CS214704B2 - Method of making the new derivatives of the phenothiazine - Google Patents

Abstract

The invention relates to new phenothiazine derivatives of the general formula (I) or an acid addition salt thereof, <IMAGE> wherein R stands for a group of the general formula (IIa), (IIb) or (IIc), <IMAGE> and in these latter formulae X stands for hydrogen, a C1-4 alkyl group, halogen atom or a nitro group and n is equal to 1, 2 or 3, with the proviso that if n is equal to 2 or 3, the X substituents attached to the aromatic ring may be the same or different. The compounds are useful as neuroleptic agents.

Description

The term "halogen atom" refers to fluorine, chlorine, thunder and iodine. C 1 -C 4 alkyl groups may form straight or branched chain groups such as methyl, ethyl, -n-propyl, isopropyl, o-butyl, tert-butyl and the like.

Preferred representatives of the novel compounds of formula (I) are those in which R represents a group of formula (IIa), (IIb) or (IIc) in which the groups X is hydrogen, chloro, methyl, tert-butyl or nitro and n is 1; 2 or 3, with the proviso that when -o is 2 or 3, the substituents X may be the same or different.

Particularly preferred representatives of the novel compounds of formula (I) are the following derivatives and their pharmaceutically acceptable acid addition salts, especially hydrochlorides and fumarates:

2-Trifluoromethyl-10-. [.03- (4- (2-hydroxyethyl) piperazinyl-1] propyl] phenothiazine-3,5-dimethylphenoxyisobutyric acid ester, 2-trifluoromethyl-10-

- [3- (4- (2-Hydroxyethyl) piperazinyl-1) propyl] phenothiazin-2- (6-methoxy-2-oaphthyl) cyclopionic acid and 2-triillimethylmethyl ester: ^ O-

- [- 3- (4- (2-hydroxyethyl) piperazin-1-yl) propyl] phenothiazin-4-chlorophenoxyisobutyrone.

The novel compounds of the present invention are novel esters of 2-fluoromethyl-10- [3- (4- (2-hydroxyethyl / piperazinyl-1) propyl] phenothiazine (hereinafter referred to as flufenazioy) formed with carboxylic acids of formula IIIa, IIIb - or - IIIc,

ОНь

O-C-C-OH

I - 6

СНз (lilac)

X - and n are as defined above.

The acid addition salts of the novel compounds of formula (I) are formed with pharmaceutically acceptable mineral acids (such as hydrochlorides, sulfates, phosphates, and the like) or organic acids (such as ethanesullooates, fumarates, maleates, succinates, tartrates). , citrates, gluconates, saccharinates and the like).

As already mentioned, the invention relates to a process for the preparation of the novel phenothiazine derivatives of the general formula I, wherein R is as defined above, and to their pharmaceutically acceptable acid addition salts. According to the process of the invention, 2-trifluoromethyl-10- [3- (4- (2-hydroxyethyl) piperazinyl-1) propyl] phenothiazine or an ester-functional derivative thereof is reacted with a carboxylic acid of formula IIIa, IIIb or IIIc wherein X and n are as defined above, or with a functional ester-forming derivative thereof. If desired, the compound of formula (I) may be converted into its addition salt or the base of formula (I) may be liberated from the salt by methods known per se.

Among the functional derivatives of flufenazine capable of forming the - ester, alkali salts (especially sodium salt) - and active esters (such as chloride) are preferred. Among the carboxylic acids of formulas IIIa, IIIb and IIIc, the following compounds are mentioned:

phenoxyisobutyric acid, mono-.alpha.-.beta.-trimethylphenoxyisobutyric acid (such as 2,3-, 2,4-, 2,5-, 2,6-

3,5-dimethylthioxybutyric acid), mono- and di-tert-butylphenoxyisobutyric acid (such as 4-tert-butylphenoxyisobutyric acid), methyl tert -butylphenoxyisobutyric acid, mono- and dichlorophenoxyisobutyric acid (such as 4-chlorophenoxyisobutyric acid,

2,6-dichlorophenoxy amino acid a

2,3-dichloro rfeno · · · At xyisomУsel) acid _{r-4-nitrofenc} xyisomáselná, 1- and 2-naftoxyisomáselná acid mono- and dimethylnaftoxyisomáselné acid mono- and di-t-1 ^ 101 ^ 0x1isomáselné,

214784 ethyl-tert-butylnaphthoxyisobutyric acid and related carboxylic acids and 2- [6-methoxy-2-naphthyl) propionic acid.

