JPS6043345B2 - Phenothiazine derivatives and methods for producing them - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel phenothiazine derivatives, pharmaceutical formulations containing the same, and methods for producing the same.

The novel phenothiazine derivative according to the present invention corresponds to the following general formula (1): (In the above formula (1), R is the formula (
■a), (■b) or (■c) [wherein, X is hydrogen, C
1-4 represents an alkyl group, a halogen atom or a nitro group; n is 1, 2 or 3 (however, when n is 2 or 3, the substituents X bonded to the aromatic ring are the same and may also be different)].

Also included within the scope of the present invention are pharmaceutically acceptable acid addition salts of the novel compounds having general formula (1).

As used herein, the term "halogen atom" shall refer to fluorine, chlorine, bromine and iodine.

The C1-4 alkyl group may be a linear or branched group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and the like. General formula (
In a preferred embodiment of the novel compound having 1), R is the formula (■
a), (■b) or (■c) [wherein X represents hydrogen, chlorine, methyl, tert-butyl or nitro group;
n is 1, 2 or 3 (provided that when X is 2 or 3, the substituents X may be the same or different)].

Particularly preferred embodiments of the novel compounds of general formula (1) are the following derivatives and their pharmaceutically acceptable acid addition salts (mainly their hydrochlorides and fumarates):
2-trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-
Phenothiazine-3,5-dimethylphenoxyisobutyric acid ester, 2-trifluoromethyl-10-(3-[
4-(2-hydroxyethyl)-piperazinyl-1]-
propyl)-phenothiazine-2-(6-methoxy2
-naphthyl)-propionic acid ester and 2-trifluoromethyl-10-(3-[41''(2-hydroxyethyl)-piperazinyl-1]-propyl)-phenothiazine-4-chlorophenoxyisobutyric acid ester.

The novel compound according to the present invention comprises 2-trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-phenothiazine [hereinafter referred to as flufenazine] and the formula ( ■a), (■b) or (■c) (where X and n
(as described above) is a novel ester with carboxylic acid.

Acid addition salts of the novel compounds having general formula (1) can be prepared with pharmaceutically acceptable mineral acids (e.g. hydrochlorides, sulfates, phosphates, etc.) or with organic acids (e.g. ethanesulfonate, etc.). fumarate, maleate, succinate,
tartrate, citrate, gluconate, saccharinate, etc.).

The present invention further relates to novel phenothiazine derivatives having the general formula (1), in which R is as defined above, and methods for producing their pharmaceutically acceptable acid addition salts.

According to the method of the present invention, 2-trifluoromethyl-10-
(3-[4-(2-Hydroxyethyl)-piperazinyl-1]-propyl]-phenothiazine or its estero?-forming functional derivatives with the formula (■a), (■b) or (
(c) React with the carboxylic acid [wherein X and n are as described above]. If desired, the compounds of general formula (1) can be converted into their acid addition salts or the free bases of general formula (1) can be liberated from the salts by methods known per se. Among the ester-forming fluphenazine functional derivatives, alkali metal salts (especially sodium salts) and active esters (eg chlorides) are preferred.

Carboxylic acids with formulas (■a), (■b) and (■c) include the following compounds: phenoxyisobutyric acid, mono- and dimethylphenoxyisobutyric acid (e.g. 2.3-, 2.4-, 2●5-, 2.6-1 and 3.5
-dimethylphenoxyisobutyric acid), mono and di-Te
rt-butylphenoxyisobutyric acid (e.g. 4-T
ert-butylphenoxyisobutyric acid), methyl-Ter
t-Butylphenoxyisobutyric acid, mono- and dichlorophenoxyisobutyric acid (e.g. 4-chlorophenoxyisobutyric acid, 2,6-dichlorophenoxyisobutyric acid and 2.
3-dichlorophenoxyisobutyric acid), 4-nitrophenoxyisobutyric acid, 1- and 2-naphthoxyisobutyric acid, mono and dimethylnaphthoxyisobutyric acid, mono and di-T
ert-butylnaphthoxyisobutyric acid, methyl-Ter
t-butylnaphthoxy-7isobutyric acid and related carboxylic acids,
Additionally, 2-(6-methoxy-2-naphthyl)-propionic acid. Instead of free carboxylic acids, their functional free radicals can be applied as well. Ester-forming, (■a), (■
The carboxylic acid functional derivative having b) and (■ no c) is
Even acyl compounds commonly used for the same purpose, such as alkali metal salts (e.g. sodium or potassium salts), acyl halides (preferably acyl chlorides), acid anhydrides, acid azides, reactive esters, etc. good.

