DE1098944B - Process for the preparation of phenthiazine derivatives - Google Patents

Description

GERMAN

It has been found that you can get through in 3-position an alkyl, aryl or aralkyl mercapto radical substituted phenthiazine derivatives of the general formula I.

! -SR ₁

Method of manufacture
of phenthiazine derivatives

where R _{1 is} a low molecular weight alkyl radical or an aryl or aralkyl radical and R _{2 is} a low molecular weight alkyl radical, can be obtained by using tertiary amines of the general formula II

II

wherein R ₁ and R _{2 have} the above meaning, treated with a sulfur dihalide.

The process can be carried out so that an N- {2- [N'-alkylpiperidyl- (2 ')] -ethyl- (1)} - N- {mercaptophenylj-aniline derivative in a suitable organic solvent, such as benzene or toluene, dissolved and mixed with a sulfur dihalide with stirring at room temperature or at elevated temperature. After the reaction has ended, the solvent is evaporated off under reduced pressure and the evaporation residue is taken up in a suitable water-immiscible solvent after stirring with water and with alkali lye. The residue from evaporation of the organic layer is first purified by fractionation in a high vacuum and can be converted into the salt of a suitable acid for further purification. This is particularly necessary when the phenyl nuclei of the starting material are substituted so that the reaction can result in a mixture of different isomers which differ from one another in the position of the substituents. The separation and Reindar notifier:
Sandoz AG, Basel (Switzerland)

Representative: Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr, V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Claimed priority:
Switzerland from July 31, 1957

Dr. Jany Renz, Dr. Jean-Pierre Bourquin

and Gustav Schwarb, Basel (Switzerland),

have been named as inventors

The components are then positioned by fractional crystallization of their salts.

The basic compounds prepared by the present process are oily at room temperature or crystalline and form solid, stable salts with acids.

The compounds prepared according to the process have pharmacodynamic properties which can be used therapeutically Properties, e.g. B. potentiation of the effect of narcotic, hypnotic or analgesic drugs, and are therefore suitable for preparation for anesthesia. You can also treat allergic diseases as well be used as sedatives, antispasmodics, antiemetics or neuroplegics and are also used for Treatment of various states of excitement.

As stated above, the phenthiazine derivatives obtainable according to the invention have favorable therapeutic properties Properties in which they are superior to known analog compounds. So own how emerges from the following pharmacological investigations, for example 3-methylmercapto-10- {2 '- [N-methylpiperidyl- (2 ")] - ethyl- (1')} - phenthiazine (I) and the 3-ethylmercapto-10- {2 '- [N-methylpiperidyl- (2 ")] - ethyl- (1')} - phenthiazine (II) compared to the 3-chloro-10- {2 '- [N-methylpiperidyl- (2 ")] known from British patent specification 775 280 -äthyl- (l ')} - phenthiazine a superior adrenolytic effect with reduced

109 509/563

Toxicity. The ethyl compound is similar to the well-known chlorine compound in its narcosis-potentiating effect think.

The following examples are intended to illustrate the invention Explain the procedure. The melting and boiling points are uncorrected.

^: I. method

a) Adrenolytic effect

The inhibitory effect of the compounds on the contraction caused by adrenaline was investigated the isolated seminal vesicle of the guinea pig. The effect was numerically related on the action of dihydroergotamine (DHE), a compound that is known to be a strong inhibitor of adrenaline. This was chosen as a unit.

(Literature on DHE and the method used: Rothlin et al., Helvetica Physiologica Acta, Vol. 3 [1945], p. C 43):

b) Anesthesia potentiation

The method described by Taeschler and Cerletti (Journal of Pharmacology and Experimental Therapeutics, Vol. 120 [1957], p. 179) was used here. The test animals (mouse) were injected with the substances to be examined 10 minutes before the administration of an anesthetic. The narcosis-potentiating effect of the examined substance is numerically expressed by the effective dose (ED ₅₀ ) in mg / kg. This dose is defined as being at. half of the test animals are anesthetized for at least 2 minutes if they are administered a subliminal dose of an anesthetic (20 mg / kg pentothai intravenous). ~ - ~

c) toxicity

The DL ₅₀ when administered intravenously to the rat was determined.

