US3080372A - 1-aroylalkyl-4-arylpiperidine derivatives - Google Patents

1-aroylalkyl-4-arylpiperidine derivatives Download PDF

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US3080372A
US3080372A US9742561A US3080372A US 3080372 A US3080372 A US 3080372A US 9742561 A US9742561 A US 9742561A US 3080372 A US3080372 A US 3080372A
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    • C07D211/40Oxygen atoms
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    • C07D211/62Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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    • C07D211/84Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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Description

United States Patent Office 3,080,372 Patented Mar. 5, 1963 The present invention relates to a new group of l-aroylalkyl-4-arylpiperidine derivatives of the general structural formula and the pharmaceutically useful non-toxic salts thereof wherein n is a positive integer greater than 2 and less than 5; Ar is a member of the group consisting of phenyl, halophenyl, thienyl, and anisyl; Ar is a member of the group consisting of phenyl, halophenyl, alkylphenyl of fewer than 9 carbon atoms, anisyl, and trifluoromethylphenyl; R is a member of the group consisting of hydrogen, lower alkyl, hydroxy (lower alkyl), CHO, and

i-(lower alkyl) and X is a member of the group consisting of hydrogen and methyl.

The halophenyls represented by Ar and Ar can be fluorophenyl, chlorophenyl, bromophenyl and iodophenyl while alkylphenyl can be tolyl, xylyl and ethylphenyl. Optimally, the chain represented by -(CH is trimethylene. The lower alkyl radicals referred to above can represent methyl, ethyl, propyl, butyl, amyl, and hexyl radicals.

The compounds of the foregoing structural formula in which X represents a methyl group can obviously occur in stereochemical arrangements in which the group X is in a position cis or trans to the group R. The nomenclature for these compounds has been simplified throughout this application by referring to the isomer in which the 3-methyl group is presumably in a cis position relative to the R group at position 4 as the a form, while the ,8 form presumably has the opposite or trans configuration. The presumption in regard to the assignment of stereochemistry rests on the usually reliable method of preferential solubility.

The compounds of this invention have useful pharmacological properties. In general terms they can be said to be central nervous system depressants. Specifically, they are anti-apomorphine agents, inhibit amphetamineinduced motility, induce hynotic activity as measured by the righting reflex, potentiate barbiturates, show analgesialike effects, and inhibit gastro-intestinal propulsion. The compounds where R is CO-(lower alkyl) are also useful because they demonstrate a minimum of extrapyra-midal effects. The 4-hydroxyalkyl compounds show only low extrapyramidal effects while the corresponding 4- hydroxy compounds have very pronounced extrapyramidal effects.

The organic bases of this invention form pharmaceutically acceptable salts with a variety of inorganic and strong organic acids including sulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, citric, lactic, maleic, malic, succinic, tartaric, Cinnamic, acetic, ben zoic, gluconic, ascorbic, and related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. Among such esters are methyl chloride and bromide, ethyl chloride, propyl chloride, butyl chloride, isobutyl chloride, benzyl chloride and bromide, phenethyl bromide, naphthylmethyl chloride, dimethylsulfate, diethylsulfate, methyl benzene sulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

The compounds of this invention can be prepared by the condensation of an aroylalkyl halide of the formula Ar-CO-Alk-Halogen with an appropriately selected 4-arylpiperidine. The reaction can be carried out in an inert solvent such as an aromatic hydrocarbon e.g. benzene, toluene, Xylene, a lower alkanol e.g, ethanol, propanol, butanol, or a lower alkanone e.g. acetone, butanone, pentanone. In certain cases the reaction may be usefully accelerated by the use of elevated temperatures.

The aroylalkyl halides used as intermediates can be prepared conveniently by the Friedel-Crafts reaction including its milder variation employing, for example, 'y-chlorobutyryl chloride and benzene or an appropriately substituted benzene such as toluene and xylene, a halogenated benzene such as chlorobenzene, bromobenzene, and fiuorobenzene, or an alkoxybenzene such as anisole and phenetole.

These intermediates can also be prepared by treating an w-haloallcanonitrile with the appropriate arylmagnesium bromide followed by acid hydrolysis of the adduct.

The 4-arylpiperidine intermediates of the formula wherein Ar, R and X are defined as above which are used in the condensation described above are prepared from a compound of the formula The nitrogen of this compound is protected by reaction with benzyl chloride or p-toluenesulfonyl chloride to give, after heating with thionyl chloride, a compound of the formula o1oH2oH2-1 oHzoHo1 wherein Y is benzyl or p-toluenesulfonyl. Treatment of this dihalide with an arylacetonitrile and s'odamide in toluene yields a piperidine of the formula where Y is hydrogen, reduction of the esters with lithium aluminum hydride does not always give the corresponding carbinol. In this case, when Ar is substituted aryl, the alcohol is the predominant product while when Ar is phenyl, reduction stops at the aldehyde.

CHzOH spacers To prepare the related ketones of this invention, the cyanopiperidines described above (Y=p-tosy1) are treated with an alkylmagnesium halide. The sulfuric acid hydrolysis of the Grignard complex can be carried out in such a way that the blocking group Y is also removed and the product is then a ketone having the following formula Alternately, when X=methyl, after the hydrolysis of the Grignard complex, the blocking tosyl group can be re- O-(lower alkyl) moved by mixing the sulfonamide with a 30% solution (lower alkyl) HN L Ar For those substituted piperidines in which R is methyl,

an alternate method of preparation is available which starts with an appropriate acetophenone. The acetophenone is heated with ethyl cyanoacetate, acetic acid, and ammonium acetate in benzene. The condensation product of the above reaction is stirred with sodium ethoxide and cyanoacetamide to give a compound of the formula This substituted glutarimide is heated in a mixture of sulfuric acid and acetic acid to give a 3-aryl-3-methyl-glutaric acid. Reduction of this acid with lithium aluminum hydride gives the corresponding glycol and this is heated with either hydrogen bromide or thionyl chloride to give the dihalide of the formula on; ornomz Ar \CH2CH2Z wherein Z is bromine or chlorine. The dihalide is heated with benzylamine in a sealed tube to give a 1-benzyl-4- aryl-4-methylpiperidine. Hydrogenation of the amine over palladium-on-charcoal at room temperature and atmospheric pressure brings about-debenzylation to give the desired 4-aryl-4-methylpiperidine.

To obtain the intermediate piperidines having only an aryl group in the 4-position, an appropriately substituted a-methylstyrene is condensed with formaldehyde and ammonium, chloride to give a 4-aryl-1,2,3,6-tetrahydropyridine which, on catalytic reduction, gives the 4-arylpiperidine.

Alternately, these 4-arylpiperidines can be prepared by reaction of N-benzyl-4-piperidone with an appropriate aryl Grignard reagent or with an aryllithiurn compound to give the N-benzyl-4-arylpiperidine-4-ol or N-benzyl-3- methyl-4-arylpiperidin-4-ol. Dehydration of the alcohol obtained in this way yields an olefin, or a mixture of the two possible olefins. When this olefin is hydrogenated over a palladium-on-charcoal catalyst, not only is the double bond reduced, but the molecule is debenzylated to give the desired 4-arylpiperidine or 3-methyl-4-arylpiperidine.

The compounds which constitute this invention and their preparation will appear more fully from a consideration of the following examples which are given for the purpose of illustration only and are not to be construed as limiting the invention in spirit or in scope. In these examples, quantities are indicated as parts by weight.

Example 1 A Grignard reagent of m-fluorophenylmagnesium bromide is prepared by reacting 6.7 parts of magnesium with 94.5 parts of m-bromofiuorobenzene in parts of ether. Then 21 parts of v-chlorobutyronitrile in 64 parts of other are added and the mixture is refluxed under nitrogen for two hours with stirring. The mixture is then allowed to stand at room temperature for 15 hours and the excess Grignard reagent is decomposed by the addi tion of 56 parts of concentrated hydrochloric acid and 50 parts of water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is distilled to yield 'y-chloro-m-fiuorobutyrophenone boiling at about -125 C. at 2 mm. pressure.

By substituting equivalent quantities of starting materials in the procedure given above, the following compounds are obtained:

' ,2-dichlorobutyrophenone 'y-Chloro-4-methoxybutyrophenone 'y-Chloro-3 -rnethoxybutyrophenone ,3-dichlorobutyrophenone Example 2 To a suspension of 341 parts of aluminum chloride in 1740 parts of carbon disulfide are added 96 parts of fluorooenzene with stirring and cooling. While the temperature is maintained at about 10 C., 141 parts of v-chlorobutyryl chloride are added. After the addition is completed, the cooling bath is removed and the stirring is continued for 2 hours. The reaction mixture is poured into ice water. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and the residue is distilled to yield 7- chloro-p-fluorobutyrophenone boiling at about 136-142" C. at 6 mm. pressure.

By substitution of bromobenzene for fluorobenzene in the procedure of the above paragraph and otherwise following the procedure outlined therein, there is obtained -chloro-4-bromobutyrophenone.

Example 3 To a solution of 592 parts of N-tosyl-bis-(2-chloroethyl)amine and 234 parts of benzyl cyanide in 1566 parts of toluene, there is added with vigorous stirring and cooling over a period of 30 minutes a suspension of 344 parts of sodamide in toluene. The temperature of the reaction mixture is raised slowly to reflux and refluxing is continued for 2 hours. The mixture is cooled to 10 C. and 800 parts of ice water is added slowly. The resultant precipitate is filtered, Washed with 2-propanol, and dried or yield 1-tosyl-4-phenyl-4-cyanopiperidine.

