US3408356A - Long chain esters of 4'-fluoro-4-[4-hydroxy-4-(alpha, alpha, alpha-trifluorotolyl)piperi-dino]butyrophenone and the like - Google Patents

Long chain esters of 4'-fluoro-4-[4-hydroxy-4-(alpha, alpha, alpha-trifluorotolyl)piperi-dino]butyrophenone and the like Download PDF

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US3408356A
US3408356A US484125A US48412565A US3408356A US 3408356 A US3408356 A US 3408356A US 484125 A US484125 A US 484125A US 48412565 A US48412565 A US 48412565A US 3408356 A US3408356 A US 3408356A
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butyrophenone
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Zola P Horovitz
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ER Squibb and Sons LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4

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  • This invention relates to new derivatives of compounds having valuable therapeutic properties and pharmaceutical compositions containing the same.
  • novel therapeutically active compounds of this invention include those having the general Formula I Rx R:
  • R and R each is hydrogen, halogen (preferably chloro or fluoro), trifiuoromethyl, lower alkyl or lower alkoxy; R is hydrogen or lower alkyl; and Y is higher alkyl, higher alkenyl, higher alkynyl, aryl, w-carboalkoxy (higher alkyl) or diphenyl-(hydroxymethyl).
  • the terms higher alkyl, higher alkenyl and higher alkynyl as employed herein include both straight and branched chain radicals of more than five carbon atoms up to about 17 carbon atoms.
  • aryl as employed herein includes substituents derived from monocyclic and bicyclic aryl carboxylic acids, and may be substituted or unsubstituted and further may be represented by the formulae R or R R wherein each R may be hydrogen, lower alkyl, lower alkoxy or halogen (e.g. chloro or bromo) and R is preferably hydrogen, lower alkyl or lower alkoxy, and most preferably, R is hydrogen or lower alkyl.
  • R may be hydrogen, lower alkyl, lower alkoxy or halogen (e.g. chloro or bromo) and R is preferably hydrogen, lower alkyl or lower alkoxy, and most preferably, R is hydrogen or lower alkyl.
  • aryl carboxylic acids examples include benzoic, o-toluic, 2,6-dimethylbenzoic, 2,6-dimethylanisic, o-bromobenzoic, o-chlorobenzoic, 2,6-dichlorobenzoic, naphthoic acid, dimethylnaphthoic acid and other like acids.
  • the preferred compounds of this invention are those wherein R is halo, especially fiuoro, R is trifiuoromethyl, R is hydrogen, Y is a higher alkyl radical of from six to seventeen carbon atoms, especially 6 to 8 and 10 to 12 carbon atoms and R is in the para position, and R is in the meta position.
  • the compounds of this invention are especially adapted for parenteral administration, as more fully discussed hereinafter, they are preferably administered in the form of their free esters.
  • the compounds readily form acid-addition salts, which may be utilized in the preparation of the free esters or the purification thereof and can also be used for parenteral formulations.
  • Acids useful for preparing the acid-addition salts include, inter alia, inorganic acids such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid, and organic acids such as oxalic, tartaric, citric, pamoic, fumaric, acetic, maleic and succinic acid.
  • the compounds of this invention are therapeutically active substances which are utilizable as tranquilizing agents, particularly in the treatment of mental disorders such as schizophrenia. These compounds differ from the corresponding lower alkanoic acid ester derivatives or the free hydroxyl derivatives in that they are significantly longer acting when administered parenterally and thus, when injected subcutaneously, for example, in a suitable vehicle, yield a long acting tranquilizing drug which need only be administered at comparatively infrequent intervals, e.g., depending on the needs of the individual patient, twice a week to once every two or three weeks. 7
  • the compounds of this invention can be prepared by interacting a compound of the general Formula IV (H) OH Q-C-lower alkylene-N 31 wherein the symbols have the same meaning as in Formula I, with an acyl halide (preferably acyl chloride) of the formula: YCO-halide, wherein Y is as hereinbefore defined; the reaction preferably being conducted in an organic solvent, such as chloroform, for the reactants.
  • an acyl halide preferably acyl chloride
  • YCO-halide preferably acyl chloride
  • the foregoing starting materials may be prepared by reacting in an inert organic solvent such as the aromatic hydrocarbons an unsubstituted or substituted benzoylalkyl halide of the Formula V O %-lower alkylene-hal 1 wherein R has 'the sa me meaning as delned previously, and" hal representsa halogen, preferably chlorine, with an appropriately substitutedpiperidine of the Formula wherein R and R have the same meaning as in Formula 1.
