DE3013502C2 - [2 "- (Trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "" ylpiperazin-4 "" - yleth-2 "" "- yl)] ester, method for the production of 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" "- yläth-2'" "- yl)] - ester, a process for Production of the same as well as medicaments containing these compounds, in particular those with neuroleptic effects.

2-Trifluoromethyl-10- {3 '- [4 "- (2'" - hydroxyethyl) -piperazine-1 "-yl] -n-propyl} -phenthiazine (fluphenazine) and several esters of the same are known different fatty acid esters of 2-trifluoromethyl-10- {3 '- [4 "- (2'" - hydroxyethyl) -piperazin-1 "-yl] -n-propyl} -phenthiazine (HL YaIe and F. Sowinski, J. Am. Chem. Soc. 82 [1960], 2039; HL Yale, AI Cohen and F. Sowinski, J. Med. Chem. 6 [1963], 347), esters of 2-trifluoromethyl-10- {3 '- [ 4 "- (2 '" - hydroxyethyl) -piperazin-1 "-yl] -n-propyl} -phenthiazine with 3,4,5-trimethoxybenzoic acid (L. Toldy, I. Töth and J. Borsy, Acta Chim. Acad . Sci. Hung. 43 [1965], 253) and esters of 2-trifluoromethyl-10- {3 '- [4 "- (2'" - hydroxyethyl) -piperazin-1 "-yl] -n-propyl} - phenthiazine with 1-adamantanecarboxylic acid (HL Yale, J. Med. Chem. 20 [1977], 302).

The duration of the neuroleptic effects 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 fluphenazine decanoate is used (JE Groves, MR Mandel, Arch. Gen. Psychiatry 32 [1975], 893). This compound exerts its neuroleptic effect in human therapy after injection 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-adamantanecarboxylic acid ester. Other esters, for example of enanthic acid [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "'- ylpiperazin-4 "" -yläth-2 "" '- yl)] - esters, show a shorter duration of action (about 1 to 2 weeks) and acetic acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop -3 '"- ylpiperazin-4" "- yläth-2'" "- yl)] - ester has one of the duration of action of 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.

From the above it follows 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 '"- yIpiperazin-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 invention [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 '"- ylpiperazin-4" "-ylath-2'" "- yl )] esters (fluphenazine esters) are powerful, superior neuroleptics, that is to say the phenthiazine structure-reducing movement activity or mobility activity (SMS), anesthesia-potentiating, the conditioned reflex (CAR) inhibiting, the vomiting caused by apomorphine counteracting or this antagonizing and cataleptic Have 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) -phenthiazine-10" -yl- according to the invention specified below (n-prop-3 '' '- ylpiperazin-4' '' '- yleth-2' '' '' - yl)] - ester 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 in [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 '"- ylpiperazin-4" "- yläth-2'" "- yl) ] -est were previously unknown.

The invention therefore relates to [2 "- (trifluoromethyl) -phenthiazine-10" -yl- (n-prop-3 "'- yIpiperazin-4""-yleth-2'"'' - yI)] esters of the more 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, chlorine or a nitro group and n is 1 or 2, where, in the event that n is 2, the Xs can be identical or different,

stands,

as well as their acid addition salts.

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.

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' "- ylpiperazin-4" "-yläth-2 '" "- yl)] - ester, 2- (6'-methoxynaphth-2'-yl) -propionic acid- [2" - (trifluoromethyl) -phenthiazine-10 "-yl- (n-prop-3 '"-ylpiperazin-4" "- ylath-2'" "- yl)] - ester and 2- (4'-chlorophenoxy) -isobutyric acid- [2" - (trifluoromethyl) -phenthiazine-10 "-yl- (n -prop-3 '"- ylpiperazin-4" "- yläth-2'" "- yl)] - esters and their acid addition salts, especially hydrochlorides and fumarates.

The acid addition salts of the [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 '"- ylpiperazin-4" "- yleth-2'" "- yl)] esters of the general formula I according to the invention can be those with pharmaceutically usable inorganic acids, for example hydrochlorides, sulfates or phosphates, or organic acids, for example ethyl sulfates (ethanesulfonates), fumarates, maleinates, succinates, tartrates, citrates, gluconates or saccharinates or saccharates.

