DE1076135B - Process for the preparation of phenthiazine derivatives - Google Patents

Description

GERMAN

It has been found that new ones can be substituted in the 3-position by an alkyl or aralkyl mercapto radical Phenthiazine derivatives of the general formula I

L ..

N '
H

wherein R _{1 has} the above meaning with a tf-halomethylpiperidyl derivative of the general formula III

H ₂

Halogen -CH ₂ -CH CH ₈
CH ₂ CH ₂

III

35

where R _{2 has} the above meaning and halogen is a chlorine, bromine or iodine atom, condenses. The process is carried out, for example, in such a way that a phenthiazine derivative of the general formula II substituted in the 3-position by an alkyl or aralkyl mercapto group is dissolved in a suitable organic solvent, e.g. B. benzene, toluene, xylene, o-dichlorobenzene and nitrobenzene, dissolved and in the presence of an alkaline condensing agent such as alkali metals or compounds thereof, such as hydroxides, amides, hydrides or alkoxides, e.g. B. sodium or potassium hydroxide, sodium amide, sodium metal, lithium hydride, sodium tert-butoxide, process for preparation
of phenthiazine derivatives

in which R _{1 is} an alkyl or aralkyl group and R _{2 is} a low molecular weight alkyl group, can be obtained by using phenthiazines of the general formula II

Applicant:
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 23 November to 20 December 1956
and February 22, 1957

Dr. Jany Renz, Dr. Jean-Pierre Bourquin,

Leo Ruesch and Gustav Schwarb, Basel (Switzerland),

have been named as inventors

with a / 5-halomethylpiperidyl derivative of the general Formula III is reacted at room temperature or at an elevated temperature.

The reaction can also be carried out without a solvent by melting the reactants together are, although with a reduction in the yield, also due to the presence of a condensing agent can be dispensed with.

After the reaction has ended, the reaction mixture is shaken out with water and the solvent is removed evaporated under reduced pressure; However, the new substances can also be extracted from the reaction mixture through dilute mineral or organic Acids extracted and eliminated from the aqueous phase by adding alkalis or ammonia will. The bases are in benzene or some other water immiscible solvent taken up and then freed from the solvent by evaporation again. The bases can go through Purified distillation in a high vacuum and converted into a suitable salt with organic or inorganic Acids are transferred.

The new compounds prepared by the present process have those for those already known Phenthiazine derivatives of similar constitution, characteristic pharmacodynamic properties, but are better tolerated and more effective than

909 757/483

Connections of a similar constitution. This is z. B. from comparative experiments in which the following Connections were compared:

I. 10- (N-methyl - /? - pipecolyl) -phenthiazine (known

from application C 7333 IVb / 12p),
II. 3-methylmercapto-10- (N-methyl - /? - pipecolyl) -phenthiazine (according to the invention),

III. 3-ethylmercapto-10- (N-methyl- / S-pipecolyl) -phenthiazine (according to the invention),

IV. 3-n-Propylmereapto-10- (N-methyl - /? - pipecolyl) -phenthiazine (according to the invention).

The inhibition of adrenaline was determined in the isolated seminal vesicle of the guinea pig, the anesthesia potentiation in the mouse, ie the effective dose in mg / kg intravenously, which was obtained when subliminal doses of 5-ethyl-5-isoamyl-lm.ethyl-thiobarbituric acid were administered. Sodium leads to anesthesia in at least 50% ■ of the test animals (ED ₅₀ ).

The results can be seen in the following table:

II
III
IV

Relative value

of inhibition

of adrenaline

11 = 100

100
330
185

Anesthesia potentiation
ED ₅₀ mg / kg
intravenous

18th
3.8
11.5
14th

LD50 mouse

mg / kg
intravenous

41
63

However, they are also particularly suitable for outpatient treatment in mild cases with psychiatric indications Treatment. The new phenthiazine derivatives also serve as intermediate products for production of remedies.

The substitution sites in the phenthiazine ring are numbered as follows:

For the preparation of the heterocyclic compound of the above general formula III, 1-methylpiperidyl- (3) -carbinol with a boiling point of ₇ 110 to 112 ° C. is used as a starting point. The halogenation of the primary hydroxyl group takes place according to known processes.

The 3-S division required as starting material with an alkyl mercapto or aralkyl mercapto group Substituted phenthiazines are obtained by treating N- (m-alkylmercapto- or -aralkylmercapto-phenyl) anilines with elemental sulfur in the presence of small amounts of iodine as a catalyst or with sulfur dihalides manufactured. The aniline derivatives mentioned are in turn accessible by condensation of m-alkylmercapto- or aralkylmercapto-anilines with o-chlorobenzene acid and decarboxylation of the so obtained N- (m-alkylmercapto- or -aralkylmercapto-phenyl) -anthranilic acid.

