DE1100635B - Process for the preparation of phenthiazine derivatives - Google Patents

Description

Process for the preparation of phenthiazine derivatives The invention relates to Process for the preparation of new phenthiazine derivatives, their salts and quaternary Ammonium derivatives.

The new compounds correspond to the general formula In this formula, X denotes a hydrogen or halogen atom or an alkyl, alkoxy or low-molecular acyl radical or a cyano, methylthio, methanesulfonyl, dimethylsulfamyl or trifluoromethyl radical. A represents a low molecular weight alkylene radical and n corresponds to the number 0 or 1. R represents a hydrogen atom or a methyl radical and Z a low molecular weight acyl, an alkoxycarbonyl, a low molecular weight alkanesulfonyl, a carbaminyl or a sulfamyl radical, these radicals being optionally substituted can be, in particular a morpholinocarbonyl or morpholinosulfonyl radical.

If X is a halogen atom, this can be a chlorine, bromine, Be fluorine or iodine, however a chlorine atom is the preferred halogen atom is. Under a low molecular weight residue in the case of X, as in the case of the rest Symbols, a radical with a maximum of 4 carbon atoms should be understood.

The divalent hydrocarbon radical A can contain 2 to 4 carbon atoms in a straight or branched chain, the nitrogen atom of the phenthiazine ring being separated from that of the piperidine ring by at least 2 carbon atoms. For example, A can be one of the following chains mean. The preferred products according to the invention contain the chain - (CH) 3- or The substituents can be located in the 2-, 3- or 4-position of the piperidine ridge, the 4-position being the preferred.

According to the invention, the compounds can be obtained by one of the following processes: 1. Reaction of a phenthiazine of the general formula with a piperidine of the general formula In these formulas, one of the radicals P and Q is a hydrogen atom and the other is a radical -AY, where Y is an acid radical, such as a halogen atom, e.g. B. a chlorine or bromine atom, a sulfate group, e.g. B. the methyl sulfate residue or a sulfonic acid residue, e.g. B. the p-toluenesulfonate or methanesulfonate, means. The other symbols have the meanings given above. Among the radicals Y, the chlorine and bromine atoms are the preferred radicals.

The reaction can be carried out with or without a solvent and in the presence or absence a condensing agent can be carried out.

If P is hydrogen and Q is the radical - A - Y defined above, it is advantageous, in a solvent, for example an aromatic hydrocarbon, such as toluene or xylene, an ether such as ethyl ether, or a tertiary amide, for example Dimethylformamide, in the presence of a condensing agent, preferably from the Group of alkali metals and their derivatives, such as hydrides, amides, hydroxides, Alcoholates, metal alkyls or aryls, and especially in the presence of metallic Sodium or potassium, sodium amide, powdered sodium or potassium hydroxide, lithium or sodium hydride, sodium tert-butoxide, butyllithium, phenyllithium or phenylsodium to work, preferably at the boiling point of the solvent. It is particularly advantageous, the piperidinoalkyl halide in the form of the free base in solution, for example in benzene, toluene or xylene, to use and this solution the mixture of the other reaction components in which the phenthiazine used may already be at least partially in the form of the alkali salt, to be added. In the same way, the reaction with a salt of the piperidinoalkyllialogenids carried out, but in this case it is obviously necessary to have a larger amount of condensing agent to use to reduce the acidity of the used To neutralize salt.

If the radical A is asymmetrical and, for example, one of the radicals means, a rearrangement can take place in the course of the reaction and lead to a mixture of isomers.

If Q is a hydrogen atom and P is the radical - A - Y, is it is advantageous to use an alcohol or an aromatic hydrocarbon work and as a condensing agent to an excess of the piperidine compound use.

2. Condensation of a reactive derivative of an acid with a phenthiazine compound of the general formula in which the various symbols have the meanings given above. For example, the following reactive derivatives can be used with advantage: To prepare the compounds in whose general formula Z denotes an acyl radical, the anhydrides, chlorides and esters of carboxylic acids.

For the preparation of compounds in the general formula of which Z is a Alkoxycarbonyl radical means the alkyl chlorocarbonate.

For the preparation of compounds in the general formula of which Z is a Carbaminyl radical means the carbamic acid halides or the alkyl isocyanates.