II. Results

The results are compiled in the following table. Here means

AL the adrenolytic effect, with the effect

was set by DHE = 1,
NP the anesthetic potentiating effect, ED ₅₀ in

mg / kg,
T is the toxicity, DL ₅₀ in mg / kg.

substance
No. Ri AL NP T I. SCH ₃ 1.75 3.6 71 II SC ₂ H ₅ 11 6th 54 III Cl 0.48 3.6 40

III. Conclusions

The 3-methylmercapto compound (I) has a 3.6 times stronger adrenolytic effect than the corresponding 3-chloro compound (III), the narcosis-potentiating effect being practically unchanged. This difference is even more pronounced in the case of the ethyl mercapto compound (II). This has 23 times more adrenolytic effects than the corresponding chlorine derivative (III), while the narcosis-potentiating effect is slightly reduced (1.6 times). The toxicity of the Methyhnercaptoverbindung is around 55 ° / ₀ that the Äthylmercaptoverbindung about 75% of the corresponding chloro compound.

The comparison experiments show that the type of substitution in the phenothiazine ring a decisive factor for the pharmacological effect of these compounds Has meaning. When the chlorine atom is replaced by the methyl mercapto or ethyl mercapto group compounds are obtained with approximately the same narcosis-potentiating effect, somewhat lower toxicity and significantly increased adrenolytic effect.

example 1

3-methylmercapto-10- {2 '- [N-methyl-

piperidyl (2 ")] - ethyl (1 ')} - phenthiazine
340 g of N- {m-methyl mercaptophenyl} -N- {2- [N'-methylpiperidyl- (2 ')] -ethyl} -anffin ( _{boiling point OlO1} = 216 ° C.) are dissolved in 5000 to 6000 ecm of benzene and added while stirring with a solution of 103 g of freshly distilled sulfur dichloride in 1000 ecm of benzene. The hydrochlorides separate out after a short time. The mixture is left to stand for 20 minutes at room temperature, the solvent is evaporated off under reduced pressure as soon as the reaction has ended and the residue is stirred with 2500 ecm of water and enough 3N sodium hydroxide solution until the mixture has an alkaline reaction. The precipitated bases are extracted by shaking three times with 1000 ecm of chloroform each time and the combined chloroform extracts dried over 300 to 400 g of potassium carbonate are evaporated under reduced pressure. The evaporation residue is fractionated in a high vacuum. At a pressure of 0.06 mm of mercury, some starting material is still transferred up to 225 ° C. The at Kp. _0j02 = 225-235 ⁰ C for continuous main fraction contains two isomeric bases which are separated by fractional crystallization of the fumarates.

25 g of the base mixture and 8.3 g of fumaric acid are dissolved in 300 ecm of boiling ethanol, filtered and left to stand at room temperature, the fumarate of 3-Methyhnercapto-10- {2 '- [N-methylpiperidyl- (2 ")] - ethyl- (l ')} - phenthiazine precipitates in crystalline form and the isomeric compound remains in solution. After recrystallization from 100 ecm boiling ethanol, the salt melts at 158 to 160 ° C. (decomposition). The fumarate shows a mixed melting point with an authentic sample of the Compound prepared by another method no depression. The free base, 3-Methyhnercapto-10- {2 '- [N-methy] piperidyl- (2 ")] - ethyl- (1')} - phenthiazine melts at 72 to 74 ⁰ C, the hydrochloride at 158 to 160 ⁰ C (sintering from 153 ° C). The tartrate crystallized with -1 mol of water of crystallization, mp = 130 ° C (decomposition, sintering from 70 ⁰ C).

Example 2

3-ethylmercapto-10- {2 '- [N-methyl-

piperidyl (2 ")] - ethyl (1 ')} - phenthiazine

354 g of N- {m-ethylmercaptophenyl} -N- {2- [N'-

methylpiperidyl (2 ')] - ethyl} aniline (bp. _{0> 005} = 206 ° C) in 5000 to 6000 ecm benzene and mixed with a solution of 103 g of freshly distilled sulfuric acid while stirring