  • an inert organic solvent such as the aromatic hydrocarbons an unsubstituted or substituted benzoylalkyl halide of the Formula V O %-lower alkylene-hal 1 wherein R has 'the sa me meaning as delned previously, and" hal representsa halogen, preferably chlorine, with an appropriately substitutedpiperidine of the Formula wherein R and R have the same meaning as in Formula 1.
  • acyl halide reactants may be menacid and octadecynoic acid; the acyl chlorides of the alkadienoic acids, such as heptadienoic acid, octadien'oic acid, (alkyl)-octadienoic acid (e.g., 7-rmethyl-octadienoic acid), and nonadienoic acid; the acyl chlorides of the carboalkoxyalkanoic acids, such as carbomethoxyoctan'oic acid, carbomethoxydccanoic acid and carbornethoxyundecanoic acid; the acyl chloride of aryl carboxylic acids, such as benzoic acid, o-toluic acid, dimethylbenzoic acid, dimethylanisic acid, o-bromobenzoic acid, o-chlorobenzoic acid, napthoic acid, dimethylnapthoic acid,'diphenylacetic acid and dich
  • acyl halides described hereinbefore may be prepared by heating an acid of the formula Y-COOH, wherein Y is as hereinbefore defined, with two parts by weight, of a thionyl halide, preferably thionyl chloride or thionyl bromide, alone, or in the presence of an anhydrous solvent, such as chloroform or benzene, under reflux for a period of about three hours, concentrating to remove the excess thionyl halide (and any solvent present), and then distilling to obtain the resultant acyl halide, YCO-halide, wherein Y is as herein before defined.
  • a thionyl halide preferably thionyl chloride or thionyl bromide
  • an anhydrous solvent such as chloroform or benzene
  • the free bases when initially formed, 'can be converted to acid-addition salts by treatment with the desired acid.
  • This reaction is preferably conducted in an inert organic solvent under substantially anhydrous conditions by treating the base with the acid, whereby the acid-addition salt is formed.
  • the compounds of this invention in the form of their free'basic esters or acid addition salts, are dissolved of long chain fatty acids and mixtures of these and other oils; the compound preferably being present in a concentration to give about,10 mg. to about 300 mg,
  • EXAMPLE 1 concentrated to about 50 ml., cooled and diluted withabout 450 ml.-of anhydrous ether. To this cooled solution is added about -10 ml. of ethereal hydrogen chloride. The crystalline solid which separates is filtered, and the solid recrystallized from a mixture of alcohol and ether to give the product.
  • step (b) Preparation of the heptanoic acid ester of 4'-fluor0 4 [4 hydroxy 4 (a,cz,oz trifluoro m tolyl) piperidino]butyrophenone.An ice-cooled mixture of the hydrochloride obtained in step (a), 500 ml. of 5% aqueous potassium carbonate solution and 1000 ml. of ether are stirred until all the solid has reacted. The ether layer is separated, dried and concentrated to give the product.
  • Octanoyl chloride Octanoic Lauroyl chloride Lauric Stearoyl chloride Stearic Z-Heptenoate 2-Nonenoate 2-Heptenoylchloride 2-Nonenoyl chloride 2,2-diethylbutyric acid ester of 4'-fluoro -[4-hydroxy-f4- v (a, t,a-trifiuoro-m-tolyl)piperidino] acetophenone I To 19.3 g. of 4'-fiuoro-[4*hydroxy-4-(a,a,a-trifluorom-tolyl)piperidino]acetophenone in one liter of dry chloroform is added, dropwise, 8.9 g. of 2,2-dietl1'y'l-' butyroyl chloride" in '100' ml; of dry chloroform.
  • the precipitated solid is filtered and recrystallized from dry acetone to give the 2,2-diethylbutyric acid ester of 4'-fiuoro-[4-hydroxy-4- (a,a,ct trifluoro m tolyl)piperidino]acetophenone, salt with maleic acid.
  • the solid is recrystallized from anhydrous acetone-ether to yield the hydrochloride salt of the 10-undecenoic acid ester of 2'-trifiuoromethyl-4-[4- hydroxy-4- p-chlorophenyl) -piperidino] butyrophenone.