Acyl chloride has been found to be a particularly preferred acylating agent. Esterification can be carried out in an inert solvent such as benzene, toluene, chloroform, dichloroethane and the like. The compound of general formula (1) can be converted into an acid addition salt according to a known method, or
Alternatively, the base can be liberated from the salt.

The starting material of formula (■c) is known [J. T. Harr
isOnNB. LevislP. NelsOnlW. R
OOkslJ. Med. ChemJ Fu203 (1970
)].

The aryloxyisobutyric acids used as starting materials are partially known, and the new derivatives of general formulas (■a) and (■b) can be prepared by methods known per se [Bargellnllnlll.
Gazz. Chim. Ital. Department, 334 (1906
)] from suitable phenols or naphthols. These acids can be converted to their functional derivatives by known procedures; acyl chlorides can be prepared, for example, by reacting individual carboxylic acids with thionyl chloride. The present invention further provides at least one general formula (1)
or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, and a conventional inert and non-toxic solid or liquid pharmaceutical carrier.

Examples of carriers include calcium carboxylate, magnesium stearate, talc, starch, mannitol,
Cellulose, water, gelatin, benzyl alcohol, sesame oil, etc. can be applied. Pharmaceutical formulations can be solid (e.g. tablets, capsules, coated tablets, suppositories, etc.) or liquid (e.g. tablets, capsules, coated tablets, suppositories, etc.).
Injectable solutions or suspensions, syrups)? It can be provided in the form of The following are particularly preferred as pharmaceutical preparations:
Injectable composition with sustained action, comprising 2-5% of a base of general formula (1) dissolved in sesame oil or peanut oil; oral administration comprising 0.25-10 mg of the nifumarate of this base. tablet; composition for injection containing 0.25-0.5% water-soluble salt; additionally about 0.1% active ingredient;
Syrups and solutions containing. Pharmaceutical formulations can be prepared by methods known in the pharmaceutical industry.

The novel compounds of general formula (1) and their pharmaceutically acceptable acid addition salts are useful neurodepressants with greater neurodepressant activity than fluphenazine and its known esters.

Several fluphenazine esters, such as esters with various fatty acids [H. L. YaIe and F. SOw
inski,. J. Anl. Chem. SOc. ? ,2
039 (1960)]: H. L. YaIelA. I.
Cohen and F. Sowinski. ．． J. Med.
Chem. Foot, 347 (1963)], ester with 3,4,5-trimethoxybenzoic acid [L. ToldyNI
．． T6th and J. BOrsylActaChim. A
cad. Sci. Hung. Dan, 253 (1965)]
and esters with 1-adamantanecarboxylic acid [H. L
．． Yale. ．． J. Med. Chem. ? , 302(1
977)] has already been described in the literature. The duration of the neurodepressant effect of the esters was examined by injecting an oily solution into living organisms. Fluphenazine decanoate is clearly the most preferred among the known esters and is widely applied in clinical practice [J. E. GrOveslM. R. Mandel, Ar.
c. Cen. Psychiatryl? , 893 (19
75)]. This compound exhibits neurodepressant effects for 3-4 weeks when injected into the human body as a solution in sesame oil. Similar results were observed in animal studies of 1-adamantanecarboxylic acid esters.

Other esters (e.g. enawatate) have a shorter duration of neuroinhibitory action (approximately 1-2 weeks), whereas acetate has the same duration of activity as fluphenazine base. observed. No data on the biological effects of other esters are described in the literature. From the foregoing it can be seen that esterification is not always advantageous. For compounds with related structures,
There is even data showing that esters do not have the neurodepressant effects of the starting active drugs [H. L. Yale. ．．
J. Med. Chem. ? , 304 (1977), Re
See mark 7]. Therefore, the biological properties of esters cannot be predicted as they vary for individual compounds. It is therefore clear that the new fluphenazine esters of general formula (1) are potent neurodepressants, i.e. they exhibit all the biological effects characteristic of the phenothiazine structure (decreased locomotor activity, anesthetic effects). It was not foreseeable that the drug would exhibit potentiation, suppression of conditioned responses, antagonism of emesis and catalepsy-inducing activity by apomorphine.

