DE3013502A1 - ANGLE CLAMP ON 2 '' - (TRIFLUORMETHYL) -PHENTHIAZINE-10 '' - YL- (N-PROP-3 '' '- YLPIPERAZIN-4' '' '- YLAETH-2' '' '' - YL) ANGLE CLAMP FIRST, METHOD FOR PRODUCING THE SAME AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

The invention relates to new [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" -ylpiperazin-4 "" "-yleth-2" "" - yl) ] esters, a process for the preparation of the same and medicaments containing these compounds, in particular those with neuroleptic effects.

There are already 2-trifluoromethyl-10- {3 '- [4 "- (2" "- hydroxyethyl) -piperazin-1" - yl] -n-propyl} -phenthiazine (fluphenazine) and several esters of the same known. Various fatty acid esters of 2-trifluoromethyl-10- {3 '- [4 "- (2" "- hydroxyethyl) -piperazin-1" - yl] -n-propyl} -phenthiazine (HL Yale and F. Sowinski, J. Am. Chem. Soc. 82 [1960], 2 039; HL Yale, AI Cohen and F. Sowinski, J. Med. Chem. 6 [1963], 347), ester of 2-trifluoromethyl-10- {3 '- [4 "- (2" "- hydroxyethyl) -piperazin-1" - yl] -n-propyl} -phenthiazine with 3,4,5-trimethoxybenzoic acid (L. Toldy, I. Tóth and J. Borsy, Acta Chim. Acad. Sci. Hung. 43 [1965], 253) and esters of 2-trifluoromethyl-10- {3 '- [4 "- (2"' - hydroxyethyl) -piperazine-1 '' -yl] -n-propyl} -phenthiazine with 1-adamantanecarboxylic acid (HL Yale, J. Med. Chem. 20 [1977], 302).

The duration of the neuroleptic effect of the above esters was examined by injecting their oily solutions. The most advantageous representative of this group of compounds in pharmacy was capric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 '' '' '-yl)] ester or the fluphenazine decanoate is used (JE Groves, MR Mandel, Arch. Gen. Psychiatry 32 [1975], 893). This compound exerts its neuroleptic effect in human therapy after being injected in the form of a solution in sesame oil for 3 to 4 weeks. Similar results obtained in animal experiments have been reported for the 1-adamantane carboxylic acid ester. Other esters, for example enanthic acid [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth-2" "" '-yl)] - esters, show a shorter duration of action (about 1 to 2 weeks) and the acetic acid [2 "- (trifluoromethyl) -phenthiazin-10" - yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 "" "" - yl)] - ester has one of the duration of action of the 2-trifluoromethyl-10- {3 '- [4' '- (2' '' - hydroxyethyl) -piperazin-1 '' - yl] -n-propyl} -phenthiazine base, identical duration of action. Nothing at all was mentioned in the literature about the biological effects of other esters.

It follows from the above that the esterification itself does not necessarily give advantages; In the case of similar compounds, data are even known which show that the esters do not have the neuroleptic effect of the basic compound at all (H. L. Yale, J. Med. Chem. 20 [1977], 304, 7th comment).

The invention is based on the object of providing new [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 "" " '-yl)] - esters with superior pharmacological, in particular neuroleptic, effects, to provide a process for the preparation of the same and medicaments containing these compounds.

The above has surprisingly been achieved by the invention.

It was found that the new [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" -ylpiperazin-4 "" - yleth-2 '' '' '-yl)] esters or fluphenazine esters are powerful, superior neuroleptics, i.e. the phenthiazine structure-reducing movement activity or motility activity (SMS), anesthesia-potentiating, the conditioned reflex (CAR) inhibiting that caused by apomorphine

Have vomiting counteracting or this antagonizing and cataleptic effects to an increased extent, which is surprising, especially in view of the above facts with regard to the prior art. Furthermore, it was surprisingly found that the effect of the [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" -ylpiperazin-4 "" - yleth- 2 '' '' '- yl)] esters occurs both when their oily solutions are injected with delay and when their salts are administered orally and when the solutions of their soluble salts are injected and when their solutions or syrups are administered. It should also be noted that the latter application forms with [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yläth-2 ' '' '' -yl)] esters were previously unknown.

The invention therefore relates to [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 """- yl) )] - ester of the general formula

I, wherein

R for a remainder of the general formulas

IIa,

IIb respectively

IIc,

in which latter

X denotes hydrogen, an alkyl radical having 1 to 4 carbon atoms, halogen or a nitro group and

n is 1, 2 or 3,

where, in the case that n is 2 or 3, the X can be the same or different,

stands,

as well as their acid addition salts.

The term "halogen" includes fluorine, chlorine, bromine and iodine atoms. The alkyl radicals with 1 to 4 carbon atoms can be straight-chain or branched, for example methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl radicals.

The alkyl radical for which X can stand is preferably a methyl or tert-butyl radical.

