CA1128940A - Phenothiazine derivatives and a process for the preparation thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to new esters of 2-trifluoro-methyl-10[3-4-/2-hydroxyethyl/-piperazinyl-1)-propyl]-pheno-thiazine and pharmaceutically acceptable acid addition salts of these esters, furthermore to a process for the preparation of the new compounds. The acylating agents used in the prepara-tion of the esters are substituted or unsubstituted phenoxy-or naphthoxyisobutyric acids and functional derivatives there-of capable of forming an ester. 2-(6-Methoxy-2-naphthyl)-propionic acid and its functional derivatives can also be applied as acylating agents.
The new compounds according to the invention possess valuable neuroleptic effects. The oily solutions of the free bases exert protracted effects when administered as an injec-tion. The biological activities of the new compounds are more favorable than those of the known flufenazine decanoate and flufenazine, respectively.

Description

112~39~0 Tha inve~tion r01ate~ to new phenothiezine derivativea and pharmaaeutical oomposltlon~ aontainl~g the ~eeme, further-more to a proce~e ~or the prepar~tion thereof.
~he nflw phenothiazlne derivatlves eacor~ing to the in-~entton oorre~pond to t~e general ~ormula (I), ~ ~ ~ C~3 (I) /CH2/3~ CH2-CH2 .

~herein R repre~ent~ a group o~ the general ~ormula (IIa), (IIb) or (IIc), )-- O - C - C -. ~ 1 11 C~I3 o ~IIa) ~n X ~ - C -(IIb) CH30 ~ CH - C - IIIc) -'` ` 112~99~

and in these latter formulae X stands for hydrogen, a Cl 4 alkyl group, halogen atom or a nitro group and n is equal to 1, 2 or 3, with the proviso that if n isequal to 2 or 3, the X substituents attached to the aromatic ring may be the same or different.
The pharmaoe utically acoeptable acid addition salts of the new comr pounds having the general form~la tI) are also embraoed by the scope of the invention.
The term "halogen atom" refers to fluorine, chlorine, bromine and iodine. The Cl 4 alkyl groups may be straight-chained or branched groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.-butyl, etc.
Preferred representatives of the new compounds having the general formula (I) are those in which R represents a group of the general formula (IIa)(IIb) or (IIc), and in these latter formulae X stands for hydrogen, chlorine, methyl, tert.-butyl or nitro group and n is equal to 1, 2 or 3, with the provisothat if n is equal to 2 or 3, the X substituents may be the same or different.
Particularly preferred representatives of the new ccmpcurdb of the general formLla (I) are the following derivatives and their phanmaoe utic~lly acoeptable acid addition salts, primarily the hydrochlorides and fumarates:

2-trifluoromethyl-10-[3-(4-/2-hydroxyethyl/-piperazinyl-1-)-propyl]-pheno-thiazine-3,5-dimethylphenoxy-isobutyric acid ester, 2-trifluoromethyl-10-[3-(4-/2-hydroxyethyl/-piperazinyl-1)-propyl]-phenothiazine-2-(6-methoxy-2-naphthyl)-propionic acid ester, and ;~

2-trlrluoromethyl-10- ~-(4-/2-h~droxyethy V -pipqrazlnyl-l)-propy ~ -ph~nothiazlne-4-chlorophenoxy-lsobutyric acld e~ter.
~ he new ¢ompoun~ s¢cording to ~he inventlon ere new esters oP 2-trifluoro~ethyl-10~ 4-/~-~ydro~yethyl/_piper-azlnyl-1)-propy_7-phenothiezine (further on: ~lufenazine) rormed with carboxylio ecid~ o~ th~ general ~ormulae (IIIa), (IIIb) or (IIIc), ~ O - C - C - OH
~ CH3 o (IIIa) ~ ~ 3 (IIIb) ~ CH - C - OH
CH3 ~ CH3 0 - (IIIc) wherein ~ and n sre ~8 de~ined above.
The acid addition salts o~ the new ¢ompounds having the general ~ormula (I) are ~ormsd with pharmaceutlcally acceptable mineral a¢id~ (such a9 the hydrochlorides, sul~ates, phosphabes~ et¢.) or orgsnic a¢id~ (su¢h as the ethanesul~on-~tes, ~umarat~ mal~ates, ~uccinstes, t~rtrates, citrates, - 112894~