A solution of n-propylmagnesium bromide is prepared by adding a solution of 25 parts of n-propyl bromide in 80 parts of ether to 5 parts of magnesium. To this solution is added a suspension of 25 parts of 1tosyl-4- phenyl-4cyanopiperidine in 240 parts of anhydrous toluene. The mixture is refluxed for 3.5 hours before it is cooled and decomposed with 100 parts of 2 N hydrochloric acid. This mixture is refluxed for 30 minutes and filtered. The water layer is separated and extracted twice with toluene, and the combined toluene solutions are dried over potassium carbonate. The toluene is evaporated and the residue is taken up in 60 parts of 80% sulfuric acid and heated for 45 minutes at -170 C. The cooled reaction mixture is poured onto ice, alkalized with 50% sodium hydroxide solution and extracted with ether. Distillation of the ether extracts gives the desired base. To obtain the hydrochloride the crude amine remaining after removal of the ether is again dissolved in ether and hydrogen chloride gas is introduced into the solution. This gives 4-butyryl-4-phenylpiperidine hydrochloride melting at about 164-166" C.

If the above procedure is repeated using a substituted benzyl cyanide in the first step in place of benzyl cyanide and using methylrnagnesium iodide or ethylmagnesium bromide in place of propylmagnesium bromide in the second step the following compounds are obtained:

4-acetyl-4-(3-tolyl)piperidine boiling at about 152- 156 C. (1.5 mm).

4-acetyl-4-(4-tolyl)piperidine boiling at about 155- 160 C. (2 mm.)

4 acetyl 4-(4-fluorophenyl)piperidine hydrochloride melting at about 215.5-217.5 C.

4-acetyl-4-(3-chlorophenyl)piperidine boiling at about 174-180 C. (2 mm.)

4 acetyl 4-(4-chlorophenyl)piperidine hydrochloride melting at about 272.6-273.4 C.

4-propionyl-4-(4-tolyl)piperidine boiling at about 150 C. (3 mm.)

4-propionyl-4-(4-chlorophenyl)piperidine boiling at about 172 C. (2.5 mm.)

Example 4 A mixture of 54 parts of 1-tosyl-4-(4-tolyl)4-cyanopiperidine and 125 parts of 75% sulfuric acid is heated at ISO-160 C. for 1 hour. The condenser is arranged for distillation and the mixture is cooled to 110 C. At this temperature 280 parts of methanol is added over a period of 3.5 hours. When the addition is complete distillation is continued until no more distillate is collected. The cooled residue is poured into ice water and alkalized. The alkaline solution is extracted with ether and the ether solution is dried over sodium sulfate. Distillation gives 4-rnethoxycarbonyl-4-tolylpiperidine boiling at about l52154 C. (1.5 mm.). To obtain the hydrochloride, hydrogen chloride gas is passed through the ether solution of the piperidine.

If the above procedure is repeated with the appropriate starting materials the following compounds are obtained:

4-ethoxycarbonyl-4-(4-fluorophenyl)piperidine hydrochloride melting at about 138.5-140 C.

4-ethoxycarbonyl-4(4-chlorophenyl)piperidine boiling at about 186 C. (8 mm.)

Example 5 To an emulsion of 3.79 parts of lithium aluminum hydride in 150 parts of tetrahydrofuran is added portionwise a solution of 16 parts of 4-methoxycarbonyl-4-(4- tolyl)piperidine in 60 parts of tetrahydrofuran at a temperature of about 64 C. with stirring. After the addition is complete, the mixture is refluxed for 6 hours. The cooled reaction mixture is decomposed by successive addition of 3.8 parts of water, 3.8 parts of a sodium hydroxide solution and 11.4 parts of water. The mix ture is stirred for minutes and then allowed to stand for 12 hours. The precipitate which forms is separated by filtration and dissolved in dilute hydrochloric acid. 28 parts of sodium potassium tartrate is added. The solution is alkalized and a precipitate of 4-hydroxymethyl-4-(4-tolyl)piperidine forms when chloroform is added. The product melts at about 232-233 C.

When the procedure described above is used for the reduction of 4-ethoxycarbonyl-4-(4-chlorophenyl)piperidine by lithium aluminum hydride, the product is 4-hydroxymethyl 4 (4-chlorophenyl)piperidine melting at about 218.5220.6 C.

Example 6 A mixture of 52 parts of benzyl chloride, 26.4 parts vof 4-ethoxycarbonyl 4 (4-fiuorophenyl)piperidine, 70

parts of sodium carbonate and 240 parts of toluene is refluxed for 4 hours. The cooled reaction mixture is 6 filtered and the filtrate is acidified with dilute hydrochloric acid. The acid aqueous solution is alkalized and extracted with chloroform. The organic solution is dried over sodium sulfate and distilled to give 1-benzyl-4- ethoxycarb onyl-4(4afluorophenyl piperidine.

To a suspension of 3.29 parts of lithium aluminum hydride in parts of anhydrous ether is added portionwise under a nitrogen atmosphere a solution of 29 parts of l-benzyl 4 ethoxycarbonyl-4-(4-fiuorophenyl)piperidine in 240 parts of anhydrous ether. After the addi tion is complete the mixture is refluxed for 12 hours. After cooling to 20 C. the mixture is decomposed by the portionwise addition of 20 parts of Water. The precipi tate is filtered oil and recrystallized from benzene to give l-benzyl 4 hydroxyrnethyl 4 (4-fiuorophenyl)piperidine melting at about -l50.8 C.

A solution of 18 parts of 1bcnzyl-4-hydroxymethyl- 4(4-fluorophenyl)piperidine in a mixture of 6 parts of concentrated hydrochloric acid, 48.5 parts of distilled water and parts of 2-propanol is debenzylat-e'd by catalytic hydrogenation under atmospheric pressure and at a temperature of about 3236 C. with 5.8 parts of a 10% palladium-on-charcoal catalyst. After the calculated amount of hydrogen is taken up hydrogenation is stopped and the hot solution is filtered. The solvent is distilled from the filtrate and the residue is alkalized. 4-hydroxymethyl 4 (4-tluorophenyl)piperidine precipitates. This product melts at about 202.5203.6 C.

If the above procedure is repeated with 4-ethoxycarbonyl-4-phenylpiperidine in place of 4-ethoxycarbonyl- 4--(4-fiuorophenyl)piperidine, the product is 4-hydroxymethyl-4-phenylpipericline melting at about 169.4170.2 C.

Example 7 To a mixture of 119 parts of 2-hydroxyethyl-2-hydoxypropylamine and 54 parts of sodium carbonate heated in 450 parts of water to 70 C., is added 190.5 pars of 4-toluenesufonyl chloride and the resultant mixture is heated at 95 C. for 1 hour, cooled and filtered. The filtercake is extracted with ether and the extract evaporated. The residue is taken up in 2-propanol. To this solution is added petroleum ether and the resulting solution is chilled to 20 C. The precipitate is collected and recrystallized from a mixture of ethanol and acetone to yield N-(Z-hydroxyethyl) N (2-hydroxvpropyl)-4- toluenesulfonamide melting at about 66.2-68.2 C.

A mixture of 450 parts of this compound and 690' parts of thionyl chloride is heated at 125 C. for 1 hour, cooled, and the excess thionyl chloride evaporated. The residue is taken up in dry toluene and this solution is then reduced in volume to yield N-(2-'chloroethyl)-N-(Z-chloropropyl)4-toluenesulfonamide. A solution of 400 par-ts of this compound and 152 parts of sodamide in toluene is heated to about 45 C. Then 110 parts of phenylacetonitrile is added portionwise and the resulting mixture is heated under reflux for 2 hours. After standing from 5-6 hours at room temperature, the mixture is washed with water and then evaporated. The residue is then treated with hot methanol. The resulting mixture is filtered and both the insoluble portion and the filtrate are saved. After recrystallization from butanol, the insoluble portion melts at about 2l72l8 C. and is called the [3 form of l-(4-toluenesulfonyl)3-methyl-4-phenyl- 4-cyanopiperidine. The filtrate is then concentrated to give the a form of this compound which melts at about 143.5146 C.

A mixture of 71.5 parts of the )3 form of the compound prepared above, 71.5 parts of potassium hydroxide, and 700 parts of ethylene glycol is heated at C. for 9 hours and then poured into water. The resultant suspension is filtered and the filtrate is acidified with bydrochloric acid to precipitate the B form of 1-(4-toluenesulfonyl 3 rnethyl-4-phenyl4-carboxypiperidine, which melts at about 209.52l1.4 C. The a form of 1-(4- toluenesulfonyl)3-methyl 4 phenyl 4 carboxypiperidine melting at about 173.4-175.8 C. is prepared in the same way.

A mixture of 20 parts of the ,8 form of 1-(4-toluenesulfonyl)-3-methyl-4-phenyl-4-carboxypiperidine and 225 parts of thionyl chloride is stirred until a clear solution is obtained. The excess thionyl chloride is removed and the residue is dissolved in methanol. This solution is then stirred and heated under reflux overnight and chilled at C. to give the B form of 1-(4-toluenesulfonyl)-3- methy1-4-pheny1-4-methoxycarbonylpiperidine melting at about 137.4140.3 C. The a form of this compound is prepared by using the procedure described above and melts at about 94.595.4 C.

A mixture of 78 parts of the ,8 form for l-(4-toluenesulfonyl) 3 methyl-4-phenyl-4-methoxycarbonylpiperidine, 59 parts of phenol and 500 parts of a saturated solution of hydrogen bromide in acetic acid is stirred at room temperature for about 20 hours. Ether is then added and the resulting solution is extracted with water. The aqueous layer is rendered alkaline with sodium hydroxide and the basic solution is extracted with ether. The ethereal solution is then dried and concentrated. Distillation of the residue yields the {3 form of 3-methyl-4 phenyl-4-methoxycarbonylpiperidine, which melts at about 191-l92.2 C. after purification. The a form of this compound is prepared in a similar manner.