Instead of the free carboxylic acid, the corresponding functional derivatives can equally well be used.

Functional ester-forming carboxylic acid derivatives of formulas IIIa, IIIb and IIIc may be -acyl compounds commonly used for the same purpose as alkali metal salts (e.g. sodium or potassium salts) acyl halides (preferably acyl chlorides), acid anhydrides, acid azides, reactive esters and the like. Acyl chlorides have been found to be particularly preferred acylating agents. The esterification may be carried out ^one in an inert solvent such as benzene, toluene, chloroform, dichloroethane and the like.

The compounds of formula (I) may be converted to their acid addition salts or the base may be liberated from their salts by methods well known in the art.

The starting material of formula IIIc is known (J.T. Harrison, B. Levis, P.Nelson, W.Rooks, J. Med. Chem. 13, 203 (1970)). The aryloxyisobutyric acids used as starting materials are known in part. The novel derivatives of formulas IIIa and IIIb can be prepared from the corresponding phenols or naphthols by methods known per se (Bargellini, Gazz. Chim. Ital. 36, 334 (190-6)). These acids can be converted to their functional derivatives by known methods. Acyl chlorides can be prepared, for example, by reacting the corresponding carboxylic acids with thionyl chloride.

The invention further relates to pharmaceutical compositions comprising as active ingredient at least one compound of the formula I or a pharmaceutically acceptable acid addition salt thereof together with a conventional inert, non-toxic, solid or liquid pharmaceutical carrier. As the carrier, for example, calcium carbonate, magnesium stearate, talc, starch, mannitol, cellulose, water, gelatin, benzyl alcohol, sesame oil and the like can be used. The pharmaceutical compositions may be prepared in solid form (such as tablets, capsules, coated tablets, suppositories, and the like) or in liquid form (e.g., injectable solutions or suspensions, syrups and the like). Of the pharmaceutical compositions, particularly preferred are prolonged-release injectables comprising 2 to 5% of a base of formula I dissolved in sesame or peanut oil, oral tablets containing 0.25 to 10 mg of difumarate base, injectable mixtures containing 0.25-0.5% aqueous solution of water-soluble salt - and syrups - and solutions containing about 0.1% active ingredient.

Pharmaceutical compositions are made by methods well known in the pharmaceutical industry.

The novel compounds of formula (I) and their pharmaceutically acceptable acid addition salts are valuable neuroleptic agents with neuroleptic effects that outperform those of flufenazine and its known esters. Numerous flufenazine esters have been described in the literature as esters formed with various fatty acids (H. L. Yale and F. Sowmski, J. Am. Chem. -Soc. 82, 2093- (1960);

HL Yale I. Cohen а I ⁷ . -S.dwmski, J - Med. Chem. 6, 347 (1963)], an ester of 3,4,5-trimethoxybenzoic acid (L. Toldy, I. Toth and J. Borsy, Acta Chim. Acad. Sci. Hung. 43 , 253 (1965), and 1-adamantanecarboxylic acid ester (HL Yale, J. Med. Chem. 20, 302 (1977)).

The duration of the neuroleptic effect of the above esters was tested by injection with their oily solutions on a living organism. Flufenazinedecanoate, which has been tested, is the most preferred of the known esters, is widely applied in clinical practice - (J. E. Groves, M.R. Mandel, Are. Gen. Psychiatry 32, 8.93 (1975)). This compound, when injected into humans in the form of a solution in sesame oil, exhibits a neuroleptic effect for 3 to 4 weeks. Similar results were observed with l-adamantanecarboxylic acid ester in animal tests. The duration of the neuroleptic effects of other esters (such as enanthate) is shorter (about 1-2 weeks), while the duration of action identical to that of flufenazine base was observed for acetate. For other esters, no biological activity data has been found in the literature.

It follows from the foregoing that esterification is not necessarily advantageous. Such data are also known for compounds of related structure and show that the esters do not achieve the neuroleptic effects of the parent drug [H. L. Yale, J. Med. Chem. 20, 304 (1977), see note 7). As a result, the biological properties of the esters cannot be predicted because they vary with the individual compounds.

