DE1084266B - Process for the preparation of phenthiazine derivatives with basic substitution in the 10-position - Google Patents

Description

Process for the preparation of basic substituted in the 10-position Phenthiazine derivatives It is already known that certain phenthiazine derivatives pharmacologically are effective. The German patent specification 1012 915 relates, for. B. the production of 10- (3'-aminopropyl) -phenthiazines, which optionally in the phenthiazine ring can be substituted.

It has been found that new therapeutically valuable compounds of the phenthiazine series of the general formula can be obtained where "alkylene" c is a straight-chain or branched alkylene radical, R1 is a hydrogen or halogen atom or an acetyl or low molecular weight alkoxy radical, R2 is the radical of an optionally base substituted low molecular weight aliphatic alcohol and x is an integer between 0 and 2, if one a) Phenthiazines of the general formula with halocarboxylic acid esters of the formula Hal- (CH2) x-COORZ wherein »alkylene (<, R1, R2 and x have the above meaning and Hal means a halogen atom, condensed and then optionally the nitrogen-containing phenthiazine-10-carboxylic acid ester formed by reaction with a transesterifies other, optionally basic substituted, low molecular weight aliphatic alcohol or b) a phenthiazine derivative of the general formula with an amino compound of the general formula HZN- (CH2) x-COOR2 in which "alkylene" c, Ri, R2 and x have the above meanings and Hal means a halogen atom. These new phenthiazine compounds have superior pharmacological properties, in particular anesthesia-potentiating and adrenolytic effects.

The narcosis-potentiating effect was tested on mice. For that was the animals were injected intravenously with 30 mg / kg of thiopental and the duration of anesthesia was measured. In addition, after pretreatment of the animals 30 minutes before the thiopental administration, with 25 mg / kg intraperitoneally of a phenthiazine derivative also determined the duration of anesthesia.

The quotient from the duration of anesthesia of those pretreated with phenthiazine derivatives Animals and the duration of anesthesia of the control animals that have not been pretreated represents the so-called »Exponentiation index @ <: The exponentiation index indicates how many times longer the z. B. anesthesia caused by thiopental in those pretreated with phenthiazines Animals in comparison with the control animals that have not been pretreated.

The effect of the following phenthiazine derivatives was investigated: Compound potentiation index I. Phenthiazinyl- (10) -propyl- (3 ') -carb- Amic acid ethyl ester tartrate produced represents according to example below) 12.7 II. Phenthiazinyl- (10) -propyl- (3 ') - carb- Amic acid methyl ester tartrate (according to Example 2 below). . . . . . . . . 5.5 III. 10- [3 '- (methyl-piperazinyl) -propyl] - phenthiazine tartrate (according to »Medicinal Mittelforschung «1958, p. 199) ...... 1.3 IV. 10- (3'-aminopropyl) -phenthiazine (ge according to German patent specification 1012915) 1; 0 The values obtained thus show that the products produced according to the invention have a much better anesthetic potentiating effect than comparable known phenthiazine derivatives.

Furthermore, the adrenolytic effect of the above products on mice comparatively checked:

The animals died without protective pretreatment after an intramuscular injection - of 5 mg / kg adrenaline within 30 minutes. If the animals were pretreated 30 minutes before the adrenaline injection with a dose of 25 mg / kg - one of the above-mentioned phenthiazine derivatives by intraperitoneal injection, the results listed in the table below were obtained. You designate the. Percentage of animals that did not die after appropriate pretreatment due to adrenaline injection. _ Connection - percentage of protected animals I 1000 / ' 1I 1000 / ' III 600 /, IV 00/0 The products obtained according to the invention thus proved to be far superior to the known phenthiazine derivatives listed above and used for comparison, also with regard to the adrenolytic effect.