gluoonates, saccharinates, etc.).
m e invention relates further to a process for the preparation of new - phenothiazine derivatives having the general formula (I), wherein R i5 as de-fined above, and phanmaceutically acceptable acid addition salts thereof.
According to the process of the invention 2-trifluDromethyl-10-[3-(4-/2-hydroxy-ethyl/-piperazinyl-l)-propyl]-phenothiazine or a functional derivative thereof capable of form m g an ester is reacted with a carboxylic acid of the general formula (IIIa), (IITb) or (IIIc), wherein X and n are as defined above, or with a functional derivative thereof capable of forming an ester. If desired, a oom-pound of the general formula (I) can be con~erted into its acid addition salt, or the free base of the general formula (I) can be liberated from its salt by methods known per se.
Of the functional derivatives of flufenazine capable of ester formation, the alkali metal salts (particularly the sodium salt) and the active esters (such as the chloride) are preferred. Of the carbcxylic acids having the general formula (IIIa), (IIIb) and (IIIc) the followLng are ~entioned: phenoxy-isobutyric acid, mano- and dimethylphenoxyisabutyric acids (such as 2,3-, 2,4-, 2,5-, 2,6- and 3,5-dimethylph~noxyisobutyric acid), mDno- and di-tert.-butyl-phenoxyisobutyric acids (such as 4-tert.-butylphenoxyisabutyric acid), methyl- -tert.-butylphenaxyisobutyric acids, mono- and dichlorDphenoxyisobutyric acids (such as 4-chlorophenoxyisobutyric acid, 2,6-dichlor~phenaxyisQbutyric acid and 2,3-dichlorophenoxyisobutyric acid), 4-nitrophenaxyisobutyric acid, 1- and 2-naphthoxyisobutyric acids, mono- and dimethylnaphthQxyisobutyric acids, mono-~ and di-tert.-butyl-naphthoxyisobutyric acids, methyl-,~ :

tert.-butyln~phbhoxyisobutyric aclds and related cerboxylle acids, ~ur~hermore 2-(6-methoxy-2-naphthyl)-propionic ecid.
In~teed o~ the free cerboxylle a¢lds the respactive iun¢tlonel derlvetlves can be applled es well.
The functionel derlvatives Or the carboxylic seids having bhe generel formulee (IIIe), (IIIb) end (IIIe) eepeble Or osber formation may be acyl compounds commonly applied for the semQ purpose, such 8~ alkali metal selbs (e.g. sodlum or pots~sium salbs)~ ecyl halides tpre~erably scyl chlorides), acld anhydride~, ecid szides, reacbive esters, etc. Aeyl ehlor_ ides~proved bo be particularly preferrqd aeylating egents.
~steriri¢at~on can be performed in an inerb solvenb, such as benzene, toluene, chloroform, dichloroethane, etc.
~he compounds o~ the gew ral formula (I) een be conver~-ed into their acid addition salbs or~bhe beses can be liberet-ed irom~ their salts by methods well known in the art.
he starting ~ub`stenee Or ~the formula (IIIe) is known (J.T.-Harrlson, B. Levis, P. Nelson,~ W. Rook~, J. ~ed. Chem.
~ a~ 203 /1970/). ~he eryloxyisobutyric ecids applied es stsrt-- 20 ing ~ubstsnces are known in part; bhe new derlvstives Or the general rormulee (IIIa) and ~IIIb) can be prepared from the approprlabe phenols or naphthols~by method~ known per 8e (Bergellini, Gàzz. Chim. Ibal. 36, 334 /1906~). The~e acids ; ¢an be cooverted into their functional derivatives by known ~rocedurea; the acyl chlorides can be prepared e.g. by react-lng the respeetive carboxylic acids with bhionyl chloride.
The invenbion relate3 furbher bo pharmacèuticsl ~ompo-~ltions-conteining a sctive agent at least one compound o~
; the general ~ormula (I) or a pharmaceutically acceptable acid addltlon selt thereof together with a conventional inert, ' ~

