SE175403C1 - - Google Patents

Description

Inventors: RM Jacob, RJ Horclois and E Suau Priority begard iron on 15 January, 15 March and 25 September 1957 (France) The present invention relates to a process for producing new phenothiazine derivatives having the general formula: X / - \, A - NN - (C1-12) nCON \ / R2 as well as their salts and quaternary ammonium derivatives. In the formula I, A represents a matt, double, aliphatic, straight or branched chain aliphatic carbon radical containing 2-4 carbon atoms, Y a sulfur atom or a radical -SO- or -SO 2 -, X a hydrogen atom or halogen atom or a lower alkyl, alkyloxy , a cyl- or carbalkoxy radical, a syano-, methylthio-, methanesulfonyl- or dimethylsulfamide radical, while H1 and R, denote hydrogen atoms, lower alkyl radicals or benzyl or cyclohexyl radicals, the radical: -N 'avert may denote a pyrrolidine-, or morpholine radical and n denotes 1 or 2. By a lower radical is meant a radical having 1-4 carbon atoms.

These new derivatives can be prepared by reacting a compound of formula II II \ / N \ / 1 R with a compound of formula Q - (CH 2) .CON R, in which -R represents a hydrogen atom, a radical A - Z, a radical - A —NNH to which for Q correspond respectively a radical ZA —NN / \ HNN- \ or a residue Z, wherein Z represents a residue of a. reactive ester and the other symbols have the meaning given above.

The condensation can be carried out without solvents, it is generally advantageous to work in an inert organic solvent, such as an aromatic hydrocarbon, preferably benzene, toluene or xylene, an ether, for example ethyl ether, or an amide, for example dimethylformamide. It is generally convenient to use an alkaline condensing agent. An alkali metal or an alkali metal derivative such as hydroxide is suitably used; hydride, amide or alcoholate.- - Work at room temperature or at a higher temperature according to the nature of the reagents and possibly the antifreeze and condensing agent.

The condensation reaction may possibly be followed by an oxidation of the group Y to give one. sulfone. or sulfoxide.

The new phenothiazine derivatives prepared according to the present invention have valuable pharmacodynamic properties. They are above all very active. BOM sedatives, antiemetics ° eh: antihistamines.

/ R, a radical 2 - - The following results from comparative tests between on the one hand the following products prepared according to the invention and on the other hand 1- / 3'- (3 "-chloro-10" -phentiazinyl) propyl / - 4-acetoxyethylpiperazine according to U.S. Pat. No. 2,766,235 and hereinafter referred to as product 0, show the good pharmacodynamic properties of the present products.

Significance of the symbols Xn —N '/ BI R, A2Cl1 —NH, 14Cl1 - NHCHs 1Cl1 - N (C1-13) 29 - OCH3 1 - N (CH3) 2 3Cl2 - NH2 4Cl2 - N (CH2) 2 The following tests were performed: Potential for anesthesia by means of ether The product is administered, which is to be examined in rats subcutaneously at a dose of 20 mg / kg. Thirty minutes later, the knobs are inserted into a clock, where a certain amount of ether is evaporated. Once the anesthesia has entered, the knobs are removed from the watch and the duration of the anesthesia is recorded in minutes in the open air.

Winter and Flatakers test / J. Pharm. Exp. Ther. 103, 93 (1951) / One compares graphically, in comparison with untreated animals, the dose (DE 2 in mg / kg) which, at least 90 minutes before the test, reduces the spontaneous activity of the rat by 50%. This dose (DE so) is given in the table below.

Tensile test Determine the dose (DE, o) of the product, which is fed per os in rats 90 minutes before the test, or 50% of the animals are unable to stand up on a horizontal span.

Antihistamine effect - Bovet-Staub's test The number of toxic doses of histamine, administered intraventively, which guinea pigs can cure after a 30 minute treatment subcutaneously with 20 mg / kg of the test product is recorded.