It is preferred that the halogen X can represent is chlorine.

A preferred group of the compounds according to the invention are those in which X represents hydrogen, the methyl or tert-butyl radical, chlorine or the nitro group and R and n are defined as above, where the X can be identical or different.

Particularly preferred compounds according to the invention are the following: 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazine -4 '' '' - yleth-2 '' '' '- yl)] - ester, 2- (6'-methoxynaphth-2'-yl) -propionic acid- [2 "- (trifluoromethyl) -phenthiazine-10 '' -yl- (n-prop-3 '' '- ylpiperazin-4' '' '- yleth-2' '' '' - yl)] - ester and 2- (4'-chlorophenoxy) isobutyric acid [ 2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" -ylpiperazin-4 "" - yleth-2 "" "- yl)] - esters and their Acid addition salts, especially hydrochlorides and fumarates.

The acid addition salts of the invention

[2 "- (Trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" -ylpiperazin-4 "" "-yleth-2" "" - yl)] - ester of General formula I can be those with pharmaceutically usable inorganic acids, for example hydrochlorides, sulfates or phosphates, or organic acids, for example ethyl sulfates (ethanesulfonates), fumarates, maleates, succinates, tartrates, citrates, gluconates or saccharinates or saccharates.

The [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 """- yl)] - In other words, esters are esters of 2-trifluoromethyl-10- {3 '- [4 "- (2""- hydroxyethyl) -piperazin-1" - yl] -n-propyl} -phenthiazines {fluphenazines} with carboxylic acids the general formulas

IIIa,

IIIb

respectively

IIIc,

where X and n are as defined above.

The invention also relates to a process for the preparation of the compounds according to the invention, which is characterized in that 2-trifluoromethyl-10- {3 '- [4 "- (2""- hydroxyethyl) -piperazin-1" - yl ] -n-propyl} -phenthiazine or reactive derivatives thereof capable of ester formation with carboxylic acids of the general formulas

IIIa,

IIIb

respectively

IIIc, where X and n are defined as above, or are or are reacted with reactive derivatives capable of forming esters, whereupon the obtained [2 "- (trifluoromethyl) -phenthiazin-10" - yl- ( n-prop-3 '' '- ylpiperazin-4' '' '- yleth-2' '' '' - yl)] ester of the general formula I can be converted into acid addition salts by reaction with acids or the acid addition salts obtained from [2 '' - (Trifluoromethyl) -phenthiazin-10 '' - yl- (n-prop-3 '' '- ylpiperazin-4' '' '- yleth-2' '' '' - yl)] - ester of the general formula I in the free [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yläth-2" "" - yl) ] ester bases of the general formula I or into other acid addition salts thereof.

Advantageously, as reactive derivatives of 2-trifluoromethyl-10- {3 '- [4 "- (2" "- hydroxyethyl) -piperazin-1" - yl] -n-propyl} -phenthiazines alkali derivatives, which are capable of ester formation, especially alkali salts, especially the sodium derivative, or active esters, especially the chloride, can be used.

The following carboxylic acids or their reactive derivatives can advantageously be used as carboxylic acids of the general formulas IIIa, IIIb or IIIc: phenoxyisobutyric acid, mono- and dimethylphenoxyisobutyric acids, for example 2,3-, 2,4-, 2,5-, 2,6- and 3,5-dimethylphenoxyisobutyric acids, mono- and di-tert-butylphenoxyisobutyric acids, for example 4-tert-butyl-phenoxyisobutyric acid, (methyl) - (tert-butyl) -phenoxyisobutyric acids, mono- and dichlorophenoxyisobutyric acids, for example 4-chlorophenoxyisobutyric acid, 2,6-dichlorophenoxyisobutyric acid and 2,3-dichlorophenoxyisobutyric acid, 4-nitrophenoxyisobutyric acid, naphth-1-oxyisobutyric acid,

Naphth-2-oxyisobutyric acid, mono- and dimethylnaphthoxyisobutyric acids, mono- and di-tert-butylnaphthoxyisobutyric acids and (methyl) - (tert-butyl) -naphthoxyisobutyric acids and 2- (6'-methoxynaphth-2'-yl) propionic acid.

As reactive derivatives of the carboxylic acid of the general formula IIIa, IIIb or IIIc capable of ester formation, alkali metal salts, acid halides, acid anhydrides, mixed acid anhydrides, acid azides or active esters can advantageously be used. Of these, the acid chlorides have proven to be particularly advantageous acylating agents.

The esterification can be carried out in an inert solvent. Benzene, toluene, chloroform or dichloroethane, for example, can be used as the reaction medium.