Thus, the novel flufenazine esters of formula (I) could not be expected to be potent neuroieptic agents, ie they have all the biological characteristic effects of the phenothiazine structure (decreased motor activity, potentiation of narcotic effects, suppression of conditional response, apomorphine-induced antagonism and cataleptogenic activities) . It was not possible to predict that the novel esters of the formula I were effective when injected as oil solutions (causing a prolonged action), administered orally in the form of their salts, injected as aqueous solutions - water-soluble salts - and applied as - solutions or syrups. The latter forms of administration have so far been unknown for flufenazine esters. In addition, as shown in the following tables, the biological characteristics of the novel compounds of formula (I) are preferable to those of the known flufenazinedecanoate and flufenazine.

Table 1

Conditional response suppression (CAR) in rats

Compound Percentage increase in CAR after single 10 mg / kg i.m.

benefits li week 1 week 2 week 3 week 4

Fluphenazine-3,5-dimethylphenoxyisobutyric acid ester in sesame

oil —97 ^x —94 x —77 x —19 - 17 Flufenazine-ester -2- (6-methoxy-2-naphthyl) propionic acid in sesame oleji —98x —96x —89 ^x —28 —20 Fluorophenic acid ester -4-chlorotenoxylbutyrate in sesame oil —91 times —80x —47 —25 -15 Fluteηazindeka ⁱ noát in sesame oil — 98x —79 x —49 —24 —26

^x p <0.001

P: statistically significant (see U. Graf, K. Stange,, I. Henning: Fonmulae and Tables for Mathematical Statistics, Springer Verlag, Berlin-Heidelberg-New York, 1966, pp. 77 and 78).

со

LO

Tfl со

ю о со 1? ^

о ш

Ю СО

CD CD

CD CD

O CO o CD гЧ s

гЧ o r4

CD

CO ю

'Ф д Έ!

O)

СО o o rO o co

About CD tH д ф ХЗ ф

> cd N

О Он

СО

Д

Ф> 'cd

> ω rS о

Он

O r-i> r— <rS ч5 Д

Д

Ф o o

O Рч

о Υ-Ϊ cd Д • rH д ф> ω

Д О ω

It can be seen from Table 1 that suppression of the conditional response of rats is more effective for both 3,5-dimethylphenoxyisobutyric acid ester and 2 - (- 6-methoxy-2-naphthyl) propionic acid ester than the known flufenazinedecanoate at week 2 protracted effect], while the acid ester

4-chlorophenoxyisobutyric has the same effect as the reference substance. Similar results are observed in dogs (see Table 2), the new esters of formula I suppress apomorphine-induced vomiting for a third week more strongly than the known flufenazinedecanoate, and the duration of action of the novel compounds is longer than that of the known compounds.

Salts of the novel esters of formula I, especially fumarates, are well resorbable upon oral administration and reduce spontaneous motor activity (SMA) and suppress conditional response (CAR) to the same extent as flufenazine (see Tables 3 and 4).

Table 3

Mouse Spontaneous Motor Activity (SMA) Suppression on an Animex Device

Compound The percentage decrease in SMA after an oral dose of 10 mg / kg

Ih 2h 3h 24h 48h 72h Difumarate fluphenazine acid-3,5-dimethylphenoxyisobutyric -76 ^x —85 ^х —87x —8 —6 —5 Flufenazine-Difumarate -2- (6-m-ethoxy-2-naphthyl) propionic acid 88x —97 ^х —86x —11 4-2 + 6 Fluphenazine-4-chlorophenoxyisobutyric acid difumarate -80x —92 ^х —92x - - Flufenazinedihydrochloride —94x —96x —98x —14 4-13 —16

^x p <0.001

Table 4

Conditional response suppression (C AR) in rats

Compound Percentage decrease CAR po an oral dose of 10 mg / kg Ih 124 h 48 h 72 h Fluphenazine-3,5-dimethylphenoxyisobutyric acid difumarate —96x —89x —33 —11 Fluphenazine-2- (6-methoxy-2-naphthyl) propionic acid difumarate —88 x —87x —18 —5 Flufen- difumarate azine-4-chlorophenoxyisobutyrate —96x —93x —35 —5 Flufenazinedihydrochlorid —97 x —96 · ^χ —26 —5

^x p <0.001

The cataleptic effect of the novel compounds of formula I is also identical to that of flufenazine (see Table 5). Moreover, in view of the dosages given in Tables 3 to 5, which refer to the amount of free bases introduced in the form of their salts, the effects achieved by the introduction of one part by weight of flufenazine can already be readily achieved using the novel compounds of the present invention. of the invention in an amount equal to 0.6 to 0.7 parts by weight of flufenazine. The toxicity of the novel compounds is also favorable with respect to their therapeutic use.