To an emulsion of 3.79 parts of lithium aluminum hydride in 140 parts of tetrahydrofuran is added portionwise a mixture of 17 parts of 3ot-methyl-4-carbomethoxy-4- phenylpiperidine in 60 parts of tetrahydrofuran with stirring and refluxing. Refluxing is continued for an additional 6 hours before the reaction mixture is cooled and decomposed successively with 3.8 parts or" water, 3.8 parts of 15% sodium hydroxide solution and 11.4 parts of water. After standing for 12 hours the mixture is filtered. The filtrate is dried over sodium sulfate and the solvent is evaporated. The oily residue is dissolved in 200 parts of diisopropyl ether and hydrogen chloride gas is introduced into the solution. The precipitated solid is filtered off and dissolved in water and the aqueous solution is made alkaline and extracted with toluene. The organic solvent is evaporated and the solid residue is washed with 56 parts of cooled diisopropyl ether to give 3a-methyl-4-hydroxymethyl-4-phenylpiperidine melting at about 137-1389 C.

. Example 8 By substituting ethanol for methonol in the fourth paragraph of Example 7 and otherwise following the pro cedure outlined therein and also in the fifth paragraph of that example the a and #3 forms of 3-rnethyl-4-phenyl-4- ethoxycarbonylpiperidine are obtained.

To a solution of 21 parts of 3-methyl-4-ethoxycarbonyl 4-phenylpiperidine in 120 parts of tetrahydrofuran is added a suspension of 1.8 parts of lithium aluminum hydride in 80 parts of tetrahydrofuran. After refluxing the mixture for 6 hours it is cooled and decomposed by the addition of 4 parts of Water, 4 parts of 15% sodium hydroxide solution and 12 parts of water successively. The mixture is allowed to stand for 12 hours at room temperature before it is filtered. The filtrate is dried over magnesium sulfate and the solvent is evaporated. Recrystallization of the solid residue from diisopropyl ether gives 3,8-methyl-4-formyl-4-phenylpiperidine melting at about 107108.4 C.

A mixture of 8.5 parts of 3,8-methyl-4-formyl-4phenylpiperidine, 4 parts of hydrazine hydrate, 7 parts of potassium hydroxide and 40 parts of ethylene glycol is heated for 2 hours at 145-150 C. Water which forms is distilled oil and the residue is heated for 8 hours at 180-190 C. The reaction mixture is poured into Water and extracted with ether. After drying the ether solution over potassium carbonate, the solvent is evaporated. A solution of the residue in diisopropyl ether is prepared and hydrogen chloride gas is introduced into it to give 3,8,4-di- 8 methyl-4-phenylpiperidine hydrochloride melting at about 2l0.52l2 C.

Example 9 A solution of methylmagnesium iodide is prepared by the addition of 106.5 parts of methyl iodide in 48 parts of anhydrous ether to 14.5 parts of magnesium in 96 parts of ether. This solution is heated to about 70 C. and a solution of 106.5 parts of 1-(p-tosyl)-3a-methyl-4- cyano-4-phenylpiperidine in 480 parts of anhydrous toluene is added. The mixture is stirred and heated at C. for 4 hours. The cooled reaction mixture is decomposed with 300 parts of water. Three hundred parts of concentrated hydrochloric acid is added and the mixture is stirred and heated at 110 C. for 6 hours. The organic layer is separated from the cooled mixture and dried over potassium carbonate. The solvent is evaporated and the residue is recrystallized from a mixture of diisopropyl ether and benzene to give l-(4-tosyl)-3a-methyl-4-acetyl- 4-phenylpiperidine melting at about 107.5l09 C.

A mixture of 65 parts of the above sulfonamide, 49 parts of phenol, and 270 parts of a 30% solution of hydrogen bromide in acetic acid is stirred for 16 hours at room temperature. The reaction mixture is poured into 1200 parts of ether and extracted with water. The aqueous layer is separated, alkalized, and extracted. The organic solution is dried over potassium carbonate and distilled to give 3a-methyll-acetyl-4-phenylpiperidine boiling at about l34-l38 C. at 0.2 mm. pressure.

By substituting equivalent quantities of the appropriate starting materials in the above procedure, the following compounds are obtained:

3a-methyl-4-propionyl-4-phenylpiperidine boiling at about l36138 C. at 0.7 mm. pressure.

35 methyl-4-acetyl-4-phenylpiperidine hydrochloride To a solution of 10 parts of 4-acetyl-4-phenylpiperidine in 80 parts of ethanol is added over a period of 5 minutes 1.4 parts of sodium borohydride. The resultant mixture is refluxed for 1.5 hours before it is decomposed with 4 parts of 5 N hydrochloric acid. Removal of the solvent leaves a residue which is alkalized and extracted with chloroform. The chloroform solution is dried over sodium sulfate and the solvent is evaporated. After recrystallization from Z-butanone, the residue melts at -14l C. This product is 4 (l -hydroxyethyl)-4- phenylpiperidine.

If appropriate 4-acyl-4-pl1enylpiperidines are substituted for the l-acetyl-4-phenylpiperidine and the above proceddure is repeated the following compounds are obtaine 4-(1 hydroxypropyl) 4 phenylpiperidine boiling at about 153-156 C.

4-( l-hydroxybutyl)-4-phenylpiperidine melting at about 108.4-l10.2 C.

Example I] A mixture of 6.55 parts of lithium aluminum hydride in parts of ether is heated to reflux and a solution of 4% parts of 4-ethoxycarbonyl-4-phenylpiperidine in 160 parts of ether is added. The mixture is refluxed for 5 hours before it is decomposed with 6 parts of 20% sodium hydroxide solution. The precipitate is filtered off, washed with benzene and filtered again. The combined filtrates are dried over potassium carbonate and concentrated to yield 4-formyl-4-phenylpiperidine melting at about 104-105 C.

A mixture of 11 parts of 4-formyl-4-phenylpiperidine, 7 parts of hydrazine hydrate, 10 parts of potassium hydroxide, and 57 parts of ethylene glycol is heated for 3 hours at 145-180 C. After heating the mixture for an additional hour at 180 C. it is poured into water and extracted with ether. The ether extract is dried over potassium carbonate and distilled to give 4-rnethyl- 4-phenylpiperidine boiling at about 103 C. (3 mm.). It hydrogen chloride gas is passed through an ether solution of this amine, the product is 4-methyl-4-phenylpiperidine hydrochloride melting at about 240-241 C.

Example 12 A mixture of 23 parts of 4-acetyl-4-(4-chlorophenyl)- piperidine, parts of hydrazine hydrate, 100 parts of ethylene glycol and 17.5 parts of potassium hydroxide is heated for 3 hours at 145 C. The water which forms is distilled off and the residue is further heated for 10 hours at 180 C. The ethylene glycol is distilled from the reaction mixture and the residue is poured into Water and extracted With ether. The ether solution is dried over sodium sulfate and distilled to give 4-ethyl-4-(4- chlorophenyDpiperidine boiling at about 125-130 C. (2-3 mm.).

Example 13 A mixture of 16 parts of 4-acety1-4-(4-fluorophenyl)- piperidine, 7.25 parts of hydrazine hydrate, 11.2 parts of potassium hydroxide and 90 parts of ethylene glycol is heated at 195200 C. for 5 hours. 150 parts of water is added to the cooled reaction mixture. The aqueous layer is extracted with ether and the ether layer is separated, dried over potassium carbonate, and distilled to give 4- ethyl-4-(4-fiuorophenyl)piperidine boiling at about 113- 116 C. at 2 mm. pressure.

Example 14 A mixture of 296 parts of 4-ethylacetophenone, 230 parts of ethyl cyanoacetate, 100 parts of acetic acid, 40 parts of ammonium acetate and 400 parts of benzene is stirred and refluxed for 6 hours in a vessel provided with a Dean and Stark trap. After the calculated amount of Water is separated the reaction mixture is cooled and washed with 2000 parts of water. The organic layer is separated, dried over magnesium sulfate, and distilled to give ethyl 1-(4-ethylphenyl)ethylidenecyanoacetate boiling at about ISO-156 C. (0.4 mm.).

To a solution of 21 parts of sodium in 640 parts of ethanol is added 77 parts of cyanoacetamide. and the mixture is stirred for 15 minutes before 225 parts of ethyl 1-(4-ethylphenyl)ethylidenecyanoacetate is added por-tionwise. The mixture is stirred at room temperature for 70 hours before it is decomposed with 1500 parts of water and acidified with dilute hydrochloric acid. The resultant precipitate is filtered off and recrystallized from ethanol to give B-methyl-fl-(4-ethylphenyl)-a,a'-dicyanoglutarimide melting at about 219.5221 C.

A stirred mixture of 90 parts of fi-methyl-B-(4-ethylphenyl)-a,a'-dicyanoglutarimide, 594 parts of sulfuric acid, 396 parts of Water and 324 parts of acetic acid is refluxed for 96 hours. The reaction mixture is cooled and poured into 800 parts of Water. The solid which precipitates is B methyl 8 (4-ethylphenyl) glutaric acid which melts at about 137-139 C.