In the phenthiazine derivatives of the general formula II used as starting compounds, R ₁ can be an alkyl group, such as a methyl, ethyl, propyl, butyl and amyl group, or an aralkyl group, such as a benzyl group. In the piperidyl derivatives of the general formula III, R _{2 is} a low molecular weight alkyl group, such as the methyl, ethyl, propyl or butyl group.

The following examples are intended to explain the invention.

example 1

The mixture is heated 50 g of 3-Methylmercaptophenthiazin (F. 138 to 140 ⁰ C) with 9.55 g of finely powdered Natriumami d in 200 cc of anhydrous xylene at a

Bath temperature of 180 ° C for 2 hours to reflux. Without heating to interrupt is allowed within IV2 hours a solution of 33.8 g of l-methyl-3-chloromethylpiperidine (Kp. 69 _n ° C) in 35 cc of anhydrous xylene is added dropwise. After a further 3 hours of heating, the reaction mixture is cooled and, after adding 10 g of ammonium chloride, shaken out three times with 75 ecm of water each time. The xylene solution is extracted once with 275 ecm, then twice with 50 ecm 15% tartaric acid, the tartaric acid extract is washed with 150 ecm benzene and made alkaline with 90 ecm concentrated sodium hydroxide solution (phenolphthalein). The precipitated oily base is taken up in 400 ecm benzene. The benzene layer, dried over potash, is filtered and evaporated under reduced pressure. The evaporation residue is distilled in a high vacuum, after separating a forerun that goes over at a pressure of 0.01 mm of mercury to 206 ° C, the main fraction, 3-methylmercapto-10- (N-methyl - /? - pipecolyl) -phenthiazine. The analytically pure base has a boiling point of _{0> 01} 207 ° C.

When adding a solution, cooled to 0 ° C., of 10.95 tartaric acid in 1600 ecm ethyl acetate With the solution of 26 g of the free base in 250 ecm of ethyl acetate, the tartrate of 3-methylmercapto-10- (N-methyl - ^ - pipecolyty-phenthiazins falls the end. The salt containing V2 moles of water of crystallization decomposes above 140 ° C. with foam formation after sintering from 75 ° C.

The same substance can also be obtained by using finely powdered sodium hydroxide in place of sodium amide. As a solvent in this case, for. B. o-dichlorobenzene ( _{boiling point 76O} 179 ° C) is used. The yield is slightly lower with xylene. The reaction is advantageously carried out by stirring the reaction mixture vigorously so that a fine sodium hydroxide suspension is formed, and ensuring that the water formed is continuously removed using a reflux condenser with a water separator.

Example 2

The condensation of 50 g of 3-ethylmercaptophenthiazine (mp 95 to 97 ° C) and 32 g of 1-methyl-3-chloromethylpiperidine in the presence of 9.1 g of finely powdered sodium amide by the method described in Example 1 gives 3-ethylmercapto-10 - (N-methyl- / J-pipecolyl) - phenothiazine, boils _ool 222 ° C at Kp.. The tartrate melts at 140 ° C with formation of bubbles after sintering above 75 ° C.

Example 3

The condensation of 50 g of 3-isopropylmercaptophenthiazine (F. 118 to 120 ⁰ C) and 30.4 g of 1-methyl-3-chloromethylpiperidm in the presence of 8.56 g of finely powdered sodium amide by the method described in Example 1 gives 3-isopropylmercapto-

Ci ^ in, which _{boils at bp 0> 01} 216 ° C. The tartrate contains Va moles of crystal water. It decomposes above 140 ° C with foam formation after sintering above 75 ° C.

Example 4

The condensation of 50 g of 3-n-propylmercaptophenthiazine (F. 107 to 109 ⁰ C) and 30.4 g of 1-methyl-3-chloromethylpiperidine in the presence of 8.56 g of finely powdered sodium amide according to the method described in Example 1 gives 3- n-Propylmercapto-10- (N-methyl - /? - pipecolyl) -phenthiazine, which _{boils at bp 0) 01} 225 ° C. The tartrate melts at 145 ° C with formation of bubbles after sintering above 85 ° C.

Example 5

The condensation of 30 g of 3-n-butylmercaptophenthiazine (mp 104 to 106 ° C) and 17.4 g of 1-methyl-3-chloromethylpiperidine in the presence of 4.9 g of finely powdered sodium amide according to the method described in Example 1 gives 3- n-Butylmercapto-10- (N-methyl - /? - pipecolyl) -phenthiazine, which _{boils at b.p. OiO1} 223 ° C. The tartrate decomposes at 100 ° C with foam formation after sintering above 80 ° C.