The carboxylic acid which can be used as starting material of the formula IIIc in the process according to the invention, namely 2- (6'-methoxynaphth-2'-yl) propionic acid, is known (JT Harrison, B. Levis, P. Nelson, W. Rooks: J. Med Chem. 13: 203 [1970]). Some of the aryloxyisobutyric acids of the general formulas IIIa and IIIb which can be used as starting materials in the process according to the invention are known, while the new ones may have been prepared from the corresponding phenol or naphthol in a manner known per se (Bargellini: Gazz. Chim. Ital. 36 [ 1906], 334). The reactive derivatives of these acids capable of forming esters can also have been prepared by processes known per se. The acid chlorides can, for example, have been prepared from the corresponding carboxylic acids with thionyl chloride.

Furthermore, pharmaceuticals according to the invention are which

1 or more of the compounds according to the invention as an active ingredient or active ingredients, expediently contained together with customary pharmaceutical formulations, such as inert, non-toxic solid or liquid pharmaceutical carriers, are provided.

As already mentioned, the compounds according to the invention have valuable pharmacological, in particular neuroleptic, effects which are similar to those of the known 2-trifluoromethyl-10- {3 '- [4 "- (2" "- hydroxyethyl) -piperazine-1" - yl] -n-propyl} -phenthiazines and its known esters.

Tables I to V below show the results of pharmacological investigations with compounds according to the invention and the comparison substances 2-trifluoromethyl-10- {3 '- [4 "- (2" "- hydroxyethyl) -piperazin-1" - yl ] -n-propyl} -phenthiazine dihydrochloride and capric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 ' '' '' yl)] - ester compiled.

Table I Acute toxicity in mice and rats

Table II Inhibition of the conditioned defense reflexes (CAR) in rats in the swing box (shuttle box)

Table III Counteracting Apomorphine Induced Vomiting in Dogs

Table IV Inhibition of spontaneous motor activity (SMA) in mice in the Animex apparatus

Table V Inhibition of the conditioned defense reflexes (CAR) in rats in a swing box (shuttle box)

Table VIa Cataleptic effect in mice

Table VIb Cataleptic effect in rats

It can be seen from Table I above that the toxicity of the compounds according to the invention is approximately the same as that of the comparison substances. Table II above shows that when determining the inhibition of the conditioned defense reflexes (CAR) in rats in the second week relevant for this experiment, both the 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid [2 '' - (trifluoromethyl) -phenthiazin-10 '' - yl- (n-prop-3 '' '- ylpiperazin-4' '' '- yleth-2' '' '' - yl)] - ester as well as the 2- (6'-Methoxynaphth-2'-yl) -propionic acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" " -yläth-2 '' '' '- yl)] - ester of the comparison substance capric acid- [2' '- (trifluoromethyl) -phenthiazin-10' '- yl- (n-prop-3' '' - ylpiperazin-4 ' '' '-yläth-2' '' '' - yl)] - ester and 2- (4'-chlorophenoxy) -isobutyric acid- [2 '' - (trifluoromethyl) -phenthiazin-10 '' - yl- (n-prop-3 '' '- ylpiperazin-4' '' '- yläth-2' '' '' - yl)] - ester achieved the effectiveness of the comparison substance mentioned. From the above Table III it can be seen that all the compounds according to the invention that were investigated also in the 3rd week inhibited the vomiting caused by apomorphine more strongly than the comparison substance capric acid- [2 "- (trifluoromethyl) -phenthiazin-10" - yl- ( n-prop-3 '' '- ylpiperazin-4' '' '- yläth-2' '' '' - yl)] - ester and also the duration of action of the compounds according to the invention was longer (effect even in the 7th week ) than that of the comparison substance (in the 7th week no more effect at all).

From the above Tables IV and V it can be seen that the salts of the compounds according to the invention are well absorbed orally and the spontaneous motor activity (SMA) and the conditioned defense reflexes (CAR) to the same extent as the salt of the comparison substance 2-trifluoromethyl-10- { 3 '- [4' '- (2' '' - hydroxyethyl) -piperazin-1 '' - yl] -n-propyl} -phenthiazine decrease. From Tables VIa and VIb above it emerges that the cataleptic effect of the compounds according to the invention with that of 2-trifluoromethyl-10- {3 '- [4 "- (2" "- hydroxyethyl) -piperazin-1" - yl] -n-propyl} -phenthiazines or capric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "-yleth-2" "" "- yl )] - esters is identical.

Particularly with regard to the results of the above Tables I, IV, V and VIa, however, it must be taken into account that if the doses or LDtief50 - or EDtief50 values of the salts examined are based on the 2-trifluoromethyl-10- {3 '- [4' ' - (2 "" - hydroxyethyl) -piperazin-1 "-yl] -n-propyl} -phenthiazine content of the same can be obtained, which can be seen with the compounds according to the invention by introducing an approximately 0.6-fold 2-trifluoromethyl-10- { 3 '- [4' '- (2' '' - hydroxyethyl) -piperazin-1 '' - yl] -n-propyl} -phenthiazine amount in the body to be treated, based on the amount of 2-trifluoromethyl-10- {3 '- [4' '- (2' '' - hydroxyethyl) -piperazin-1 '' - yl] -n-propyl} -phenthiazine salt even introduced 2-trifluoromethyl-10- {3 '- [4' '- (2 '' '- hydroxyethyl) -piperazin-1' '- yl] -n-propyl} -phenthiazine amount, the same effect as with the 2-trifluoromethyl-10- {3' - [4 "- (2" '-hydroxyäthyl) -piperazin-1' '- yl] -n-propyl} -phenthiazine itself was achieved, the toxicity also being favorable in the former case.