For the preparation of compounds in the general formula of which Z is a Sulfamyl radical means the sulfamic acid halides.

For the preparation of the compounds in the general formula of which Z is a Alkanesulfonyl radical means the alkanesulfonic acid halides.

The new phenthiazine derivatives can be in their salts and quaternary Ammonium derivatives are transferred.

The salts can act on the new phenthiazine derivatives by the action of acids can be obtained in suitable solvents. Used as an organic solvent for example alcohols, ethers, ketones or chlorine-containing solvents; as Inorganic solvents are advantageously used with water. The educated Salt precipitates, if appropriate after concentration of the solution, and is filtered off or decanting.

The quaternary ammonium derivatives can by implementing the new Phenthiazine derivatives with esters, optionally in an organic solvent, can be obtained at ordinary temperature or, more rapidly, with gentle heating.

The new phenthiazine derivatives of the formula 1 can optionally by physical methods such as distillation, crystallization, chromatography, or by chemical methods such as formation of salts, their crystallization and Decomposition in an alkaline medium. In these operations the type of anion of the salt does not matter, the only condition is that the salt is well defined and easily crystallizable.

The new phenthiazine derivatives have valuable pharmacodynamic properties Properties and in particular represent extremely effective means of damping of the nervous system, excellent means of potentiating anesthesia, sedatives, effective antiemetics and analgesics.

For therapeutic use one can use the new compounds in the form the bases or in the form of pharmaceutically usable ones, d. H. in the doses used Use non-toxic salts and quaternary ammonium derivatives. The bases and however, the above salts are the preferred form of use; H. the one in which undesirable side effects occur to a minimum and the main effect is the strongest.

The salts can be used as examples of pharmaceutically acceptable salts of mineral acids, for example the hydrochlorides, sulfates, nitrates and phosphates, or of organic acids, for example the acetates, propionates, succinates, Benzoates, fumarates, maleates, oxalates, tartrates, methanesulfonates, ethane disulfonates, Salicylates, phenolphthaleinates and methylene-bis-ß-oxynaphthoates, as well as substitution products these acids are called.

As examples of pharmaceutically usable quaternary ammonium derivatives be the derivatives of inorganic or organic acids, for example the Chlorine, bromine or iodine methylates, ethylates, allylates or benzylates, the methyl or ethyl sulfates, the Benzene sulfonates and the substitution products of these compounds mentioned.

The new compounds can be in pure form, or together with a Diluent or coated. All pharmaceutical Common forms can be used, especially those that are suitable for administration by oral, rectal or parenteral routes. The doses depend on the one you want therapeutic effect, the method of administration, the duration of treatment and the type of the living being. They are generally between 0.1 and 10 mg / kg animal weight. In human medicine, a daily dose of 20 to 600 mg can be taken orally and Administer 10 to 500 mg of the phenthiazine compound parenterally.

Test report As already mentioned above, according to the invention Compounds available are very beneficial therapeutic in various respects Properties, whereby they are superior to known analogous compounds. How out As can be seen from the comparative tests below, the compared is according to the invention obtainable compound of the 3-chloro-10- (3'-piperidinopropyl) -phenthiazine known from British patent specification 716230 with regard to the sedative effect (test on the thread) and with regard to the analgesic Effect (modified test according to D'Amour and Smith, technique according to Hesse) superior. The compound obtainable according to the invention shows a significantly better effect.

Comparative experiments The compound 3-chloro-10- obtainable according to Example t [3 '- (4 "- acetamidopiperidino) - propyl] - phenthiazine was used with the British Patent 716 230 known 3-chloro-10- (3'-piperidinopropyl) -phenthiazine compared. The following comparative tests were carried out. a) Test on the thread The dose (DE50) of the product is determined which is the case with peroral administration 90 minutes before the experiment in the mouse 500in the animal incapable of a pull-up to be carried out on a horizontally stretched thread. b) Modified D'Amour test and Smith Man uses an electro-optical device that enables a Heat rays on the tail of a mouse, which are located in a suitable device located to collect. An untreated mouse curls its tail under the The pain starts to take effect after about 3 to 4 seconds. On the other hand one observes that the mice treated with the product to be examined, which the heat rays Hold for 30 seconds, fully analgesized.