  • Example 4 yields the hydrochloride salt of lO-decanoic acid ester of 4-fiuoro-[4-hydroxy-4-(a,a,a-trifiuoro-m-tolyl)piperidino]-acetophenone.
  • EXAMPLE 8 Parenteral Formulation A.50 g. of the heptonic acid ester of 4'-fiuoro-4-[4-hydroxy-4-(a,a,a-trifiuoro-m-tolyl) piperidino]butyrophenone is dissolved in 1000 ml. of sesame oil, U.S.P. The solution is sterile filtered and packaged aseptically for parenteral administration.
  • EXAMPLE 10 Parenteral Formulation C.-A solution of 50 g. of the heptanoic acid ester of 4'-fiuoro-4-[4-hydroxy-4-(a,a,a trifiuoro-m-tolyl)piperidino]butyrophenone, 1.5 g. aluminum monostearate (purified) diluted to 1000 ml. with sesame oil, U.S.P., is sterile filtered and packaged aseptically for parenterial administration.
  • esters of Examples 2 to 7 may be formulated similarly to the compositions of Examples 8 to 10.
  • R is selected from the group consisting of halogen, trifiuoromethyl and lower alkoxy; R is selected from the group consisting of halogen, trifluoromethyl and lower alkyl; R is selected from the group consisting of hydrogen and lower alkyl, and Y is selected from the group consisting of alkyl of 6 to 17 carbons, alkenyl of 6 to 17 carbons, W-carbomethoxy-alkyl wherein the alkyl has 6 to 17 carbons, phenyl, halophenyl, and diphenyl (hydroxy methyl) and the acid addition salts thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

United States Patent ABSTRACT OF THE DISCLOSURE This invention relates to long chain esters of 4'-fluoro- 4 [4 hydroxy 4-(a,u,oz-trifiuorotolyDpiperidino]butyro phenone and related compounds having the formula O 0 C-Y ll R C-lower alkyleue-N which are produced by interacting an appropriately substituted or unsubstituted [(4-hydroxy 4 phenyl)piperidino1acetophenone or the like with a long chain acyl halide and which are useful as long acting transquilizers.
This invention relates to new derivatives of compounds having valuable therapeutic properties and pharmaceutical compositions containing the same.
The novel therapeutically active compounds of this invention include those having the general Formula I Rx R:
i (I? O C-Y C-lower alkylene-N wherein R and R each is hydrogen, halogen (preferably chloro or fluoro), trifiuoromethyl, lower alkyl or lower alkoxy; R is hydrogen or lower alkyl; and Y is higher alkyl, higher alkenyl, higher alkynyl, aryl, w-carboalkoxy (higher alkyl) or diphenyl-(hydroxymethyl). The terms higher alkyl, higher alkenyl and higher alkynyl as employed herein include both straight and branched chain radicals of more than five carbon atoms up to about 17 carbon atoms.
The term aryl as employed herein includes substituents derived from monocyclic and bicyclic aryl carboxylic acids, and may be substituted or unsubstituted and further may be represented by the formulae R or R R wherein each R may be hydrogen, lower alkyl, lower alkoxy or halogen (e.g. chloro or bromo) and R is preferably hydrogen, lower alkyl or lower alkoxy, and most preferably, R is hydrogen or lower alkyl. Examples of the aryl carboxylic acids which may be employed include benzoic, o-toluic, 2,6-dimethylbenzoic, 2,6-dimethylanisic, o-bromobenzoic, o-chlorobenzoic, 2,6-dichlorobenzoic, naphthoic acid, dimethylnaphthoic acid and other like acids.
The preferred compounds of this invention are those wherein R is halo, especially fiuoro, R is trifiuoromethyl, R is hydrogen, Y is a higher alkyl radical of from six to seventeen carbon atoms, especially 6 to 8 and 10 to 12 carbon atoms and R is in the para position, and R is in the meta position.
Since the compounds of this invention are especially adapted for parenteral administration, as more fully discussed hereinafter, they are preferably administered in the form of their free esters. The compounds, however, readily form acid-addition salts, which may be utilized in the preparation of the free esters or the purification thereof and can also be used for parenteral formulations. Acids useful for preparing the acid-addition salts include, inter alia, inorganic acids such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid, and organic acids such as oxalic, tartaric, citric, pamoic, fumaric, acetic, maleic and succinic acid.