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llZ8940 nan-toxic, solid or liquid pharmaceutical c ærier. As c ærier e.g. calcium bonate, magnesium ste æate, talc, starch, mannitol, cellulose, water, gela-tine, benzyl alcohol, sesame oil, etc. can be applied. The ph rmaceutical com-positians may be provided in solid (such as tablets, capsules, ooated tablets, suppositories, etc.) or liquid (such as injectable soluticns or suspensians, syrups, etc.) form. Of the pharmaoeutical oompositions the followmg æe part-icularly preferred: injectable compositians with protracted effects, containing 2 to 5 % of a base having the general formula (I) dissolved in sesame oil or peanut oil; tablets for oral administratian cantaining 0.25 to 10 mg of the difumæate of the hase; injectable compositians comprising a 0.25 to 0.5 %
aqueous solutian of a water-soluble salt; furthermore syrups and solutians can-taining about 0.1 % of active agent.
me pharmaoe utical compositions are prepared by methods well known in the pharmaceutical ndustry.
m e new oompounds of the general formula (I) and their pharmaoe utically acoeptable acid additian salts are valuable neuroleptic agents with neuroleptic effects exceeding those of flufenazine and its known esters. Several esters of flufenazine, such as esters formed with various fatty acids (H.L. Yale and F.
Sowinski, J. ~m. Ch3m. Soc. 82, 2039 /1960/; H.L. Yale, A.I. Cbhen and F.
Sowinski, J. Med. Chem. 6, 347 /1963/), the ester formed with 3,4,5-trimethoxy-benzoic acid (L. Tbldy, I. Toth and J. Borsy, A~ta Ch~m. Acad. Sci. Hung. 43, 253 /1965/) and the ester formed with l~ad~m~neane~arbcK~lic acid (H.L. Yale, J.
Med. Chen~ 20, 302 /1977/) have been described in the literature.
me duratian of the neuroleptic effect of the above 112894~

esters was examined by injecting thelr oily ~olutions into living organisms. Flufenazine decanoate~ which proved bo be tlle most preferred of the kno~n esters, is widely applied ln the clinicsl prectice ~J.E. Gro~es, M.R. ~endel, Arc. Gen.
Psychiatry ~, 893 /1975/). This compound, when injected into humens as a solution formod with sesame oil, exerts neuroleptlc activity for 3 to 4 weeks. Similar results were observed ~ith the l-edamentenecarboxylic acid ester in tests on enlmels.
The duretion o$ the neuroleptic effects of other e~ters ~suoh as the enanthate) is shorter (about 1 to 2 weeks), ~herees for She ecetate a duretion of activity identical to thet of ~luren-azine base was observed. No date can bè found in the litereture ebout the biologicel effects of other esters.
It follows from the above that esberification is not necessarily advsntegeous; with compounds oY related structures even such deta are known which indi¢ate that the esters do not possess the neuroleptic effects of the starting active ege~t (H.~. Yele, J. ~ed. Chem. 20, 304 /1977/, see Remark 7). Con- -seque~tlg, the biologicel properties of the esters cannot b~
predicted as they vary with the individual compounds.
Thus it was not aforeseen that the ne~ flu~enezine esters of the general formula (I) ere strong neuroleptic egents, i.e. th~t they show all the biological effects charscteri~tic o~ the phenothiflzine structure (reduction of motoric activity~
potenti~tio~ of the effects of narcoti¢q, inhibition of con-ditioned re~ponse, antagonization of emesi~ provoked by epo-morphine end ¢ataleptogenic activity~. It could not be predi¢ted either that the new esters o~ the general formula (I) are effecbive when injected as oily solutions (producing protracted e~ect), introduced orally in the form oY tlleir salts, injected , ` 112894~) _ g _ es egueous solutions Or the weter-eoluble selt~ end ep~lled eo ~olutione or syrupe. ~hese latter for~e o~ ad~lnietretion ~ere unknown ao rer ~or tlurenazine esters. Yoreover~ e~ it e~peers from the rollowlog tsbles, the biologtcal cherecter-letics o the no~ compounde heviog the general rormule (I) Jre mora edvantegeou~ tban bhose Or the known ~lurenezine deconoete end rlu~enazine, respectively.

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It appears from Table 1 that in the inhibition of conditioned avoid-ance response on rats both the 3,5-dimethylphenoxyisobutryric acid ester and the 2-(6-methoxy-2-naphthyl)-propionic acid est~r is more effective than the kncwn flufenazme decanoate on week 2 (the period determLning the protracted effect), whereas the 4-chlorophenoxyisobutyric acid ester has the same activity as the reference substanoe. Similar results were observed on dogs (see Table 2); the new esters of the general formula (I) inhibited the emesis provoked by apomor-phine even on the third week more strongly than the known flufenazine decanoate, and the duration of effect was longer for the new compounds than for the known substanoe.
The salts of the new esters having the general formula (I), particular-ly the fumarates, are well resorbed after oral admunistration and reduoe the spontaneous motoric activity (SM~) and the conditioned avoidanoe response (CAR) to the same extent as flufenazine (see Tables 3 and 4).
The cataleptogenic effect of the new compounds having the general formula (I) is also identical to that of flufenazine (see Table 5). Furthermore, considering that the dosages indicated in Tables 3 to 5 refer to the amounts of the free bases introduoed in the fonm of their salts, it can be seen that the effects appea!ring after the introduction of one part by weight of flufenazine can already be produ oed by applying the new compounds according to the invention in amaunts equivalent to 0.6 to 0.7 parts by weight of flufenazine. Ihe toxici-ties of the new compounds are also favourable with respect to their thera-peutical utilization.