To a stirred solution of 22.6 parts of lithium aluminum hydride in 240 parts of tetrahydrofuran is added portionwise a solution of 72.5 parts of fi-methyl-B-(4-ethylphenyl) gluta-ric acid in 400 parts of tetrahydrofuran. This mixture is refluxed for 5 hours before it is decomposed With Water. The precipitate is filtered ofi and the solvent is evaporated from the filtrate. Recrystallization of the residue from benzene yields 3-methyl-3-(4-ethylphenyDpentane-LS-diol melting at about 82.583.5 C.

A thick long tube is charged with a mixture of parts of 3-methyl-3-(4-ethylpheny1)pentane-l,5-diol and 120 parts of 48% hydrobromic acid and cooled to -10 C. After the mixture is saturated with gaseous hydrogen bromide, the tube is sealed and the mixture is refluxed for 10 hours at 100 C. The reaction mixture is poured into water. The water is extracted with ether 10 and the resultant ether solution is dried and distilled to give 1,5-dibromo-3-methyl-3-(4-ethylphenyl)pentane boiling at about 151-153" C. (0.1 mm.).

A mixture of 20 parts of the above dibromide, 24.5 parts of benzylarnine and parts of toluene is heated in a sealed tube for 64 hours. The reaction mixture is filtered and the filtrate is washed with water. The organic layer is dried over potassium carbonate and the solvent is evaporated. The residue is dissolved in anhydrous diisopropyl ether and hydrogen chloride gas is introduced. The precipitated hydrochloride is filtered oif and heated with Water. This gives 1-benzyl-4-methyl-4- (4-ethylphenyl)piperidine hydrochloride melting at about 275-277 C.

A mixture of 14.5 parts of l-henzy1-4-methyl-4-(4- ethylphenyDpiperidine hydrochloride, 320 parts of 2-pro panel and 200 parts of distilled water is debenzylated under atmospheric pressure at room temperature in the presence of 6 parts of 10% palladium-on-charcoal catalyst. Hydrogenation is stopped after the calculated amount of hydrogen is taken up. The mixture is filtered and the solvent is evaporated. An aqueous solution of the residue is alkalized and extracted with ether. The ether solution is dried over potassium carbonate and the solvent is evaporated. The resultant residue is dis solved in diisopropyl ether and hydrogen chloride gas is introduced into the solution to precipitate 4-methyl-4 (4-ethylphenyl)'piperidine hydrochloride melting at about 261-263.2 C.

By substituting the appropriate acetophenone in the above procedure the following compounds are obtained:

4-methyl-4-(4-tolyl)piperidine hydrochloride melting at about 241.5243 C.

4-rnethyl-4-(3-tolyl)piperidine hydrochloride melting at about 2082l0 C.

4 methyl 4 (4 fluorophenyl)piperidine hydrochloride melting at about 224-2255 C.

4 methyl 4 (4 chlorophenyl) piperidine hydrochlo ride melting at about 232235 C. e

4 methyl 4 (4 bromophenyl) piperidine hydrochlo ride melting at about 258-259" C.

Example 15 A solution of phenyl lithium, prepared from 6.3 parts of lithium, 70.7 parts of bromobenzene, and parts of anhydrous ether is added portionwise to 54.8 parts of 1-benzyl-3-methyl-4-piperidone While a gentle reflux is maintained. After the addition is complete, refluxing is continued for about 2 hours. This reaction is carried out under a nitrogen atmosphere. The mixture is then decomposed by the addition of Water and the layers are separated. The aqueous layer is extracted with ether and the combined organic layer and the ether extract are dried. Hydrogen chloride gas is passed through the solution and the precipitate Which forms is collected on a filter and then dissolved in water. The aqueous solution is rendered alkaline to a pH of about 10 and the oil which forms is separated. The pH is then'adjusted to about 13 and the solution is extracted with ether. The ethereal solution is dried and then hydrogen chloride gas is passed through the solution. The salt which precipitates is recrystallized from a 6:4:1 mixture of butanone, acetone, and Z-propanol by chilling at 20 C. to yield 1-benzyl-3a-rnethyl-4-phenylpiperidin-4-o1 hydrochloride melting at about 180-183" C.

A mixture of 66.3 parts of 1-benzyl-3-methyl-4-phenylpiperidin-4-ol hydrochloride, 254.3 parts of potassium pyrosulfate and 480 parts of anhydrous Xylene is refluxed for 24 hours. A solid forms on standing. The solvent is decanted and the precipitated solid is divided between a mixture of about 2000 parts of water and 1600 parts of chloroform. The water solution is separated, alkalized, and extracted With 400 parts of chloroform. The organic solution is washed with 500 parts of 5% sodium hydroxide solution and separated. The

from the filtrate.

assen /a combined organic solutions are dried over potassium carbonate and filtered and the filtrate is concentrated to about 200 parts. The residue is diluted wtih 800 parts of ether and hydrogen chloride gas is introduced into the solution. The precipitated hydrochloride is filtered oil, washed with acetone and recrystallized from a mix ture of acetone and Z-propanol to give 1-benzyl-3-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride melting at about 239.6240.6 C.

A mixture of 30 parts of 1-benzyl-3-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine hydrochloride, 280 parts of 2-propanol and 150 parts of distilled Water is hydrogenated under atmospheric pressure and at a temperature of about 35 C. With 12 parts of a 10% palladium-oncharcoal catalyst. Hydrogenation is stopped when the calculated amount of hydrogen is taken up. The filtrate is treated with asbestos and filtered. The filtrate is concentrtaed to about 200 parts, 150 parts of Water is added and the solution is again concentrated this time to 150 parts. The residue is alkalized and saturated with ether. The ether solution is dried over potassium carbonate and hydrogen chloride gas is introduced. This gives S-methyl- Example 16 A mixture of 17.2 parts of 4-(4-chlorophenyl)-1,2,3,6- tetrahydropyridine, 320 parts of Z-propanol, 109 par-ts of water and 9 parts or" concentrated hydrochloric acid is hydrogenated under atmospheric pressure and at a temperature of about 30 C. with 15 parts of a 5% palladiumon-charcoal catalyst. After the calculated amount of hydrogen is taken up, hydrogenation is stopped and the mixture is filtered hot. The catalyst is treated with a mixture of 100 parts of Water and 160 parts of metha- 1101 at 55 C. and filtered again. The solvent is evaporated from the combined filtrates and the residue is taken up in 300 parts of Water, a-lkalized and extracted with ether. The ether is dried over potassium carbonate and filtered and hydrogen chloride gas is introduced into the The ether is evaporated from the solution and the residue is first treated With boiling acetone and then recrystallized from 2-propanol to give 4-(4-chlorophenyl) piperidine hydrochloride melting at about 197199 C.

If 4-(4-to1yl)-l,2,3,o-tetrahydropyridine is substituted for the 4-(4-chloropl1enyl)-1,2,3,6-tetrahydropyridine in the above example, the product is 4-(4-tolyl)piperidine hydrochloride melting at about 184-186 C.

Example 17 A mixture of 4.5 parts of 'y-chlorobutyrophenone, 4.2 parts of 4-acetyl-4-phenylpiperidine, 7 parts of sodium carbonate and 0.1 part of potassium iodide in 80 parts of 4-methyl-2-pentanone is refluxed for 72 hours. The reaction mixture is filtered and the solvent is evaporated The residue is dissolved in anhydrous ether and hydrogen chloride gas is introduced into the solution. The resultant precipitate is filtered off and recrystallized from 2-pnopanol to give l-(y-benzoylpropyD- 4 acetyl-4-phcnylpiperidine hydrochloride melting at about 175.6177 C. The free base of this compound has the formula OCH:

By following the above procedure and reacting 'ychlorobutyrophenone or v-chloro-4-fluorobutyrophenone with the appropriate 4-acyl-4-arylpiperidine the following compounds are obtained:

1 ('y-benzoylpropyl)-4-acetyl-4-(4-fiuorophenyl)piper idine hydrochloride melting at about 2l2214.5 C.

1 ('y benzoylpropyl)-4-acetyl-4-(4-chloropheny1)piperidine hydrochloride melting at about 210211 C.

1 [y (4-fluorobenzoyl)propyl]-4-acetyl-4-pheny1pi= peridine hydrochloride melting at about l91.5-192.8 C.

1 (4-fiuorobenzoyl)propyl]-4-acetyl-4-(4-fluorophenyl)piperidine hydrochloride melting at about 213- 215 C.

1 ['y fiuorobenzoyl)propyl1-4-acetyl-4-(4-chlorophenyl)piperidine hydrochloride melting at about 190- 190.8" C.

1 ('y benzoylpropyl)-4-propionyl-4-(4-chlorophenyl)piperidine hydrochloride melting at about 192- 193.4 C.

l ['y (4-iluorobenzoyl)propyl] -4-propionyl-4-phenylpiperdine hydrochloride melting at about l63.5164.5 C.

1 (4-fluorobenzoyl)propyl]-4-propionyl-4-(4- tolyl)piperidine hydrochloridermelting at about 162.5- 163.5 C.

1 (4-fluorobenzoyl)propyl]-4-propionyl-4-(4- chlorophenyDpiperidiue hydrochloride melting at about 16917l C.

Example 18 A mixture of 6 parts of 'y-chlorobutyrophenone, 7 parts of 4-phenyl-4-propionylpiperidine, and parts of xylene is heated in a sealed tube for 19 hours at about 120 C. The mixture is filtered and the filtrate evaporated. The oily residue is extracted With ether. Dry hydrogen chloride gas is passed through the ether solution and the solid which precipitates is collected on a filter and dried to yield 1-(' -benzoylpropyl)-4-phenyl-4-propionylpiperidine hydrochloride melting at about 176177.5 C.

