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Publication numberUS3194733 A
Publication typeGrant
Publication dateJul 13, 1965
Filing dateJan 28, 1963
Priority dateApr 26, 1961
Publication numberUS 3194733 A, US 3194733A, US-A-3194733, US3194733 A, US3194733A
InventorsMerrill Reynold C, Yale Harry L
Original AssigneeOlin Mathicson Chemical Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Phenothiazine compositions and method of treating mental disorders
US 3194733 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent 3,194,733 PHENGTIHAZINE CUMEQSHTIGNS AND METHQD 0F TREATKNG MENTAL DISORDERS Harry L. Yale, New Brunswick, and Reynold C. Merrill,

Short Hills, N.J,, assignors to Qiin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Jan. 28, 1963, Ser. No. 254,459

11 Claims. (Cl. 167-65) This invention relates to new acid esters of phenothiazines having valuable therapeutic properties, pharmaceutical compositions containing the same, and processes for the preparation there.

This application is a continuation-inpart of a previous application Serial No. 105,548, filed April 26, 1961, now abandoned.

The therapeutically active compounds of this invention include phenothiazines of the general Formula I wherein n is a positive integer of more than 6 and is preferably a positive integer of from 7 to 12. The term ary 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 wherein each R may be hydrogen, lower alkyl, lower alkoxy or halogen (e.g. chloro or brorno) 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, dimethylnapthoic acid and other like acids.

The preferred compounds of this invention are those wherein X is chloro or trifluorornethyl and Y is a higher alkyl, higher alkenyl or higher alkynyl radical of from six to fourteen carbon atoms, lower alkylor lower alkoXy-substituted aryl or w-carboalkoX3 (higl1er alkyl) of less than 13 carbon atoms. Particularly preferred are those compounds wherein X trifiuoromethyl and Y is a higher alkyl radical of from nine to fourteen carbon atoms.

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 of this invention are therapeutically active substances which are utilizable as tranquilizing (or ataractic) agents. 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.

The compounds of this invention can be prepared by interacting a compound of the general Formula II wherein X and r are as hereinbefore defined, 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 phenothiazine reactants may be mentioned: 10 [3-(Z-hydroxyethyl)piperazinopropyl]phenothiazine; l0 [3-(Z-hydroxyethyl)piperazinopropyl]-2-halo-pheno thiazines, such as 10-[3-(2-hydroxyethyl)piperazinopropyl] -2-chlorophenothiazine; 10-[3 (Z-hydroxyethyl) piperazinopropyl] 2 trifiuoromethylphenothiazine; 10-[3-(2= hydroxyalkoxyalkyl)-piperazinopropyl] 2-halo-phenothi azines, such as l0-[3-(2-hydroxyethoxyethyl)piperazinopropyl] 2-trifiuoromethylphenothiazine; 10[ 3 (2 hydroxyethyl)piperazinopropyl] 2-(lower alkyl)phenothiazines, such as 10[-3-(2-hydroxyethyl)piperazinopropyl]- Z-methylphenothiazine; 10[-3 (2-hydroxyethyl(piperazinopropyl1-2-(lower alkoxy)phenothiazines, such as 10- [-3-(Z-hydroxyethyl)piperazinopropyl1- Z-methoxyphenothiazine; 1O [3 (2 hydroxyethyl)piperazinopropyl] -2- (lower alkanoyl)phenothiazines, such as 10-[3-(2-hydroxyetliyl)piperaziuopropyl] 2-propionylphenothiazine; 10-[3-(2-hydroxyethyl)piperazinopropyl] 2-(lower alkyl mercapto) phenothiazines, such as 10[-3-(2-hydroxyethyl piperazinopropyl] Z-methylmercaptophenothiazine; 10- [3 (Z-hydroxyethyl piperazinopropyl] -2-trifluoromethylmercaptophenothiazine and 10-[(2-hydroxyethyl)piperazinopropyl] -2-methylsulfonylphenothiazine.