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C~ ~p ~ ~4 ~ 0 ~ C~ ~,o ' --` 112894 -- 16 _ The invention i~ elucidated in detsil by bhe eld of the ~ollowing non-limitlng Examples.
ExamDle 1 PreDaration of 2-trifluoromethYl-10-/~- h-~2-hYdros~-et~ V -i~erazin~l-l)-Dro~lz~henothlazine-3~5-dimethYlp-hen i~obut~ric acid ester e) Preparation o~ the crude ester base 21.7 8 ~ 2-tri~luoromethyl-10- ~ -(4-/2-hydrozyethyl/-pl~erezinyl-l)-propy y -phenothiazine ere dissolved in 180 ml oi dlchloroetha~e. 15 ml o~ triethylamine are added to the solu-tion, and bhe mi~ture is stirred and cooled with ice water.
15.7 g Or 3,5-dimethylphenoxyisobutyryl chloride are addod to the mixture in portions within 0.5 hours. The mixture is stirred et room bemperature ~or 4 hours and then refluxed ~or 3 houre.
~he miYture i9 allowed to stand overnight~ the separated tri-ethylamine hydrochloride is ~iltered of~, and the iilt-rate i8 sheken with 180 ml Or a 7% aqueous ~odium h~drocarbonate solu-tion and then with 200 ml o~ water. ~he organic phase is drled o~er sodium sul~ate, filtered, and dichloroetha~e i8 evaporated undor reduced pressure. 32 g of the crude ester base are obtained.
b) Preparation o~ the difumarate ~- ~he crude base, prepared as described in point a) abo~e, is dissolved in a boiling solution of 14.8 g-o~ rumario ecid in 250 ml of 96% ethanol. The solution is decolourized ~ith activated carbon snd ~llowed to stand at room temperature overnlght. The separated crystals are ~iltered by ~uotiont wa~hed with 50 ml o~ ethanol and dried. 24.4 ~ of the difumarate are obtained; m.p.: 156-158C. After recrystallization ~rom a ~evenfold amount of ethanol the product ~elts at 158-160C.

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c) Liberation o~ the ba~e from the difumarate 20 g o~ the di~umarate,prepared as described 1~ polnt b) above,are dissolved in a mixture of 100 ml o~ ether snd 100 ml o~ a 1~ aqueous potessium carbonate ~olution under shsking~
(In~tead o~ ether chloroform or dichloroethane csn be applled es well.) The organic phase i9 sep~rated, washed with 100 ml o~ water, dried over sodium sulrate and evaporated under reduced pres~ure. 11 g o~ the ester base are obtained.
d) Preparation of the hydrochloride 18 g o~ the base, prepsred as described in point c) - above~ are dis~olved in 40 ml of ether and the solution i8 acldi~ied to Congo red with hydroahloric acid in absoiute ethanol. The separated cr~stals ar~ filtered o~ and washed wibh ether. 13 g of the dihydrochloride are obtained~ m.p.s 130-131C (under decomposition).
- The new 3,5-dimethylpheno~yisobutyric acid and the rospective scyl chloride, applied as starting 3ubstance~ can be prepared as follows:
54.8 g o~ 3,5-dimethylphenol are dissolved in 340 ~1 o~ sceto~e. 94.8 g of sodium hydroxide pellets are added to the solution, and then 44.1 ml of chloro~orm are i~troduced dropwise, within one hour, into the resulting heteroeeneous mixture under stirring and coolingO ~he reaction mixture is refluxed ~or 5 hours, the exce~s of acetone is evaporated under reduced pre~sure, the residue is dissolved in 600 ml o~ water~
snd bhe resulting solution is acidified to pH 2 with 5 n ~` hydrochloric acid. The separated oil is dissolved ln 300 ml of chloro~orm, the organic phase is separated, washed thrioe with 120 ml of a 7~ aqueous ~odium hydrocarbaDate solution each~ and the aqueous solution is acidified to pH 2 with .