The product under investigation is administered subcutaneously in various doses administered. The mice are examined one hour after treatment. One determines that dose of product which in 500 of the animals (DA50) was insensitive to pain 15 seconds that is half the time to achieve complete analgesia enables. c) Analgesic effectiveness -Technique according to Hesse The pain is caused by Pinching of the perineum is induced with the help of pean forceps. That not analgesized Animal responds to this with a scream Pinching while that totally analgesized Animal shows no reaction. The pinching is done every 10 minutes for 3 hours performed on animals previously treated subcutaneously with the product to be investigated and that dose of product is determined which causes the above analgesia evokes.

The results are compiled in the following table. Test but Products Test Amour Hesse am Faden and Smith DE mg / kg DE, 0 mg / kg DAsOmg / kg subcutaneously po subcutaneous Substance according to Example 1 5 l 20 16 Substance according to the British Patent specification 716230 ....... 25 more than 40 70 The table above shows that the compound obtainable according to the invention is significantly more effective than the known compound.

The following examples illustrate the invention.

Example 1 A solution of 15.5 g of 3-chloro-10- (3'-chloropropyl) -phenthiazine is heated 7.8 g of 4-acetamidopiperidine in 100 cc of anhydrous ethanol with 5.3 g of powdered anhydrous sodium carbonate under reflux for 21 hours. Then you bet 2.7 again g of sodium carbonate and heated under reflux for a further 9 hours.

The ethanol is removed under reduced pressure (about 30 mm mercury column, the residue is taken up in 150 cc of water and 300 cc of ethyl acetate, stirred with 60 ccm of 4N sulfuric acid and the organic phase is separated off, which is again carried out with 15 cc of 4N sulfuric acid extracted. The aqueous acidic phases are combined alkaline it with 60 ccm sodium hydroxide solution (d = 1.33) and extract the released one Base twice with a total of 500 cc of ethyl acetate. After drying the organic Solution over anhydrous potassium carbonate, this is concentrated under reduced pressure (about 30 mm mercury column) to dryness.

The base isolated in this way (17.9 g) is a thick, pale yellow, with Oil crystallizing over time. It is converted into the hydrochloride by they are dissolved in acetone and treated with a solution of hydrogen chloride in ether. 15.6 g of 3-chloro-10- [3 '- (4 "-acetamidopiperidino) propyl] phenthiazine are obtained in this way - hydrochloride in the form of a white crystalline powder with a temperature of 204 to 210 ° C.

The 4-Acetamidopiperidin from F. = 134 to 136 "C is by catalytic Debenzylation of l-benzyl-4-acetamidopiperidine from M.P. = 140 to 142 "C by means of Palladium black obtained in methanol. The benzyl compound in turn is through Acetylation of l-benzyl-4-aminopiperidine produced by the method of Brookes et al. (Journal of the Chemical Society [London], 1957, p. 3165) from 1-benzylpiperidone- (4) is obtained.

Example 2 A solution of 22 g of 3-chloro-10- (3'-ptoluenesulfonyloxypropyl) is heated -phenthiazine and 9.5 g of 4-acetamidomethylpiperidine hydrochloride in 150ccm of anhydrous Ethanol with 10.5 g of powdered anhydrous sodium carbonate for 20 hours under reflux.

The ethanol is removed under reduced pressure (about 30 now mercury column), the residue is taken up in 250 cc of water and 100 cc of ethyl acetate, stirred with 40 cc of 4N hydrochloric acid, the aqueous phase is separated off and extracted again with 50 cc of ethyl acetate.

Then make the aqueous phase with 30 ccm sodium hydroxide solution (d = 1.33) alkaline and extracted the liberated base with 150 and then with 100 cc of ethyl acetate. After drying the organic solution over anhydrous Potassium carbonate is concentrated under reduced pressure (about 15 mm mercury column) to Dry up.

After recrystallizing the residue from acetonitrile, one obtains 13.9 g of 3-chloro-10- [3 '- (4 "-acetamidomethylpiperidino) propyl] -phenthiazine in the form of a white crystalline powder of m.p. = 106 to 107 "C.

The 4-acetamidomethylpiperidine hydrochloride of F. = 184 "C is by catalytic hydrogenation of 4-acetamidomethylpyridine hydrochloride (the base melts at 89 to 90 "C) in aqueous ethanol in the presence of Adams platinum at ordinary Received pressure.