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} -phentiazine or reactive derivatives thereof capable of ester formation with carboxylic acids of the general formulas

(IIIa),

(IIIb)

respectively

(IIIc),

wherein X and n are defined as above, or are reacted with reactive derivatives capable of forming esters in a manner known per se, whereupon the obtained [2 "- (trifluoromethyl) -phenthiazine-10" -yl- (n-) prop-3 '"- ylpiperazin-4" "- yläth-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 of [2" - (trifluoromethyl) -phenthiazine -10 "-yl- (n-prop-3" '- ylpiperazin-4 "" - yläth-2' "" - yl)] - ester of the general formula I in the free [2 "- (trifluoromethyl) -phenthiazine- 10 "-yl- (n-prop-3 '" - ylpiperazin-4 "" - yleth-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) -piperazine-1 "-yl] -n-propyl} -phenthiazines, alkali derivatives, especially alkali salts, are capable of forming esters , 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-butylphenoxyisobutyric acid, (methyl) - (tert-butyl) -phenoxyisobutyric acids, mono- and dichlorophenoxyisobutyric acids, for example 4-chlorophenoxy-isobutyric 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) - ) naphthoxyisobutyric acids and 2- (6'-methoxynaphth-2'-yl) propionic acid.

As reactive derivatives of the carboxylic acids of the general formulas 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. As a reaction medium, for example, benzene, toluene, chloroform or

Dichloroethane can be used.

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

As already mentioned, the compounds according to the invention have valuable pharmacological, in particular neuroleptic, effects which exceed those of the known 2-trifluoromethyl-10- {3 '- [4 "- (2'" - hydroxyethyl) -piperazin-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) -phenthiazine-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 a swing box

Table III

Counteracts vomiting caused by apomorphine in dogs

Table IV

Inhibition of spontaneous motor activity (SMA) in mice in the Animax apparatus

Table V

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

Table VIa

Cataleptic effects on mice

Table VIb

Cataleptic effects on 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. From the above table II it can be seen that in the determination of the inhibition of the conditioned defense reflexes (CAR) in rats in the 2nd week relevant for this experiment, both the 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid [2 " - (trifluoromethyl) -phenthiazin-10 "-yl- (n-prop-3 '" - ylpiperazin-4 "" - yläth-2 ""' - yl)] - ester as well as the 2- (6'-methoxynaphth- 2'-yl) propionic acid [2 "- (trifluoromethyl) -phenthiazine-10" -yl- (n-prop-3 "'- ylpiperazn-4" "- yiath-2'" "- yl)] ester the comparison substance capric acid [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 '"- ylpiperazin-4" "- yleth-2'" "- yl)] - ester were superior and the

2- (4'-Chlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazln-10" -yl- (n-prop-3 "'- ylpiperazin-4" "- yleth-2" "' - yl) From Table III above, it can be seen that all the compounds according to the invention that were tested also inhibited apomorphine-induced vomiting more strongly in the 3rd week than the comparison substance capric acid- [2 "- (trifluoromethyl) -phenthiazine -10 "-yl- (n-prop-3 '" - ylpiperazln-4 "" - yläth-2' "" - yl)] - ester and the duration of action of the compounds according to the invention was longer (effect also in the 7th Week) than that of the comparison substance (no more effect at all in the 7th week).

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. Tables Vla and VIb above show that the cataleptic action of the compounds according to the invention of the des 2-Trifluoromethyl-10- {3 '- [4 "- (2'" - hydroxyethyl) -piperazin-1 "-yl] -n-propyl} -phenthiazines or capric acid- [2" - (trifluoromethyl) -phenthiazine-10 "-yl- (n-prop-3 '" - ylpiperazin-4 "" - yleth-2' "" - yl)] - ester.

Especially with regard to the results of the above Tables I, IV, V and Vla, however, it must be taken into account that if the doses or LD [low] 50 or ED [low] 50 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 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' " -hydroxyäthyl) -piperazin-1 "-yl] -n-propyl} -phenthiazine amount, the same effect as with the 2-trifluoromethyl-10- {3 '- [4" - (2' "- hydroxyethyl) -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. The following may be mentioned as advantageous preparations: 2 to 5% injection solutions with delayed action of the [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 '"- ylpiperazin-4" "- yleth- 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 "'- ylpiperazin-4" "- yläth-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)] esters can be used in human therapy in adults advantageously administered in daily doses of 1.5 to 120 mg will. The preferred daily dose of 2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "' - ylpiperazin-4" "- yleth -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

