Note: Descriptions are shown in the official language in which they were submitted.
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)
CH3
~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
;~
1128940
- 4 -
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),
CH3
~ 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-
,~ :
1128940
- 6 -
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,
' ~
' : .
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~
- 8 -
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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Z8940
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.
- 12 -
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1128940
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- 15 _ llZ894~
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--` 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.
i:`
.
"
1128940
-- 17 --
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~
- 19 -
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
-- 20 --
~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-
- 22 -
tj~, ~S
394
" -- 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
~ ~.
.
,. . .
.