TABLE 5

Cataleptogenic effect and acute toxicity in mice and rats

Compound

Catalepsia ED 50 mg / kg per mouse p.o. Acute toxicity

LD 50 mg / kg per mouse p

1 h 3 h • 6 h 24 h 48 h 24 h Flufenazine-Difumarate -3,5-dimethylphenoxy- isomáselné 5.9 5.6 5.2 4.7 > 25.0 > 400.0 Flufenazine-Difumarate -2- [6-methoxy-2-naphthyl) propionic acid 8.2 4.1 3.4 13.0 > 25.0 > 400.0 Flufenazine-Difumarate -4-chlorophenoxyisobutyr 7.0 4.9 4.3 11.0 > 25.0 > 400.0 Flufenazinedihydrochlorid 12.5 2.1 3.7 5.9 > 12.5 > 400.0 Compound in sesame oil Catalepsy ED 50 mg / kg Acute on rats i. m. toxicity LD50 mg / kg in rats i. m. 5 h 24 h 48 h 72 h 7 days 24 h Flufenazine-3,5- ester -dimethylphenoxyisobutyric Flufenazine-2- ester .10.0 4,5 20,0 · 32.0 82.0 > 200 - [6-mc thoxy-2-na and f-1) - -propionové 12.5 16,0 ' 34.0 34.0 > 80.0 > 2100 Flufenazindecanoate 8.0 15.0 31.0 35.0 > 80.0 > 200

The invention is illustrated in detail by the following non-limiting examples.

Example 1

Preparation of 2-Trifluoromethyl-10- [3- [4- / 2-hydroxyethyl / piperazinyl-1) propyl] phenoxyazin-3,5-di-methylphenoxyisobutyric acid ester

a] Preparation of the crude ester base

2.:1,7 g of 2-trifluoromethyl-10- [3- [4- (2-hydroxyethyl / piperazin-1-yl) propyl] phenothiazine is dissolved in 180 ml of dichloroethane, 15 ml of triethylamine are added to the solution and the mixture is stirred and cooled with ice water. To the mixture is added portionwise over 0.5 hour 15.7 g of 3,5-methyl-oxo-iso-isobutyryl chloride. The mixture was stirred at room temperature for 4 hours and then refluxed for 3 hours. The mixture is allowed to stand overnight, the separated triethylamine hydrochloride is filtered off and the filtrate is shaken with 180 ml of 7% aqueous sodium bicarbonate solution and then with 200 ml of water. The organic phase was dried over sodium sulfate, filtered and the dichloroethane was evaporated under reduced pressure. 32 g of crude ester base are obtained.

b) Preparation of difumarate

The crude base prepared as described in (a) above is dissolved in a boiling solution of 14.8 g of fumaric acid in 250 ml of 96% ethanol. The solution was decolorized with activated carbon and allowed to stand at room temperature overnight. The separated crystals are filtered off with suction, washed with 50 ml of ethanol and dried. There were obtained 24.4 g of difumarate, m.p. 156-158 ° C. After recrystallization from a seven-fold amount of ethanol, the product melts at 158-160 ° C.

c) Release of the base from the difumarate g of the difumarate prepared as described in (b) above is dissolved in a mixture of 100 ml of ether and 100 ^; ml of 10% aqueous potassium carbonate solution with shaking. [Instead ·· ether equally well may be chloroform or dichloroethane). The organic layer was separated, washed with 100 ¹ mL of water, dried over sodium sulfate and evaporated under reduced pressure ·. 11 g of ester base are obtained.

d) Preparation of hydrochloride g of the base, prepared as described in c) above, is dissolved in 40 ml of ether and the solution is acidified to Congo red with a solution of hydrochloric acid in absolute ethanol. The separated crystals were filtered off and washed with ether. 13 g of the dihydrochloride of melting point 130 DEG-131 ^{O |} C (dec.).