llZ8940 -- 18 _ 5 n hydrochloric acid. 'rhe separHted free acid is t~ken up ln 130 ml oP chloroform, the ch~oroform ~olution i~ separated, eshed with 100 ml o~ water, dried over sodium ~ul~ate end ersporated under reduced pressure. 56.3 g of a cry~telllne 5 product are obtained upon standl~s; m.p.s 54-~oa. Arter re-cry~tellization from a 1.5-fold emount o~ petroleum ether pure 3,5-dimethylphenoxyl~obutyric acid is obtained; m.p.s 63-64C. ~he acyl chloride can be prepared, however, al80 from the crude product.
30 g oî 3,5-dimethylphenoxyisobutyric aaid, prepared es de~cribed above~ are dissolved in 150 ml o~ dry benzene.
48 ml of thio~Yl chloride are added to the solution, and the re~ulting mixture is refluxed ~or 3 hoursO Benzene and the esces~ o~ thio~rl chloride are evaporated under reduced pres~ure~
~nd the residue is distilled in vacuo. 20 g of 3,5-dimethyl-phe~osYi~obutyryl chloride are obtained; bop~ 115-119&/
0.6-0.8 mm Hg.
lixamPle 2 Pre~aration of 2-tri~luoromethYl-10-/~ /2-h~vdro~r-ethYv-~iperaziD:yl-l)-propyl7-~henothiazine-2~5-dimeshyl~hen os~isobutYrlc acid ester difumarate One proceeds as described in Example 1 with the dirference that 2,5-dimethylphenosyisobutyryl chloride i~
~epplied,lnstead of 3~5-dimethylphenoxyisobutyryl chloride.
Tho resultiD~ difumsrate melts at 152-154C after recrystsllisa-tion from ethanol.
2,5-Dimethylphenoxyisobutyric acid, applied as start-ub~tawe~ i8 prepared as deacribed in ~ample 1 with the d1fference that 2,5-dimethylphenol is applied instesd of ~,5-~llmethylphenol. ~he scid melts at 98-100C. Thi~ compou~d 112894~

i~ converted lnto 2,5-dimethylpheno~yisobut~ryl chloride a~
described in Exemple 1~ b.p.s 100-1~8C/0.6-1 mm Hg.
~xa~le ~
Pre~aratlon of 2-trifluoromethYl-10-/~-~4-/2-~Ydrox~-et~yl/-Di~rszinyl-l)-Dro~yl7-Dhenothlazine-2.6-dimeth~
phenoxyl~obut~ric acid ester di~umarate One prooeeds as described in Example 1 with the dif~erence bhat 2~6-dimethylphenoxyisobutyryl chloride is applied, instesd of 3,5-dimethylphenoxyisobutyryl chloride. ~he result-ing d1fumsrste melts at 136-138C aftor recrystallization from a 3sl mixture of ethanol and methanol.
The new 2,6-dimethylphenoxyisobutyric acid, applled as sterting substance~ is prepared as described in ~xample 1 wlth the difference that 2,6-dimethylphenol is utilized.instead oi ~,5-dimethylphenol. ~he resulting crude produc~ i~ converted into 2,6-dimethylphenoxyisobutyryl chloride as described i~
Exemple 1 with the difference that arter rePluxing the misture, benzene and the excess of thionyl chloride are evaporsted undor reduced pressure, the residue is di~solved in benzene, and O benze~e is e~aporated under reduced pressure. The resulting crude acyl chloride is applied in the process without purificetion.
Examnle 4 PreParation o~ 2-trifluoromethyl-10~ 4-~2-hydrox~-e thY~ era zinyl-l) -~rop~l7-phenothia zine-phenox~isobutyric _cid ester difumarate One pro¢eeds as described in ~xample 1 ~ith the differe~ce that the known pheno~yisobutyryl chloride (C.A.
Bischoff~ Ber. ~3, 934 /1900/) is applied instead of 3,5-dimeth-ylphe~oxyi90butYrYl chloride. The resulting di~umarate melts at 15~-154C after recry~tallization from ethanol.