The medicaments according to the invention can contain, for example, calcium carbonate, magnesium stearate, talc, starch, mannitol, cellulose, water, gelatin, benzyl alcohol or sesame oil as carriers. The pharmaceutical preparations according to the invention can be in solid form, for example as tablets, capsules, coated tablets or suppositories, or in liquid form, for example as injection solutions, suspensions or syrups. As beneficial

The following preparations should be mentioned: 2 to 5% injection solutions with delayed action of [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" '-yläth-2' '' '' - yl)] - ester bases of the general formula I in sesame oil or peanut oil, orally administrable tablets with a [2 "- (trifluoromethyl) -phenthiazin-10" - yl- (n- prop-3 '' '- ylpiperazin-4' '' '- yläth-2' '' '' - yl)] - ester difumarate active ingredient content of 0.25 to 10 mg and 0.25 to 0.5% aqueous injection solutions of the water-soluble [2 "- (trifluoromethyl) -phenthiazine-10" -yl- (n-prop-3 "" - ylpiperazine-4 "" - yleth-2 "" "- yl)] ester salts and also syrups and solutions with a content of about 0.1% of the active ingredients according to the invention.

The preparation of the pharmaceutical preparations according to the invention can have been carried out according to methods known per se from the pharmaceutical industry.

The [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 "" "- yl)] - In human therapy in adults, esters can advantageously be administered in daily doses of 1.5 to 120 mg. The preferred daily dose of 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4' '' '-yläth-2' '' '' - yl)] - ester is 6 to 11 mg.

The invention is explained in more detail using the following examples:

example 1

2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth -2 '' '' '- yl)] - ester

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine- (3,5-dimethylphenoxy) -isobutyric acid ester}

a) Preparation of the crude 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4' '' '-yläth-2' '' '' - yl)] - esterbase

21.7 g of 2-trifluoromethyl-10- {3 '- [4 "- (2" "- hydroxyethyl) -piperazin-1" - yl] -n-propyl} -phenthiazine were dissolved in 180 cm3 dichloroethane . 15 cm 3 triethylamine were added to the solution and the mixture was mixed with 15.7 g of 3,5-dimethylphenoxyisobutyric acid chloride in several portions for ½ hour while stirring or shaking and cooling with ice-cold water. The reaction mixture was stirred or shaken for 4 hours at room temperature and then heated to boiling for 3 hours. It was then left to stand overnight, the precipitated triethylamine hydrochloride was filtered off and the filtrate was extracted by shaking with 180 cm3 of a 7% aqueous sodium bicarbonate solution and 200 cm3 of water. After drying over anhydrous sodium sulfate, the dichloroethane was distilled off under reduced pressure. So 32 g (97.2% of theory) of the crude 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" - yl- (n-prop- 3 '' '- ylpiperazin-4' '' '- yläth-2' '' '' - yl)] - esterbase. b) Preparation of 2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 " '' -yläth-2 '' '' '- yl)] - esterdifumarates

The crude 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 '' '' - yläth-2 '' '' '- yl)] - ester base was dissolved in a solution of 14.8 g of fumaric acid in 250 cm3 of 96% ethanol at the boiling point. The solution was clarified with activated charcoal and left at room temperature overnight. The precipitated crystals were filtered off with suction, washed with 50 cm3 of ethanol and dried. Thus, 24.4 g (56.1% of theory, based on the crude 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 '' '- ylpiperazin-4' '' '- yläth-2' '' '' - yl)] - ester base, and thus 54.5% of theory, based on the 2-trifluoromethyl- 10- {3 '- [4' '- (2' '' - hydroxyethyl) -piperazin-1 '' - yl) -n-propyl} -phenthiazine) 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" -ylpiperazin-4 "" - yleth-2 "" "- yl)] - ester difumarate with obtained a melting point of 156 to 158 ° C. The melting point after recrystallization from 7 times the amount of ethanol was 158 to 160 ° C. c) Preparation of 2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 " '' -yläth-2 '' '' '- yl)] - ester base from 2- (3', 5'-dimethylphenoxy) -isobutyric acid- [2 '' - (trifluoromethyl) -phenthiazin-10 '' - yl- (n-prop-3 '' '- ylpiperazin-4' '' '- yleth-2' '' '' - yl)] - ester difumarate