Eleven parts of 4-butyryl-4-phenylpiperidine is reacted with 4.5 parts of 'y-chlorobutyrophenone according to the procedure in the above paragraph. The product is 1- (y-benzoylpropyl)-4-butyryl-4-phenylpiperidine melting at about 181-484 C.

Example 19 A mixture of 4.8 parts of 'y-chloro-4-fiuorobuty-rophenone, 4.99 parts of 4-acetyl-4-(3-chlorophenyl)piperidine, 6.4 parts of sodium carbonate and 0.1 part of potassium iodide in 120 parts of 4-methyl-2-pentanone is refluxed for 72 hours with stir-ring. The cooled reaction mixture is filtered and the solvent is evaporated from the filtrate. The residue is taken up in parts of 4 N hydrochloric acid and filtered. Cooling the filtrate to room temperature gives 1-['y-(4-iiuorobenzoyl)propyl]-4- acetyl-4-(B-chlorophenyl)piperidine hydrochloride melting at about 190.4-192" C.

If 4-acetyl-4-(3-tolyl)piperidine is substituted for the 4-acetyl-4-(3-chlorophenyl)piperidine in the above procedure, there is obtained 1-[ y-(4-fluorobenzoyl)propy1]- 4-acetyl-4-(3-tolyl)piperidine hydrochloride melting at about 174-175" C.

Example 20 Substitution of 4-acetyl-4-(3-tolyl)piperidine for the 4- acetyl-4-(4atolyl)piperidine in the above procedure gives l-(w benzoylpropyl)-4-acetyl-4-(3-tolyl)piperidine rne1ting at about 95.8-96.2 C.

Example 21 A mixture of 5.2 parts of 'y-chloro-4-fluorobutyrophenone, parts of 4-acetyl-4-(4-tolyl)piperidine, 7.3 parts of sodium carbonate and 0.1 part of potassium iodide in 150 parts of 4-rnethyl-2-pentanone is refluxed for 72 hours with stirring. The reaction mixture is filtered and the solvent is evaporated from the filtrate. The oily residue is dissolved in 24 parts of 2-propanol and mixed with a solution of 2.1 parts of oxalic acid dihydrate in 40 parts of 2-propanol. The mixture is first boiled and subsequently cooled to room temperature and the solid which precipitates is recrystallized from 2-propanol to give 1- (4 fluorobenzoyl)propyl] 4 acetyl 4 (4- toly-l)piperidine oxalate melting at about 90-100" C. with decomposition.

Substitution of 3-methyl-4-acetyl-4-phenylpiperidine for the 4-acetyl-4 (4-tolyl)piperidine in the above procedure gives 1-[' -(4-fluorobenzoyl)propyl]-3-methyl-4- acetyl-4-phenylpiperidine oxalate melting at about 165- 167.6" C.

If 3-methyl-4 propionyl-4-phenylpiperidine is substituted for the 4-acetyl-4-(4-tolyl)piperidine in the above procedure there is obtained 1-['y-(4-fluorobenzoyl)propyl]-3-methyl-4-propionyl-4-phenylpiperidine oxalate melting at about 184.2186.4 C.

When the above procedure is repeated with 'y-chlorobutyrophenone and 3 methyl 4-propionyl-4-phenylpiperidine as the reactants, there is obtained l-(y-benzoylpropyl)-3-methyl-4-propionyl-4-phenylpiperidine oxalate melting at about 162-163 C.

Example 22 piperidine hydrochloride melting at about l95196.4 C.

Substitution of 'y-chloro-4-fluorobutyrophenone for the 'y-chlorobutyrophenone in the above procedure gives 1- ['y (4 fluorobenzoyDp-ropyl] 3 methyl 4 acetyl- 4-phenylpiperidine hydrochloride melting at about 213.5-

Example 23 A mixture of 4.5 parts of 'y-chlorobutyrophenone, 9.5 parts of 4-phenyl-4-formylpiperidine, 0.1 part of potassium iodide and 100 parts of toluene is heated in a sealed tube at about 150 C. for 72 hours. The cooled miX- ture is filtered and the solvent is evaporated from the filtrate. The residue is dissolved in ether and filtered to remove impurities. The filtrate is saturated with hydro gen chloride gas and the solid which precipitates is collected on a filter, recrystallized from 2-pr-opanol and dried to yield the hydrochloride of 1-( benzoylpropyl)-4-phenyl-4-formylpiperidine melting :at about 196197.9 C.

By substituting -chloro-4-fluorobutyrophenone for the -y-chlorobutyrophenone in the above example, there is obtained 1- ['y-(4-fluorobenzoyl) propyl] -4-phenyl-4-formylpiperidine hydrochloride melting at about 195-1968 C.

The free base of this compound has the formula Example 24 A mixture of 7 parts of -chloro-4-fluorobutyrophenone, 4.6 parts of 3B,4-dimethyl-4-phenylpiperidine, 8 parts of sodium carbonate and 0.1 part of potassium iodide in parts of 4-methyl-2-pentanone is refluxed for 78 hours. The reaction mixture is filtered and the solvent is evaporated from the filtrate. The residue is dissolved in anhydrous diisopropyl ether and hydrogen chloride gas is introduced into the solution. This precipitates the 1-['y-(4fluorobenzoyl)propyl]-3;3,4-dimethy-l-4-phenylpiperidine hydrochloride which melts at about 189-192 C. after recrystallization from a 1:1 mixture of 2-propanol and acetone.

By substituting the appropriate star-ting materials in the above procedure the following compounds are obtained:

1-( benzoylpropyl)-3 8,4-dimethyl-4-phenylpiperidine hydrochloride melting at about 208.5-210 C.

1 (7 benzoylpropyl)-3fl-methyl-4-formyl-4-phenylpiperidine hydrochloride melting at about 214-215 C.

1 ['y (4-fluorobenzoyl)propyl]-3B-methyl-4-formyl- 4-phenylpiperidine hydrochloride melting at about 202- 204 C.

1 ['y (2 thenoyl)propyl]-4-formy1-4-phenylpiperidine hydrochloride melting at about 214-215 .5 C. after recrystallization from 2-propanol.

Example 25 A mixture of 4 parts of y-chloro-4-fluorobutyrophenone, 4 parts of 4-hydroxymethyl-4-(4-chlorophenyl)- piperidine, 6.4 parts of sodium carbonate and 0.1 part of potassium iodide in 200 parts of 4-methyl-2-pentanone is refluxed for 72 hours. The reaction mixture is filtered and the filtrate is concentrated and cooled. The precipitated solid is recrystallized from 2-propanol to give 1- (4 fluorobe-nzoyl)propyl]-4-hydroxymethyl-4-(4- chlorophenyD-piperidine melting at about 126-127 C. This compound has the formula 0 r--ii-omomom-U By substituting the appropriate starting materials in the above procedure the following compounds are obtained:

1-[v-(4-fluorobenzoyl)propyl] 4 hydroxymethyl-4- (4-tolyl)piperidine melting at about 106-108 C.

l-(y-benzoylpropyl)-4-hydroxymethyl-4 phenylpiperdine melting at about 127.6-l28.6 C.

Example 26 A mixture of 4.2 parts of -chlorobutyrophenone, 4.8 parts of 4-(4-fiuorophenyl)-4-hydroxymethylpiperidine, 10 parts of sodium carbonate, 0.1 part of potassium iodide and 240 parts of 4-methyl-2-pentanone is refluxed vfor 32 hours and then filtered. The solvent is evaporated from the filtrate and the residue is triturated with ether. The solid which forms is collected on a filter and recrystallized from a 2:1 mixture of benzene and ether. The white granular powder of l-( -benzoylpropyl)-4-(4-fluorophenyl)-4-hydroxymethylpiperidine melts at about 128.8- l30.6 C. The hydrochloride of this compound is formed by passing dry hydrogen chloride gas through an ethereal solution of the base and then collecting the precipitate.

By substituting the appropriate starting material in the above procedure the following compounds are obtained:

1(y-benzoylpropyl)-4-(4-to1yl) 4 -hydroxymethylpiperidine melting at about 147-l47.8 C.

l-['y-(4-fiuorobenzoyl)propyl]-4-phenyl 4 hydroxymethylpiperidine melting at about 95.4-96.l C.

1-[ -(4-fluorobenzoyl)propyl]-4-(4-fluorophenyl 4 hydroxymethylpiperidine melting at about 126.5128.4 C.

CHzOH drogen chloride gas is passed through the filtrate.

1- ['y- (4-fiuorobenzoyl) propyl] -4-phenyl-4- (l-hydroxybutyl)piperidine hydrochloride melting at about 89- l01.8 C.

Example 27 4-methyl-4-(4-fiuorophenyl)piperidine is obtained from 4.5 parts of the corresponding hydrochloride by dissolving the salt in water, alkalizing the solution, extracting with ether, and evaporating the solvent from the other solution. The resultant crude base is refluxed for 60 hours with 4 parts of 'y-chloro-4-fiuorobutyrophenone 4.7 parts of sodium carbonate and 0.1 part of potassium iodide in 120 parts of 4-methyl-2-pentanone. The cooled reaction mixture is filtered and the solvent is evaporated from the filtrate. The residue is dissolved in diisopropyl ether and hydrogen chloride gas is introduced into the solution. The precipitated hydrochloride is recrystallized from a mixture of acetone and 2-propanol to give 1- ['y- (4-fiuorobenzoyl propyl] -4-methyl-4- l-fluorophenyl)piperidine hydrochloride melting at about 218- 219 C.