The novel 3,5-dimethylphenoxyisobutyric acid and the corresponding acyl chloride used as starting material can be prepared as follows:

54.8 g of 3,5-dimethylphenol are dissolved in 340 ml of acetone. 94.8 g of sodium hydroxide pellets are added to the solution, and 44.1 ml of chloroform are added dropwise to the resulting heterogeneous mixture over 1 hour, with stirring and cooling. The reaction mixture is refluxed for 5 hours, excess acetone is evaporated under reduced pressure, the residue is taken up in 60 ml of water and the resulting solution is acidified to pH 2 with 5 N hydrochloric acid. The separated oil is dissolved in 300 ml of chloroform, the organic phase is separated, washed three times with 120 ml of a 7% aqueous sodium bicarbonate solution each time, and the aqueous solution is acidified to pH 2 with 5 N hydrochloric acid. The separated free acid is taken up in 130 ml of chloroform, the chloroform solution is separated, washed with 100 ml of water, dried over sodium sulphate and evaporated under reduced pressure. On standing, 56.3 g of crystalline product are obtained, m.p. 54-60 ° C. Crystallization from 1.5 times the amount of petroleum ether gave pure 3,5-dimethylphenoxyisobutyric acid, m.p. 63-64 ° C. However, the aryl chloride can also be prepared from the crude product.

g of 3,5-dimethylphenoxyisobutyric acid prepared as described above is dissolved in 150 ml of dry benzene. Thionyl chloride (48 ml) was added to the solution and the resulting mixture was refluxed for 3 hours. The benzene and excess thionyl chloride were evaporated under reduced pressure and the residue distilled in vacuo. Is 20 g of 3,5-dimethylphenoxyisoibutyryl chloride having a boiling point of 115-119 ° C / 80 _? to 107 Pa.

Example 2

Preparation of 2-Trifluoromethyl-10- [3- (4-hydroxyethyl) piperazinyl-1-propyl] -phenothiazine-2,5-dimethylphenoxyiso-butyric acid difumarate

The procedure was as described in Example 1 except that 2,5-dimethylphenoxyisobutyryl chloride was used instead of 3,5-dimethylphenoxyisobutyryl chloride. The resulting difumarate melts at 152-154 ° C after recrystallization from ethanol.

The 2,5-dimethylphenoxyisobutyric acid used as the starting material is prepared as described in Example 1, except that 2,5-dimethylphenol is used instead of 3,5-dimethylphenol. The acid melts at 98-10 ° C. This compound was converted to 2,5-dimethylphenoxyisobutyryl chloride as described in Example 1. Its melting point was 100 to 108 ° C / 80 to 133 Pa.

Example 3

Difumarate Preparation of 2-trifluoromethyl-1-10- (3- (4- / 2-hydroxyethyl / -piperazin ^ -l) propyl] ^phenyl, phenothiazine-2,6-dimethylphenoxyisobutyric

The procedure is as described in Example 1 except that 2,6-dimethylphenoxy isobutyryl chloride is used instead of 3,5-dimethylphenoxyisobutyryl chloride. The resulting difumarate melts at 136-138 ° C, after recrystallization from a 3: 1 mixture of ethanol and methanol.

The new 2,6-dimethylphenoxyisobutyric acid used as the starting material is prepared as described in Example 1, except that 2,6-dimethylphenol is used instead of N, N -dimethylphethiol. The resultant crude product is converted to a 2-butyryl chloride as described in Example 1, except that after refluxing the mixture, benzene and excess thionyl chloride are evaporated under reduced pressure, the residue is dissolved in benzene and the benzene is evaporated off under reduced pressure. reduced pressure. The resulting crude acyl chloride is used in the process without purification.

Example 4

Difumarate Preparation of 2-trifluoromethyl-1-10- [3- (4- / 2-hydroxyethyl methyl ^d / ^{-piperazinyl:} 1) -propyl] f enothiazinf enoxyisomáselné

The procedure was as described in Example 1 except that phonoxyisobutyryl chloride was used instead of 3,5-dimethylphenoxyisobutyryl chloride [CA Bischoff, Ber. 33, 934 (1900)]. The resulting difumarate melts at 1'52 to 154 ^O C after recrystallization from ethanol.