Among the suitable acyl halide reactants may be mentioned the acyl chlorides of higher alkanoic acids, such as heptanoic acid, octanoic acid, Z-ethylheptanoic acid, 2,2-diethylbutyric acid, capric acid, lauric acid, tridecyclic acid, myristic acid, palmitic acid, and stearic acid; the acyl chlorides of higher alkenoic acids, such as 2-heptenoic acid, 2-nonenoic acid, citronellic acid, undecylenie acid and oleic acid; the acyl chlorides of the alkynoic acids, such as heptynoic acid, octynoic acid, nonynoic acid, decynoic acid, dodecynoic acid, tri-decynoic acid and octadecynoic acid; the acyl chlorides of the alkadienoic aids, such as heptadienoic acid, octadienoic acid, (alkyl)-octa dienoic acid (e.g., 7-methyl-octadien-oic acid), and nonadienoic acid; the acyl chlorides of the carboalkoxyalkanoic acids, such as carbomethoxyoctanoic acid, carbomethoxydecanoic acid and carbomethoxyundecanoic acid; the acyl chlorides of aryl carboxylic acids, such as benzoic acid, o-toluic acid, dirnethylbenzoic acid, dimethylanisic acid, o-bromobenzoic acid, o-chlorobenzoic acid, napthoic acid, dimethylnaphthoic acid, benzilic acid and dichloroas benzoic acid; the acyl chlorides of the carboalkoxy alkenoic acids such as w-carbomethoxyundecylenic acid, (.0- 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, YC-halide, wherein Y is as hereinbefore defined.

In addition to the foregoing general procedure, to prepare compounds of Formula I, an alternate procedure may be employed. In this alternate procedure, compounds of Formula II are employed as starting materials, which starting materials are first reacted with a halogenating agent, such as thionyl chloride or thionyl bromide, to yield compounds of general Formulae III.

s (III) wherein X is as hereinbefore defined and B is halogen, which are also new compounds of this invention.

The compounds of Formula 111 are then reacted with. a suitable alkali metal salt of the carboxylic acids of the formula Ii Y- (Q) wherein Q is an alkaline metal (cg, Na, K, etc.) and Y is as hereinbefore defined to yield respectively the new final products of Formula I.

A further alternate procedure for obtaining the compounds of this invention involves the reaction of the compound of the Formula IV.

II Halogen-(011 C H O) C-Y wherein Y and r are as hereinbefore defined.

Another alternate suitable method of preparing the compounds of this invention involves the reaction of a 4, compound of Formula II with a compound having the formula i Y (LJ 0 (alltyl) wherein Y is as hereinbefore defined, in the presence of a trace amount of sodium methoxide catalyst, to yield compounds of Formula I. l

The compounds of the formula may be prepared by esterifying a suitable acid of the formula Y COOH, wherein Y is as hereinbefore defined, with a lower alkanol, e.g., methanol or ethanol, in the presence of an acidic catalyst, e.g., sulfuric or hydrochloric acid, or with an alkylating agent, such as diazomethane or diazoethane, to yield compounds of the formula Y-i O (alkyl) wherein Y is as hereinbefore defined.

To prepare the preferred compositions ofthis invention, the compounds ofthis invention, in the form of their free basic esters, are dissolved or suspended in a parenterally acceptable liquid vehicle. For prolonged action, the compounds are formulated in an oil such as peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these and other oils; the compound preferably being present in a concentration to give about 20 mg. to about 300 mg. or" the compound per n11. The preferable route of administration of these formulations is subcutaneous.

The following. examples illustrate the invention (all temperatures being in centigradc):

Example 1.Acid chloride of heptafnoic chloride 30 gm. of heptanoic acid and 60 gm. of thionyl chloride are mixed, kept at room temperature for one hour, refluxed for three hours, concentrated until free of thionyl chloride and the residue distilled to give the acid chloride of heptanoic acid.

Similarly, following the procedure set forth in Example 1, but substituting an equivalent amount of thionyl bromide for thionyl chloride there is obtained the acid bromide of heptanoic acid.