The compounds of this invention are therapeutically active substances which are utilizable as tranquilizing agents, particularly in the treatment of mental disorders such as schizophrenia. These compounds differ from the corresponding lower alkanoic acid ester derivatives or the free hydroxyl derivatives in that they are significantly longer acting when administered parenterally and thus, when injected subcutaneously, for example, in a suitable vehicle, yield a long acting tranquilizing drug which need only be administered at comparatively infrequent intervals, e.g., depending on the needs of the individual patient, twice a week to once every two or three weeks. 7
The compounds of this invention can be prepared by interacting a compound of the general Formula IV (H) OH Q-C-lower alkylene-N 31 wherein the symbols have the same meaning as in Formula I, with an acyl halide (preferably acyl chloride) of the formula: YCO-halide, wherein Y is as hereinbefore defined; the reaction preferably being conducted in an organic solvent, such as chloroform, for the reactants. Among the suitable reactants may be mentioned:
4'-fiuoro-4- [4-hydroxy-4- (05,02, a-triflu oro-m-tolyl) piperidino] butyrophenone,
4-fiuoro- [4-hydroXy-4- u,a,a-trifluoro-m-tolyl) piperidino] acetophenone,
2-trifiuoromethyl-4- [4-hydroxy-4- (p-chlorophenyl) piperidino1butyrophenone,
3 '-ethoxy- [4-hydroxy- (4-o-tolyl)piperidino] acetophenone, and
4-b romo- [3 -ethyl-4-hydroxy-4- (p-bromophenyl) piperidino1acetophenone.
The foregoing starting materials may be prepared by reacting in an inert organic solvent such as the aromatic hydrocarbons an unsubstituted or substituted benzoylalkyl halide of the Formula V O %-lower alkylene-hal 1 wherein R has 'the sa me meaning as delned previously, and" hal representsa halogen, preferably chlorine, with an appropriately substitutedpiperidine of the Formula wherein R and R have the same meaning as in Formula 1.
Among the suitable acyl halide reactants may be menacid and octadecynoic acid; the acyl chlorides of the alkadienoic acids, such as heptadienoic acid, octadien'oic acid, (alkyl)-octadienoic acid (e.g., 7-rmethyl-octadienoic acid), and nonadienoic acid; the acyl chlorides of the carboalkoxyalkanoic acids, such as carbomethoxyoctan'oic acid, carbomethoxydccanoic acid and carbornethoxyundecanoic acid; the acyl chloride of aryl carboxylic acids, such as benzoic acid, o-toluic acid, dimethylbenzoic acid, dimethylanisic acid, o-bromobenzoic acid, o-chlorobenzoic acid, napthoic acid, dimethylnapthoic acid,'diphenylacetic acid and dichlorobcnzoic acid; the acyl chlorides of the carboalkoxy alkenoic acids such as w-carbomethoxyundecylenic acid, w-carbomethoxydodecylenic acid; and the acyl chlorides of the carboalkoxyalkynoic acids, such as w-carbomethoxyundecylynic acid, w-carbomethoxydodecylynic acid, and other like acids.
All of the acyl halides described hereinbefore may be prepared by heating an acid of the formula Y-COOH, wherein Y is as hereinbefore defined, with two parts by weight, of a thionyl halide, preferably thionyl chloride or thionyl bromide, alone, or in the presence of an anhydrous solvent, such as chloroform or benzene, under reflux for a period of about three hours, concentrating to remove the excess thionyl halide (and any solvent present), and then distilling to obtain the resultant acyl halide, YCO-halide, wherein Y is as herein before defined.
The free bases, when initially formed, 'can be converted to acid-addition salts by treatment with the desired acid. This reaction is preferably conducted in an inert organic solvent under substantially anhydrous conditions by treating the base with the acid, whereby the acid-addition salt is formed.
To prepare the preferred compositions of this invention, the compounds of this invention, in the form of their free'basic esters or acid addition salts, are dissolved of long chain fatty acids and mixtures of these and other oils; the compound preferably being present in a concentration to give about,10 mg. to about 300 mg,
I we e preferably about 12 to about 25 mg., of the compound 1 The following examples illustrate thein vention (all temperatures being in Centigrade).