Furthermore, 3-chloro-10- (3'-ethylaminopropyl) -phenthiazine is known from Swiss patent 314 494. This compound shows a lower anesthetic potentiating effect than the comparable 3-chlorophenthiazinyl (10) -propyl-3'-carbamic acid ethyl ester that can be prepared according to the invention: Compound potentiation index 3-chloropheniazinyl- (10) -propyl- (3 ') - carbamic acid ethyl ester hydro- chloride (manufactured according to the discovery) ....................... 6.27 3-chloro-10- (3'-ethylaminopropyl) - phenthiazine hydrochloride (according to Swiss patent specification 314494) ....................... 4.04 The phenthiazinyl- (10) -ethyl-dimethyl- carbäthoxymethylammoniumchlorid, which also belongs to the prior art and is known from French patent specification 1028 112, is also the N- [Phenthia zinyl- (10) -äthyl- (2 ') used for comparison and which can be prepared according to the invention. )] - inferior to glycine ethyl ester in the narcosis-potentiating effect: Compound potentiation index N- [Phenthiazinyl- (10) -ethyl- (2 ')] - gly- cinethyl ester (manufactured according to Invention). . . . . . . . . . . . . . . . . . . . . 2.75 Phenthiazinyl- (10) -ethyl-dimethyl- carbethoxymethyl ammonium chloride rid (according to French patent scripture 1028 112) ............... 1.14 The test for anesthesia-potentiating effect was carried out according to the method described above.

Example 1 Phenthiazinyl (10) propyl (3 ') carbainic acid ethyl ester 51.2 g of 10- (3'-aminopropyl) -phenthiazine are dissolved in 80 ccm of absolute ethyl alcohol. A solution of 24.5 g of ethyl chlorocarbonate is added to this solution with stirring in 80 ccm of absolute ethanol added in portions over a period of 15 minutes, the temperature being kept below 50 ° C. by cooling. After a few minutes, especially when scratching with a. Glass rod, crystals fall out, which are sucked off and washed with ether. Yield: 29 g; F. = 220 to 222 ° C (from alcohol).

Tartrate: 12 g of phenthiazinyl (10) propyl (3 ') carbamic acid ethyl ester are dissolved in 240 ccm of hot alcohol and filtered. After cooling down, 5 g Tartaric acid, dissolved in dioxane ether, added, whereby nothing precipitates. After addition 10 g of tartrate of the base used are obtained from ether. F. = 223 to 225 ° C.

Example 2 Phenthiazinyl (10) propyl (3 ') carbamic acid methyl ester 51.2 g of 10- (3'-aninopropyl) -phenthiazine (0.2 mol) are dissolved in 80 cc of absolute alcohol dissolved hot, and after cooling a solution of 21 g of methyl chloroformate, dissolved in 80 cc of absolute alcohol, added slowly with stirring, with heat of reaction occurs. After cooling, the addition of 300 cc of ether causes the precipitation of Pale pink crystals brought about, which sucked off and dried in a vacuum desiccator will. Yield: 34 g; F. = 217 to 219 ° C (from alcohol).

Tartrate: 28 g of phenthiazinyl- (10) -propyl- (3 ') -carbamic acid methyl ester are dissolved hot in 300 ccm of absolute alcohol and then for so long with a solution tartaric acid is added to ether until the precipitation of crystals has ended. Afterward is suctioned off, washed with ether and dried. Yield: 26 g; F. = 227 to 228 ° C.

Example 3 Phenthiazinyl (10) propyl (3 ') carbamic acid dimethylaminoethyl ester 12 g of phenthiazinyl (10) propyl (3 ') carbamic acid ethyl ester are mixed with 36 g Dimethylaminoethanol mixed and the mixture after the addition of 1.8 ccm 50 / jger sodium methylate solution Heated to 120 ° C for 2 hours. After distilling off the excess dimethyl aminoethanol the residue is taken up in 100 ccm 20 ° / jger acetic acid and the solution with Ether shaken out. This acetic acid solution is separated and with 50 to 100 ccm 5 N sodium hydroxide solution made alkaline, whereby the phenthiazinyl- (10) -propyl- (3 ') - carbamic acid dimethylaminoethyl ester separates.

Hydrochloride: After taking up the base in dioxane and drying the solution with potash, hydrogen chloride is passed in until saturation and then the hydrochloride is precipitated with ether. Yield: 9 g; F. = 209 to 211'C (from alcohol-ether).

Example 4 N- [Phenthiazinyl- (10) -propyl- (3 ')] -glycine methyl ester 51.2g 10- (3'-aminopropyl) -phenthiazine are dissolved in 80 ccm of absolute alcohol and mixed with a solution of 24.5 g of methyl chloroacetate in 100 cc of absolute alcohol added and the mixture is then left to itself at 40 ° C. for 5 to 6 hours. so is mixed with about 2000 to 2500 ccm of ether, the N- [phenthiazinyl- (10) -propyl- (3 ')] -glycine methyl ester initially sticks to the vessel wall, but when scratched with the glass rod falls off the wall in crystalline form. Yield: 26 g; F. = 205 to 206 ° C (with decomposition).