Example 3 A solution of 7.5 g of 3-chloro-10- [3 '- (4 "-aminopiperidino) -propyl] -phenthiazine A solution of 1.98 g of potassium cyanate in Add 10 cc of water and leave to stand for 16 hours.

The reaction liquid is made with 5 ccm sodium hydroxide solution (ct = 1.33) alkaline and extracted the liberated base twice with 100 cc of ethyl acetate each time.

After drying the organic solution over anhydrous potassium carbonate one concentrates on the water bath to dryness. The solid residue is expelled in Presence of 20 cc of ethyl acetate, filtered and washed with the same solvent and dries in the desiccator under a pressure of about 15 mm Quick silver column.

7.1 g of 3-chloro-10- [3 '- (4 "-carbaminylaminopiperidino) -propyl] -phenthiazine in the form of a white crystalline powder from F. = 120 to 124 "C.

The 3-chloro-10- [3t- (4 "-aminopiperidino) propyl] -phenthiazine is a thick oil, which is obtained by deacetylating 3-chloro-10- [3'- (4 "-acetamidopiperidino) propyl] -phenthiazine by heating under reflux with 3N hydrochloric acid for 5 hours obtained and which is used as a crude product.

Example 4 A solution of 7.5 g of 3-chloro-10- [3 '- (4 "-aminopiperidino) propy0-phenthiazine, 2.3 g of methanesulfonyl chloride and 1.6 g of pyridine in 75 cc of anhydrous toluene for 2 hours under reflux. Then the reaction liquid is diluted with 100 cc of ether and stirred with a solution of 4.5 cc methanesulfonic acid in 150 cc water. To Separating the acidic aqueous phase, this is done with 40 ccm sodium hydroxide solution (d 1.33) alkaline and extracted the liberated base with ethyl acetate. The organic solution is dried over anhydrous potassium carbonate and concentrated a pressure of 20 mm of mercury to dryness.

The residue is redissolved in 100 cc of benzene and filtered Solution for chromatography through a column with 100 g of aluminum oxide. One elutes one after the other with benzene, with mixtures of benzene and ethyl acetate Esters of increasing concentration and finally with pure ethyl acetate.

After evaporation of the solvent, 5.9 g of purified 3-chloro-10- [3'- (4 "-methanesulfonamidopiperi- dino) -propyl] -phenthiazine, which after recrystallization from 3 parts of benzene and 2 parts of cyclohexane a white-cream colored crystalline Powder with a temperature of 129 to 131 ° C.

Example 5 A solution of 27.8 g of 3-chloro-lOr (3'-chloropropyl) -phenthiazine is heated and 15.1 g of 4- (N-methylacetamido) piperidine in 270 ccm of anhydrous ethanol with 9.6 g powdered sodium carbonate under reflux for 24 hours. Then you bet 4.8 again g of sodium carbonate are added, the mixture is refluxed for a further 8 hours and the reaction is ended Another addition of 4.8 g of sodium carbonate by refluxing for 15 hours.

The ethanol is then removed under reduced pressure (about 30 mm Mercury column), the residue is taken up in 200 ccm of water and extracted twice with 400 ccm of ethyl acetate each time. The organic phase is extracted with 250 ccm 2.5 N hydrochloric acid, makes the acidic aqueous phase with 80 ccm sodium hydroxide solution (d = 1.33) alkaline and extracted the liberated base with ethyl acetate. After the organic solution has been dried over anhydrous potassium carbonate, it is concentrated reduced pressure (about 30mm mercury column) to dryness.

The residue is redissolved in 400 cc of benzene and the solution is filtered for chromatography through a column with 350 g of aluminum oxide and eluted with the solvents mentioned in example 4. Obtained after evaporation of the solvent one 26.6 g of oily base, which one by dissolving in ethanol and adding a solution of Hydrogen chloride in ether converted into the hydrochloride. 25.9 g of 3-chloro-10- [3 '- (4 "-N-methylacetamidopiperidino) propyl] -phenthiazine hydrochloride are obtained in this way in the form of a white-cream-colored crystalline powder from F. = 210 to 213 "C.