a) 2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl-

(n-prop-3 '"- ylpiperazin-4" "- yleth-2'" "- yl)] - esterbase

There were 21.7 g of 2-trifluoromethyl-10- {3 '- [4 "- (2"' - hydroxyethyl) -piperazin-1 "-yl) -n-propyl} -phenthiazine in 180 cm [high] 3 dichloroethane 15 cm [high] 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 1/2 hour while stirring or shaking and cooling with ice-cold water Stirred or shaken for hours at room temperature and then heated to boiling for 3 hours.Then it was left to stand overnight, the precipitated triethylamine hydrochloride was filtered off and the filtrate was mixed with 180 cm 3 of a 7% aqueous sodium bicarbonate solution and 200 cm high ] 3 water. After drying over anhydrous sodium sulfate, the dichloroethane was distilled off under reduced pressure, giving 32 g (97.2% of theory) of the crude (2- (3 ', 5'-dimethylphenoxy) isobutyric acid [2 "- (trifluoromethyl) -phenthiazine- 10 "-yl- (n-prop-3 '" - ylpiperazin-4 "" - yleth-2 ""' - yl)] ester base.

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

The crude 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3' "-ylpiperazin-4) prepared according to section a) above "" -yläth-2 '"" - yl)] - ester base was dissolved in a solution of 14.8 g of fumaric acid in 250 cm [high] 3 96% ethanol at the boiling point. The solution was clarified with activated charcoal and overnight The precipitated crystals were suction filtered, washed with 50 cm [high] 3 ethanol and dried. This gave 24.4 g (56.1% of theory, based on the crude 2- (3 ', 5'- Dimethylphenoxy) isobutyric acid [2 "- (trifluoromethyl) -phenthiazine-10" -yl -) - n-prop-3 "'- ylpiperazln-4" "- yleth-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 a Schme 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) 2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3' "- ylpiperazin-4" "- yleth-2 ' "" yl)] - ester base from 2- (3'5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 '"- ylpiperazin-4" "-yläth-2 '" "- yl)] - ester difumarate

There were 20 g of 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazine-10" -yl- (n-prop-3' "- prepared as described in section b) above. ylpiperazin-4 "" - yläth-2 '"" - yl)] - ester difumarate in a mixture of 100 cm [high] 3 ethers (instead of ether, chloroform or dichloroethane could also be used) and 100 cm [high] 3 one 10% strength aqueous potassium carbonate solution dissolved with shaking or stirring. The organic phase was separated off, washed with 100 cm 3 of water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. 11 g (72.6% of theory, based on this on the 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "' - ylpiperazin-4" "- yleth-2) used '"" -yl)] - ester difumarate, and thus 39.6% of theory, based on the 2-trifluoromethyl-10- {3' - [4 "- (2 '" - hydroxyethyl) -piperazine-1 "- used yl) -n-propyl} -phenthiazine) 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (t rifluoromethyl) -phenthiazin-10 "-yl- (n-prop-3 '" - ylpiperazin-4 "" - yleth-2' "" - yl)] ester base.

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

18 g of 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazine-10" -yl- (n-prop-3' "- prepared as described in section c) above were 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 showed an acidic reaction on congo red Precipitated crystals were filtered off and washed with ether, thus yielding 13 g (63.9% of theory, based on the 2- (3 ', 5'-dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazine-10 "-yl- (n-prop-3 '" - ylpiperazin-4 "" - yleth-2' '' '' - yl)] - ester base, and thus 25.3% of theory, based on the 2-trifluoromethyl used -10- {3 '- [4 "- (2'" - hydroxyethyl) -piperazine-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 ) he keep.