The following results were obtained: • Product abc Minutes DE „mg / kg DE mg / kg per osper os d Number of doses A 18 0.6 4.2 - B 19 - - 1100 C 27 2 5,1400 D 23 - - 1400 F 24 1,8 6, - E 26 3 7,1000 0 18 2,6,900 For therapeutic purposes, these derivatives are suitably used in the form of bases or addition salts containing pharmaceutically acceptable anions, such as chlorohydrates, phosphates, sulphates, maleates, fumarates, citrates and tartrates. They can also be used in the form of quaternary ammonium derivatives obtained by the action of slightly toxic esters, such as chlorides, bromides, iodides and toluenesulfonates, of alkyl, for example methyl or ethyl, benzyl or the like.

The following non-limiting examples show how the invention can be put into practice. The melting points have been determined at Kofler Bank.

Example 1. Boil for 20 hours under reflux and stir 9 g of 143 '- (3 "-chloro-10" -phentiazinyl) -propyl] -piperazine with 3.3 g of N-dimethylchloroacetamide, 2 g of dry potassium carbonate and 75 ml of anhydrous toluene. 100 ml of distilled water are added and the toluene solution is washed first with 50 ml and then with 30 ml of water. The toluene layer is shaken with 50 ml of 10% hydrochloric acid. Decant the acidic aqueous layer, hi & base with 20 ml of sodium hydroxide solution (d = 1.33) and extract the base Ire times with 50 ml of ether. The ether layer is dried over sodium sulphate and evaporated to dryness. 11 g of the crude base are obtained. By adding ether, containing 10 g of hydrogen chloride gas, 11 g of chlorohydrate are obtained. With dilute sodium hydroxide solution, the base can be liberated, which is extracted with benzene and recrystallized from 250 ml of heptane. 7 g of 143 '- (3 "-chloro-10" -phentiazinyl) -propyl] -4- (dimethylcarbamoylmethyl) -piperazine, mp 134 ° C are obtained.

Example 2. Boil for 20 hours under reflux and stir 7.2 g of 143 '- (3 "-chloro-10" -phentiazinyl) -propyl-piperazine with 2.1 g of chloroacetamide, 2.8 g of potassium carbonate and 75 ml of anhydrous toluene . 100 ml of distilled water are added and the toluene solution is washed first with 50 ml and then with 30 ml of water. The toluene layer is shaken with 50 ml of 10% hydrochloric acid. Decant the acidic aqueous layer, freeze the base with 20 ml of sodium hydroxide solution (d = 1.33) and extract the base once with 50 ml of chloroform. The chloroform layer is dried over sodium sulfate and evaporated to dryness. Recrystallization from the isotherm in isopropanol gives 6 g of 1- [3 '- (3 "-chloro-10" -phentiazynyl) -propyl] -4-carbamoylmethyl-piperazine, mp 134 ° C.

Example 3. Following the procedure of Example 2, starting with Iran, 2.15 g of 2-chloropropionamide give, by recrystallization from a mixture of cyclohexane and benzene, 6.5 g of 1- (3 '- (3 "-chloro-10" - phentiazynyl) -4-carbamoylethyl-piperazine, m.p. 128 ° C.

Example 4. Starting from Example 2 starting from 2.8 g of 2-N-dimethylchloropropionamide, 5.3 g of acidic dimaleate of 143 '- (3 "-chloro-10" -phentiazinyl) are obtained with maleic acid in ethyl acetate. ) -propyl11-4-dimethyl-carbamoylethyl-piperazine, m.p. 180 ° C.

Example 5. Following the procedure of Example 2, starting from 3 g of N-diethylchloroacetamide, 7 g of base can be isolated, from which the chlorohydrate in isopropanol is prepared. 5.5 g of dichlorohydrate of 143 '- (3 "-chloro-10" -phentiazynyl) -propyl] -4-diethylcarbamoylethyl-piperazine, m.p. 128 ° C.

