature and is introduced into a mixture of ice and concentrated hydrochloric acid while stirring. After heating the mixture to room temperature, the benzene layer is separated from the hydrochloric acid and oil layer which is washed with benzene. The hydrochloric acid and oil layer is diluted, while stirring, with an amount of water sufficient to cause substantially all the oil to be dissolved. The resulting aqueous solution is then rendered alkaline by the addition of 40% sodium hydroxide solution, while stirring, and the alkaline solution is extracted with ether. The combined ether extracts are dried over anhydrous potassium carbonate and are concentrated by evaporation of the ether. 83.5 g. of the crude base are obtained as residue in the form of a dark oil. A light oil boiling at 98.degree. to 103.degree. C./0.01 mm. Hg is recovered by distillation of said crude oil in a high vacuum. The oil solidifies to crystals on standing for a short period of time. After recrystallization from aqueous dimethylformamide, the resulting 1-methyl-4,4-diphenylpiperidine has a melting point of 71.degree. to 73.degree.C. EXAMPLE 3 1-Ethyl-4,4-diphenylpiperidine When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine starting material by 1-ethyl-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in the presence of aluminum chloride, 15 g. of crude 1-ethyl-4,4-diphenylpiperidine base boiling at 110.degree. to 123.degree. C./0.01 mm. Hg are obtained. Its acid addition salt with maleic acid is produced by the addition of maleic acid to its acetone solution. The maleic acid salt melts at 239.degree. to 240.degree. C. EXAMPLE 4 1-Isopropyl-4,4-diphenylpiperidine When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-isopropyl-3-benzoyl-4- hydroxy-4-phenylpiperidine and reacting 55 g. thereof with benzene in the presence of anhydrous aluminum chloride, 33 g. of crude 1-isopropyl-4,4- diphenylpiperidine base boiling at 117.degree. to 125.degree. C./0.01 mm. Hg. are obtained in the form of a yellowish viscous oil. On adding isopropanol saturated with hydrogen chloride to its acetic acid ethyl ester solution, the crystalline hydrochloride precipitates. After recrystallization from isopropanol, the hydrochloride melts at 267.degree. C. EXAMPLE 5 1-Phenethyl-4,4-diphenylpiperidine When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-phenethyl-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in the presence of anhydrous aluminum chloride, 15 g. of 1-phenethyl-4,4-diphenylpiperidine base are obtained. On adding ether saturated with hydrogen chloride to its acetic acid ethyl ester solution, the crystalline hydrochloride precipitates. After recrystallization from isopropanol, the hydrochloride melts at 202.degree. to 204.degree. C. EXAMPLE 6 1-Isopropyl-4-phenyl-4-(p-tolyl)piperidine When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-isopropyl-3-(p-toluoyl)-4-hydroxy-4-(p-tolyl)piperidine and reacting 20 g. thereof with benzene in the presence of 30 g. of aluminum chloride, 17 g. of the hydrochloride of 1-isopropyl-4-phenyl-4-(p-tolyl)piperidine are isolated on decomposing the reaction mixture with a mixture of ice and hydrochloric acid. After recrystallization from isopropanol, the hydrochloride is obtained in colorless leaflets of the melting point 271.degree. to 273.degree. C. EXAMPLE 7 1-(3-Methoxypropyl)-4,4-diphenylpiperidine 30 g. of 1-(3-methoxypropyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine are suspended in 225 ml. of anhydrous benzene. 50 g. of finely pulverized, anhydrous aluminum chloride are added thereto within 20 minutes, while stirring. The reaction temperature increases during said addition up to 60.degree. C. The reaction mixture is then kept at from 50.degree. to 55.degree. C. for about 1 hour, is cooled to room temperature, and is added to a mixture of ice and concentrated hydrochloric acid. The benzene layer is separated from the aqueous layer by means of a separating funnel and is washed once with dilute hydrochloric acid. The combined aqueous layers are rendered alkaline by the addition of 40% sodium hydroxide solution. The precipitated base is separated by repeated extraction with ether. The combined ether extracts are dried over anhydrous potassium carbonate and the ether is distilled off. 21 g. of the crude base remain as residue. On distillation in a high vacuum, pure 1-(3-methoxypropyl)-4,4-diphenylpiperidine is obtained in the form of a light oil boiling at 130.degree. C./0.01 mm. Hg. The crystalline fumaric acid salt of said base is obtained by the addition of the calculated amount of fumaric acid to the solution of the base in isopropanol. After recrystallization from isopropanol, the fumaric acid salt melts at 189.degree. to 190.degree. C. EXAMPLE 8 1-(1-Phenyl-2-propyl)-4,4-diphenylpiperidine When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-(1-phenyl-2-propyl)-3- benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in the presence of anhydrous aluminum chloride, 1-(1-phenyl-2-propyl)-4,4- diphenylpiperidine hydrochloride is isolated on decomposing the reaction mixture with a mixture of ice and concentrated hydrochloric acid. The yield of the crude hydrochloride amounts to 16 g. After recrystallization from isopropanol, its melting point is 172.degree. to 174.degree. C. EXAMPLE 9 1-(2-Hydroxyethyl)-4,4-diphenylpiperidine When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-(2-hydroxyethyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in the presence of anhydrous aluminum chloride, 10 g. of 1-(2-hydroxyethyl)-4,4-diphenylpiperidine base boiling at from 160.degree. to 167.degree. C./0.01 mm. Hg are obtained. The hydrochloride obtained from the isopropanol solution of said base has a melting point of 219.degree. to 221.degree. C. EXAMPLE 10 1-Benzyl-4,4-diphenylpiperidine When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-benzyl-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in the presence of anhydrous aluminum chloride and decomposing the reaction product with a mixture of ice and hydrochloric acid, 14 g. of the hydrochloride of 1-benzyl-4,4-diphenylpiperidine are isolated in crystalline form. After recrystallization from isopropanol, the