EXAMPLE 1 concentrated to about 50 ml., cooled and diluted withabout 450 ml.-of anhydrous ether. To this cooled solution is added about -10 ml. of ethereal hydrogen chloride. The crystalline solid which separates is filtered, and the solid recrystallized from a mixture of alcohol and ether to give the product.
(b) Preparation of the heptanoic acid ester of 4'-fluor0 4 [4 hydroxy 4 (a,cz,oz trifluoro m tolyl) piperidino]butyrophenone.An ice-cooled mixture of the hydrochloride obtained in step (a), 500 ml. of 5% aqueous potassium carbonate solution and 1000 ml. of ether are stirred until all the solid has reacted. The ether layer is separated, dried and concentrated to give the product.
Similarly, by substituting an equivalent amount of the following acyl chlorides for the heptanoyl chloride'in step (a) of Example 1, and following the procedure of steps (a) and (b), the indicated ester is obtained.
Acyl chloride: Ester:
Octanoyl chloride Octanoic Lauroyl chloride Lauric Stearoyl chloride Stearic Z-Heptenoate 2-Nonenoate 2-Heptenoylchloride 2-Nonenoyl chloride 2,2-diethylbutyric acid ester of 4'-fluoro -[4-hydroxy-f4- v (a, t,a-trifiuoro-m-tolyl)piperidino] acetophenone I To 19.3 g. of 4'-fiuoro-[4*hydroxy-4-(a,a,a-trifluorom-tolyl)piperidino]acetophenone in one liter of dry chloroform is added, dropwise, 8.9 g. of 2,2-dietl1'y'l-' butyroyl chloride" in '100' ml; of dry chloroform. The
mixture is then reflux'edfor two hours and concentrated until free of chloroform. The residual oil is added to a suspension of 20 g. of sodium bicarbonate in 200ml. of
ice water and 500 ml. of ether. The mixture" is shaken carefully until no further evolution; of carbon dioxide occurs, theether layer is separated, dried and conce'n trated to give 2,2 diethylbutyric acid ester of"4-'fluo'ro,-
acetophenone.
EXAMPLE 3 2,2-diethylbutyric acid ester of 4'-fiuoro-[4-hydroxy-4- -(a,a,oz trifiuoro m tolyl piperidinoJacetophenone, salt with maleic acid 10.2 g. of the product obtained in Example 2 is dissolved in 50 ml. of dry chloroform, the solution is cooled, and a saturated solution of 2.32 g. of maleic acid in dry acetone is added dropwise. The precipitated solid is filtered and recrystallized from dry acetone to give the 2,2-diethylbutyric acid ester of 4'-fiuoro-[4-hydroxy-4- (a,a,ct trifluoro m tolyl)piperidino]acetophenone, salt with maleic acid.
EXAMPLE 4 undecenoic acid ester of 2' trfiuoromethyl-4-[4- hydroxy 4 (p chlorophenyl)piperidino]butyrophenone Following the procedure set forth in Example 2 but substituting 10.1 g. of IO-undecenoyl chloride for 2,2- diethylbutyroyl chloride and 21.3 g. 2'-trifluoromethyl-4- [4 hydroxy-4-(p-chlorophenyl) piperidinoJbutyrophenone for the acetophenone starting material yields the IO-undecenoic acid ester of 2'-trifluoromethyl-4[4-hydroxy-4- (p-chlorophenyl)piperidino]butyrophenone. 11.8 g. of this material are dissolved in 100 ml. of dry chloroform, the solution is cooled, and ml. of a 1 molar solution of hydrogen chloride in anhydrous ether is added, dropwise, with stirring. The clear solution which forms is evaporated free of solvents and the residue triturated with anhydrous ether. The solid is recrystallized from anhydrous acetone-ether to yield the hydrochloride salt of the 10-undecenoic acid ester of 2'-trifiuoromethyl-4-[4- hydroxy-4- p-chlorophenyl) -piperidino] butyrophenone.
EXAMPLE 5 Decanoic acid ester of 4'-fluoro-[4-hydroxy-4-(ot,a,a trifiuoro-m-tolyl piperidino] acetophenone Following the procedure set forth in Example 2, but substituting 9.5 g. of decanoyl chloride for 2,2-diethylbutyroyl chloride, there is obtained the decanoic acid ester of 4-fiuoro-[4-hydroxy-4-(u,a,a-trifluoro-m-tolyl) piperidino]acetophenone. Treatment of 10.8 g. of this material according to the procedures set forth in Example 4 yields the hydrochloride salt of lO-decanoic acid ester of 4-fiuoro-[4-hydroxy-4-(a,a,a-trifiuoro-m-tolyl)piperidino]-acetophenone.