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 cm [high] 1 of acetone. To the solution, 94.8 g of granular sodium hydroxide was added, and then 44.1 cm [high] 3 of chloroform was added dropwise to the resulting heterogeneous mixture over 1 hour with cooling and stirring. 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 cm 3 of water and the resulting solution was acidified to a pH of 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 of a 7% aqueous sodium bicarbonate solution and the aqueous phase was brought to a pH of 5N hydrochloric acid. Acidified value of 2. 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 1 1/2 times the amount of petroleum ether, the 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 cm [high] 3 of anhydrous benzene. After adding 48 cm [high] 3 thionyl chloride, the reaction mixture was heated to boiling for 3 hours. The benzene and 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

The procedure was as described in Example 1, but with the difference that the starting substance used was 2,5-dimethylphenoxyisobutyric acid chloride in place 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 "' - ylpiperazin-4" "-yläth-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 the preparation of 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) -phenthiazine-10" -yl -] - (n-prop-3 "' - ylpiperazin-4" "- yleth-2 "" '-yl)] - 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) -phenthiazine-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, with the difference that 2,6-dimethylphenol was used instead of 3,5-dimethylphenol and in the second stage (Production of chloride) 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" "- yleth- 2 "'" - yl)] ester difumarate was used as the starting substance for further conversion.

Example 4

2-Phenoxyisobutyric acid [2 '- (trifluoromethyl) -phenthiazin-10'-yl- (n-prop-3 "-ylpiperazin-4"' - yleth-2 "" - yl)] 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) -phenthiazin-10" -yl- (n-prop-3 "'- ylpiperazin-4" "- yleth-2'" "- yl)] -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 substance in place 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" "- yleth) obtained -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 be 2- (4'-chlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 "'- ylpiperazin-4" "- yl) -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

The procedure described in Example 1 was repeated, but with the difference that the starting substance used was 2,6-dichlorophenoxyisobutyric acid chloride 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 "' - ylpiperazin-4" "-yläth-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) -phenthiazine-10" -yl-

(n-prop-3 "'- ylpiperazin-4" "- yleth-2" "' - yl)] - 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 "' - ylpiperazin-4" "-yläth-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 in Example 1, 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

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], 1601) 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" "- yleth) obtained -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

The procedure described in Example 1 was followed, 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 "'- yl-piperazin- 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" "- yleth-2' "" -yl)] - ester difumarate

The procedure described in Example 1 was followed, but with the difference that the known 2- (6'-methoxynaphth-2'-yl) propionic acid chloride (JT 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 '"- ylpiperazine -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

The procedure was as described in Example 1, but with the difference that the starting substance used was 4-tert-butylphenoxyisobutyric acid chloride 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 '"-ylpiperazin-4" "-yläth-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 8 60 303) according to the procedure for the preparation of the starting substance of Example 1, but with the difference that 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.

Claims (6)

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, chlorine or a nitro group and n is 1 or 2, where, in the event that n is 2, the Xs can be identical or different, stands, as well as their acid addition salts. 2. 2- (3 ', 5'-Dimethylphenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3' "- ylpiperazin · 4" "- yleth-2 ' "" -yl)] - ester and its acid addition salts. 3. 2- (6'-Methoxynaphth-2'-yl) -propionic acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 '"- ylpiperazin-4" "- yleth- 2 '"" - yl)] - ester and its acid addition salts. 4. 2- (4'-Chlorophenoxy) -isobutyric acid- [2 "- (trifluoromethyl) -phenthiazin-10" -yl- (n-prop-3 '"- ylpiperazin-4" "- yleth-2" "' - yl)] ester and its acid addition salts. 5. Process for the preparation of the compounds according to claim 1 to 4, characterized in that 2-trifluoromethyl-10- {3 '- [4 "- (2'" - hydroxyethyl) -piperazine-1 "- yl] -n-propyl} -phenthiazine or reactive derivatives thereof capable of ester formation with carboxylic acid of the general formulas (IIIa), (IIIb) respectively (IIIc), wherein X and n are as set out in claims 1 to 6, or are reacted with reactive derivatives capable of ester formation, whereupon the obtained [2 "- (trifluoromethyl) -phenthiazine-10" -yl- (n-prop- 3 "'- ylpiperazin-4" "- yläth-2" "' - yl)] - ester of the general formula I converted into acid addition salts by reaction with acids or the resulting acid addition salts of the [2" - (trifluoromethyl) -phenthiazine-10 " -yl- (n-prop-3 "'- ylpiperazin-4" "- yläth-2" "' - yl)] - esters of the general formula I in the free [2" - (trifluoromethyl) -phenthiazine-10 "- yl- (n-prop-3 '"- ylpiperazin-4" "- yläth-2'" "- yl)] ester bases of the general formula I or converted into other acid addition salts thereof. 6. Medicaments, characterized by a content of 1 or more compounds according to claim 1 to 4 as active ingredient or active ingredients.