Example 6

The mixture is heated 30 g of 3-Isobutylmercaptophenthiazin (F. 94 to 96 ° C) with 4.9 g of finely powdered sodium amide in 130 cc of anhydrous xylene at a bath temperature of 18O ⁰ C for 2 hours to reflux. Without interrupting the heating, a solution of 17.4 g of 1-methyl-3-chloromethylpiperidine ( _{boiling point} 69 ° C.) in 18 ecm of anhydrous xylene is added dropwise within IV2 hours. After a further 3 hours of heating, the reaction mixture is cooled and, after adding 10 g of ammonium chloride, shaken out three times with 100 ecm of water each time. The xylene solution is extracted once with 175 ecm, then three times with 30 ecm aqueous 15% tartaric acid each time, the tartaric acid extract is washed with 100 ecm benzene and made alkaline with 60 ecm concentrated sodium hydroxide solution (phenolphthalein). The precipitated oily base is taken up in 200 ecm benzene. The benzene layer, dried over potash, is filtered and evaporated under reduced pressure. The evaporation residue is distilled in a high vacuum; after separation of passing over at a pressure of 0.005 mmHg to 206 ° C-forward to catch the passing over under the same pressure at 206 to 208 ⁰ C main fraction, 3-Isobutylmercapto-10- (N-methyl- / S-pipecolyl) -phenthiazin , on. The analytically pure base has a boiling point of _{0> 005} 207 ° C. When a solution, cooled to 0 ° C., of 7.3 g of tartaric acid in 1100 ecm of ethyl acetate is added to the solution of 19.4 g of the free base in 175 ecm of ethyl acetate, this falls Tartrate of 3-isobutylmercapto-10- (N-methyl - /? - pipecolyl) -phenthiazine. The salt containing V2 mol of crystal water melts at 120 ^° C. after sintering from 85 ^° C.

Example 7

The condensation of 30 g of S-sec-butylmercaptophenthiazine (mp 88 to 90 ° C) and 17.4 g of 1-methyl-3-chloromethylpiperidine (bp ₁₁₁ 69 ° C) in the presence of 4.9 g of finely powdered sodium amide after The method described in Example 6 gives 3-sec-butylmercapto-10- (N-methyl-ye-pipecolyl) -phenthiazine, which _{boils at a boiling point of> 005} 206 ° C. The tartrate melts at 110 ° C with formation of bubbles after sintering above 80 ° C.

Example 8

30 g of 3-benzylmercaptophenthiazine (mp 155 to 157 ° C.) are heated with 4.37 g of finely powdered sodium amide in 130 ecm of anhydrous xylene at a bath temperature of 180 ° C. for 2 hours under reflux. Without heating to interrupt is allowed within 1 Vs hours a solution of 15.5 g of l-methyl-3-chloromethylpiperidine (Kp. 69 _n ° C) in 15 cc of anhydrous xylene is added dropwise. After a further 3 hours of heating, the reaction mixture is cooled and, after adding 10 g of ammonium chloride, shaken out three times with 100 ecm of water each time. The xylene solution is extracted once with 175 ecm, then three times with 30 ecm of aqueous 15% wine

ao acid, washes the tartaric acid extract with 100 ecm benzene and makes it alkaline with 60 ecm concentrated sodium hydroxide solution (phenolphthalein). The precipitated oily base is taken up in 200 ecm benzene. The benzene layer, dried over potash, is filtered and evaporated under reduced pressure. The evaporation residue is distilled in a high vacuum; after separating a forerun that passes over at a pressure of 0.007 mm of mercury to 235 ° C., the main fraction, 3-benzylmercapto-10- (N-methyl - /? - pipecolyl) -phenthiazine, which passes over under the same pressure at 235 to 237 ° C., is collected , on. The analytically pure base has a _{boiling point of 0007} 236 ° C.

When adding a solution, cooled to 0 C, of 3.93 g of tartaric acid in 600 ecm of ethyl acetate with the solution of 11.35 g of the free base in 100 ecm of ethyl acetate, the tartrate of 3-benzylmercapto-10- (N-methyl-yff-pipecolyl) falls -phenthiazine from. The salt containing 1 mol of water of crystallization melts at 120 ° C (decomposition) after sintering above 90 ° C.

Claims (1)

Claim: Process for the preparation of phenthiazine derivatives of the general formula I. CH ₂ CH ₂ where R _{1 is} an alkyl or aralkyl group and R _{2 is} a low molecular weight alkyl group, characterized in that phenthiazines of the general formula II -SR ₁ wherein R _{1 has} the above meaning, with a / J-halomethylpiperidyl derivative of the general 8th Formula III where R _{2 has} the above meaning and halogen ■■ 72 means a chlorine, bromine or iodine atom, condensate / ^C \ siert.
Halo-CH ₂ -CH CH ₂ CH ₂ /
N Publications considered: ¹ German patent application C7333IVb / 12p (be R ₂ 10 announced on September 9, 1954). © 909 757/483 2.60