Similarly, following the procedure set forth in Example 2 but substituting equivalent amounts of diphenylacetyl chloride, heptynoyl chloride, 8-carbomethoxy octanoyl chloride, 2,6-dimethylbenzoyl chloride, 2,6-dichlorobenzoyl chloride, o-bromobenzoyl chloride and o-chlorobenzoyl chloride for the 2,2-diethylbutyroyl chloride yields respectively, the diphenylacetic acid, heptynoic acid, S-carbomethoxyoctanoic acid, 2,6-dimethylbenzoic acid, 2,6-dichlorobenzoic acid, o-bromobenzoic acid, and ochlorobenzoic acid esters of the starting compounds of Examples 2 to 5.
EXAMPLE 6 S-carbomethoxyoctanoic acid ester of 4'-flu oro-4-[4- hydroxy 4 (ct,nz,et trifluoro p tolyl)piperidino] butyrophenone Following the procedure set forth in Example 2, but substituting 22.0 g. of S-carbomethoxyoctanoyl chloride for the 2,2-diethylbutyroyl chloride and 41.0 g. of 4'- butyrophenone for the m-tolyl starting material, there is obtained the 8-carbomethoxyoctanoic acid ester of 4- fiuoro-4- [hydroxy-4- a,a,a-trifluoro-p-tolyl) piperidino] butyrophenone. Treatment of 11.8 g. of this product in accordance with the procedure set forth in Example 3 yields the maleic acid salt.
Similarly, following the above procedure, but substituting equivalent amounts of IO-carbomethoxydecanoyl chloride and ll-carbomethoxyundecanoyl chloride for 8- carbomethoxyoctanoyl chloride, the respective IO-carbomethoxydecanoic acid and 1l-carbomethoxyundecanoic acid esters are obtained. 1
EXAMPLE 7 Benzilic acid ester of 4'-fiuoro-4-[4-hydroxy-3-methyl-4- a,a,a,-trifiuoro-m-tolyl) piperidino] butyrophenone (a) To 4.23 g. of 4'-fiuoro-4-[4-hydroxy-3-methyl-4- (u,a,u,-trifluoro-m-tolyl)piperidino]butyrophenone in ml. of chloroform is added 2.65 g. of 2,2-bis-phenyl-2- chloroacetyl chloride in 25 ml. of chloroform. The mixture is refluxed for 24 hours and concentrated to give the ester with 2,2-bis-phenyl-2-chloroacetic acid, hydrochloride.
(b) The product from (a) in 50 ml. of ether, 250 ml. of water and 1.7 g. of sodium bicarbonate are stirred and heated at 35 for one hour. The ether layer is separated, dried and concentrated to give the free benzilic acid ester.
EXAMPLE 8 Parenteral Formulation A.50 g. of the heptonic acid ester of 4'-fiuoro-4-[4-hydroxy-4-(a,a,a-trifiuoro-m-tolyl) piperidino]butyrophenone is dissolved in 1000 ml. of sesame oil, U.S.P. The solution is sterile filtered and packaged aseptically for parenteral administration.
EXAMPLE 9 Parenteral Formulation B.A suspension of 56 g. of micronized heptanoic acid ester of 4'-fluoro-4-[4-hydroxy- 4- (a,a,a-trifiuoro-m-to1yl) piperidino] -butyrophenone, hydrochloride, 0.36 g. of lectihin N.F., 0.18 g. of Tween and 1.68 g. of aluminum monostearate (purified), diluted to 1000 ml. with sesame oil is prepared under sterile conditions and packaged ase tically for parenteral administration.
EXAMPLE 10 Parenteral Formulation C.-A solution of 50 g. of the heptanoic acid ester of 4'-fiuoro-4-[4-hydroxy-4-(a,a,a trifiuoro-m-tolyl)piperidino]butyrophenone, 1.5 g. aluminum monostearate (purified) diluted to 1000 ml. with sesame oil, U.S.P., is sterile filtered and packaged aseptically for parenterial administration.