There were 20 g of 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" - yl- (n-prop-3') prepared as described in section b) above. '' -ylpiperazine-4 '' '' - yläth-2 '' '' '- yl)] - ester difumarate in a mixture of 100 cmh3 ether (instead of ether, chloroform or dichloroethane could be used) and 100 cmh3 of a 10 % aqueous potassium carbonate solution dissolved with shaking or stirring. The organic phase was separated off, washed with 100 cm high 3 water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. So 11 g (72.6% of theory, based on the 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" - yl- (n- prop-3 '' '- ylpiperazin-4' '' '- yläth-2' '' '' - yl)] - ester difumarate, and thus 39.6% of theory, based on the 2-trifluoromethyl-10- { 3 '- [4' '- (2' '' - hydroxyethyl) -piperazin-1 '' - yl) -n-propyl} -phenthiazine) 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2' '- (trifluoromethyl) -phenthiazin-10 "-yl- (n-prop-3" "-ylpiperazin-4" "" - yleth-2 "" "- yl)] ester base. d) Preparation of 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 " '' -yläth-2 '' '' '- yl)] - esterdihydrochlorides

18 g of 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" - yl- (n-prop-3') were prepared as described in section c) above. '' -ylpiperazin-4 '' '' - yläth-2 '' '' '- yl)] - ester base dissolved in 40 cm high 3 ether and a mixture of absolute ethanol and hydrochloric acid was added until the reaction mixture turned acidic to Congo red showed. The precipitated crystals were filtered off and washed with ether. So 13 g (63.9% of theory, based on the 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" - yl- (n- prop-3 '' '- ylpiperazin-4' '' '- yläth-2' '' '' - yl)] - ester base, and thus 25.3% of theory, based on the 2-trifluoromethyl-10- { 3 '- [4' '- (2' '' - hydroxyethyl) -piperazin-1 '' - yl) -n-propyl} -phenthiazine) 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2' '- (trifluoromethyl) -phenthiazin-10 "-yl- (n-prop-3" "-ylpiperazin-4" "" -yleth-2 "" "- yl)] - ester dihydrochloride with a melting point of 130 to 131 ° C (with decomposition) obtained.

The new 3,5-dimethylphenoxyisobutyric acid chloride used as the starting substance has been prepared as follows:

54.8 g of 3,5-dimethylphenol were dissolved in 340 cm3 of acetone. 94.8 g of granular sodium hydroxide were added to the solution, whereupon 44.1 cm3 of chloroform was added dropwise to the resulting heterogeneous mixture with cooling and stirring over 1 hour. The reaction mixture was heated to boiling for a further 5 hours, the excess

Acetone was evaporated off under reduced pressure, the residue was dissolved in 600 cmh3 of water and the resulting solution was acidified to pH 2 with 5N hydrochloric acid. The separated oil was dissolved in 300 cm high 3 chloroform, the separated organic phase was extracted 3 times with 120 cm high 3 each of a 7% aqueous sodium bicarbonate solution and the aqueous phase was acidified to a pH of 2 with 5 N hydrochloric acid. The precipitated free 3,5-dimethylphenoxyisobutyric acid was taken up in 130 cm high 3 chloroform and the separated chloroform phase was shaken with 100 cm high 3 water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. On standing, 56.3 g of a crystalline product with a melting point of 54 to 60 ° C. were obtained. After recrystallization from 1½ times the amount of petroleum ether, pure 3,5-dimethylphenoxyisobutyric acid with a melting point of 63 to 64 ° C. was obtained. However, the crude product was also suitable for the production of their acid chloride.

30 g of the above 3,5-dimethylphenoxyisobutyric acid was dissolved in 150 cm3 of anhydrous benzene. After adding 48 cm 3 thionyl chloride, the reaction mixture was heated to boiling for 3 hours. The benzene and the excess thionyl chloride were evaporated off under reduced pressure and the residue was distilled off under reduced pressure. 20 g (36.9% of theory, based on the 3,5-dimethylphenol used) of 3,5-dimethylphenoxyisobutyric acid chloride with a boiling point of 115 to 119 ° C. / 0.6 to 0.8 mm Hg were obtained.

Example 2

2- (2 ', 5'-Dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth -2 '' '' '- yl)] - ester difumarate

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine-2,5-dimethyl-phenoxy-isobutyric acid ester difumarate}

The procedure was as described in Example 1, but with the difference that the starting substance used was 2,5-dimethylphenoxyisobutyric acid chloride instead of the 3,5-dimethylphenoxyisobutyric acid chloride. After recrystallization from ethanol, the 2- (2 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazine) obtained -4 '' '' - yleth-2 '' '' '- yl)] - ester difumarate has a melting point of 152 to 154 ° C.

The new 2,5-dimethylphenoxyisobutyric acid chloride used as the starting substance was prepared analogously to the procedure for preparing the starting substance of Example 1, but with the difference that 2,5-dimethylphenol was used in place of the 3,5-dimethylphenol. The 2,5-dimethylphenoxyisobutyric acid obtained had a melting point of 98 to 100 ° C. and the 2,5-dimethylphenoxyisobutyric acid chloride obtained therefrom analogously to that given in Example 1 had a boiling point of 100 to 108 ° C. / 0.6 to 1 mm Hg.