The 4- (N-methylacetamido) piperidine used as the starting substance from F. = 73 to 75 "C is obtained by catalytic debenzylation of l-benzyl-4- (N-methylacetamido) -piperidine obtained from the F. = 57 to 580 C by means of pallate dium black in methanol The latter piperidine derivative is in turn obtained by acetylation of 1-benzyl-4-monomethylaminopiperidine manufactured. The l-benzyl-4-monomethylaminopiperidine of Kr 1.6 = 40 to 143 "C each is made from l-benzylpiperidone- (4) by reductive amination with monomethylamine in Presence of Adams platinum made.

Example 6 One works as described in Example 3, but goes of 7.75 g of 3-chloro-10- [3 '- (4 "-monomethylaminopipendino) propyl] -phenthiazine and 1.98 g of potassium cyanate.

This gives 6.6 g of 3-chloro-10- {3 '- [4 "- (N-carbariinyl-N-methylamino) -piperidino] -propyl} -phenthiazine, after recrystallization from ethyl acetate, a white crystalline powder from F. = 150 to 152 "C.

The 3-chloro-10- [3 '- (4 "-monomethylaminopiperidino) used as starting substance - propyl] - phenthiazine is a thick oil that is produced by deacetylation of 3-chloro-10- [3 '- (4 "-N-methylacetamidopiperidino) -propyl] phenthiazine prepared by refluxing with 6N hydrochloric acid for 7 hours and used as a raw product.

Example 7 The procedure is as described in Example 4, but it is possible of 8 g of 3-chloro-10- [3 '- (4 "-monomethylaminopiperidino) propyl] -phenthiazine, 2.47 g methanesulfochloride and 1.63 g pyndine from; The crude base is dissolved in 160 cc of benzene, chromatographed on 80 g of aluminum oxide and successively with Benzene and a mixture of 9 parts of benzene and 1 part of ethyl acetate eluted.

This gives 5.3 g of purified 3-chloro-10- [3 '- (4 "-N-methylmethane-sulfonamidopiperidino) - propyl3 -phenthiazine, which after recrystallization from a mixture of benzene and cyclohexane (3: 5) is in the form of a white crystalline powder with a melting point of 134 to 136 "C.

Example 8 A solution of 10.8 g of 3-chloro-10- [3 '(4 "-monomethylaminopiperidino) is heated - propyl] - phenthiazine, 4.5 g of morpholinocarbonyl chloride and 2.5 g of pyridine in 60 cc of chloroform under reflux for 2 hours.

The reaction mixture is then diluted with 100 cc of chloroform and washed three times with 250 ccm of water each time, the organic phase is dried over anhydrous potassium carbonate and concentrated to dryness under reduced pressure (about 30 mm of mercury).

The oily residue is redissolved in 160 cc of benzene and filtered the solution for chromatography through a column with 150 g of aluminum oxide. One elutes successively with benzene, with mixtures of benzene and ethyl acetate with increasing Concentration of ester and finally with pure ethyl acetate.

After evaporation of the solvent and recrystallization of the solid Residue from ethanol gives 5.85 g of 3 - chlorine -10 (3 '- [4 "- (N-morpholinocarbonyl-N-methylamino) -piperidino] -propyl} -phenthiazine in the form of a white-cream-colored crystalline powder with a F. = 115 to 117 "C.

Example 9 A solution of 11.5 g of 3-chloro-10- [3 '- (4 "-monomethylaminopiperidino) - propyl] - phenthiazine, 3 g of triethylamine and 5.6 g of morpholinosulfochloride in 100 cc of chloroform under reflux for 2 hours.

The chloroform is then removed under reduced pressure (approx mm of mercury), takes up the residue in 100 ccm of n-butanol and washes the Solution with 100 ccm of water and 2.76 g of potassium carbonate. After drying the organic Layer over potassium carbonate is concentrated under reduced pressure (about 20 now mercury column) dry up.

The solid residue is washed by treating it with ethyl acetate rubbed in, and recrystallized it from n-propanol. 6.3 g of 3-chloro-10- {3 '- [4 "- (N-morpholinosulfonyl - N -methylamino) -piperidino] propyl} -phenthiazine in the form of a pale yellow crystalline powder of F. = 137 "C.

Example 10 One works as described in Example 3, but works of 12.4 g of 3-methoxy-10- [3 '- (4 "-monomethylaminopiperidino) -propyll-phenthiazine, 80 ccm of n-hydrochloric acid and 3.8 g of potassium cyanate.