Described of the product in the title of the invention Example No. - -a Example 6. If one proceeds according to Example 2 and gives frail 3.3 g of chloroacetomorpholide, after recrystallization from ethyl acetate 6.4 g of 1- [3 '- (3 "-chloro-10) are obtained "-phentiazynyl) -propyl] -4-morpholinocarbonylmethyl-piperazine, m.p. 128 ° C.

Example 7. If one mar according to Example 2 and starting from 3.2 g of chloroacetopiperidide, one can isolate a base from which the chlorohydrate is prepared in isopropanol. 4.8 g of dichlorohydrate of 1- [3 '- (3 "-chloro-10" -phentiazynyl) -propyl] -4-piperidinocarbonylmethyl-piperazine, mp 225 ° C are obtained.

Example 8. Starting from Example 2 starting from 3.0 g of chloroacetopyrrolidide, 8 g of base can be isolated, from which the dichlorohydrate of 1- [3 '- (3 "-chloro-10" -fentiazinyl) is prepared in isopropanol. - propyl] - 4-pyrrolidino - carbonylmethyl - piperazine, m.p. 245 ° C.

Example 9. 11 g of p-toluenesulfonal are boiled for 4 hours under reflux and stirring. of 3- (3'-methoxy-10'-phentiazynyl) -propanol with 4.6 g of 1-dimethylcarbamoylmethyl-piperazine and 3.5 g of potassium carbonate in 75 ml of methyl ethyl ketone. 60 ml of the methyl ethyl ketone are driven off and taken up in 50 ml of chloroform. Wash twice with 25 ml of water. The chloroform layer is shaken with 60 ml of N hydrochloric acid. Decant the acidic aqueous layer, hi & base with 15 ml of sodium hydroxide solution (d = 1.33) and extract the base three times with 20 ml of chloroform. The chloroform layer is dried over sodium sulfate and evaporated. The chlorohydrate is prepared in isopropanol. It melts at 225 DEG C. Upon transition to the base and crystallization from ether, 4.3 g of 143 '- (3 "-methoxy-10" -lentiazinyl) propyl] -4-dimethyl-carbamoylmethylpiperazine, m.p. 95 DEG C., are obtained.

1-Dimethylcarbamoylmethyl-piperazine is obtained by boiling for 16 hours under reflux 24.4 g of N-dimethylchloroacetamide with 69 g of anhydrous piperazine, 30 g of sodium iodide and 800 ml of methyl ethyl ketone. But drive off 780 ml of the methyl ethyl ketone and take up with 200 ml of benzene. The excess piperazine is cooled and filtered. Distillation under vacuum. 28 g of 1-dimethylcarbamoylmethyl-piperazine are obtained, which boil at 105109 ° C / 0.3 mm Hg.

Example 10. If the procedure is as in Example 9 and the mixture is boiled for 17 hours under reflux and 11.2 g of p-toluenesulfonate of 1- (3'-chloro-10'-phentiazynyl) -2-propanol are obtained, 3.5 g are obtained. 141 '- (3 "- chloro-10" -phentiazynyl) -2'-propyl] -4-dimethylcarbamoylmethyl-piperazine, from which the dichlorohydrate is prepared in isopropanol, m.p. 230 ° C.

Example 11. Boil for 16 hours under reflux and stir 6.5 g of 10- (2'-chloroethyl) -phentiazine with 4.6 g of 1-dimethylcarbamoylmethyl-piperazine, and 3.5 g of potassium carbonate in 75 ml of xylene. In the manner previously described, only 9 g of the crude base from which the dichlorohydrate is prepared in methanol are isolated, m.p. 215 DEG C. The base is liberated by the action of alkali to give 1- [2 '- (10 "-phentiazinyl) -ethyl] ] -4-dimethylcarbamoylmethyl-piperazine, m.p. 95 ° C.