Example 3

2- (2 ', 6'-Dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "-yleth -2 '' '' '- yl)] - ester difumarate

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine-2,6-dimethyl-phenoxy-isobutyric acid ester difumarate}

The procedure was as described in Example 1, but with the difference that the starting substance used was 2,6-dimethylphenoxyisobutyric acid chloride instead of the 3,5-dimethylphenoxyisobutyric acid chloride. After recrystallization from a mixture of ethanol and methanol in a volume ratio of 3: 1, the 2- (2 ', 6'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" - yl- (n-prop-3 '' '- ylpiperazin-4' '' '- yleth-2' '' '' - yl)] - ester difumarate has a melting point of 136 to 138 ° C.

The new 2,6-dimethylphenoxyisobutyric acid chloride used as the starting substance was prepared analogously to the procedure for preparing the starting substance of Example 1, but with the difference that 2,6-dimethylphenol was used in place of the 3,5-dimethylphenol and in the second stage (Chloride production) After heating to the boiling point, the benzene and the excess thionyl chloride were distilled off under reduced pressure, the residue was dissolved in benzene, and the benzene was evaporated off under reduced pressure. The crude 2- (2 ', 6'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 " '' -yläth-2 '' '' '- yl)] - ester difumarate was used as the starting substance used for further implementation.

Example 4

2-Phenoxyisobutyric acid [2 '- (trifluoromethyl) -phenthiazin-10'-yl- (n-prop-3 "- ylpiperazin-4" "-yleth-2" "- yl)] ester difumarate

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine-phenoxy-isobutyric acid ester difumarate}

The procedure was as described in Example 1, but with the difference that the known phenoxyisobutyric acid chloride (C. A. Bischoff, Ber. 33 [1900], 934) was used as the starting substance in place of the 3,5-dimethoxyisobutyric acid chloride. After recrystallization from ethanol, the 2-phenoxyisobutyric acid- [2 '- (trifluoromethyl) -phenthiazin-10'-yl- (n-prop-3' '- ylpiperazin-4' '' - yleth-2 '' '') -yl)] - ester difumarate has a melting point of 152 to 154 ° C.

Example 5

2- (4'-Chlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazine-10" -yl- (n-prop-3 "" -ylpiperazin-4 "" "- yleth-2 ' '' '' yl)] - ester difumarate

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine-4-chlorophenoxy-isobutyric acid ester difumarate}

The procedure was as described in Example 1, but with the difference that the known 4-chlorophenoxyisobutyric acid chloride (D. J. Osborne and R. L. Wein, Science 114 [1951], 92) was used as the starting material instead of the 3,5-dimethylphenoxyisobutyric acid chloride. After recrystallization from ethanol, the 2- (4'-chlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 ') '' '-yläth-2' '' '' - yl)] - ester difumarate has a melting point of 164 to 166 ° C.

For this 2- (4'-chlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth- 2 '' '' '- yl)] - ester difumarate could the 2- (4'-chlorophenoxy) -isobutyric acid- [2' '- (trifluoromethyl) -phenthiazin-10' '- yl- (n-prop-3' ' '-ylpiperazin-4' '' '- yläth-2' '' '' - yl)] - ester base with a melting point of 54 to 56 ° C can be released according to the procedure described in Example 1, section c).

Example 6

2- (2 ', 6'-dichlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth -2 '' '' '- yl)] - ester difumarate

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine-2,6-dichlorophenoxy-isobutyric acid ester difumarate}

The procedure was as described in Example 1, but with the difference that 2,6-dichlorophenoxyisobutyric acid chloride was used as the starting substance instead of 3,5-dimethylphenoxyisobutyric acid chloride.

After recrystallization from ethanol, the 2- (2 ', 6'-dichlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazine) obtained -4 '' '' - yleth-2 '' '' '- yl)] - ester difumarate has a melting point of 160 to 162 ° C.

The new 2,6-dichlorophenoxyisobutyric acid chloride used as the starting substance was prepared analogously to the procedure for preparing the starting substance of Example 1, but with the difference that 2,6-dichlorophenol was used in place of the 3,5-dimethylphenol. The 2,6-dichlorophenoxyisobutyric acid chloride obtained had a boiling point of 120 to 126 ° C./1 to 1.5 mm Hg.

Example 7

2- (2 ', 3'-dichlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" -ylpiperazin-4 "" -yleth -2 '' '' '- yl)] - ester difumarate

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine-2,3-dichlorophenoxy-isobutyric acid ester difumarate}

The procedure was as described in Example 1, but with the difference that the new 2,3-dichlorophenoxyisobutyric acid chloride was used as the starting substance in place of the 3,5-dimethylphenoxyisobutyric acid chloride. After recrystallization from ethanol, the 2- (2 ', 3'-dichlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazine) obtained -4 '' '' - yleth-2 '' '' '- yl)] - ester difumarate has a melting point of 154 to 156 ° C.