llZ8940 ~xamDle 5 Prel~aretion of 2-trifluoromeS~Yl-10~ /2-~YdroxY-etb;rl/-~iPerazin.Yl-l) -~roDyl7-~henothiazine~¢hloro~henox~r-isobutyric acid ester diPum~rate One proceeds as described in ~xample 1 with the dl~rerence t}~t the known 4-chlorophenoxyisobutyr~l chloride (D.J. Osborne and R.L. Wein, Science 114~ 92 /1951/) is applied, instead of 3~5-dimethylphenoxyisobutyryl chloride. The result-ing di~umarate melts at 164-166C after recrystallization from iO ethanol.
~he base, melti~g at 54-56C~ is liberated ~rom the di~um~rate as described in point c) of Example 1.
ExamPle 6 Pre~aration o~ 2-trifluoromethyl-10-/~ /2-h~tdrox~-o~ari30butYric acid ester difumarate One proceeds as described in ~xample 1 with the dl~erence that 2,6-di¢hlorophenoxyisobutyryl chloride i~
- epplied,instead of 3~5-dimethylphenoxyisobutyryl chloride.
-20 The resultiDg difumarate melts ab 160-162C after recrystallisa-tion ~rom ethanol.
~he new 2,6-dichlorophenoxyisobutyric acid~ applied a~
atarting sub~tance, is prepared as described in Example 1 with the d~fference that 2,6-dichlorophenol i8 utilized~instead o~
3~5-dimethylphenol. The resulting crude acid is converted into 2~6-dichlorophenoxyisobutyryl chloride, boiling at 120_126C/
1-1.5 mm Hg~ a9 described in l~xample 1.
l~xa m~le 7 Preparation of 2_txifluoromethyl-10-/~F_(4--/2_h~YdroxY-~0 eth~ erazinyl-1)-Propyl7-Phenothiaæine-2,3-dichloro~hen-` 1~2894~

oxyisabutyric acid ester difumarate Gne proceeds as described in Example 1 with the differenoe that the - new 2,3-dichlorophenoxyisobutyryl chloride is applied, instead of 3,5-dimethyl-phenaxyisobutyryl chloride. The resulting difumarate melts at 154-156C after recrystallization from ethanol.
2,3-Dichlorophenoxyisabutyric acid, applied as starting substanoe, is prepared as described in Example 1 with the difference that 2,3-dichlorcphenol is utilized, instead of 3,5-dimethylphenol. The acid melts at 94-96 &. This cc0pound is o~n~erted into 2,3-dichlorophenoxyisabutyryl chloride, boiling at 120-124C/0.4-0.6 mm Hg, as described in Example 1.
Example 8 Preparation of 2-trifluoromethyl-10-[3-(4-/2-hydroxyethyl/-piperazinyl-l)-propyl]-phenothiazine-4-nitropbenoxyisobutyric acid ester difumarate Cne proceeds as described in Example 1 with the differerce that the knwwn 4-nitrophenoxyisobutyryl chloride (C.A. Bischoff, Ber. 33, 1601 /1900/) isapplied, instead of 3,5-dimethylphenoxyisobutyryl chloride. me resulting difumarate melts at 170-172C after recrystallization from ethanol.
s Example 9 Preparation of 2-trifluoromethyl-10-[3-(4-/2-hyd m xyethyl/-piperazinyl-l)-propyl]-phenothiazine-l-naphthaxyisabutyric acid ester difumarate one proceeds as described in Example 1 with the differenoe that the known 1-naphthaxyisabutyryl chloride (Frdl. 4, 105) is applied, instead of 3,5-dimethylphenoxyisabutyryl chloride. The resulting difumarate melts at 149-151C
after recrystallization from ethanol.

.
~ ' l~Z894~) Example 10 Preparation of 2-trifluoromethyl-10-[3-(4-/2-hydroxyethyl/-piperazinyl-l)-propyl]-phenothiazine-2-(6-~ethoxy-2-naphthyl)-propionic acid ester difumarate One proceeds as described in Example 1 with the differen oe that the kncwn 2-(6-methoxy-2-naphthyl)-propionyl chloride (J.T. Harrison et al., J. Med.
Ch~m. 13, 203 /1970/~ i5 applied, instead of 3,5-dimethylphenoxyisobutyryl chloride. The resulting difumarate melts at 152-154C after recrystallization from e~hanol. The purified ester base can be prepared as described in point c) of Example 1.
Example 11 Preparation of 2-trifluoromethvl-10-[3-(4-/2-hvdroxYethyl/-piperazinyl-.. . _ _ l)-propyl]-phenothiazine-4-tert.-butyl-phenoxyisobutyric acid ester difumarate Gne proceeds as described in Example 1 with the differen oe that 4-tert.-butyl-phenoxyisobutyric acid chloride is applied, instead of 3,5-dimethylphenoxy-isobutyryl chloride. The resulting difumarate nmelts at 160-162 & after re-crystallization from ethanol.