The esters of Examples 2 to 7 may be formulated similarly to the compositions of Examples 8 to 10.
What is claimed is:
1. A compound of the formula O I 0 II ll C-lower alkylene-N :0 Y
wherein R is selected from the group consisting of halogen, trifiuoromethyl and lower alkoxy; R is selected from the group consisting of halogen, trifluoromethyl and lower alkyl; R is selected from the group consisting of hydrogen and lower alkyl, and Y is selected from the group consisting of alkyl of 6 to 17 carbons, alkenyl of 6 to 17 carbons, W-carbomethoxy-alkyl wherein the alkyl has 6 to 17 carbons, phenyl, halophenyl, and diphenyl (hydroxy methyl) and the acid addition salts thereof.
2. Heptanoic acid ester of 4'-fluoro-4-[4-hydroxy-4- (u,u,u-trifluoro-m-tolyl)-piperidino]butyrophenone.
3. Undecenoic acid ester of 4-fiuoro-4-[4-hydroxy-4 (a,a,m-trifiuoro-m-tolyl)-piperidino]butyrophenone.
4. Decanoic acid ester of 4-fluoro-4-[4-hydroxy-4- a,a,a-trifiuoro-m-tolyl -piperidino] butyrophenone.
5. Heptanoic acid ester of 4'-fiuoro-4-[4-hydroxy-4- (u,a,a-trifiuoro-p-tolyl)-piperidino]butyrophenone.
(References on following page) 7 8 I References Cited 4 v OTHER REFERENCES UNITED STATES PATENTS Janssen, J. Med. Chem., Vol. 2, pp. 31, 35, 41, 43, and 2,589,943" 3/19'52 Jensen 260 29413 44 (196m- Y 1 3/l959 p vm "F" 260 294:3 5 (1g-I6a6rfer et al. J. Pharm Pharmac, 18, Pp. 150160,
FOREIGN T P HEN-RY R. JILES, Primary Examiner. 963,639 7/1964 Great Brltam.
. 397 77 2 1 Switzerland. 7 E. LEWIS, A. D. SPEVACK, Assistant Examiners. V
US484125A 1965-08-31 1965-08-31 Long chain esters of 4'-fluoro-4-[4-hydroxy-4-(alpha, alpha, alpha-trifluorotolyl)piperi-dino]butyrophenone and the like Expired - Lifetime US3408356A (en)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3919243A (en) * 1967-12-01 1975-11-11 Us Army Substituted piperidinium chlorides
US4032531A (en) * 1969-12-03 1977-06-28 The United States Of America As Represented By The Secretary Of The Army Piperidine derivatives
US4075346A (en) * 1975-07-17 1978-02-21 Sumitomo Chemical Company, Limited CNS depressant γ-(secondary amino)-ortho-nitro-butyrophenones
DE3024305A1 (en) * 1979-06-28 1981-01-22 Janssen Pharmaceutica Nv PARENTERAL TRACKABLE PSYCHOTROPESIC MEDICINE WITH LONG-TERM EFFECT
US4303663A (en) * 1974-04-18 1981-12-01 Sumitomo Chemical Company, Limited Butyrophenone compounds
EP0260070A1 (en) * 1986-09-11 1988-03-16 H. Lundbeck A/S The acetic acid ester of haloperidol and pharmaceutical compositions thereof
EP0270282A3 (en) * 1986-12-03 1990-03-14 H. Lundbeck A/S Oleic acid esters and pharmaceutical compositions
US5428036A (en) * 1990-10-03 1995-06-27 H. Lundbeck A/S Sertindole prodrugs, compositions and use
US5643784A (en) * 1990-12-04 1997-07-01 H, Lundbeck A/S Indan derivatives
US5658921A (en) * 1992-06-12 1997-08-19 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US5665725A (en) * 1991-06-13 1997-09-09 H. Lundbeck Piperidine derivatives having anxiolytic effect
WO1998018769A1 (en) * 1996-10-31 1998-05-07 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Sustained-release derivatives of hydroxylated analogs of substituted 1-[2[bis(aryl)methoxy]ethyl]-piperazines and -homopiperazines and their use as noncompetitive antagonists of dopamine reuptake

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US2589943A (en) * 1941-10-01 1952-03-18 Ferrosan As 4-aryl-4-acyl-oxy-piperidines
US2880211A (en) * 1959-03-31 Chcoochj
GB963639A (en) * 1960-10-20 1964-07-15 Arnold Heyworth Beckett New piperidine derivatives and processes for preparing the same