By following the above procedure and reacting 'ychloro-4-fiuorobutyrophenone with the appropriate piperidine the following compounds are obtained:

1-[ -(4-fiuorobenzoyl)propyl]-4-methyl 4 (4-chlorophenyl)piperidine hydrochloride melting at about 218- A mixture of 9.2 parts of v-chlorobutyrophenone, 14.9

parts of 4-phcnylpiperidine, 0.01 part of potassium iodide,

and 120 parts of toluene is heated in a sealed tube for 72 hours at about l40-150 C. After cooling the mixture is partitioned between water and ether and then separated. The ethereal layer is dried over potassium carbonate and filtered. Dry hydrogen chloride is passed through the filtrate. The precipitate formed is recrystallized from a 3:2 mixture of acetone and 2-propanol to yield l-(v-benzoylpropyl)-4-phenylpiperidine hydrochloride melting at about 198-200 C. The compound has the formula Example 29 A mixture of 6.2 parts of 'y-chlorobutyrophenone, 6.4

' parts of 4-(4-tolyl)piperidine, 11 parts of sodium carbohate, and 120 parts of 4-methyl-2-pentanone is refluxed for 90 hours, and filtered. The filtrate is diluted with ether to a volume of about 800 parts and filtered. Hy-

The

id solid precipitated is collected on a filter, crystallized from acetone, and dried to yield l-('y-benzoylpropyD-4-(4- tolyUpiperidiue hydrochloride melting at about 174- 176" C.

Example 30 The free base of 4-(4-chlorophenyl)piperidine hydrochloride is liberated by dissolving 6.25 parts of the salt in water and rendering the solution alkaline. The solution is extracted with ether. The ether extract is dried and evaporated. The residue is refluxed with 5.5 parts of 'y-chlorobutyrophenone, 8.5 parts of sodium carbonate, 0.01 part of potassium iodide, and 100 parts of 4-rncthyl- Z-pentanone for hours with stirring. The mixture is filtered While hot and the filtrate is chilled at -20 C. to yield a precipitate. After drying, the White amorphous powder of 1('y-benzoylpropyl)-4-(4-chlorophenyl)piperidine melts at about 100.4102.2 C. The filtrate is then diluted with anhydrous ether. Dr hydrogen chloride gas is passed through the solution to yield a precipitate which is collected on a filter. After drying, the hydrochloride of l-(y-benzoylpropyl) 4- (4 chlorophenyl)piperidine melts at about 190-19? C.

Example 31 The base of 4-(Z-methoxyphenyl)piperidine hydrochloride is liberated by dissolving 9.5 parts of the salt in water, rendering the solution alkaline, and extracting the free base with toluene. The toluene solution is dried and evaporated to about 50 parts. This solution, 3.8 parts of 'y-chlorobutyrophenone, 0.01 part of potassium iodide, and parts of toluene are heated in a sealed tube for 70 hours at about C. and then filtered. To the filtrate is added 400 parts of ether. The mixture is Washed with water, dried, and filtered. Dry hydrogen chloride gas is passed into the filtrate. The precipitate is cohected on a filter, crystallized from a 5:2 mixture of acetone and ethanol by chilling at 20 C., and dried to yield the pale-yellow, micrmcrystalline powder of 1-('ybenzoylpropyl) 4 (Z-rnethoxyphenyl)piperidine hydrochloride melting at about l57l58.4 C.

Example 32 The base of 4-phe'nylpiperidine hydrochloride is liberated by dissolving 12 parts of the salt in water and rendering the solution alkaline. The base is then extracted with ether. The ethereal extract is dried over potassium carbonate and evaporated. The residue, 6 parts of -chloro-4-fluorobutyrophenone, 0.01 part of potassium iodide, and 80 parts of toluene is heated in a sealed tube for 72 hours at about C. The mixture is partitioned between Water and ether and then separated. The organic solution is washed with water, dried over potassium carbonate, and filtered. Dry hydrogen chloride gas is passed through the filtrate. The solvent is evaporated and the residue triturated with 3:1 mixture of acetone and 2-propanol. This solution is chilled at 20 C. and filtered. The filtrate is evaporated. The residue is dissolved in a 5:1 mixture of acetone and 2-propanol. After chilling at 20 C. the precipitated solid is collected on a filter and dried to yield the brown amorphous powder of 1-['y-(4-fiuorobenzoyl)propyl]-4-phenylpiperidine hydrochloride melting at about 231-232.3 C. With decomposition.

Example 33 A mixture of 6.9 parts of 'y-chloro-4-fiuorobutyrophenone, 6.4 parts of 4-(4-tolyl)piperidine, 11 parts of sodium carbonate, and 120 parts of 4-methyl-2-pentanone is refluxed for 90 hours. The mixture is filtered and the filtrate is evaporated. The residue is dissolved in anhydrous ether. Hydrogen chloride gas is passed through the solution and the precipitated solid is collected on a filter, dissolved in a 10:1 mixture of acetone and Z-propanol, decolo rized with activated charcoal, and cooled to yield the shiny crystals of 1-['y-(4-fiuorobenzoyl)propyl]-4-(4 tolyl)piperidine hydrochloride melting at about 240.3- 242 C. The compound has the formula Example 34 The free base of 4-(4-chlorophenyl)piperidine is liberated by dissolving 6.2 parts of the salt in water and rendering the solution alkaline. The base is then extracted with ether. The ethereal extract is dried over potassium carbonate and evaporated. The residue, 6 parts of -chloro-4fiuorobutyrophenone, 8.5 parts of sodium carbonate, 0.01 part of potassium iodide, and 100 parts of 4-methyl-2-pentanone is refluxed with stirring. The mix ture is filtered while hot. The filtrate is chilled at 20 C. to yield a precipitate. After drying, the yellow crystalline powder of 1-['y-(4-fluorobenzoyl)propyl]4-(4-chlorophenyl)piperidine melts at about 98.5-l01 C.

Example 35 The free base of 9.5 parts of 4-(2-methoxyphenyl)piper-idine hydrochloride is liberated by dissolving 9.5 parts of the salt in an aqueous solution and rendering the solution alkaline. The base is extracted with toluene. The toluene extract is dried over potassium carbonate, and evaporated to a volume of about 50 parts. The residue, 4.2 parts of 'y-chloro-4-fluor'obutyrophenone, 0.01 part of potassium iodide, and 100 pants of toluene are heated in a sealed tube at about 120 C. for about 70 hours and then filtered. To the filtrate is added 400 parts of ether. The organic mixture is washed with water and dried over potassium carbonate. Dry hydrogen chloride gas is then introduced into the solution. The precipitated solid is collected on a filter and crystallized from a 25:2 mixture of acetone and Z-propanol. The pale-yellow, crystalline powder of 1-[ -(4-fluorobenzoyl)propyl]4-(2-methoxyphenyl)pipe-ridine hydrochloride melts at about 215- 216 C.

By substituting 'y,2-dichlorobutyrophenone for 'ych loro- 4-fluorobutyrophenone in the above procedure, l-[y-(Z- chlorobenzoyl)propyl] 4 (2 methoxyphenyDpiperidine hydrochloride is obtained. Likewise, by substituting 6 parts of 'y-chloro-4-brcmobutyrophenone for 4.2 parts of 'y-chloro-4-fluorobutyrophenone in the above procedure, 1-['y-(4-bromobenzoyl)propyll-4-(Z-methoxyphenyl)piperidine hydrochloride is obtained. The compound has the formula Example '6 A mixture of 5.5 parts of y-chlorobutyrophenone, 4.5 parts of 4-methyl-4-phenylpiperidine, 8.2 parts of sodium carbonate, 0.01 part of potassium iodide, and 80 parts of .4-methyl-2-pentanone is refluxed for about 70 hours. The mixture is filtered. The filtrate is evaporated and the residue is dissolved in anhydrous ether. Dry hydrogen chloride gas is passed through the filtrate. The precipitated solid is collected on a filter, crystallized from 2-propanol, and dried to yield the white amorphous powder of l-( y-benzoylpropyl) 4 methyl 4 phenylpiperidine hydrochloride melting at about 208-209.5 C.

By substituting the appropriate starting material in the above procedure, the following compounds are obtained:

l-(y-benzoylbutyl) 4 methyl 4 phenylpiperidine hydrochloride melting at about 2165-2187 C.

1-['y-(4-fluorobenzoyl)propyl] 4 methyl 4 phenylpiperidine hydrochloride melting at about 235 .5-236.5 C.

1-['y-(4-metl1oxybenzoyl)propyl] 4 methyl-4-phenylpiperidine hydrochloride melting at about 2l2-213 C.

l-(y-benzoylpropyl) 4 (4-methoxypheny1)piperidine hydrochloride melting at about 190-193 C.

18 1-[' -(4-fiuorobenzoyl)propyl] 4 (4-methoxyphenyl) piperidine hydrochloride melting at about 20l.5-2()3 C.

1-[w-(3-methoxybenzoyl)propyl] 4 methyl-4-phenylpiperidine hydrochloride.

Example 37 A mixture of 3.6 parts of y-chlorobutyrophenone, 4 parts of 4-ethyl-4-phenylpiperidine hydrochloride, 7.7 parts of sodium carbonate, and parts of 4-meth'yl-2- pentan'one is refluxed for 64-90 hours and filtered. The filtrate is evaporated and the residue is dissolved in anhydrous ether. Dry hydrogen chloride gas is passed through the solution. The precipitated solid is crystallized from a mixture of 2-propanol and acetone to yield the white amorphous powder of 1-('y-benzoylpropyl)-4- ethyl-4-phenylpiperidine hydrochloride melting at about 186-187 C.