The crude base (14 g) is dissolved in 300 cc of a mixture of benzene and ethyl acetate (9: 1) and filtered the solution for chromatography through a column with 120 g Aluminum oxide. It is then eluted successively with a mixture of benzene and ethyl acetate with increasing concentration of ester and then with pure ethyl acetate. After evaporation of the solvent, 4.6 g of 3-methoxy-1043 '- [4 "- (N-carbaminyl-N-methylamino) -piperidino) -propyl} -phenthiazine are obtained, which after recrystallization from acetonitrile a white crystalline powder of F. = 116 to -118 "C.

The 3 - methoxy - 10 - [3 '- (4 "-monomethylaminopiperidino) propyl] -phenthiazine forms a thick oil, which is obtained by deacetylating 3-methoxy-10- [3 '- (4 "-N-methylacetamidopiperidino) propyl] -phenthiazine obtained by refluxing with 6N hydrochloric acid. The latter phenthiazine compound is in turn by condensation of 3-methoxy-10- (3'-chloropropyl) -phenthiazine with 4- (N-methylacetamido) piperidine by heating in ethanol in the presence of sodium carbonate produced under reflux.

Example 11 One works as described in Example 5, but works of 5.55 g of 3-methoxy-10- (3'-chloropropyl) -phenthiazine, 4.1 g of 4- (N-morpholinocarbonyI-N methylamino) piperidine, a total of 3.8 g of sodium carbonate and 150 cc of ethanol.

The crude base is dissolved in 75 cc of benzene and the solution is filtered Chromatography through a column containing 75 g of aluminum oxide and eluting sequentially with the same solvents that are mentioned in Example 3.

After evaporation of the solvent, 4 g of purified oily are obtained Phase that is converted into the acidic maleate. After recrystallization from ethanol 3.66 g of acidic maleate of 3-methoxy-1043 '- [4 "- (N-morpholinocarbonyl - N - methylamino) - piperidino] - propyl phenthiazins in the form of a white crystalline Powder from F. = 174 to 1760C.

The 4- (N-morpholinocarbonyl-N-methylamino) piperidine used as the starting substance is made by catalytic debenzylation of l-benzyl-4- (N-morpholinocarbonyl-N-methylamino) piperidine obtained from F. = 101 to 103 "C by means of palladium black in methanol.

The last-mentioned piperidine derivative is in turn by reaction of morpholinocarbonyl chloride with l-benzyl-4-monomethylamino-piperidine of Kr.1.6 = 140 to 143 "C made.

Example 12 The procedure is as described in Example 3, but it is possible of 7 g of 3-cyano-10- [3 '- (4 "-monomethylaminopiperidino) propyl] -phenthiazine, 1.75 g Potassium cyanate and 40.5 cc of n-hydrochloric acid.

After recrystallization of the crude base from ethyl acetate 4.15 g of 3-cyano-10-f3 '- [4 "- (N-carbaminyl-N-methylamino) -piperidino] -propyl) -phenthiazine in the form of a yellow crystalline powder from F. = 146 to 148 "C.

The 3 - cyano - 10 - [3 '- (4 "- monomethylaminopiperidino) propyl] phenthiazine is a thick yellow oil obtained by deacetylating 3 - cyano - 10 - [3 '- (4 " - N methylacetamidopiperidino) propyl] -phenthiazine in ethanol solution 18 hours of refluxing with 3N hydrochloric acid is prepared. That last The phenthiazine derivative mentioned is in turn produced by the condensation of 3-cyano-10- (3'-chloropropyl) -phenthiazine with 4- (N-methylacetamido) piperidine by heating in ethanol in the presence of sodium carbonate obtained under reflux.

Example 13 One works as described in Example 3, but works of 10.2 g of 3-dimethylsulfamyl-l 0-C3 '- (4' '-monomethylaminopiperidino) propyl] -phenthiazine, 1.83 g of potassium cyanate and 47.5 ccm of n-hydrochloric acid.

The reaction mixture is diluted with 200ccm of water and done through Adding potassium carbonate alkaline and extracts the liberated base with ethyl acetate. After drying the organic phase over anhydrous Potassium carbonate is concentrated below reduced pressure (about 30 mm of mercury) dry up.