Example 12. Boil for 4 hours under reflux and stir 6 g of 3-dimethylsulfamido-phentiazine with 50 ml of xylene and 1 g of sodium amide. Man to-. then add 5.5 g of 1- (3 'chloropropyl) -4-dimethylcarbamoylmethyl-piperazine dissolved in 30 ml of xylene dropwise over 0.5 h. It is boiled for another 16 hours during a flood. In the above procedure, 5 g of 143 '- (3 "-dimethylsulfamido-10" -phentiazynyl) -propyl] -4-dimethyl-carbamoylmethylpiperazine are isolated, which is converted to the dimethanesulfonate, m.p. 165 ° C.

43 g of dichlorohydrate of 1- (3'-chloropropyl) -4-dimethyl-carbamoylmethyl-piperazine, m.p. 225 ° C, are obtained by the action of 18 g of thionyl chloride in 300 ml of chloroform on 31 g of 1- (3'-hydroxypropyl) - 4-dimethylcarbamoylmethyl-piperazine converted to the dichlorohydrate.

31.5 g of 1- (3'-hydroxypropyl) -4-dimethylcarbamoylmethyl-piperazine, bp 172 ° C / 0.4 mm Hg, are obtained by reacting 15.7 g of 1-chloro-3-propanol at 130 ° C with 59 ° C. g 1-dimethylcarbamoylmethyl-piperazine. The same compound can also be prepared by the action of N-dimethylacetamide on 1- (3'-hydroxypropyl-piperazine).

Example 13. Boil for 7 hours under reflux on a water bath 2.2 g of 143 '- (3 "-chloro-10" -phentiazynyl) -propyl] -4-pyrrolidinocarbonylmethyl-piperazine with 20 ml of methyl iodide. Concentration gives 2.7 g of diiodomethylate of the corresponding phenothiazine, which, after recrystallization from 95% ethanol, melts at 242 DEG C.

Example 14. By boiling for 10 hours under Aterflode and stirring 7.2 g of 143 '- (3 "-chloro-10" -phentiazynyl) -propyl] -piperazine with 2.2 g of N-methylchloroacetamide, 2.8 g of potassium carbonate and 75 ml of toluene. Add 100 ml of distilled water and decant. The toluene layer is shaken with 50 ml of 10% hydrochloric acid, decanted, the hi & base with sodium hydroxide solution and extracted with chloroform. 6.3 g of 14-3 '- (3 "-chloro-10" -phentiazinyl) -propyl] -4-methylcarbamoylmethyl-piperazine dichlorohydrate are evaporated and obtained by the action of a solution of chloroacetic acid in ether on the base dissolved in isopropanol 220 ° C.

Example 15. Starting from Example 4 to give 3.5 g of N-cyclohexylchloroacetamide, 7 g of 143 '- (3 "-chloro-10" -phentiazinyl) -propyl-4-cyclohexylcarbamoylmethyl-piperazine, m.p. 130 ° C, after recrystallization from ethyl acetate. Example 16. Starting from Example 4 starting from 4 g of N-benzylchloroacetamide, 11 g of 143 '- (3 "-chloro-10" -phentiazinyl) -propyl] -4-benzylcarbamoylmethyl-piperazine dichlorohydrate are obtained, m.p. ° C.

Example 17. Following the procedure of Example 4 starting from 6 g of 143 '- (3 "-cyano-10" -phentiazinyl) -propyl-piperazine and 2.8 g of chloroacetopyrrolidide, 6.8 g of base are obtained, of which in ethanol with 3.5 g of maleic acid, 8.5 g of acid dimaleate of 1- [3 '- (3 "-cyano-10" -phentiazynyl) -propyl] -4-pyrrolidinocarbonylmethyl-piperazine, m.p. 180 DEG C.

Example 18. Boil for 20 hours under reflux and stirring 4.5 g of p-toluenesulfonate of 3- (3'-methylthio-10'-phentiazynyl) -propanol with 4 g of 1-4-pyrrolidinocarbonylmethyl-piperazine, m.p. 90 ° C , and 80 ml of methyl ethyl ketone. 4.8 g of the base can be isolated by conventional treatment, from which 5 g of acidic dimaleate of 143 '- (3 "-methylthio-10" -phentiazinyl) -propyl are prepared with 2.3 g of maleic acid ] -4-pyrrolidinocarbonylmethyl-piperazine, m.p. 170 ° C. 1-Pyrrolidinocarbonylmethyl-piperazine, m.p. 90 ° C, is obtained by condensing chloroacetopyrrolidide with anhydrous piperazine in methyl ethyl ketone by boiling for 16 hours under reflux in the presence of sodium iodide.