Tartrate: 20 g of N- [phenthiazinyl- (10) -propyl- (3 ')] -glycine methyl ester are dissolved in 200 ccm of hot alcohol, filtered and with 400 ccm saturated solution of tartaric acid in ether (containing 9.2 g of tartaric acid) and by adding ether it causes the tartrate to precipitate. It will be after recrystallization obtained from alcohol-tetrahydrofuran 14 g. F. = 207 to 209 ° C.

Example 5 N- [Phenthiazinyl- (10) -propyl- (3 ')] -glycinepiperidinoethyl ester 19 g of N- [phenthiazinyl- (10) -propyl- (3 ')] -glycine methyl ester are mixed with 75 g of piperidinoethanol and 3.7 ccm 5 ° / @ ger sodium methylate solution and heated to 120 ° C for 4 hours. After the excess piperidinoethanol has been distilled off, it is dissolved in dilute hydrochloric acid taken up and shaken out with ether in a separating funnel. After alkalizing with Potash, the resulting oil is taken up in tetrahydrofuran and over potassium carbonate dried. Then with a solution of oxalic acid in dioxane ether is made to completion added to the precipitation. After suctioning off and washing with ether, 9 g of oxalate are obtained of N- [phenthiazinyl- (10) -propyl- (3 ')] -glycine piperidinoethyl ester. F. = 130 to 132 ° C (from alcohol-acetone).

Example 6 N- [Phenthiazinyl- (10) -propyl- (3 ')] -glycine methyl ester 8 g of 10- (3'-bromopropyl) -phenthiazine and 4.5 g of glycine methyl ester are stored at 70 to 80 ° C melted together and held at this temperature for 5 hours. The reaction product is taken up in 90 ccm hot, absolute ethyl alcohol, from a little undissolved filtered off and mixed with 180 ccm of a 2.5% strength tartaric acid solution in ether-dioxane. It is left to stand overnight, some of the tartrate of the base obtained precipitating out. The precipitation is completed by stirring in ether. After vacuuming, drying and recrystallization from alcohol-tetrahydrofuran gives 3.6 g of N- [phenthiazinyl- (10) -propyl- (3 ')] -glycine methyl ester tartrate obtained from m.p. = 205 to 208 ° C.

Example 7 3-Chloropheniazinyl- (10) -propyl- (3 ') -carbamic acid ethyl ester 6 g of 3-chloro-10- (3'-aminopropyl) -phenthiazine became hot in 20 cc of absolute alcohol dissolved, filtered and with stirring dropwise with 2.2 g of ethyl chloroformate offset. The reaction solution is allowed to stand at room temperature for 1 to 2 hours and then, by stirring in 200 cc of absolute ether, 3-chlorophenthiazinyl- (10) -propyl- (3 ') -carbamic acid ethyl ester is precipitated as the hydrochloride. Yield: 2.8 g; F. = 221 to 224 ° C after recrystallization Alcohol petroleum ether.

Claims (1)

PATENT CLAIM: Process for the preparation of phenthiazine derivatives of the general formula with basic substitution in the 10-position wherein "alkylene" is a straight-chain or branched alkylene radical, R1 is a hydrogen or halogen atom or an acetyl or low molecular weight alkoxy radical, R2 is the radical of an optionally base substituted low molecular weight aliphatic alcohol and x is an integer between 0 and 2, characterized in that one a) Phenthiazines of the general formula with halocarboxylic acid esters of the general formula Hal - (CH2) @ - COO R2 where "alkylene", R1, R2 and x have the above meaning and Hal is a halogen atom, condensed and then optionally the phenthiazine ester formed by reaction with another, optionally basic substituted low molecular weight aliphatic alcohol transesterified or b) a phenthiazine of the general formula with an amino compound of the formula H2N- (CHz) x-COORz in which "alkylene", R1, R2 and x have the above meanings and Hal means a halogen atom. Documents considered: USA. U.S. Patent No. 2,830,987; Swiss patent specification No. 314 494; French Patent No. 1028 112; Richter-Anschütz, "Chemistry of Carbon Compounds", 1928, Vol. 1, pp. 482 and 542.