The residue is dissolved in 150 cc of benzene and the solution is filtered for chromatography through a column with 150 g of aluminum oxide. One elutes with Mixtures of ethyl acetate and methanol with 5, 10 and 50 ° l0 alcohol.

After evaporation of the solvent and recrystallization from acetonitrile 4.5 g of 3-dimethylsulfamyl-10 - (3 '- [4 "- (N - carbaminyl - N-methylamino) piperidino] propyl} phenthiazine are obtained in the form of a yellow crystalline powder of F. = 8106 to 112 "C.

The 3-dimethylsulfamyl -10- [3 '- used as starting substance (4 "-monomethylamin9piperidino) - propyl] -phenthiazine is a thick yellow oil, prepared by the same process as the corresponding 3-cyano compound will.

Example 14 One works as described in Example 3, but works of 9 g of I-trifluoromethyl-10- [3 '- (4' '-monomethylaminopiperidino) propy0j-phenthiazine, 1.95 g of potassium cyanate and 45 ccm of n-hydrochloric acid.

The crude base (10 g) is dissolved in 200 cc of benzene and filtered Solution for chromatography through a column with 150 g of aluminum oxide. One elutes successively with mixtures of ethyl acetate and methanol with 5 and 100in Alcohol. After evaporation of the solvent, 6.5 g of 3-triauromethyl-10-3 '- [4 "- (N-carbaminyl-N-methylamino) -piperidino] -propyl} phenthiazine, which after recrystallization from a mixture of benzene-cyclohexane (2: 5) in the form of a pale yellow crystalline Powder from F. = 137 to 139 "C is present.

The 3-trifluoromethyl-10- [3 '- (4 "-monomethylaminopiperidino) propyl] -phenthiazine used as the starting substance is a thick oil made by the same process as the corresponding 3-cyano compound will be produced.

Example 15 38.8 g of 3-chloro-10- [3 '- (4 "-aminomethylpiperidino) propyl] -phenthiazine are heated and 25 cc formamide for 2112 hours at 130 to 140 "C.

After cooling, 100 cc of water are added and the mixture is stirred with 300 cc Benzene. The organic phase is separated off, washed with water and dried over anhydrous potassium carbonate and concentrated under reduced pressure (about 30 mm mercury column) dry up.

After reconnecting the solid residue obtained from acetonitrile one 37.9 g of 3-chloro-10- [3 '- (4 "-formamidomethylpiperidino) - propyl] - phenthiazine in the form of a cream-colored crystalline powder with a temperature of 105 to 106 ° C.

The 3-chloro-10- [3 '- (4 "-aminomethylpiperidmo) propyl] -phenthiazine used as the starting substance is a yellow oil that is used in the form of the crude product and that you go through Deacetylation of 3-chloro-10- [3 '- (4 "- acetamidomethylpiperidino) - propyl] - phenthiazine by boiling under reflux for 12 hours with 4N hydrochloric acid.

Example 16 In a solution of 8.3 g of 3-chloro-10- [3 '- (4 "-aminomethylpiperidino) -propyl] -phenthiazine and 2.6 g of triethylamine in 80 cc of toluene are left in a solution of 2.43 in 20 minutes Pour g of methyl chloroformate into 10 cc of toluene. Then you stir with ordinary Temperature 15 hours.

50 cc of water and 8 cc of 4N hydrochloric acid are added and the two are separated aqueous phase, which is made alkaline with 5 cc sodium hydroxide solution (d = 1.33). Man the liberated base is extracted with 150 cc of ethyl acetate and dried the organic phase over potassium carbonate and concentrated under reduced pressure (approx 30 mm mercury column) to dryness.

The oily residue is dissolved in 200 cc of benzene and the solution is filtered for chromatography through a column containing 30 g of aluminum oxide and eluting with a Mixture of benzene and ethyl acetate (9: 1). Obtained after evaporation of the solvent one 6.5 g of purified base, which one by dissolving in isopropanol and adding an ethereal Hydrochloric acid solution converted into the hydrochloride. 5.4 g of 3-chloro-10- [3 '- (4 "-carbomethoxyaminomethylpip eridino) propyl] phenthiazine hydrochloride in the form of a white crystalline powder from F. = 189 to 190 ° C.