Example 19. 2.15 g of 143 '- (3 "-chloro10" -phentiazinyl) -propyl] -4-carbamoylethyl-piperazine, m.p. 128 ° C, are dissolved in 10 ml of N hydrochloric acid and 15 ml of water, then at room temperature then gradually add 10 ml of nitric acid (d = 1.38). At this point, an intense red-violet color appears during the release of nitrous gases. The color disappears in a few minutes, after which a cloudy, pale yellow solution remains. Cool and add 20 ml of sodium hydroxide solution (d = 1.33) after 5 minutes. The precipitated base is extracted three times with 20 ml of chloroform. Dry over potassium carbonate and then evaporate in a water bath. Recrystallization from benzene gives 1.6 g of 1- [3'- (3 "-chloro-9" -oxo-10 "-phentiazinyl) -propyl] -4-carbamoylethylethyl-piperazine, mp 176 ° C.

Example 20. A solution of 4.8 g of p-toluenesulfonate of 3- (3'-chloro-9 ', 9'-dioxo-10'-phentiazynyl) -propanol and 4 g of 1-pyrrolite linocarbonylmethyl piperazine in 80 ml of methyl ethyl ketone. The solvent is driven off at normal pressure, the residue is taken up in 50 ml of water and extracted with 50 ml of chloroform. The chloroform solution is washed four times with 30 ml of water, dried over anhydrous sodium sulfate, driven off the solvent at a pressure of 13 mm Hg while heating to 80 ° C. The remaining crude base is dissolved in a mixture of equal parts of benzene and cyclohexane. the solution is passed through an alumina column for chromatography. Elution with a mixture of equal parts of benzene and ethyl acetate isolates the pure base. There is thus obtained 143 '- (3 "-chloro-9", 9 "-dioxo-10" -phentiazinyl) -propyl- -4-pyrrolidinocarbonylmethyl-piperazine in the form of a white crystal powder, mp 176 ° C.

Claims (1)

1. Patent Claim:. for the preparation of phentiazine derivatives having pharmaceutical properties, characterized in that a compound of formula II \ V \ i at a temperature between room temperature and 200 ° C is reacted with a compound of formula RI Q - (CH2) ,, - CON, R 2 in which formulas Y represents a sulfur atom or an SO or SO 2 radical, X represents a vale or halogen atom or a lower alkyl, alkyloxy, acyl or carbalkoxy radical, a cyano, methylthio, methanesulfonyl or dimethylsulfamide radical, R represents a water atom, a radical -AZ, a radical / \ —A— N NH, against which Q represents a radical ZA.— NN—, / a radical / \ EN and a residue Z, respectively, wherein Z represents the residue of a reactive ester, and A represents a divalent, matte, aliphatic, straight or branched chain hydrocarbon radical containing 2-4 carbon atoms, and R 1 and R 2, represent hydrogen atoms, alkyl radicals containing up to 4 carbon atoms or benzyl or cyclohexyl radicals or together with the adjacent quaver atom form a pyrrolide , piperidine or mother folin radical, saint n denotes 1 or 2, to form an equation of the general formula - X ,, R, A —NN— (CH2) 11CON \ • R, after which • the condensation may be followed by an oxidation of ten final compounds, i which Y represents S or SO, for the formation of the corresponding phenothiazines where Y represents SO or SO, and, where appropriate, the conversion of the base into a salt or a quaternary ammonium derivative, Anforda, publications: Patent Specifications from Norway 88 388 USA 2 766 235, 2 627 517. Stockholm 1961. Kungl. Boktr. P. A. Norstedt & Sorter. 610089