In addition, the new ester of general formula (1) can be used when injected as an oily solution (producing a sustained action), when administered orally in the form of its salt, when injected as an aqueous solution of a water-soluble salt, and when administered as a solution or syrup. It could not have been predicted that it would be effective when applied as a drug. These dosage forms were previously unknown for fluphenazine esters. Furthermore, as shown in the table below, the biological properties of the new compound having general formula (1) are as follows:
The biological properties are more beneficial than the known fluphenazine decanoate and fluphenazine. Table 1 shows that 3,5-dimethylphenoxyisobutyric acid ester and 2-(6-methoxy2-
Both naphthyl-propionate esters were more effective than the known fluphenazine decanoate after two weeks (this period determines the sustained action), while
It can be seen that 4-chlorophenoxyisobutyric acid ester has the same activity as the control substance.

Similar results are observed for dogs (see Table 2).
The new esters of general formula (1) are known to cause apomorphine-induced emesis even after 3 weeks. fluphenazine decanoate, and the duration of its action was longer with the new compound than with the known substance. General formula (1)
Among the salts of the novel esters, especially the fumarate salt, which is well reabsorbed after oral administration and reduces locomotor activity (SMA) and conditioned avoidance response (CAR) to the same extent as fluphenazine.
) (see Tables 3 and 4).

The catalepsis effect of the new compounds having the general formula (1) is also consistent with that of fluphenazine (see Table 5).

Furthermore, taking into account that the doses shown in Tables 3, 4 and 5 refer to the free base equivalent amount of the drug administered in the form of its salt, the effect that appears after administration of 1 part by weight of fluphenazine is:
Fluphenazine 0.6 to 0
．． This can already occur by administering an amount equivalent to the heel dose. The toxicity of the new compounds is also favorable for therapeutic use. The present invention will be explained in detail with reference to the following examples, but the invention is not limited thereto.

Example 12 - Preparation of trifluoromethyl-10-(3-[4-(2-hydroxyethyl)piperazinyl-1]-propyl)-phenothiazine-3●5-dimethylphenoxyisobutyric acid ester (a) Preparation of crude ester base 2 -trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-
21.7y of phenothiazine in 180ml of dichloroethane
Let it dissolve in the liquid.

15 ml of triethylamine are added to this solution, the mixture is stirred and cooled with ice water. Add 3●5-dimethylphenoxyisobutyryl chloride 15 to this mixture within 3 powders.
．． Add 7y little by little.

The mixture is 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 separated off, and the solution is shaken with 180 ml of 7% aqueous sodium bicarbonate solution and then with 200 ml of water. The organic phase is dried over sodium sulfate, filtered and the dichloroethane is evaporated under reduced pressure. As a result, crude ester base 32y is obtained. (b) Preparation of Nifumarate Salt The crude base prepared as described in (a) above was mixed with fumaric acid (14.8y) in 96% ethanol (250ml).
Dissolve in medium boiling solution.

This solution is decolorized with activated charcoal and left overnight at room temperature. The separated crystals were filtered by suction, washed with 50 ml of ethanol,
and dry. As a result, 24.4y of the nifumarate salt is obtained (melting point: 156-158°C). After recrystallization from 7 times the volume of ethanol, the melting point of the product is 158-160°C.

(c) Liberation of base from nifumarate Salt 20 of nifumarate prepared as described in (b) above.
y is dissolved with shaking in a mixture of 100 ml of ether and 100 ml of 10% aqueous potassium carbonate solution.

(Chloroform or dichloroethane can be applied as well instead of ether.) Separate the organic layer and add 100 ml of water
1, dried over sodium sulfate and evaporated under reduced pressure. As a result, ester base 11y is obtained. (d) Preparation of hydrochloride The base 18y prepared as described in (c) above was dissolved in 40 ml of ether,
This solution was diluted with a solution of hydrochloric acid in absolute ethanol to Congo Red (C
Acidify until OngOred).

The separated crystals are separated and washed with ether. As a result, dihydrochloride 13y is obtained. Melting point: 130-131℃
(Disassembly). The novel 3,5-dimethylphenoxyisobutyric acid and its acyl chloride compounds applied as starting materials can be prepared as follows.

3●5-dimethylphenol 54.8y to acetone 34
Dissolve in 0ml.