Example 2.Heptanoz'c acid ester of 10-[3-(2-hydr0xyethyl) piperzzzinopropyl] -2-zrifluoromethylphenothiazine (2.) Preparation of the lzeptzmoic acid ester of 10- [3-(2- lzydroxyethyl)piperazinopropyl] Z-Irifluoromethylphenothiazz'ne, dihydrochloride, hemihydrare.To a stirred solution of 30.6 g. of 10-[3-(2-hydroxyethyl)pi perazinopropyl]-2-trifiuoromethylphenothiazine in 300 ml. of dry chloroform is added, dropwise, 11.9 g. of heptanoyl chloride in 50 ml. of dry chloroform. Subsequen ly, the reaction mixture is stirred and heated under reflux for five hours, cooled, and shaken with 5% aqueous hydrochloric acid. The dried chloroform solution is concentrated to about 50 ml., cooled and diluted with about 450 ml. of anhydrous ether. To this cooled solution is added about 10 ml. of ethereal hydrogen chloride. The crystalline solid which separates is boiled for about five minutes with 200 ml. of benzene. The solid first dissolves and then crystallizes from boiling mixture. The cooled mixture is filtered, and the solid recrystallized from methyl ethyl ketone to give about 19.6 g. of the product, M.P. about 184- 185 (dec.).

(b) Preparation of the heptaizoic acid ester of 10-[3- (2 lzydroxyethyl)piperazinopropyl] 2 trifluoromethylphen0thiazine.An ice-cooled mixture of the dihydrochloride obtained in step (a), 500 m1. of 5% aqueous potassium carbonate solution and 1080 ml. of other are stirred until all the solid has reacted. The ether layer is sepa- 5 rated, dried and concentrated to give about 18.8 g. of prodnet as a viscous pale yellow oil, 11 1.5485.

Similarly, by substituting an equivalent amount of the following acyl chlorides for the heptanoyl chloride in step (a) of Example 2, and following the procedure of steps (a) and (b), the indicated ester is obtained:

Acyl chloride Ester Gctanoyl chloride Octanoic Lauroyl chloride Laurie Stearoyl chloride Stearic Similarly, following the procedure set forth in Example 1 but substituting an equivalent amount of l-O[3-(2-hydroxyethoxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazine for 10 [3-(Z-hydroxyethyi)piperazinopropyl]-2-trifiuoromethylphenothiazine yields the heptanoic acid ester of 10-[3-(Z-hydroxyethoxyethyl)piperazinopr0 pyl] -2-trilluoror1ethylphenothiazine.

Example 3.2,2-dietlzylbutyric acid ester of l--[3(2-hydroxyctlzyl)pipemzinopropyl] 2 ti'i lzloromethylphenothiazine To 39.3 g. of lO-[3-(Z-hydroxyethyl)piperazinopropyl} Z-triiluorornethylphenothiazine in one liter of dry chloroform is added, dropwise, 33.8 g. of 2,2-diethylbutyroyl chloride in 100 ml. of dry chloroform. The mixture is then refluxed for two hours and concentrated until free of chloroform. The residual oil is added to a suspension of 40 g. of sodium bicarbonate in 400 ml. of ice water and 5 00 ml. of ether. The mixture is shaken carefully until no further evolution of carbon dioxide occurs, the ether layer is separated, dried and concentrated to give 2,2-diethylbutyric acid ester of 1%-[3-(2-hydroxyethyl)piperazinopro pyl]-2-trifiuoroniethylphenothiazine, as a pale yellow oil.

Example 4.2,2-dietlzylbtlzyric acid ester 0 -[3-(2-1231- droxyetlzyl)piperazinopropyl] Z-trifluoromethylphenozlziazlnc, salt with 2 moles of mal-zic acid 11.6 g. of the product obtained in Example 2 is dissolved in 50 ml. of ry chloroform, the solution is cooled,

and a saturated solution of 4.64 g. of maleic acid in dry acetone is added dropwise. The precipitated solid is ill tered and recrystallized from dry acetone to give the 2,2-

diethylbutyric acid ester of 10-[3-(2-hydroxyethyl)piperazinepropyl]-Z-trifluoromethylphenothiazine, salt with two moles of nialeic acid, having a melting point of about 167- Example 5 .'Stezzric acid ester of 1 0- {3- Z-hydroxyethyl pi pemzirzo pro pyl -2 -tri ltzor0r/letlzyl phcnotlliaziite Following the procedure set forth in Eample 3, but substituting 57.5 g. of stearoyl chloride for 2,2-diethylbutyroyl chloride yields the stearic acid ester of lO-[3-(2-1ydroxyethyl) piperazinopropyl] 2-triiluoromethyl phenothiazine, first as a pale yellow oil which later crystallizes spontaneously to a solid, having a melting point of about 33-34 C. Example 6.Stearic acid ester of 10-[3-(2-hydr0xetlzyl)- piperazinopropyl]-2-triflu0r0metlzyl phenothiazine, di-

hydrochloride 14.1 g. of the product of Example 5 are dissolved in 50 ml. of dry chloroform, the solution is cooled, and 40 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 residual oil induced to granulate. The solid is recrystallized from anhydrous'acetone-ether to yield stearic acid ester of 10- [3 (2 hydroxyethyl)piperazinopropyl] 2 trifluoro methyl phenothiazine, dihydrochloride having a melting point of about -8l C.