hydrochloride melts at 239.degree. C. EXAMPLE 11 1-(2-Phenoxyethyl)-4,4-diphenylpiperidine When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-(2-phenoxyethyl)-3- benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in the presence of anhydrous aluminum chloride, 13 g. of 1-(2-phenoxyethyl)- 4,4-diphenylpiperidine are obtained. Its boiling point is 145.degree. C./0.01 mm. Hg. The compound yields a fumaric acid salt melting at 199.5.degree. C. The starting materials of the formulae II or IIa are dissolved or suspended in an aromatic hydrocarbon having the formula ##STR7## wherein R.sub.3 has its above-ascribed meaning. In the preferred embodiment anhydrous benzene or toluene is used as the aromatic hydrocarbon. The Friedel-Crafts catalyst, preferably anhydrous aluminum chloride or ferric chloride, or another Lewis acid, such as antimony pentachloride, tin tetrachloride or zinc chloride, is used in at least stoichiometric amounts in relation to compounds II and IIa, e.g. in a molar ratio of catalyst: II or IIa of from about 6:1 to 2:1, preferably of from about 5:1 to 4:1, whereas the aromatic hydrocarbon having the formula ##STR8## wherein R.sub.3 has its above-ascribed meanings, has two functions: it serves as a reactant and its stoichiometric excess serves as solvent or suspending medium in which the reaction proceeds. The reaction is preferably carried out while cooling or at an elevated temperature, preferably at temperatures between 0.degree. C. and 120.degree. C., in particular between 25.degree. and 75.degree. C., or at the boiling temperature of the solvent or of the suspension. Usually, the Friedel-Crafts-type catalyst is added to the reaction mixture at room temperature. Thereby, the temperature of the mixture increases as the reaction proceeds. The condensation is completed by continuing heating the mixture, for example on a water bath, for a short period of time. The reaction product, which is a complex of the catalyst and the final product of formula I, Ia or I*, is readily decomposed by pouring the reaction mixture into a mixture of ice water and concentrated acid, e.g. hydrochloric acid or sulfuric acid. On addition of the acid the compounds of formula I, Ia or I* can be isolated in the form of their acid-addition salts, which are readily crystallized from polar solvents, e.g., acetic acid alkyl esters, lower alkanols, ethers or ketones. The acid-addition salt is converted into the corresponding free base of formula I, Ia or I* by rendering alkaline an aqueous acid solution containing I, Ia or I* by the addition thereto of an aqueous alkaline solution, whereby the mixture is cooled. The alkalized mixture can be extracted with ether. The ether extracts contain the 4,4-diarylpiperidine base and are dried over known drying agents or desiccants. By evaporation of the ether the crude base is obtained as a residue which is purified by distillation or by recrystallization, e.g., from aqueous dimethylformamide, lower alkanols or ketones. The acid-addition salts of the 4,4-diphenylpiperidine compounds of formula I are produced by methods known to the art, for instance, by dissolving the base in a suitable solvent wherein the respective salt is insoluble and adding thereto the corresponding acid which may also be dissolved in a suitable solvent. The hydrochloride can be obtained directly by decomposing the reaction product, obtained by proceeding as described hereinabove, with ice water-hydrochloric acid. Of course, not only acid-addition salts with inorganic acids, such as the hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and others, can be produced but also acid-addition salts with organic acids, such as the salts with acetic acid, propionic acid, and other alkanoic acids, maleic acid, fumaric acid, lactic acid, citric acid, malic acid, tartaric acic, succinic acid, glycine, alanine and other amino acids, benzoic acid, salicyclic acid, phthalic acid, furoic acid, nicotinic acid, isonicotinic acid, and others. The preferred acid addition salts are, of course, those salts which are substantially non-toxic and pharmaceutically acceptable in amounts administered. Said stimulating effect manifests itself by increased attentiveness, alertness, and vigilance without causing locomotory activity accompanied by restlessness and without inducing aggressiveness. The central nervous system (CNS) stimulating 4,4-diphenylpiperidines of formulae I, I*, Ia through Ie and their therapeutically-acceptable acid-addition salts thus possess considerable advantages over the heretofore known and used central nervous system stimulating agents of the amphetamine type. In contrast to said amphetamine-type compounds the compounds of formulae I, I*, Ia through Ie do not cause a pronounced increase in blood pressure nor general stimulation of the sympathetic nervous system. Due to these pharmacological properties the compounds have proved of value in therapy for all indications in which stimulation of the central nervous system is required, such as in the treatment of chronic fatigue, depressions especially in certain psychotic, senile, and psychoneurotic patients, obesity, and others. Therefore the compounds of formulae I, I*, Ia through Ie and their pharmacologically-compatible salts with organic or inorganic acids are useful as medicaments; furthermore the compounds of formula Ib are valuable intermediates for the preparation of compounds of formulae Ic, Id and Ie. It has been found, that the CNS stimulating compounds of the invention, while exhibiting similar stimulation of the central nervous system as the addicting drugs, do not cause habituation, tolerance and hence do not lead to drug-addiction. On repeated daily chronic administration of the same dose of the new substances to mice, rats and dogs, the same degree of stimulation has been reproduced. The animals tested did not develop habituation or tolerance as a consequence of repeated administration. Disruption of a continuous treatment over more than ten days did not provoke the appearance of withdrawal symptoms. "To be the sum of all parts, in one place, at one time" - Andrew Graybeal -------------------------------------------------------------------------------