94.8 y of sodium hydroxide pellets are added to this solution, and then 44.1 ml of chloroform are added dropwise into the resulting heterogeneous mixture within 1 hour with stirring and cooling.
The reaction mixture is refluxed for 5 hours, excess acetone is evaporated under reduced pressure, the residue is dissolved in 600 mL of water, and the resulting solution is acidified to pH 2 with hydrochloric acid. The separated oil was dissolved in 300 ml of chloroform, the organic phase was separated, and each 120 ml of a 7% aqueous sodium bicarbonate solution was added.
and the aqueous solution is acidified to pH 2 with hydrochloric acid. The separated free acid was dissolved in chloroform (130ml).
The chloroform solution is separated, washed with 100 ml of water, dried over sodium sulfate and evaporated under reduced pressure. After standing, 56.3 da of crystalline product is obtained (melting point: 54-60°C). After recrystallization from 1× volume of petroleum ether, pure 3●5-dimethylphenoxyisobutyric acid is obtained (melting point: 63-?°C).

However, acyl chloride compounds can also be prepared from crude products. 3,5-dimethylphenoxyisobutyric acid 309 prepared as described above was added to 150 ml of anhydrous benzene.
Let it dissolve in the liquid.

48 ml of thionyl chloride are added to this solution and the resulting mixture is refluxed for 3 hours. Benzene and excess thionyl chloride are evaporated under reduced pressure, and the residue is distilled under reduced pressure. As a result, 3,5-dimethylphenoxyisobutyryl chloride 20y is obtained. Boiling point: 115-119 C/0.6
~0.87WLHg0 Example 22-trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-phenothiazine-2.5
-Preparation of dimethylphenoxyisobutyric acid ester nifumarate The same procedure as in Example 1 is repeated.

However, 2●5-dimethylphenoxyisobutyryl chloride is used instead of 3●5-dimethylphenoxyisobutyryl chloride. The melting point of the obtained nifumarate is
After recrystallization from ethanol, the temperature is 152-154°C.
The 2,5-dimethylphenoxyisobutyric acid used as a starting material was substituted for 3●5-dimethylphenol by
- Prepared according to the procedure described in Example 1 using 5-dimethylphenol.

The melting point of this acid is ~100°C. This compound is converted to 2,5-dimethylphenoxyisobutyryl chloride in the same manner as in Example 1. Boiling point: 100-108℃/0
．． 6~1w! THgO Example 3 2-trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-
Preparation of phenothiazine-2●6-dimethylphenoxyisobutyric acid ester nifumarate The same procedure as in Example 1 is repeated.

However, 2●5-dimethylphenoxyisobutyryl chloride is used instead of 3●5-dimethylphenoxyisobutyryl chloride. The melting point of the obtained nifumarate is
136-138 C after recrystallization from a 3:1 mixture of ethanol and methanol. The novel 2,6-dimethylphenoxyisobutyric acid used as starting material is 3
- Prepared according to the procedure of Example 1 using 2●6-dimethylphenol instead of 5-dimethylphenol.
The crude product obtained is converted to 2,6-dimethylphenoxyisobutyryl chloride in the same manner as in Example 1.
However, after refluxing the mixture, benzene and excess thionyl chloride are evaporated under reduced pressure, and the residue is dissolved in benzene.
Then, the benzene is evaporated under reduced pressure. The crude acyl chloride compound obtained is applied to this method without purification. Example 4 2-trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-
Phenothiazine-phenoxyisobutyric acid ester nifumarate The same procedure as in Example 1 is repeated.

However, instead of 3●5-dimethylphenoxyisobutyryl chloride, a known phenoxyisobutyryl chloride [C. A. BischOfflBer. ? ,934(1
900)] is used. The melting point of the obtained nifumarate is
After recrystallization from ethanol, the temperature is 152-154°C.
Example 5 Preparation of 2-trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-phenothiazine-4-chlorophenoxyisobutyric acid ester nifumarate as in Example 1. Repeat the operation.

However, instead of 3,5-dimethylphenoxyisobutyryl chloride, known 4-chlorophenoxyisobutyryl chloride [D. J. Oslx) Rne and R. L. W
einlScience Tsukisui 92 (1951)] is used. The melting point of the obtained nifumarate salt is 164-166° C. after recrystallization from ethanol. (C) of Example 1
The base is liberated from this nifumarate in the same manner as (melting point: 54-56°C).