Example 7.I0-undecencic acid ester 0 10-[3-(2-hydroxyetlzyl)pipemzinopropyl] Z-trifluoromethylphen0- tltiaziite Following the procedure set forth in Example 3 but substituting 41.5 g. of lO-undecenoyl chloride for 2,2-diethylbutyroyl chloride yields the lil-undecenoic acid ester of it) [3 (2 hydroxyethyl)piperazine propylJ-Z-triiluoroniethylphenothiazine, as a pale yellow oil. Treatment of 12.4 g. of this material according to the procedure set forth in Example 6 yields the dihydrochloride salt of the lil-undecenoic acid ester of ll)-[3-(2-hydroxyethyl(piperazinopropyl] 2 trifluoromethylphenothiazine, having an MP. of about 153155 C.

Example 8.Decaiz0ic acid ester 0 1G-[3-(2-hydr0xyethyl piper-czinopropyl] -2-triflu0r0methylphenothiazine Following the procedure set forth in Example 3, but substituting 39.3 g. or" decanoyl chloride for 2,2-diethylbutyroyl chloride, there is obtained the decanoic acid ester of i0 [3 (Z-hynoxyethyl)piperazincpropyl]-2-trifiuoro ethylphenothiazine, as a pale yellow oil. Treatment of .l g. of this material according to the procedures set orth Example 6 yields the dihydrochloride salt of 10- ecanoic acid ester of 1Q-[3-(Z-hydroxyethyl)piperazino- I opyl]-Z-trifiuoromethylphenothiazine, having an MP. of about l75l76 C.

Example 9.10-[S-(Z-chloroetlzyl) piperazimpmpyl} 2-trifiu0r0methylphenothiazine To 21.9 g. of l0-[3-(hydroxyethyl)piperazinopropyl]- Z-trifiuoromethylphenothiazine in 250 ml. of dry benzei e is added 7.1 g. of thionyl chloride. The mixture is kept overnight, heated for 3 hours under reflux, cooled and treated with an excess of ethereal hydrogen chloride. The

recipitated solid is filtered and recrystallized from absolute ethanol-anhydrous ether to give 18.4 g. of lO-[S- (Z-chloroethyl)piperazinopropyl] 2 trifluorornethylphenothiazine as the dihydrochloride, MP. 224225 (dec.).

Following the procedure of *Example 9, but substituting an equivalent amount of thionyl bromide for thionyl chloride, ields 10-[3-(Z-bromoethyl)piperazinopropyl}- Z-triliuoroinethylphenothiazine.

Similarly, following the procedure of Example 9, but substituting an equivalent amount of 10-[3-(2-hydroxyethoxyethyl)piperazinopropyl] 2 trifluorornethylphenathiazine for 10-[3-(Z-hydroxyethyl)piperazinopropyl] 2- trifluoromethylphenothiazine, yields 10 [3 (2 chloroethoxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine.