5 6

dichloride in 1000 ecm benzene. After a short time, 5,000 to 6,000 ecm of benzene separate and the hydrochloride is added to each other. The mixture is allowed to stand stirring with a solution of 103 g of freshly distilled for 20 minutes at room temperature, evaporated, sulfur dichloride in 1000 ecm of benzene. After a short time as soon as the reaction has ended, the solvent separates the hydrochloride from. The pressure is reduced and the residue is stirred for 20 minutes at room temperature, mixed with 2500 ecm of water and so much 3N sodium hydroxide solution until it evaporates, as soon as the reaction has ended, the solution mixture gives an alkaline reaction. The mixture of the releasing bases under reduced pressure and stirred up is extracted by shaking out three times with stand with 2500 ecm of water and as much 3N sodium hydroxide solution, 1000 ecm of chloroform each time, and the mixture reacts alkaline for over 300 to until the mixture. The mixture of the combined chloro-precipitated bases, dried from 400 g of potassium carbonate, is evaporated under reduced pressure by shaking out mold extracts three times. extracted with 1000 ecm of chloroform each time and the combined dried over 300 to 400 g of potassium carbonate, dried over the evaporation residue is fractionated under high vacuum. After separating a at a pressure of chloroform extracts under reduced pressure to-0.008 mm of mercury to 22O ⁰ C for continuous forward evaporated. The evaporation residue is collected in a high vacuum and fractionated under the same pressure at 220 to 15. After separating off a main fraction which distills at a pressure of 228 ° C. 0.005 mm mercury column to 22O ⁰ C passing over

The solution of 20 g of base mixture in ethyl acetate? you catch them under the same pressure at 220

Ester is made up of the main fraction distilling up to 226 ° C with a solution of the calculated amount of wine.

acid is added to ethyl acetate, the tartrate being a solution of 22 g of base mixture in acetic acid

des 3-Äthylmercapto-10- {2 '- [N-methylpiperidyl- (2 ")] - 20 ethyl ester is mixed with a solution of the calculated amount

ethyl- (l ')} - phenthiazine precipitates. After standing in room tartaric acid, ethyl acetate is added, the

temperature is filtered off. The compound melts "with tartrate des 3-isopropylmercapto-10- {2 '- [N-methylpiper-

135 ° C (decomposition, sintering from 7O ⁰ C). The mixed melt- idyl- (2 ")] - ethyl- (1 ')} - phenthiazine precipitates. After standing

point with an authentic sample which is filtered off after one at room temperature. The connection

The connection produced by other methods does not show any 25 melts at 120 ^° C. (decomposition, sintering from 70 ^° C.). Of the

Depression. The free base, 3-ethylmercapto-10- {2 '- [N-me- mixed melting point with an authentic sample of the

thylpiperidyl- (2 ")] - ethyl- (1 ')) - phenthiazine, boils in the case of a compound prepared by a different process

Bp-0.008 = 225 ° C and melts at 57 to 59 ° C. shows no depression. The free base, 3-isopropyl-

_E. _. ,. mercapto-10- {2 '- [N-methylpiperidyl- (2 ")] - ethyl- (l')} - phen-

jseispiei ο ^ thiazine, boils at _{b.p. 01005} = 223 ° C and melts at

3-n-propylmercapto-10- {2 '- [N-methyl- 73 to 75 ⁰ C.

piperidyl- (2 ")] - ethyl- (1 ')} - phenthiazine Example 5

368 g of N- (mn-propylmercaptophenyl) -N-. ".",,
{2- (N'-methyl _P iperidyl- (2 ')] -ethyl} -anuine (bp _{o 01} = 198' C) ^^ f ^ f ^ u '^ iu -P ^ thyl-L SOOO to 6000 ecm benzene and 35 pipendyl- (2 ")] - äthyl- (1 ')} - phenth ₁ azm
with a solution of 103 g of freshly distilled one dissolves 382 g of N- {mn-butylmercaptophenyI} -N- (2- [N'-sulfur dichloride in 1000 ecm of benzene. After a short time methylpiperidyl- (2 ')] -ethyl} -aniün ( Kp. _OlO1 = 204 ⁰ C) in separate out the hydrochlorides from. the mixture is allowed 5000 to 6000 cc of benzene and added with stirring for 20 minutes at room temperature for, a solution evaporated from 103 g of freshly distilled sulfur Didas solvent when the reaction is complete is, under 40 chloride in 1000 ecm benzene. After a short time, reduced pressure and the residue is stirred off with the hydrochloride. The mixture is allowed to 20 ml-2500 ecm of water and so much 3N sodium hydroxide solution until it is at room temperature, evaporates as soon as the mixture reacts alkaline. The mixture of the precipitated reaction has ended, the solvent is extracted by shaking three times with reduced pressure each time and stirring the residue with 1000 ecm of chloroform and the rest he 300 to 45 2500 ecm of water and so much 3N sodium hydroxide solution, until the 400 g of potassium carbonate dried combined chloro mixture reacts alkaline. The mixture of the precipitated form extracts evaporated under reduced pressure. Bases are poured out three times with jelOOOccm. The evaporation residue is fractionally extracted with chloroform in a high vacuum and the potassium renated over 300 to 400 g. After separating off a combined chloroform extracts dried at a pressure of 0.01 mm carbonate and mercury column passing over to 242 ° C., 50 begins to evaporate under reduced pressure. The evaporation residue under the same pressure at 242 to 250 ⁰ C is fractionated in a high vacuum. After distilling off the main fraction. separate one at a pressure of 0.005 mm Mercury