Example 6 Preparation of 2-trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-phenothiazine-2●6-dichlorophenoxyisobutyric acid ester nifumarate Example 1 and Repeat the same operation.

However, 2*6-dichlorophenoxyisobutyryl chloride is used instead of 3*5-dimethylphenoxyisobutyryl chloride. The melting point of the obtained nifumarate is
After recrystallization from ethanol, the temperature is 160-162°C.
The new 2,6-dichlorophenoxyisobutyric acid used as starting material is prepared according to the procedure of Example 1 using 2●6-dichlorophenol instead of 3●6-dimethylphenol.

The crude acid obtained is converted to 2,6-dichlorophenoxyisobutyryl chloride in the same manner as in Example 1. boiling point:
120-126°C/1-1.5 order HgO Example 7 2-trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-phenothiazine-2●3-dichlorophenoxyiso Preparation of butyrate ester nifumarate The same procedure as in Example 1 is repeated.

However, the novel 2●3-dichlorophenoxyisobutyryl chloride is used instead of 3●5-dimethylphenoxyisobutyryl chloride. The melting point of the obtained nifumarate salt is 154-156° C. after recrystallization from ethanol. The 2,3-dichlorophenoxyisobutyric acid used as starting material is prepared according to the procedure of Example 1 using 3◆5-dimethylphenol.

The melting point of this acid is 94-96°C. This compound is converted to 2,3-dichlorophenoxyisobutyryl chloride in the same manner as in Example 1. Boiling point: 120-124℃/0
．． 4-0.6wnHg0 Example 82-Trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-phenothiazine-4-
Preparation of nitrophenoxyisobutyric acid ester nifumarate The same procedure as in Example 1 is repeated.

However, instead of 3,5-dimethylphenoxyisobutyryl chloride, known 4-nitrophenoxyisobutyryl chloride [C.I. A. BischOff. ．． Ber. ?
, 1601 (1900)]. The melting point of the obtained nifumarate was 170-1 after recrystallization from ethanol.
It is 77C. Example 9 2-trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-.1]-propyl)
- Preparation of phenothiazine-1-naphthoxyisobutyric acid ester nifumarate The same procedure as in Example 1 is repeated.

However, instead of 3●5-dimethylphenoxyisobutyryl chloride, a known 1-naphthoxyisobutyryl chloride (Frdl. Research, 105) is used. The melting point of the difumarate obtained is 14 after recrystallization from ethanol.
The temperature is 9 to 151°C. Example 10 2-trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-
Phenothiazine-2-(6-methoxy-2-naphthyl)
- Preparation of propionic acid ester nifumarate The same procedure as in Example 1 is repeated.

However, instead of 3●5-dimethylphenoxyisobutyryl chloride, the known 2-(6-methoxy-2-naphthyl)-propionyl chloride [J. T. HarrisO
nno et al., J. Med. Chem. Bl2O3 (1970
)] is used. The melting point of the obtained nifumarate salt is 152-154° C. after recrystallization from ethanol. The purified ester base can be prepared in the same manner as in Example 1 (c). Example 112-trifluoromethyl-10-(3
-[4-(2-hydroxyethyl)-piperazinyl-1
]-Propyl)-phenothiazine-4-Tert-butylphenoxyisobutyric acid ester nifumarate The same procedure as in Example 1 is repeated.

However, 4-Tert-butylphenoxyisobutyryl chloride is used instead of 3●5-dimethylphenoxyisobutyryl chloride. The melting point of the obtained nifumarate salt is 160-167 C after recrystallization from ethanol. 4-Tert-butylphenoxyisobutyryl chloride used as a starting material is the known 4-Te
rt-butylphenoxyisobutyric acid (W.G.M.JO
Prepared according to the procedure of Example 1 from nes et al., UK Patent No. 860303).

However, after refluxing the mixture, benzene and excess thionyl chloride are evaporated under reduced pressure, and the residue is dissolved in benzene.
Then, the benzene is evaporated under reduced pressure. The crude acyl chloride compound obtained can be applied to this method without purification. 2-
The following esters of trifluoromethyl-10-(3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl)-phenothiazine are also prepared analogously to the previous example: 2,4,6-trimethylphenoxy Isobutyric acid ester, 2●6-di-tert-butyl-4-
Methylphenoxyisobutyric acid ester, methyl-naphthoxyisobutyric acid, dimethyl-naphthoxyisobutyric acid ester, methyl-Te
rt-butylnaphthoxyisobutyric acid ester, and di-tert-butylnaphthoxyisobutyric acid ester.