Example 10.2,6-dimethyl-p-anisic acid ester 0 10-[3-(2- hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothz'azine To 2.7 g. of potassium 2,6-dirnethyl-p-anisoate in 25 ml. of N,N-dimethylforinarnide is added 4.38 g. of 10- [3-(2-chloroethyl)piperazinopropyl] 2 trifiuoroniethylphenothiazine, the mixture is stirred and heated for 5 hours at cooled, diluted with water and. the pH adjusted to 10 with 10% aqueous sodium hydroxide solution. The mixture is extracted with ether and the ether extracts are dried and concentrated to yield the 2,6-dimethyl-p-anisic acid ester of 10- [3 (2 hydroxyethyl) piperazinopropyl]-2-tritluoromethylphenothiazine. This product in 50 ml. of anhydrous other is then reacted with 1.5 g. of maleic acid in 10 ml. of dry acetone, and the resultant precipitated product is filtered to yield the di- M he n maleic acid salt of 2,6-dimethyl-p-anisic acid ester of 10-[3-(Z-hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine, having a M.P. of about 160-161 C. Following the procedure set forth in Example 10, but substituting an equivalent amount of [3 (2 chloroethoxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazine for 10 [3 (2 chloroethyl)piperazinopropyl] 2 trifluoromethylphenothiazine, yields the 2,6- dimethyl-p-anisic acid ester of 10-[3-(2-hydroxyethoxyethyl) piperazinopropyl] 2-trifiuoromethylphenothiazine. Similarly, following the procedure set forth in Example 10, but substituting equivalent amounts of sodium heptanoate; potassium naphthoate; potassium benzilate, sodium heptynoate; potassium-Z-heptenoate; sodium S-carbomethoxy octanoate; potassium 2,6 dimethylbenzoate; sodium 2,6-dichlorobenzoate; potassium o-bromobenzoate; and potassium o chlorobenzoate for potassium 2,6-dimethyl-p-anisoate, yields respectively, the heptanoic acid; naphthoic acid; benzilic acid, heptynoic acid; heptenoic acid; S-carbomethoxyoctanoic acid; 2,6-dimethylbenz0ic acid; 2,6-dichlorobenzoic acid; o-bromobenzoic acid; and o-chlorobenzoic acid esters of l0-[3-(2-hydroxyethyl) piperazinopropyl] 2 trifiuoromethylphenothiazine.

Example 1 1 .I 0- [3- (Z-Izydroxyethyl pi peltlzinoprOPyl 1 Z-triflaoromethylphenothiazine, ester with hepttmoic acid A mixture of 3.93 g. of l0-[3-(1-piperazinyl)propyl]- 2-(trifiuoromethyl)phenothiazine, 2.0 g. of 2-bromoethyl heptanoate, (ffi-bromoethyl heptanoate is readily prepared by the reaction of heptanoyl chloride with 2-bromoethanol), 25 ml. of anhydrous toluene, 10 mg. of copper powder, 10 mg. of potassium iodide and 1.38 g. of anhydrous potassium carbonate is stirred and refluxed under nitrogen for hours. The mixture is filtered. and the filtrate concentrated to dryness to give 10-[3-(2-hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine, ester with heptanoic acid, as a viscous pale yellow oil.

Similarly, following the procedure set forth in Example 11, but substituting 2-bromoethoxyethyl heptanoate (obtained by the reaction of heptanoyl chloride with Z-bromoethoxyethanol) for 2-bromoethyl heptanoate, there is obtained 10-[3 (2 hydroxyethoxyethyl)piperazinopropyl} 2-trifiuoromethylphenothiazine, ester with heptanoic acid.

Similarly, following the procedure set forth in Example 11 but substituting equivalent amounts of Z-bromoethyl heptynoate; 2-bromoethanolbenzoate; 2-brornoethyl heptenoate 2-bromoethyl 8 carbomethoxyoctanoate for 2- bromoethyl heptanoate, yields respectively the heptynoic acid; benzoic acid; heptenoic acid; and 8-carbomethoxyoctanoate acid, esters of 10-[3-(2-hydroxyethyl)piperazinopropyl] -2-trifluoromethyl.

Example 12.8-carb0meth0xy0ctanoic acid ester of 10- [3-(2-hydroxyethyl)piperazinopropyl] 2 tl'ifluolomethylplzenothiazine Following the procedure set forth in Example 3, but substituting 42 g. of 8-carbomethoxy octanoyl chloride for the 2,2-diethylbutyroyl chloride, there is obtained the 8- carbomethoxy octanoic acid ester of 10-[3-(2-hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine, as a pale yellow oil. Treatment of 12.4 g. of this product in accordance with the procedure set forth in Example 3 yields the dimaleic salt of 8-carbomethoxy octanoic acid ester of 10-[3-(2-hydroxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazine, having a M.P. of about 157l58 C. (dec.).

Similarly, following the procedure of Example 9 but substituting equivalent amount of 10 carbomethoxydecanoyl chloride and 1l-carbomethoxyundecanoyl chloride, for 8-carbomethoxy-octanoyl chloride the respective l0 carbomethoxydecanoic acid; and 11 carbomethoxyundecanoic acid esters of l0-[3 (2 hydroxyethyhpiper azinopropyl]-2-trifiuoromethylphenothiazine are obtained.