Example 5

Preparation of 2-Trifluoromethyl-1-10- [3- (4- (2-hydroxyethyl) piperazinyl-1) propyl] phonothiazine-4-chlorophenoxyisobutyric acid difumarate

The procedure is as described in Example 1 except that the known 4-chlorophenoxyisobutyryl chloride [D. J. Osborne and R. L. Wein, Science 114, 92 (1951)] instead of 3,5-dimethylphenoxyisobutyryl chloride. The resulting difumarate melts at 164-166 ° C after recrystallization from ethanol.

The base melting at 54 to 56 ° C was liberated from the difumarate as described in step c) of Example 1.

Example 6

Preparation of 2-Trifluoromethyl-1-10- [3- (4- (2-hydroxyethyl) piperazinyl-1) propyl] phenoxythiazine-2,6-dichlorophenyloxy acid difumarate

The procedure was as in Example 1, except that 2,6-dichlorophenoxyisobutyryl chloride was used in place of 3,5-dimethylphenoxyisobutyryl chloride. The resulting difumarate melts after recrystallization from ethanol at a temperature of 160 to 162 ° C.

The new 2,6-dichlorophenyl oxyisobutyric acid used as the starting material is prepared as described in Example 1, except that 2,6'-dichlorophenol is used instead of

3,5-dimethylphenol. The starting crude acid was converted as described in Example 1

2,6-dichlorophenol, b.p. 120 DEG -126 DEG C./0.1 mm Hg;

Example 7

Preparation of 2-trifluoromethyl-10- [3- (4- (2-hydroxyethyl) piperazinyl-1) propyl] phenothiazine-2,3-dichlorophenoxyisobutyric acid difumarate

The procedure was as described in Example 1 except that the new 2,3-dichlorophenoxy isobutyryl chloride was used in place of 3,5-dimethylthioxyisobutyryl chloride. The resulting difumarate melts after recrystallization from ethanol at 154-156 ° C.

The 2,3-dichlorophenoxyisobutyric acid used as the starting material was prepared as described in Example 1, except that 2,3-dichlorophenol was used instead of 3,5-dimethylphenol. The acid melts at 94-96 ° C. This compound was converted to 2,3-dichlorophenoxyisobutyryl chloride at a boiling point of 120 to 124 ° C / 53 to 80 Pa as described in Example 1.

Example 8

Preparation of 2-trifluoromethyl-10- [3- (4- (2-hydroxyethyl) piperazinyl-1) propyl] phenothiazine-4-nitrophenoxyisobutyric acid difumarate

The procedure is as described in Example 1 except that the known 4-nitrophenoxyisobutyryichloride [CA Bischoff, Ber. 33, 1601 (1900)] instead of 3,5-dimethylphenoxyisobutyryl chloride. The resulting difumarate melts at 170 to 172 ^Q C · after recrystallization from ethanol.

Example 9

Preparation of 2-Trifluoromethyl-10- [3- (4- (2-hydroxyethyl) piperazin-1-yl) propyl] phenothiazine-1-naphthoxyisobutyric acid difumarate

The procedure is as described in Example 1 except that the known 1-naphthoxyisobutyryl chloride (Fd. 4,105) is used instead of 3,5-dimethylphenoxyisohutyryl chloride. The resulting difumarate melts after recrystallization of 2 ethanol at 149-151 ° C.

Example 10

Preparation of 2-Trifluoromethyl-1-10- [3- (4- / 2-hydroxyethyl / piperazinyl) propyl] phenylthiazin-2- (6-methoxy-2-naphthyl) propionic acid difumarate

The procedure is as described in Example 1 except that the known 2- (6-methoxy-2-naphthyl) -propionyl chloride is used [JT Harrison et al., J. Med. Chem., 13, 203 (1970)) instead. 3,5-dimethylphenoxyisobutyryl chloride. The resulting difumarate melts at 152-154 ° C after recrystallization from ethanol. The purified ester base can be prepared as described in step c) of Example 1.