Example 38 By substituting 4.3 parts of 'y-chloro-4-fluorobutyrophenone for 3.6 parts of -chlorobutyrophenone and 6.6 parts for 7.7 parts of sodium carbonate in the procedure of Example 37, thepale yellow crystalline powder of 1-[ y (4-fluorobenzoyl)propyl] 4 ethyl-4-phenylpiperidine hydrochloride melting at about 1985-1995 C. is obtained. The compound has the formula CHa-OHa Example 39 A mixture of 3.68 parts of 'y-chloro-4-fluorobutyrophenone, 3.4 parts of 4-ethyl-4-(4-fluorophenyl)piperidine, and 200 parts of 4-methyl-2-pentanone is heated 72 hours, cooled, and filtered. The filtrate is evaporated and the residue is dissolved in ether. Dry hydrogen chloride gas is passed through the ether solution. The precipitated solid is crystallized twice from a mixture of acetone and ether to give l-[ -(4-fiuorobenzoyl)- propyl]-4-ethyl 4 (4-fluorophenyl)piperidine hydrochloride melting at about 192.2-194.6 C.

Example 40 A mixture of 5.8 parts of y-chloro4-fiuorobutyropheuone, 6 parts of 4-ethyl-4-(4-chlorophenyl)piperidine, 0.01 part of potassium iodide, and parts of 4-methyl-2- pentanone is refluxed for 3 days with stirring. After cooling, the mixture is filtered and the filtrate is evaporated. The residue is dissolved in anhydrous ether and filtered to remove impurities. Dry hydrogen chloride is passed through the filtrate. The solid precipitate is collected on a filter and crystallized first from 2-propanol and then from water to yield the white amorphous powder of 1-['y-(4-fiuorobenzoyl)propyl] 4 ethy1-4-(4-chlorophenyl)piperidine hydrochloride melting at about 177.5- 179.5 C.

Example 41 the layers are separated. The ether layer is dried and filtered. Hydrogen chloride gas is passed through the filtrate. The solid precipitated is collected on a filter, boiled in a 25:8 mixture of acetone and 2-propanol, once again collected on a filter, and dried to yield l-(y-benzoylpropyl) 3-methyl 4 phenylpiperidine hydrochloride melting at about 2l4.2-215.2 C.

3 9 Example 42 The base of 3-methyl-4-phenylpiperidine hydrochloride is liberated in a manner similar to that described in Example 41 and the residue, 6.6 parts of 'y-chloro-4-fiuorobutyrophenone, 9.5 parts ofsodium carbonate, 0.01 part of potassium iodide, and 1% parts of 4-methyl-2pentanone is refluxed for 64 hours and cooled. The mixture is partitioned between water and ether and the layers are separated. The ether solution is diluted to a total volume of 600 parts, dried over potassium carbonate, and filtered. Hydrogen chloride gas is passed through the filtrate. After evaporation, the residue is treated with acetone to yield a solid which is crystallized by boiling in a :1 mixture of acetone and 2-propanol. The white amorphous powder of 1-[- -(4-fiuorobenzoyl)propyl]-3- rnethyl-4-phenylpiperidine hydrochloride melts at about 2l4-215.4 C.

Example 43 The free base of 3wmethyl-4-(S-trifluoromethylphenyD-piperidine hydrochloride is liberated as described above. The residue, 6.6 parts of 'y-chloro-4-fluorobutyrophenone, 7.4 parts of sodium carbonate, 0.0 1 part of potassium iodide, and 120 parts of 4-methyl-2-pentanone is refluxed for 40 hours and then cooled. The mixture is partitioned between water and ether and separated. The ethereal solution is dried over potassium carbonate and filtered. Hydrogen chloride gas is passed through the filtrate. The precipitated solid is collected on a filter and saved. The filtrate is evaporated. The residue and the solid are combined, triturated with hot acetone, and filtered. The filtrate is concentrated to about 50 parts to induce precipitation of l-['y-(4-fluorophenyl)- propyll 30c methyl 4 (3 trifluorornethylphenyD- piperidine hydrochloride melting at about 212.2214.4 C.

By substituting 'y,3-dichlorobutyrophenone for 'y-chloro- 4-fiuor-obutyrophenone in the above procedure, the prodnot obtained is 1'['y-(3-chlorophenyl)propyl]Got-methyl- 4-(3-trifluoromethylphenyl)piperidine hydrochloride.

Example 44 A mixture of 9.4 parts of 2-( -ch1orobutyryl)thiophene, 14.9 parts of 4-phenylpiperidine, 0.01 part of potassium iodide, and 150 parts of toluene is heated in a sealed tube for 72 hours at about Mil-150 C. and cooled. The mixture is then partitioned between ether and water and separated. The ether layer is dried over potassium carbonate. Dry hydrogen chloride gas is passed through the solution. The precipitate formed is dissolved in a hot mixture of 2-propanol and acetone and then allowed to stand overnight at room temperature to yield a precipitate. This precipitate is dried to yield the white amorphous powder of 1-['y-(2-thenoyl)propyl]-4-phenylpiperidine hydrochloride melting at about 209-2l05 C. The compound has the formula What is claimed is: l. A compound of the formula fewer than 9 carbon atoms, anisyl, and trifiuorornethylphenyl; R is a member of the group consisting of hydrogen, lower alkyl, hydroxy(lower alkyl), CHO, and

II --C-(lower alkyl) and X is a member of the group consisting of hydrogen and methyl.

2. A compound of the formula 3. 1 (4 fluorobenzoyDpropyl] 4 methyl 4- phenylpiperidine.

4. 1 (4 fluorobenzoyDpropyl] 4 ethyl 4- (lower alkyl) phenylpiperidine.

5. A compound of the formula 0 (lower allryl) Q" F- O-CHaOHzCHz-N halogen 6. 1 ['y (4 fiuorobenzoyl)propyl] 4 methyl- 4- (4-fiuorophenyl) pip eridine.

7. A compound of the formula halogen 11. 1 [v (4 fluorobenzoyDpropyl] 4 propionyl- 4-phenylpiperidine.

12. 1 ['y (4 fiuorobenzoyDpropyl] 4 acetyl 4- phenylpiperidine.

13. A compound of the formula 0 II r-Qm-omomom-u halogen 14. 1 ['y (4 fluorobenzoyhpropyll 4 acetyl 4- (4-chlorophenyl)piperidine.

15. 1 ['y (4 fiuorobenzoyl)propyl] 4 acetyl 4- 4-fiu0rophenyl pip eridine.

16. A compound of the formula 0 ll F-QC-OfizCHaCHr-N halogen 17. 1 ['y (4 fluorobenzoyUpropyl] 4 hydroxymethyl-4 4-chlorophenyl pip eridine.

II C (lower alkyl) i? O-(lower alkyl) CHzOH No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 080 372 March 5 1963 Paul A. J Janssen It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 54 for "hynotic" read hypnotic column 4 line 58 for "0t" read to column 6, line 35, for "-2-hydoxy" read 2hydroxyline 38 for "4- toluenesufonyl" read 4-toluenesulfonyl column 7, line 4.7,, for "'methonol read methanol column 11 lines 17 and l8 for "concentrtaed" read concentrated column 12' line 1 .1. for "-fluorobenzoyl)" read ----(4-fluorobenzoyl) line 63. for "-chlorobutylrophenone'" read -chlorobutyrophenone Signed and sealed this 31st day of March 1964..

(SEAL) Attest: EDWARD J. BRENNER Attesting Officer

Claims (1)