Example 13.-Preparati0n of 11 rarbomethowundecylenic acid (a) A mixture of 68.4 g. of dodecylenedioic acid, 500 ml. of methanol and 10 ml. of concentrated sulfuric acid is heated under reflux for six hours and then concentrated from the steam bath. The residual oil is cooled in ice, diluted with 250 g. of ice and extracted with ether. The ether extracts are washed and saturated aqueous sodium chloride solution, dried, concentrated and the residue distilled to give dimethyl dodecylenedioate.

(b) To 25.6 g. of the product from (a) in 250 ml. of methanol is added, dropwise and with stirring, a solution of 6.6 g. of potassium hydroxidein ml. of methanol, at room temperature. Subsequently, the mixture is stirred and refluxed for one hour and then concentrated from the steam bath. The residue is cooled, dissolved in 100 ml. of ice water and a slight excess of 10% aqueous hydrochloric acid added. The precipitated solid is filtered to give 11-carbomethoxyundecylenic acid.

In similar fashion, but starting with dodecynedioic acid, there is obtained 11-carbomethoxyundecylynic acid.

Example ]4.--10-[3-(Z-hydroxyethyl)piperazinopropyl]- Z-trzfluoromethylphenotlziazinc, ester with stearic acid A mixture of 4.37 g. of 10-[3-(2-hydroxyethyl)piperazinopropyl] 2 -trifluoromethylphenothiazine, 2.98 g. of methyl stearate and 10 mg. of anhydrous sodium methoxide are heated by means of an oil bath maintained at 100. The methanol distills as it is formed and the reaction is complete in about 3 hours. The cooled mixture is dissolved in 100 ml. of ether and the ether solution is washed with three 10 ml. portions of cold water. The dried ether solution is concentrated to dryness to give 10-[3 (2 hydroxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazine, ester with stearic acid, as a pale yellow oil. When a seed crystal of the material obtained in Example 6 is added, this product also crystallizes to a solid, M.P. about 33-34" C.

Similarly, following the procedure set forth in Example 14 but substituting equivalent amounts of methyl benzoate; methyl heptynoate; methyl heptenoate and methyl heptanoate for methyl stearate, there are obtained respectively the benzoic acid; heptynoic acid; heptenoic acid and heptanoic acid esters of l0-[3-(2-hydroxyethyl)piperazinopropyl]-2-trifiuoromethylphenothiazine.

Example 15.10-[3-(2-hydr0xyethyl)piperazinopropyl]- Z-trifluoromethylphenothiazine, ester with benzilic acid (a) To 4.37 g. of 10-[3-(Z-hydroxyethyl)piperazinopropyl]-2-trifluoromethylphenothiazine in 50 ml. of chloroform is added 2.65 g. of 2,2-bis-phenyl-Z-chloroacetyl chloride in 25 ml. of chloroform. The mixture is refluxed for 24 hours and concentrated to give l0-[3-(2-hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine, ester with 2,2-bis-phenyl-2-chloroacetic acid as a pale yellow oil.

(b) The product from (a) in'50 ml. of ether, 250 ml. of water and 0.84 g. of sodium bicarbonate are stirred and heated at 35 for one hour. The ether layer is separated, dried and concentrated to give l0-[3-(2-hydroxyethyl)piperazinopropyl] -2 trifiuoromethylphenothiazine, ester with benzilic acid.

Similarly, following the procedures set forth in Example 15, but substituting 10-[3-(2-hydroxyethoxyethyl)- piperazinopropyl]-2-trifiuoromethylphenothiazine for 10 [3-(Z-hydroxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazine yields 10 [3-(2 hydroxycthoxyethyl)- piperazinopropyl] 2 trifluoromethylphen'othiazine, ester with benzilic acid.

Example 16.Parenteral formulation A 50 g. of the heptanoie acid ester of 10-[3-(2-hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine obtained as in Example 2 is dissolved in 1000 ml. of

9 sesame oil, U.S.P. The solution is sterile filtered and packaged asceptically for parenteral administration.

Example 1 7.Parenteral formulation B A suspension of 56 g. of micronized heptanoic acid ester of -[3-(Z-hydroxyethyl)piperazinopropyl]-2 trifiuoromethylphenothiazine, prepared as in Example 2, 0.36 g. of lecithin, N.F., 0.18 g. of Tween 80 and 1.68 g. of aluminum monostearate (purified), diluted to 1000 ml. with sesame oil is prepared under sterile conditions and packaged aseptically for parenteral administration.