CH397677A (en) * 1958-04-22 1965-08-31 Res Lab Dr C Janssen Nv Process for the preparation of aroylalkylpiperidines

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2880211A (en) * 1959-03-31 Chcoochj
US2589943A (en) * 1941-10-01 1952-03-18 Ferrosan As 4-aryl-4-acyl-oxy-piperidines
CH397677A (en) * 1958-04-22 1965-08-31 Res Lab Dr C Janssen Nv Process for the preparation of aroylalkylpiperidines
GB963639A (en) * 1960-10-20 1964-07-15 Arnold Heyworth Beckett New piperidine derivatives and processes for preparing the same

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3919243A (en) * 1967-12-01 1975-11-11 Us Army Substituted piperidinium chlorides
US4032531A (en) * 1969-12-03 1977-06-28 The United States Of America As Represented By The Secretary Of The Army Piperidine derivatives
US4303663A (en) * 1974-04-18 1981-12-01 Sumitomo Chemical Company, Limited Butyrophenone compounds
US4075346A (en) * 1975-07-17 1978-02-21 Sumitomo Chemical Company, Limited CNS depressant γ-(secondary amino)-ortho-nitro-butyrophenones
DE3024305A1 (en) * 1979-06-28 1981-01-22 Janssen Pharmaceutica Nv PARENTERAL TRACKABLE PSYCHOTROPESIC MEDICINE WITH LONG-TERM EFFECT
JPS568318A (en) * 1979-06-28 1981-01-28 Janssen Pharmaceutica Nv Non oral long acting composition of haloperidol and bromperidol derivative
FR2460932A1 (en) * 1979-06-28 1981-01-30 Janssen Pharmaceutica Nv HALOPERIDOL AND BROMPERIDOL COMPOUNDS AND LONG-EFFECTIVE PARENTERAL COMPOSITIONS CONTAINING
EP0260070A1 (en) * 1986-09-11 1988-03-16 H. Lundbeck A/S The acetic acid ester of haloperidol and pharmaceutical compositions thereof
JPS6377857A (en) * 1986-09-11 1988-04-08 ハー・ルンドベツク・アクチエゼルスカベツト Acetate ester of haloperidol and its pharmaceutical composition
US4855307A (en) * 1986-09-11 1989-08-08 H. Lundbeck A/S Acetic acid ester of haloperidol
EP0270282A3 (en) * 1986-12-03 1990-03-14 H. Lundbeck A/S Oleic acid esters and pharmaceutical compositions
US5428036A (en) * 1990-10-03 1995-06-27 H. Lundbeck A/S Sertindole prodrugs, compositions and use
US5643784A (en) * 1990-12-04 1997-07-01 H, Lundbeck A/S Indan derivatives
US5665725A (en) * 1991-06-13 1997-09-09 H. Lundbeck Piperidine derivatives having anxiolytic effect
US5807871A (en) * 1991-06-13 1998-09-15 H. Lundbeck A/S Piperidine derivatives having anxiolytic effect
US6031099A (en) * 1991-06-13 2000-02-29 H. Lundbeck A/S Piperidine derivates having anxiolytic effect
US6207677B1 (en) 1991-06-13 2001-03-27 H. Lundbeck A/S Piperidine derivatives having anxiolytic effect
US5658921A (en) * 1992-06-12 1997-08-19 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US5684012A (en) * 1992-06-12 1997-11-04 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US5830896A (en) * 1992-06-12 1998-11-03 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US5837707A (en) * 1992-06-12 1998-11-17 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US6090808A (en) * 1992-06-12 2000-07-18 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
WO1998018769A1 (en) * 1996-10-31 1998-05-07 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Sustained-release derivatives of hydroxylated analogs of substituted 1-[2[bis(aryl)methoxy]ethyl]-piperazines and -homopiperazines and their use as noncompetitive antagonists of dopamine reuptake
US6387389B1 (en) 1996-10-31 2002-05-14 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Sustained-release derivatives of hydroxylated analogs of substituted 1-[2[bis(aryl)methoxy]ethyl]-piperazines and -homopiperazines and their use

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