4-tert.-~utyl-phenoxyisobutyryl chloride, applied as starting sub-stan oe, is prepared from the known 4-tert.-butyl-phenoxyisobutyric acid (W.G.M.
Jones et al., United Kingdom patent No. 860,303) as described in Example 1 with the differen oe that after refluxing the mixture, benzene and the ex oe ss of thionyl chloride are evaporated under redu oe d pressure, the residue is dissolved in benzene, and benzene is evaporated under redu oe d pressure. m e resulting crude acyl chloride is applied in the pro oe ss without purification.
The follcwing esters of 2-trifluoromethyl-10-tj~, ~S

" -- 23 _ (4-t2-hYdroxyethyl/-piperaziny~ propy ~ -phqnothlezine aro aleo prepared a8 described ln the pr~ceding Example~t 2,4~6-trlmHthylphenoxyisobutyric acld ester~
2~6-dl-tert.-butyl-4-methyl-phenoxyi~obutyrlc acid e~ter~
methyl-naphthoxyisobutyrlc aoid ester, dlmethyl-naphthoxyisobutyrlc acid ester, methyl-tert.-butyl-naphthoYyisobutyrlc acid ester, and dl-tert.-butyl-naphthoxyisobutyrlc acid ester.
ExamDle 12 Pre~aration of a harm~ceuti¢al com~osltion 2-~ri~luoromethyl-lO- ~-(4-/2-hydroxyethyl/-piper-azl~yl-l)-propy y -phenothiazine-4-chlorophenoxyisobutjric acid ester i~ applied a9 starting substance in the form o~ the ireo - -bese.
De~ot-in~eotion ~ctive agent (base) 30 mg Benzyl alcohol 12 ~g Se~ame oil (with a quallty corresponding bo the prescription of DAB.7-BRD~ Chapter "Oil for i~jection purposes"). to l ml Examle 13 Pre~aration of ~harma¢~eutical comDosltlons In the following compo~itions 2-trifluoromethyl-lO-.
~ -~4-/2-hydroxyethyl/-piperazinyl-l)-propy ~ -phenothiazlne-3~5-dimethylphenoxyi~obu~yri¢ acid ester i8 applied as ac~ive agent either in the form of the free base or a8 the difumarate.
a) De~ot-iniection Active agent (base) 25 mg Benzyl alcohol 12 mg Se~ame oil (BP 73) to l.O ml 112894~) _ 2~ -bl) ~abl~t~ .
Aative a~ent ~dl~um~rate) 1.369 ~g ~oorresponds to 1 mg Or the rree ba~e) ~nnitol 5 5 .: 5 ~icrooryatalline oellulo~e ~7 ~
~ver~ee welght Or one t~blets 100.0 b2) blet~
.
~otlve agent ~dl~umarate) 3-424 ~g (corre~ponds to 2.5 m~ o~ the ~ree b~ee) ~Dnltol ; 5 - Ylcrocry~tall~e oellulo~e ~ ~ 9~.6 -.o~
- Average ~eighb o~ o~e tablet~ 100.0 g ~ ~.

.

,. . .

.

Claims (15)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a phenothiazine derivative of the general formula (I) or an acid addition salt thereof, (I) wherein R stands for a group of the general formula (IIa), (IIb) or (IIc), (IIa) (IIb) (IIc) and in these latter formulae X stands for hydrogen, a C1-4 alkyl group, a halo-gen atom or a nitro group and n is equal to 1, 2 or 3, with the proviso that if n is equal to 2 or 3, the X substituents attached to the aromatic ring may be the same or different, which process comprises reacting 2-trifluoromethyl-10-[3-(4-/2-hydroxyethyl/-piperazinyl-1)-propyl]-phenothiazine or a functional derivative thereof capable of forming an ester with a carboxylic acid of the general formula (IIIa), (IIIb) or (IIIc), (IIIa) (IIIb) (IIIc) wherein X and n are as defined above, or with a functional derivative thereof capable of forming an ester, and, if desired, converting a compound of the general formula (I) into an acid addition salt thereof or liberating a free base of the general formula (I) from a salt thereof.