Example 18.Parenteral formulation C A solution of g. of the heptanoic acid ester of 10-[3-(2 hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine, 1.5 g. aluminum monostearate (purified) diluted to 1000 ml. with sesame oil, U.S.P., is sterile filtered and packaged aseptically for parenteral administrtaion.

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A pharmaceutical composition for parenteral administration in the treatment of mental disorders, said composition characterized by prolonged duration of activity which comprises, in combination (I) a physiologically ac tive compound of the formula wherein r is a positive integer of from one to two; X is selected from the group consisting of chloro and trifluoromethyl; and Y is selected from the group consisting of higher alkyl of from six to fourteen carbon atoms, higher alkenyl of from six to fourteen carbon atoms, higher alkynyl of from six to fourteen carbon atoms, tolyl, dimethyl benzyl, anisyl, and

wherein r is a positive integer of from one to two; X is selected from the group consisting of chloro and trifluoromethyl; and Y is selected from the group consisting of higher alkyl of from six to fourteen carbon atoms, higher alkenyl of from six to fourteen carbon atoms, higher alkynyl of from six to fourteen carbon atoms, tolyl, dimethyl benzyl, anisyl, and

0 (011;) n ii- O CH3 wherein n is a positive integer of from seven to twelve; and (II) a stable, non-toxic, pharmaoeutically acceptable, non-aqueous liquid carrier selected from the group consisting of vegetable oils, synthetic glycerol esters of long chain fatty acids and mixtures thereof; wherein the concentration of the said physiologically active compound is from about 20 mg./ml. to about 3*00 mg./ml.

3. A pharmaceutical composition for parenteral administration in the treatment of mental disorders, said composition characterized by prolonged duration of activity which comprises, in combination (I) the higher alkanoic acid ester of from seven to fifteen carbon atoms of 10-[3- (2 hydroxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazine and (If) a stable, non-toxic, pharmaceuticaily acceptable, non-aqueous liquid carrier selected from the group consisting of vegetable oils, synthetic glycerol esters of long chain fatty acids and mixtures thereof.

t. A pharmaceutical composition for parenteral administration in the treatment of mental disorders, said composition characterized by prolonged duration of activity which comprises, in combination (I) the higher alkanoic acid ester of from seven to fifteen carbon atoms of 10-[3- (2 hydroxyethyl)piperazinopropyl] 2 trifluoromethylphenothiazine and (H) a stable, non-toxic, pharmaceutically acceptable, non-aqueous liquid carrier selected from the group consisting of vegetable oils, synthetic glycerol esters of long chain fatty acids and mixtures thereof; wherein the concentration of the said higher alkanoic acid ester is from about 20 mg./ml. to about 300 rug/ml.

5. A pharmaceutical composition for parenteral administration in the treatment of mental disorders, said composition characterized by prolonged duration of activity which comprises, in combination (I) the decanoic acid ester of 10-[3-(Z-hydroxyethyl)piperazinopropyl]-2-tri fluoromethylphenothiazine and (H) a stable, non-toxic, pharmaceutically acceptable, non-aqueous liquid carrier selected from the group consisting of vegetable oils, synthetic glycerol esters of long chain fatty acids and mixtures thereof; wherein the concentration of the said decanoie acid ester of 10-[3-(Z-hydroxyethyl)piperazinopropyl]-2-trifluoromethylphenothiazine is from about 20 mg/ml. to about 300 mg./ml.

, 6. A pharmaceutical composition for parenteral administration in the treatment of mental disorders, said composition characterized by prolonged duration of activity which comprises, in combination (I) the decanoic acid ester of 19- 3- (Z-hydroxyethyl) piperazinopropyl] -2-trifluonomethylphenothiazine and (II) a stable, non-toxic, pharmaceutically acceptable, non-aqueous liquid carrier selected from the group consisting of vegetable oils, synthetic glycerol esters of long chain fatty acids and mixtures thereof.