They said the tuning

Preparation of 2-Trifluoromethyl-10- [3- (4- (2-hydroxyethyl) piperazinyl-1) propyl] phenothiazin-4-tert-butylphenoxyisobutyric acid difumarate

Proceed as described in. of Example 1, except that 4-tert-butylphenoxy-10-bis-biphenyryl chloride is used instead of 3,5-dimethylmethylphenoxy-butyryl chloride. The resulting fumarate melts after recrystallization from ethanol at a temperature of 160 to 162 ° C.

The α-tert-butylphenoxyisobutyryl chloride used as the starting material is prepared from the known 4-tert-butylphenoxyisobutyric acid (WGM Jones et al., British Patent No. 860 30: 3) as described in Example 1, with except that after refluxing the mixture, benzene and excess thionyl chloride are evaporated under reduced pressure, the residue is dissolved in benzene and evaporated under reduced pressure. The resulting crude acyl chloride is used in the process without purification.

The following 2-trifluoromethyl-101- [3- (4- / 2-hydroxyethylpiperazinyl) -1-propyl] phenothiazine esters were prepared as described in the previous examples:

2,4,6-trimethylthenoxybutyric acid ester, 2,6-di-tert-butyl-4-methylphenoxyisobutyric acid ester, methylnaphthoxyisobutyric acid ester, dimethylnaphthoxyisobutyric acid ester, methyl-tert-butylnaphthoxyisobutyric acid ester and di-tert. butylnaphthoxyisobutyric.

Example 12

Preparation of a pharmaceutical composition

214

2-Trifluoromethyl-N- [3- (4- (2-hydroxy-ethyl) -piperazines-1-1] propyl] -phenothiazine-4-chlorophenoxyisobutyric acid ester is used as the starting material in the free base form.

Depot injection:

Active ingredient (base) 30 mg

Benzyl alcohol 12 mg

Sesame oil (quality corresponds to the description given in the Regulation

DAB.7-BRD, chapter "Oil for, injection purposes") to ^ 1 ml

Example 13

Preparation of pharmaceutical mixtures

2-Trifluoromethyl-10- [3- (472-hydroxyethyl / piperazinyl-1-propyl) -phenothiazine-3,5-dimethylphenoxyisobutyric acid ester is used as the free base in the following mixtures as the free base. or - as a difumarate.

a] Depot injection:

Effective agent (base) Benzyl alcohol Sesame oil (BP · 73) 25 mg 12 mg to 1.0 ml (bl) Tablets: Active substance (difumarate) (equivalent to 1 mg of free base) 1.3 € 9 mg Mannitol 5 mg Microcrystalline cellulose Average weight 93.7 mg one tablet: 100.0 mg (b2) Tablets: Active substance (difumarate) (equivalent to 1 mg of free base) 3,424 mg Mannitol 5 mg Microcrystalline cellulose Average weight 91.6 mg one tablet: 100.0 mg

Claims (3)

SUBJECT OF THE INVENTION 1. A process for the preparation of the novel phenothiazine derivatives of the general formula (I): X is hydrogen, C 1 -C 4 alkyl, halogen or nitro and n is equal to 1, 2 or 3, provided that when n is equal to 2 or 3, X is attached. They may be the same or different to the aromatic ring, or their acid addition salts, characterized in that 2-trifluoromethyl-1043- (4- (2-hydroxyethyl) piperazinyl-1] propyl) phenothiazine or its the functional ester-forming derivative is reacted with a carboxylic acid of formula IIIa, IIIb or IIIe, who R @ 1 represents a group of the formula IIa, IIb or IIc, CHj CH ₃ (lila.) CH _S MfúHb · ^{iiib> C} H _S (IIIb) ^Chjo CH-C-OH IO ^CH i Street where X and n are as hereinbefore defined or with a functional derivative thereof capable of forming an ester and, if desired, the compound of formula I is converted to an acid addition salt or the free base of formula I is liberated from its salts. 2. A process according to claim 1, characterized in that an alkali derivative, in particular a sodium derivative or an active ester, in particular the chloride, 2-trifluoromethyl-10- - [3- (4- (2-Hydroxyethyl) piperazinyl-1) propyl] phenothiazine. 3. A process according to claim 1 or 2, characterized in that the functional ester-forming derivative is an alkali salt, an acyl halide, an acid anhydride, a mixed anhydride, an acid azide or a reactive ester, preferably acyl chloride, carboxylic acids of the formula IIIa. and IIIc.