The 2,3-dichlorophenoxyisobutyric acid chloride used as the starting substance was prepared analogously to the procedure for preparing the starting substance of Example 1, but with the difference that 2,3-dichlorophenol was used instead of the 3,5-dimethylphenol. The 2,3-dichlorophenoxyisobutyric acid obtained had a melting point of 94 to 96 ° C. and the 2,3-dichlorophenoxyisobutyric acid chloride obtained therefrom analogously to that given in Example 1 had a boiling point of 120 to 124 ° C. / 0.4 to 0.6 mm Ed.

Example 8

2- (4'-Nitrophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth-2 ' '' '' -yl)] - ester difumarate

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine-4-nitrophenoxyisobutyric acid ester difumarate}

The procedure was as described in Example 1, but with the difference that the known 4-nitrophenoxyisobutyric acid chloride (C. A. Bischoff, Ber. 33 [1900] 1 601) was used as the starting substance in place of the 3,5-dimethylphenoxyisobutyric acid chloride. After recrystallization from ethanol, the 2- (4'-nitrophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 ') '' '-yläth-2' '' '' - yl)] - ester difumarate has a melting point of 170 to 172 ° C.

Example 9

2- (Naphth-1'-oxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazine-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth- 2 '' '' '- yl)] - ester difumarate

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine-1-naphthoxy-isobutyric acid ester difumarate}

The procedure was as described in Example 1, but with the difference that the known naphth-1-oxyisobutyric acid chloride (Frdl. 4, 105) was used as the starting substance in place of the 3,5-dimethylphenoxyisobutyric acid chloride. After recrystallization from ethanol, the 2- (naphth-1'-oxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin- 4 '' '' - yleth-2 '' '' '- yl)] - ester difumarate has a melting point of 149 to 151 ° C.

Example 10

2- (6'-Methoxynaphth-2'-yl) -propionic acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" " -yläth-2 '' '' '- yl)] - ester difumarate

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine-2- (6-methoxy-2-naphthyl) propionic acid ester difumarate}

The procedure described in Example 1 was followed, but with the difference that the starting substance was used

Instead of 3,5-dimethylphenoxyisobutyric acid chloride, the known 2- (6'-methoxynaphth-2'-yl) propionic acid chloride (J. T. Harrison and coworkers, J. Med. Chem. 13 [1970], 203) was used. After recrystallization from ethanol, the obtained 2- (6'-methoxynaphth-2'-yl) propionic acid [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" -ylpiperazin-4 '' '' - yleth-2 '' '' '- yl)] - ester difumarate has a melting point of 152 to 154 ° C. The purified 2- (6'-methoxynaphth-2'-yl) -propionic acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 " '' -yläth-2 '' '' '- yl)] - ester base could be prepared according to the procedure of example 1, section c).

Example 11

2- (4'-tert-Butylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth -2 '' '' '- yl)] - ester difumarate

{2-Trifluoromethyl-10- [3- (4- <2-hydroxyethyl> -piperazinyl-1) -propyl] -phenthiazine-4-t-butyl-phenoxyisobutyric acid ester difumarate}

The procedure was as described in Example 1, but with the difference that 4-tert-butylphenoxyisobutyric acid chloride was used as the starting substance in place of the 3,5-dimethylphenoxyisobutyric acid chloride. After recrystallization from ethanol, the 2- (4'-tert-butylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazine) obtained -4 '' '' - yleth-2 '' '' '- yl)] - ester difumarate has a melting point of 160 to 162 ° C.

The 4-tert-butylphenoxyisobutyric acid chloride used as the starting substance was prepared from the known 4-tert-butylphenoxyisobutyric acid (WGM Jones and coworkers, British patent 860 303) according to the procedure for the preparation of the starting substance of Example 1, but with the difference that after after heating to the boiling point, the benzene and the excess thionyl chloride were distilled off under reduced pressure, the residue was dissolved in benzene and the benzene was evaporated off under reduced pressure. The crude 4-tert-butylphenoxyisobutyric acid chloride thus obtained was used as the starting substance for further reaction without purification.

Analogously to the above examples, the following [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 "" "" -yl)] - ester produced:

2- (2 ', 4', 6'-Trimethylphenoxy) -isobutyric acid- [2 '' - (trifluoromethyl) -phenthiazin-10 '' - yl- (n-prop-3 '' '- ylpiperazin-4' '' '-yläth-2' '' '' - yl)] - ester,

2- (2 ', 6'-Di-tert-butyl-4'-methylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazine -4 '' '' - yläth-2 '' '' '- yl)] - ester,

2- (methylnaphthoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth-2" "" '-yl)] - ester,

2- (Dimethylnaphthoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth-2" "" '-yl)] - ester,

2- (methyl-tert-butylnaphthoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 ' '' '' -yl)] - ester

and

2- (Ditert-butylnaphthoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 ' '' '' -yl)] - ester.