A solution of 25 g of base mixture in 200 ecm of vinegar supercolumn up to 224 ° C is collected

acid ethyl ester is calculated with a solution of the distillie- ^{under the same pressure at 224 to 23O 0 C}

Amount of tartaric acid in ethyl acetate added, with 55 rende main fraction. The 3n-butyl mercapto-

the tartrate of 3-n-propylmercapto-10- {2 '- [N-methyl-10- {2' - [N-methylpiperidyl- (2 ")] - ethyl- (1 ')} - phenthiazine

piperidyl- (2 ")] - ethyl- (l ')} - phenthiazine precipitates. After _boiling at bp 0j005 = 227 ° C.

Standing at room temperature is filtered off. The Ver- . .

bond melts at 120 ° C (decomposition, sintering from 70 ° C). Example 6

The mixed melting point with an authentic sample 60 3-Benzylmercapto-10- {2 '- [N-methyl-

the compound piperidyl- (2 ")] - ethyl- (1 ')} - phenthiazine produced by another process

dung does not show depression. The free base, 3-n-propyl- One dissolves 416 g of N- (m-Benzylmercaptophenyl} -N- {2- [N'-

mercapto-10- {2 '- [N-methylpiperidyl- (2 ")] -ethyl- (1')} -phen-methylpiperidyl- (2 ')] -ethyl} -aniline (bp _{0 (005} = 215 ° C)

thiazine, boils at Kp. _{0, 01} = 247 ° C. in 5000 to 6000 cc of benzene and added under stirring

Example 4 ^{6s 1} ^ ^e i ^ner solution of 103 g of freshly distilled sulfur

dichloride in 1000 ecm benzene. Divorce after a short time

dichloride in 1000 ecm benzene. After ku

3-Isopropylmercapto-10- {2 '- [N-methyl- ^ <jie hydrochloride. The mixture is allowed to 20 min

piperidyl- (2 ")] - ethyl- (l ')} - phenthiazine uten stand at room temperature, evaporates as soon as

368 g of N- {m-isopropylmercaptophenyI} -N- are dissolved, the reaction is complete, the solvent is

{2- [N'-methylpiperidyl (2 ')] - ethyl} aniline (. ₀ bp, ₀₅ = 204 ° C) 70 reduced pressure and the residue stirred with

2500 ecm of water and so much 3N sodium hydroxide solution until the mixture reacts alkaline. The mixture of the failed Bases are extracted by shaking out three times with 1000 ecm of chloroform each time and the 300 to 400 g of potassium carbonate dried combined chloroform extracts evaporated under reduced pressure. The evaporation residue is fractionated in a high vacuum. After separating a column of mercury at a pressure of 0.01 mm The flow passing over to 242 ° C is caught under the same pressure at 242 to 250 ° C distilling main fraction.

A solution of 22 g of base mixture in 200 ecm of ethyl acetate is mixed with a solution of the calculated amount of tartaric acid in ethyl acetate. l ')} - fails phenthiazins after standing at room temperature is filtered off, the tartrate contains ¹ I ₂ MoI crystal water, and melts at 105 ⁰ C (decomposition, sintering from 75 ° C) the mixed melting point with ■ an authentic sample of the other for a... The compound produced by the process shows no depression. The free base, 3-benzylmercapto-10- {2 '- [N-methylpiperidyl- (2 ")] - ethyl- (1)'} - phenthiazine, boils at bp 0 ₀₁ = 246 ° C.

Claims (1)

Claim ·. Process for the preparation of phenthiazine derivatives of the general formula I. SR ₁ wherein R _{1 is} a low molecular weight alkyl radical or an aryl or aralkyl radical and R _{2 is} a low molecular weight alkyl radical, characterized in that tertiary amines of the general formula II wherein R ₁ and R _{2 have} the above meaning, treated with a Schwefeldüialogenid. SR ₁ II Considered publications:
British Patent No. 775 280. © 109 509/563 1.61