Example 17 One works as described in Example 3, but goes of 8 g of 3-chloro-10- [3 '- (4 "-aminomethylpiperidino) -propyl] -phenthiazine, 2.01 g of potassium cyanate and 45.5 cc of n-hydrochloric acid.

After recrystallization of the crude base from ethyl acetate one 6.5 g of 3-chloro-10- [3 '- (4 "-carb aminylaminomethylpiperidino) propyl] -phenthiazine in the form of a white crystalline powder of F. = 136 "C.

Example 18 A solution of 8 g of 3-chloro-10- [3 '- (4 "-aminomethylpiperidino) propyl] -phenthiazine is heated, 2.36 g of methanesulfonyl chloride and 1.63 g of pyridine in 75 cc of anhydrous toluene for 2 hours under reflux.

After cooling, it is made alkaline with 10 cc sodium hydroxide solution (d = 1.33) and extracted with 200 cc of chloroform. After drying the organic extracts over Potassium carbonate is concentrated under reduced pressure (about 30 mm mercury column) Dry up.

The crude base thus obtained is dissolved in ethanol and added a solution of hydrogen chloride in ether converted into the hydrochloride. To Recrystallization from methanol gives 6.2 g of 3-chloro-10- [3 '- (4 "-methanesulfonamidomethylpiperidino) - propyl] - phenthiazine hydrochloride in the form of a white-cream-colored crystalline Powder from F. = 222 to 225 "C.

EXAMPLE 19 One works as described in Example 5, but works of 15.5 g of 3-chloro-10- (3'-chloropropyl) -phenthiazine, 8.5 g of 4 (N-methylacetamidomethyl) - piperidine, 10.6 g of sodium carbonate and 90 ccm of ethanol.

The crude base becomes anhydrous by dissolving it in acetone and adding Oxalic acid converted into the acidic oxalate. Obtained after recrystallization from ethanol 14.5 g of acidic oxalate of 3-chloro-10- [3 '- (4 "-N-methylacetamidomethylpiperidino) propyl] -phenthiazine in the form of a pale yellow crystalline powder of F. = 150 to 155 "C.

The 4- (N-methylacetamidomethyl) piperidine used as the starting substance from Kr.19 = 170 to 173 "C is obtained by hydrogenation of 4- (N-methylacetamidomethyl) -pyndin in the form of the hydrochloride in water and in the presence of Adams platinum at ordinary Temperature and ordinary pressure. The Pyndm derivative melts at 49 to 50 "C and is in turn obtained by acetylation of PMonomethylaminomethylpyndin by means of Acetic anhydride produced. The last-mentioned derivative from Bp 19 = 105 to 106.5 "C is obtained by reductive amination of isonicotinaldehyde with Monomethylamine made in ethanol in the presence of Adams platinum.

Claims (1)

PATENT CLAIM Process for the preparation of phenthiazine derivatives of the general formula in which X is a hydrogen or a halogen atom or an alkyl, alkoxy or a low molecular weight acyl radical or a cyano, methylthio, methanesulfonyl, dimethylsulfamyl or trifluoromethyl radical, A is an alkylene radical with at most 4 carbon atoms, n is the number 0 or 1 , R is a hydrogen atom or a methyl radical and Z is a low molecular weight acyl, an alkoxycarbonyl, a low molecular weight alkanesulphonyl, a carbamin.yl or a sulphamyl radical, these radicals being optionally substituted, especially a morpholinocarbonyl or morpholinosulphonyl radical, and salts or quaternary thereof Anunonium derivatives, characterized in that a phenthiazine derivative of the general formula with a piperidine compound of the general formula reacted, where in these formulas one of the radicals P and Q is a hydrogen atom and the other is a radical -AY, in which Y is an acid radical, or that one is a phenthiazine compound of the general formula in which the various symbols have the meanings given above, with a carboxylic acid anhydride, chloride or ester, an alkyl chlorocarbonate, a carbamic acid halide, an alkyl isocyanate, a sulfamic acid halide or an alkanesulfonyl halide, and the compounds thus obtained are converted into theirs, if appropriate by methods known per se Salts or quaternary ammonium derivatives transferred. Documents considered: British Patent Specification No. 716 227,716 230, 745 069, 774 882; Houben-Weyl, Methods of Organic Chemistry «, Vol. IX, p. 398 ff., And Vol. XI / 2, edition 1958, pp. 27 to 35 and 69 to 72.