Example 13 Preparation of a pharmaceutical formulation 2-trifluoromethyl-101 (3
-[4-(2-hydroxyethyl)-piperazinyl-1
]-propyl)-phenothiazine-4-chlorophenoxyisobutyric acid ester is used as active substance.

Depot injection (DePOt-1injecti0n) Sesame oil [DAB. 7-BRDl “Oil for injection (0i1f0ri
quality equivalent to the prescription of ``Njecti0npurp0ses)'' to make 1ml.

Example 13 Preparation of a pharmaceutical formulation In the following composition, 2-trifluoromethyl-10-(3-[
4-(2-hydroxyethyl)-piperazinyl-1]-
Propyl)-phenothiazine-3●5-dimethylphenoxyisobutyric acid ester is used as the active ingredient.

Claims (1)

[Claims] 1. Phenothiazine derivatives represented by the general formula (I) or their acid addition salts: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) {In the above formula (I), R is the formula (IIa) ), (IIb)
or (IIc) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I
Ia) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIb) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIc) [In the formula, X represents hydrogen, a C_1_-_4 alkyl group, a halogen atom, or a nitro group; n is 1, 2 or 3 (provided that
When n is 2 or 3, the substituents X bonded to the aromatic ring may be the same or different)]. 2 In the general formula (I), R is (IIa), (II
Ib) or (IIc) [wherein X represents hydrogen, chlorine, methyl, tert-butyl or nitro group; n is 1,
2 or 3 (however, when n is 2 or 3, the substituents X may be the same or different)]; their acid addition salts. 3 2-trifluoromethyl-10-{3-[4-(2
-hydroxyethyl)-piperazinyl-1]-propyl}-phenothiazine-3,5-dimethylphenoxyisobutyric acid ester, 2-trifluoromethyl-10-{3-
[4-(2-hydroxyethyl)-piperazinyl-1]
-propyl)-phenothiazine-2-(6-methoxy-
2-naphthyl)-propionic acid ester or 2-trifluoromethyl-10-{3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl}-phenothiazine-4-chlorophenoxyisobutyric acid ester or their The phenothiazine derivative or acid addition salt thereof according to claim 1 or 2, which is a pharmaceutically acceptable acid addition salt. 4 General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) {In the above formula (I), R is formula (IIa), (IIb) or (IIc)▲There are mathematical formulas, chemical formulas, tables, etc. ▼(IIa
) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIb) ▲ Mathematical formulas,
There are chemical formulas, tables, etc. ▼ (IIc) [In the formula, X is hydrogen,
C_1_-_4 represents an alkyl group, a halogen atom or a nitro group; n is 1, 2 or 3 (however, when n is 2 or 3, the substituent X bonded to the aromatic ring
may be the same or different)} The active ingredient is at least one phenothiazine derivative represented by the following or a pharmaceutically acceptable acid addition salt thereof; A neurodepressant compounded with a solid or liquid pharmaceutical carrier. 5 General formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the above formula (I), R is formula (IIa), (IIb) or (IIc) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼(IIa
) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIb) ▲ Mathematical formulas,
There are chemical formulas, tables, etc. ▼ (IIc) [In the formula, X is hydrogen,
C_1_-_4 represents an alkyl group, a halogen atom or a nitro group; n is 1, 2 or 3 (however, when n is 2 or 3, the substituent X bonded to the aromatic ring
may be the same or different)} In the method for producing a phenothiazine derivative or an acid addition salt thereof, 2-trifluoromethyl-1
0-{3-[4-(2-hydroxyethyl)-piperazinyl-1]-propyl}-phenothiazine or its ester-forming functional derivative with formula (IIIa), (IIIb) or (IIIc) ▲ mathematical formula, chemical formula, table, etc. There is ▼ (IIIa)
▲There are mathematical formulas, chemical formulas, tables, etc.▼(IIIb)▲Mathematical formulas,
There are chemical formulas, tables, etc. ▼ (IIIc) [In the formula, X and n
is reacted with a carboxylic acid or an ester-forming functional derivative of
) A method for producing a phenothiazine derivative or an acid addition salt thereof, the method comprising liberating the free base of phenothiazine derivatives or acid addition salts thereof.