'7. The method of treating patients for mental disorders which comprises parenterally administering once every two to three weeks to the said patients a small but effective amount of a composition comprising, in combination (I) a physiologically active compound of the formula wherein r is a positive integer of from one to two; X is selected from the group consisting of chloro and trifluoromethyl; and Y is selected from the group consisting of higher allryl of from six to fourteen carbon atoms, higher alkenyl of from six to fourteen carbon atoms, higher alkynyl of from six to fourteen carbon atoms, tolyl, dimethyl benzyl, anisyl and (CH2).. io-GH3 wherein n is a positive integer of from seven to twelve; and (II) a stable, non-toxic, pharmaceutically acceptable, non-aqueous liquid carrier selected from the group consisting of vegetable oils, synthetic glycerol esters of long chain fatty acids and mixtures thereof.

- l l 8. The method of treating patients for mental disorders which comprises parenterally administering once every two to three Weeks to the said patients about one milliliter of a composition comprising, in combination (I) a physiologically active compound of the formula wherein r is a positive integer of from one to two; X is 0 (CH2),,( J-O-OH wherein n is a'positive integer of from seven to twelve; and (II) a stable, non-toxic, pharmaceutically acceptable,

non-aqueous liquid carrier selected from the group c0nsisting of vegetable oils, synthetic glycerol esters of long chain fatty acids and mixtures thereof; wherein the concentration of the said physiologically active compound is from about 20 mg./ml. to about 300 mg./ml. 9. A method of treating patients for mental disorders which comprises parenterally administering once every two to three weeks, to the said patients about one milliliter of a composition comprising, in combination, the heptanoic acid ester of -[3-(Z-hydroxyethyl)piperazinopropyl]-2-trifiuoromethylphenothiazine and a stable, nontoxic, pharmaceutically acceptable non-aqueous liquid carrier selected. from the group consisting of vegetable oils, synthetic glycerol esters of long chain fatty acids and mixtures thereof; wherein the concentration of the said heptanoic acid ester of 10-[3-(2-l1ydroxyethyl)piperazinopropyl]-2-trifluoromethylphenothiazine is from aboutZO. mg./ml. to about 300 mtg/ml.

10. A method of treating patients for mental disorders which comprises parenterally administering once every 4 methylphenothiazine and a stable, non-toxic, pharmaceuti-cally acceptable non-aqueous liquid carrier selected from the group consisting of vegetable oils, synthetic glycerol esters of long chain 'fatty acids and mixtures thereof; wherein the concentration of the said higher .alkanoic acid ester of from seven to fifteen carbon atoms of 10-[3-(2- hydroxyethyl) piperazinopropyl] -2 trifiuoromethylphenothiazine is from about 20 mgJml. to about 300 mg/ml.

11. A method of treating patients for mental disorders which comprises parenterally administering once every two to three weeks, to the said patients about one milliliter of a compositioncomprising, in combination, the decanoic acid ester of 10-[3-(2-hydroxyethyl)piperazinopropyl]-2- trifiuoromethylphenothiazine and a stable non-toxic, pharmaceutically acceptable non-aqueous liquid carrier selected from the group consisting of vegetable oils, synthetic glycerol esters of long chain fatty acids and mixtures thereof; wherein the concentration of the said decanoic acid ester of 10-[3-(241ydroxyethyl)piperazinopropyl]-2-trifluoromethylphenothiazine is from about 20 mg./rnl. to about 300 mglml.

References Cited by the Examiner UNITED STATES PATENTS 2,507,193 5/50 Buckwalter l6758 2,544,272 3/51 Miller 16758 2,744,851 5/56 Halpern et al. 16758 2,892,753 6/59 Schmidt 16765 2,928,767 3/60 Gulesich 260243 3,058,979 10/62 .Ullyot 260-243 3,419,032 9/64 \Varing 16758 FOREIGN PATENTS 553,467 6/57 Belgium.

568,701 7/58 Belgium.

568,837 12/58 I Belgium.

829,246 3/60 Great Britain.

845,943 8/60 Great Britain.

OTHER REFERENCES Buckwalter, I. Am. Pharm. Assoc. Sci. Ed., vol. XLVII, No. 4, page 662, September 1958.

Voss, J. of Am. Pharm. Assoc. Sci. Ed., 43, 1954, 690, Wyman Card, May 1955.

JULIAN S. LEVITT, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

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Classifications
U.S. Classification514/225.8, 544/45
International ClassificationA61K31/00
Cooperative ClassificationA61K31/00
European ClassificationA61K31/00