Example 12

Depot injection solution

Active ingredient 2- (4'-chlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 '' '' '-yl)] - ester (as base) 30 mg

Benzyl alcohol 12 mg

Sesame oil high o) to fill up to 1 cm high 3

hocho) according to the quality of DAB. 7, FRG, paragraph "Oil for injection purposes".

Example 13

a) Depot injection solution

Active ingredient 2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2' '- (trifluoromethyl) -phenthiazin-10' '- yl- (n-prop-3' '' - ylpiperazin-4 '' '' - yläth-2 '' '' '- yl)] - ester (as base) 25 mg

Benzyl alcohol 12 mg

Sesame oil (BP 73) to fill up to 1.0 cm high 3

b) tablets

I)

Active ingredient 2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2' '- (trifluoromethyl) -phenthiazin-10' '- yl- (n-prop-3' '' - ylpiperazin-4 '' '' - yläth-2 '' '' '- yl)] - ester difumarate (the active ingredient content corresponds to 1 mg base) 1.369 mg

Mannitol 5 mg

Microcrystalline cellulose 93.7 mg

Average tablet weight 100.0 mg

II)

Active ingredient 2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2' '- (trifluoromethyl) -phenthiazin-10' '- yl- (n-prop-3' '' - ylpiperazin-4 '' '' - yläth-2 '' '' '- yl)] - ester difumarate (the active ingredient content corresponds to 2.6 mg base) 3.424 mg

Mannitol 5 mg

Microcrystalline cellulose 91.6 mg

Average tablet weight 100.0 mg

Claims (10)

1. [2 "- (Trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 """-yleth-2""" - yl)] - ester of the general formula I, wherein R for a remainder of the general formulas IIa, IIb respectively IIc, in which latter X denotes hydrogen, an alkyl radical having 1 to 4 carbon atoms, halogen or a nitro group and n is 1, 2 or 3, where, in the case that n is 2 or 3, the X can be the same or different, stands, as well as their acid addition salts. 2. [2 "- (Trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth-2" "" - yl)] - Ester according to Claim 1, characterized in that the alkyl radical for which X can stand is a methyl or tert-butyl radical. 3. [2 "- (Trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth-2" "" - yl)] - Ester according to Claim 1 or 2, characterized in that the halogen for which X can stand is chlorine. 4. 2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" " -yläth-2 '' '' '- yl)] - ester and its acid addition salts, in particular its hydrochloride or fumarate. 5. 2- (6'-Methoxynaphth-2'-yl) -propionic acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 " '' -yläth-2 '' '' '- yl)] ester and its acid addition salts, in particular its hydrochloride or fumarate. 6. 2- (4'-Chlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazine-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" "- yleth- 2 '' '' '- yl)] esters and its acid addition salts, in particular its hydrochloride or fumarate. 7. Process for the preparation of the compounds according to Claim 1 to 6, characterized in that 2-trifluoromethyl-10- {3 '- [4 "- (2" "- hydroxyethyl) -piperazin-1" - yl] -n-propyl} -phenthiazine or reactive derivatives thereof capable of ester formation with carboxylic acids of the general formulas IIIa, IIIb IIIc, wherein X and n are defined as in claims 1 to 6, or are reacted with reactive derivatives capable of ester formation, whereupon the resulting [2 "- (trifluoromethyl) -phenthiazine-10" - yl- (n-prop-3 '' '- ylpiperazin-4' '' '- yleth-2' '' '' - yl)] - ester of the general formula I converted into acid addition salts by reaction with acids or the acid addition salts obtained are converted into acid addition salts [2 "- (Trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" -ylpiperazin-4 "" "-yleth-2" "" - yl)] - ester of general formula I into the free [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" - ylpiperazin-4 "" - yleth-2 "" "" - yl)] ester bases of the general formula I or converted into other acid addition salts thereof. 8. The method according to claim 7, characterized in that as reactive derivatives of 2-trifluoromethyl-10- {3 '- [4 "- (2"' - hydroxyethyl) -piperazin-1 "- yl ] -n-propyl} -phenthiazines alkali derivatives, especially the sodium derivative, or active esters, especially the chloride, are used. 9. The method according to claim 7 or 8, characterized in that as reactive derivatives of the carboxylic acids of the general formulas IIIa, IIIb or IIIc capable of ester formation, alkali salts, acid halides, in particular acid chlorides, acid anhydrides, mixed acid anhydrides, acid azides or active esters are used. 10. Medicament, characterized by a content of 1 or more compounds according to claims 1 to 6 as active ingredient or active ingredients, expediently together with customary pharmaceutical formulations.