1. A COMPOUND OF THE FORMULA
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Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3209006A (en) * 1959-05-01 1965-09-28 May & Baker Ltd Phenylpiperidine and phenyltetrahydropyridine compounds
US3242170A (en) * 1962-01-30 1966-03-22 Bochringer Ingelheim G M B H 1-(phenyl-hydrocarbyl)-4-hydroxy-phenyl-4-carbalkoxy-piperidines
US3259624A (en) * 1961-09-06 1966-07-05 Bristol Myers Co Novel heterocyclic ketones
US3306895A (en) * 1962-06-27 1967-02-28 Richardson Merrell Inc Heterocyclic derivatives of triphenylethylenes, triphenylethanes and triphenylethanols
US3310566A (en) * 1963-11-18 1967-03-21 American Home Prod Substituted 4-piperidino-butyrophenone oximes
US3324139A (en) * 1963-09-18 1967-06-06 Tanabe Seiyaku Co 3-(3-hydroxyphenyl)-1-phenacylpiperidine compounds
US3424755A (en) * 1964-03-09 1969-01-28 Rolf Denss 4-piperidine-p-fluorobutyrophenones and related compounds
US3458521A (en) * 1964-08-05 1969-07-29 Allen & Hanburys Ltd 4-phenylpiperidine derivatives
US3511915A (en) * 1967-01-24 1970-05-12 Geigy Chem Corp Method of producing an antitussive effect
US3689492A (en) * 1965-09-10 1972-09-05 Hans Detlef Schroeder 1-{8 4{40 -OXO-4-(p-FLUOROPHENYL)-n-BUTYL-1{40 {9 -4-ACETYL-4-(m-HYDROXY-PHENYL-PIPERIDINE
US3862173A (en) * 1972-01-28 1975-01-21 Richardson Merrell Inc Olefinic 4-substituted piperidino derivatives
US3907812A (en) * 1969-07-16 1975-09-23 Sumitomo Chemical Co Butyrophenone derivatives
US3936468A (en) * 1969-10-27 1976-02-03 Sumitomo Chemical Company, Ltd. Phenylbutanol derivatives
US3965257A (en) * 1972-01-28 1976-06-22 Richardson-Merrell Inc. Compositions and methods for the treatment of the symptoms of histamine induced allergic reactions
US4081450A (en) * 1974-09-06 1978-03-28 Eli Lilly And Company 1,3,4-Trisubstituted-4-arylpiperidines and their preparation
US4146629A (en) * 1974-12-17 1979-03-27 Delmar Chemicals Limited 4-arylpiperidine derivatives
US4191771A (en) * 1974-09-06 1980-03-04 Eli Lilly And Company Analgesic method using 1,3,4-trisubstituted-4-arylpiperidines
FR2442836A1 (en) * 1978-11-29 1980-06-27 Lilly Co Eli 1,2,4,5-tetra-alkyl-4-arylpiperidines, their preparation and their therapeutic use
FR2468592A1 (en) * 1979-10-27 1981-05-08 Richardson Merrell Inc News (alkyl-4-aroyl-4-piperidino) -4 helpful butyrophenones such as antipsychotic medications, processes and intermediates for their preparation and therapeutic compositions and dosage forms containing them
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US4284636A (en) * 1979-09-04 1981-08-18 Richardson-Merrell Inc. Cinnamoylpiperidinobutyrophenone antipsychotic agents
US4303663A (en) * 1974-04-18 1981-12-01 Sumitomo Chemical Company, Limited Butyrophenone compounds
US4485109A (en) * 1982-05-07 1984-11-27 E. I. Du Pont De Nemours And Company 4-Aryl-4-piperidinecarbinols
US4550116A (en) * 1983-08-05 1985-10-29 Fordonal, S.A. Piperidine derivatives
EP0337167A1 (en) * 1988-03-28 1989-10-18 The Du Pont Merck Pharmaceutical Company 4-Aryl-4-piperidine (or pyrrolidine or hexahydroazepine) carbinols and heterocyclic analogs thereof
US5019650A (en) * 1988-03-28 1991-05-28 E. I. Du Pont De Nemours And Company 4-aryl-4-piperidine (or pyrrolidine or hexahydroazepine) carbinols and heterocyclic analogs thereof
US5086063A (en) * 1988-03-28 1992-02-04 Du Pont Merck Pharmaceutical Company 4-aryl-4-piperidine (or pyrrolidine or hexahydroazepine) carbinols and heterocyclic analogs thereof
US5364867A (en) * 1992-11-30 1994-11-15 Sterling Winthrop Inc. 4-phenylpiperdine agents for treating cns disorders
US5512584A (en) * 1991-04-16 1996-04-30 Basf Aktiengesellschaft 1,3,4-trisubstituted piperidine derivatives, the preparation and use thereof
US6825217B2 (en) 2001-10-16 2004-11-30 Endo Pharmaceuticals, Inc. Carbinols for the treatment of neuropathic dysfunction
US20070293499A1 (en) * 2006-05-18 2007-12-20 Mannkind Corporation Intracellular Kinase Inhibitors
US20090186893A1 (en) * 2007-06-08 2009-07-23 Mannkind Corporation IRE-1alpha INHIBITORS
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Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3209006A (en) * 1959-05-01 1965-09-28 May & Baker Ltd Phenylpiperidine and phenyltetrahydropyridine compounds
US3259624A (en) * 1961-09-06 1966-07-05 Bristol Myers Co Novel heterocyclic ketones
US3242170A (en) * 1962-01-30 1966-03-22 Bochringer Ingelheim G M B H 1-(phenyl-hydrocarbyl)-4-hydroxy-phenyl-4-carbalkoxy-piperidines
US3306895A (en) * 1962-06-27 1967-02-28 Richardson Merrell Inc Heterocyclic derivatives of triphenylethylenes, triphenylethanes and triphenylethanols
US3324139A (en) * 1963-09-18 1967-06-06 Tanabe Seiyaku Co 3-(3-hydroxyphenyl)-1-phenacylpiperidine compounds
US3310566A (en) * 1963-11-18 1967-03-21 American Home Prod Substituted 4-piperidino-butyrophenone oximes
US3424755A (en) * 1964-03-09 1969-01-28 Rolf Denss 4-piperidine-p-fluorobutyrophenones and related compounds
US3458521A (en) * 1964-08-05 1969-07-29 Allen & Hanburys Ltd 4-phenylpiperidine derivatives
US3689492A (en) * 1965-09-10 1972-09-05 Hans Detlef Schroeder 1-{8 4{40 -OXO-4-(p-FLUOROPHENYL)-n-BUTYL-1{40 {9 -4-ACETYL-4-(m-HYDROXY-PHENYL-PIPERIDINE
US3511915A (en) * 1967-01-24 1970-05-12 Geigy Chem Corp Method of producing an antitussive effect
US3907812A (en) * 1969-07-16 1975-09-23 Sumitomo Chemical Co Butyrophenone derivatives
US3936468A (en) * 1969-10-27 1976-02-03 Sumitomo Chemical Company, Ltd. Phenylbutanol derivatives
US3862173A (en) * 1972-01-28 1975-01-21 Richardson Merrell Inc Olefinic 4-substituted piperidino derivatives
US3965257A (en) * 1972-01-28 1976-06-22 Richardson-Merrell Inc. Compositions and methods for the treatment of the symptoms of histamine induced allergic reactions
US4303663A (en) * 1974-04-18 1981-12-01 Sumitomo Chemical Company, Limited Butyrophenone compounds
US4081450A (en) * 1974-09-06 1978-03-28 Eli Lilly And Company 1,3,4-Trisubstituted-4-arylpiperidines and their preparation
US4191771A (en) * 1974-09-06 1980-03-04 Eli Lilly And Company Analgesic method using 1,3,4-trisubstituted-4-arylpiperidines
DK153397B (en) * 1974-09-06 1988-07-11 Lilly Co Eli Analogifremgangsmaade for the preparation of 1,3,4-tri-substituted 4-arylpiperidines, or pharmaceutically acceptable acid addition salts thereof
US4146629A (en) * 1974-12-17 1979-03-27 Delmar Chemicals Limited 4-arylpiperidine derivatives
EP0013078A2 (en) * 1978-11-29 1980-07-09 Eli Lilly And Company 1,2,4,5-Tetra-alkyl-4-arylpiperidines, their production and pharmaceutical preparations containing same
EP0013078A3 (en) * 1978-11-29 1980-10-01 Eli Lilly And Company 1,2,4,5-Tetra-alkyl-4-arylpiperidines, their production and pharmaceutical preparations containing same
US4284635A (en) * 1978-11-29 1981-08-18 Eli Lilly And Company Analgesic 1,2,4,5-tetra-alkyl-4-arylpiperidines
FR2442836A1 (en) * 1978-11-29 1980-06-27 Lilly Co Eli 1,2,4,5-tetra-alkyl-4-arylpiperidines, their preparation and their therapeutic use
US4284636A (en) * 1979-09-04 1981-08-18 Richardson-Merrell Inc. Cinnamoylpiperidinobutyrophenone antipsychotic agents
US4283404A (en) * 1979-09-04 1981-08-11 Richardson-Merrell Inc. Aroylethenylpiperidinobutyrophenone antipsychotic agents
FR2468592A1 (en) * 1979-10-27 1981-05-08 Richardson Merrell Inc News (alkyl-4-aroyl-4-piperidino) -4 helpful butyrophenones such as antipsychotic medications, processes and intermediates for their preparation and therapeutic compositions and dosage forms containing them
US4485109A (en) * 1982-05-07 1984-11-27 E. I. Du Pont De Nemours And Company 4-Aryl-4-piperidinecarbinols
US4550116A (en) * 1983-08-05 1985-10-29 Fordonal, S.A. Piperidine derivatives
EP0337167A1 (en) * 1988-03-28 1989-10-18 The Du Pont Merck Pharmaceutical Company 4-Aryl-4-piperidine (or pyrrolidine or hexahydroazepine) carbinols and heterocyclic analogs thereof
US5019650A (en) * 1988-03-28 1991-05-28 E. I. Du Pont De Nemours And Company 4-aryl-4-piperidine (or pyrrolidine or hexahydroazepine) carbinols and heterocyclic analogs thereof
US5086063A (en) * 1988-03-28 1992-02-04 Du Pont Merck Pharmaceutical Company 4-aryl-4-piperidine (or pyrrolidine or hexahydroazepine) carbinols and heterocyclic analogs thereof
US5512584A (en) * 1991-04-16 1996-04-30 Basf Aktiengesellschaft 1,3,4-trisubstituted piperidine derivatives, the preparation and use thereof
US5364867A (en) * 1992-11-30 1994-11-15 Sterling Winthrop Inc. 4-phenylpiperdine agents for treating cns disorders
US6825217B2 (en) 2001-10-16 2004-11-30 Endo Pharmaceuticals, Inc. Carbinols for the treatment of neuropathic dysfunction
US20050026956A1 (en) * 2001-10-16 2005-02-03 Endo Pharmaceuticals, Inc., A Delaware Corporation Carbinols for the treatment of neuropathic dysfunction
US20070293499A1 (en) * 2006-05-18 2007-12-20 Mannkind Corporation Intracellular Kinase Inhibitors
US8604031B2 (en) 2006-05-18 2013-12-10 Mannkind Corporation Intracellular kinase inhibitors
US20110065162A1 (en) * 2007-06-08 2011-03-17 Mannkind Corporation IRE-1alpha INHIBITORS
US7858666B2 (en) 2007-06-08 2010-12-28 Mannkind Corporation IRE-1α inhibitors
US20090186893A1 (en) * 2007-06-08 2009-07-23 Mannkind Corporation IRE-1alpha INHIBITORS
US8614253B2 (en) 2007-06-08 2013-12-24 Mannkind Corporation IRE-1α inhibitors
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
US9546149B2 (en) 2007-06-08 2017-01-17 Mannkind Corporation IRE-1α inhibitors
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