2. A process as claimed in claim 1, wherein an alkali metal derivative or an active ester of 2-trifluoromethyl-10-[3-(4-/2-hydroxyethyl/-piperazinyl-1)-propyl]-phenothiazine is employed as functional derivative capable of forming an ester.

3. A process as claimed in claim 2, wherein the alkali metal derivative is the sodium salt.

4. A process as claimed in claim 2, wherein the active ester is the chloride.

5. A process as claimed in claim 1 or 2, wherein an alkali metal salt, an acyl halide, an acid anhydride, a mixed anhydride, an acid azide or a reactive ester of a carboxylic acid of general formula (IIIa), (IIIb) or (IIIc) is employed as functional derivative capable of forming an ester.

6. A process as claimed in claim 1 or 2, wherein an acyl chloride of a carboxylic acid of formula (IIIa), (IIIb) or (IIIc) is employed as functional derivative capable of forming an ester.

7. A process as claimed in claim 1, wherein starting compounds are chosen in which R represents a group of the general formula (IIa), (IIb) or (IIc) and in these latter formulae X stands for hydrogen, chlorine, methyl, tert.-butyl or nitro and n is equal to 1, 2 or 3, with the proviso that if n is equal to 2 or 3 the X substituents may be the same or different.

8. A process for preparing 2-trifluoromethyl-10-[3-(4-[2-hydroxyethyl]-piperazinyl-1)-propyl]-phenothiazine-3,5-dimethylphenoxy-isobutyric acid ester, or the difumarate or hydrochloride salt thereof, which comprises reacting 2-trifluoromethyl-10-[3-(4-[2-hydroxyethyl]-piperazinyl-1)-propyl]-phenothiazine with 3,5-dimethylphenoxyisobutyryl chloride, and, if necessary treating the free base with fumaric acid or with hydrochloric acid.

9. A process for preparing 2-trifluoromethyl-10-[3-(4-[2-hydroxyethyl]-piperazinyl-1)-propyl]-phenothiazine-2-(6-methoxy-2-naphthyl)-propionic acid ester and the difumarate and hydrochloride thereof, which comprises reacting 2-trifluoromethyl-10-[3-(4-[2-hydroxyethyl]-piperazinyl-1)-propyl]-phenothiazine with 2-(6-methoxy-2-naphthyl)-propionyl chloride and, if necessary, treating the base with fumaric acid or with hydrochloric acid.

10. A process for preparing 2-trifluoromethyl-10-[3-(4-[2-hydroxyethyl]-piperazinyl-1)-propyl]-phenothiazine-4-chlorophenoxy-isobutyric acid ester and the difumarate and hydrochloride thereof, which comprises reacting 2-trifluoro-methyl-10-[3-(4-[2-hydroxyethyl]-piperazinyl-1)-propyl]-phenothiazine with 4-chlorophenoxyisobutyryl chloride.

11. A phenothiazine derivative of general formula (I) as defined in claim 1, or an acid addition salt thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.

12. A compound as claimed in claim 11, wherein R represents a group of the general formula (IIa), (IIb) or (IIc), and in these latter formulae X stands for hydrogen, chlorine, methyl, tert.-butyl or nitro and n is equal to 1, 2 or 3, with the proviso that if n is equal to 2 or 3, the X substituents may be the same of different, whenever prepared by the process claimed in claim 7, or by an obvious chemical equivalent thereof.

13. 2-Trifluoromethyl-10-[3-(4-[2-hydroxyethyl]-piperazinyl-1)-propyl]-phenothiazine-3,5-dimethylphenoxyisobutyric acid ester, or the difumarate or hydrochloride thereof, whenever prepared by the process claimed in claim 8, or by an obvious chemical equivalent thereof.

14. 2-Trifluoromethyl-10-[3-(4-[2-hydroxyethyl]-piperazinyl-1)-propyl]-phenothiazine-2-(6-methoxy-2-naphthyl)-propionic acid ester, or the difumarate or hydrochloride thereof, whenever prepared by the process claimed in claim 9, or by an obvious chemical equivalent thereof.

15. 2-Trifluoromethyl-10-[3-(4-[2-hydroxyethyl]-piperazinyl-1)-propyl]-phenothiazine-4-chlorophenoxy-isobutyric acid ester or the hydrochloride or fumarate thereof, whenever prepared by the process claimed in claim 10, or by an obvious chemical equivalent thereof.