DE1153020B - Process for the preparation of phenthiazine derivatives - Google Patents

Description

The invention relates to a method for producing new phenthiazine derivatives with valuable Properties.

It is known that phenthiazine derivatives, in particular S-chloro-10-iy-dimethylaminopropyl) -phenthiazine, have proven themselves in therapy for potentiating narcosis, analgesia and local anesthesia as well as because of their hypothermic, adrenolytic and anti-shock effects. The 3-chloro-10- (γ-dimethylaminopropyl) -phenthiazine is a member of the series of 10- (dimethylaminoalkyl) -phenthiazines with substituents in the 3-position of the phenthiazine ring, which are resistant to the action of alkaline reagents such as sodium amide, sodium metal, sodium hydroxide , anhydrous sodium carbonate, ie, are insensitive to reagents which are used according to the usual methods for binding a dimethylaminoalkyl group to the nitrogen atom of the phenthiazine. The simultaneous presence of substituents such as OH, CHO, COOCH ₃ , COOC ₂ H ₅ , however, makes this reaction impossible in an alkaline medium.

It has now been found that valuable new 10-dialkylaminoalkyl) -phenthiazine derivatives of the general Formula: as

Method of manufacture
of phenthiazine derivatives

in which R is an α-oxyalkyl group, A is a straight group or branched alkylene radical and R 'and R "mean low molecular weight alkyl groups, thereby producing let that corresponding 3-acyl-phenthiazine derivatives with lithium aluminum hydride in reduced in a known manner.

The starting substances for this reaction can by decarboxylation of the corresponding 3-acyl-phenthiazine -10-carboxylic acid dialkylaminoalkyl esters can be prepared, e.g. B. from the γ-dimethylaminopropyl ester the 3-acetyl and 3-propionyl-phenthiazine-10-carboxylic acid, also from the y-diethylaminopropyl ester of 3-acetyl and the 3-propionyl-phenthiazine-10-carboxylic acid or from the jo-dimethylaminoethyl ester of 3-acetylphenthiazine-10-carboxylic acid.

The compounds which can be prepared according to the invention have excellent therapeutic properties; Applicant:
Establishments CLIN-BYLA, Paris

Representative: Dr. phil. Dr. rer. pole. Kurt Koehler,
Patent attorney, Munich 2, Amalienstr. 15th

Claimed priority:
France of June 30, 1955 (No. 694 883)

Josef Schmitt, L'Hay-les-Roses, Seine (France), has been named as the inventor

its hypothermic and depressive effects on nerve centers are good; in addition, they show as such a hypnotic effect that z. B. the 3 - chlorine -10 - (γ - dimethylaminopropyl) - phenthiazine does not have.

The new compounds are excreted more quickly than 3-chloro-10- (γ-dimethylaminopropyl) -phenthiazine.

The new compounds are characterized by good compatibility and the lack of in the other known Neuroplegjca side effects, such as palpitations, dryness of the Mouth, out.

example

a) Hydrochloride of γ-dimethylaminopropyl ester of 3-acetyl-phenthiazine-10-carboxylic acid

_{30 g of 3-acetyl:} phenthiazine-10-carboxylic acid chloride and 11 g (5% excess) of γ-dimethylaminopropanol in 100 ecm of anhydrous acetone are introduced into a flask fitted with a calcium chloride tube. Instead of acetone, another anhydrous organic solvent, e.g. B. benzene can be used. The mixture is refluxed one night. A clear beige-colored precipitate of the hydrochloride of γ-dimethylaminopropyl ester of 3-acetyl-phenthiazine-10-carboxylic acid forms, which is separated off, washed with ether and dried. Yield: 30g.

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Recrystallized from absolute ethanol, the hydrochloride melts with decomposition at 213 to 215 ° C.

b) 3-acetyl-10- (γ-dimethylaminopropyl) -phenthiazine

30 g of the hydrochloride of the basic ester obtained according to a) are dissolved in water and the base is released with ^χ / ιο normal caustic soda solution. The base, the γ-dimethylaminopropyl ester of 3-acetyl-phenthiazine-10-carboxylic acid, is extracted with ether, the ethereal solution is washed with water and dried with sodium sulfate. After evaporation of the ether in a water bath, 21 g of a red oil are obtained, which is dissolved in 42 ecm of decahydronaphthalene. Instead of decahydronaphthalene, an equal amount of other solvents can also be used, e.g. B. 1,3-dimethoxybenzene, quinoline or collidine. The solution is refluxed until no more CO2 escapes. After cooling, it is treated again with ether and extracted with dilute hydrochloric acid. The solution of the hydrochloride is ^{mixed with x} / io normal caustic soda solution and the base is extracted with ether. The ethereal solution is washed with water and dried with sodium sulfate. After the solvent has been separated off, 16 g of an orange-colored oil are obtained, which is used as the starting substance for the process according to the invention. Based on the acid chloride, the yield is 50%, based on the hydrochloride of the basic ester, 78%.

c) 3- (α-Oxyethyl) -10- (γ-dimethylaminopropyl) -phenthiazine and its acid oxalate

In a 3-necked flask with a mechanical Stirrer with mercury seal, a rising condenser, dropping funnel and nitrogen inlet tube is provided, 0.5 g lithium aluminum hydride and 50 ecm anhydrous ether introduced and gradually a solution of 5 g of 3-acetyl-10- (γ-dimethylaminopropyl) -phenthiazine added in 50 ecm anhydrous ether. The solution becomes discolored. A quarter of an hour after finishing ethyl acetate is added dropwise to the addition in order to decompose the excess of hydride, with diluted caustic soda solution until the aluminum precipitate dissolves, decanted off,

extracted with ether and washed with water. After drying the essential solution and distillation, 5 g of a pink oil are obtained with quantitative yield. By treating this oil with oxalic acid in acetone and recrystallizing the product from acetone, the acidic oxalate, which ^{melts at 139 to 141 °} C., is obtained.

C19H24ON2SC2H2O4:

Calculated ... C 60.28, H 6.22, N 6.70, S 7.65%; Found ... C 60.6, H 6.7, N 6.55, S 7.29%.

The production of the starting substances is not claimed.

Claims (1)

PATENT CLAIM: Process for the preparation of phenthiazine derivatives of the general formula in which R is an α-oxyalkyl group, A is a straight or branched alkylene radical and R 'and R "are low molecular weight alkyl groups, characterized in that corresponding 3-acylphenthiazine derivatives are reduced with lithium aluminum hydride in a manner known per se. Documents considered: Swiss Patent No. 298 685; Journal of the Organic Chemistry, 19: 1115 (1954).