DE1119276B - Process for the preparation of phenthiazine derivatives acylated in the 3-position - Google Patents

Description

Process for the preparation of phenthiazine derivatives acylated in the 3-position It has been found that phenthiazine derivatives acylated in the 3-position of the general formula in which Ac denotes an optionally branched acyl group, A denotes an optionally branched alkylene group and R denotes a low molecular weight alkyl radical, have excellent adrenolytic, hypotensive and potentiating properties.

- The synthesis of the compounds mentioned is carried out according to the method that 3-acylphenthiazines as such or in the form of derivatives in which the carbonyl group is protected, converted into their metal compounds, in particular sodium, potassium or magnesium compounds, and these with reactive esters basic alcohols of the general formula in which A and R have the meanings given above. To convert the 3-acylphenthiazines or their abovementioned functional derivatives into the metal compounds, however, at least 2 equivalents of a suitable metal donating compound can also be used and the basic alkylation can be carried out with the equivalent amount of a salt of reactive esters of the basic alcohols mentioned. The 3-acylphenthiazines or their functional derivatives can also be reacted with reactive esters of the basic alcohols mentioned without an additional acid-splitting agent at elevated temperature with or without a solvent and, if appropriate, under pressure.

If one uses functional descendants in the individual conversions of 3-acylphenthiazines in which the carbonyl group is protected, one cleaves after the basic alkylation has taken place, the blocking radical in a suitable manner off again.

The compounds prepared according to the process can be used as such, can be used in the form of their salts or as quaternary ammonium compounds.

The 3-acetyl-10- [N'-methylpiperidyl- (3 ') -methyl] -phenthiazine obtainable according to the process (I) was with regard to toxicity, sedative effect, spasmolysis, blood pressure and nictitating membrane contraction with the one from the documents of the German patent application C 7333 IVc / 12p known 10- [N'-methylpiperidyl (3 ') -methyl] -phenthiazine (II) compared. The following results were obtained: 1. Toxicity, mouse intravenous, DL50 (1) 55 mg / kg.

(11) 60 mg / kg.

2. Sedative effect on the "inclined plane", mouse subcutaneous, DE60 (1) at 5 mg / kg.

(11) at 50 mg / kg.

3. Spasmolysis on the isolated guinea pig intestine, 50% inhibition the anti-acetylcholine effect (1) by 2.8 mg / l.

(11) by 1.4 mg / l.

4. Blood pressure, cat intravenous, (anesthetized with chloralose urethane) (I) 1 mg / kg 1st animal: drop in blood pressure by 50 mm Hg, persistent after 1 hour, initial pressure 120 mm Hg.

2nd animal: drop in blood pressure by 60 mm Hg, permanent, initial pressure 140 mm Hg.

(11) 1 mg / kg 1 animal: drop in blood pressure by 30 mm Hg, after 6 minutes initial pressure of 140 mm Hg is reached again.

3 mg / kg 1 animal: Continuous drop in blood pressure by 60 mm Hg within 30 minutes, initial pressure 180 mm Hg.

5. Nictitating membrane, cat intravenous (anesthetized with chloralose urethane) Inhibition of the nictitating membrane contraction in the case of preganglionic electrical irritation of the cervical sympathetic nervous system: (1) 1 mg / kg 1st animal: nictitating membrane contraction abolished, no recovery within 50 Minutes.

2nd animal: nictitating membrane contraction completely abolished after 40 minutes Beginning of the recovery of the nictitating membrane reaction.

(11) 1 mg / kg 1 animal: nictitating membrane contraction reduced by a quarter, after 20 minutes the initial value was reached again.

3 mg / kg 1 animal: nictitating membrane contraction reduced by a quarter, The initial value was reached again after 30 minutes.

The process product (I) shows a clear sedative effect at the "Inclined Plane", which is about 10 mouths stronger than that of (11).

The toxicity is about the same for both products.

The parasympathicolytic effect is in (11), the adrenolytic Effect, on the other hand, is more pronounced in the product of the process.

The product of the process is more effective in terms of vasodepression in terms of blood pressure.

From these results it can be seen that the process product (I) has an effect which is similar to that of the well-known 3-chloro-10-y-dimethylaminopropylphenthiazine is very similar. Such an effect is only in the known compound (II) weakly indicated.

The effect of 10- [N'-methylpiperidyl- (3 ') -methyl] -phenthiazine is by far exceeded by the products that can be manufactured using the process.

Example 1 157 g of 3-acetylphenthiazine are mixed with 43 g of toluene-moist Sodium amide in 900 cc of dioxane warmed to 40 "C, then 120 g of N-methylpiperidyl- (4) -methyl chloride added dropwise and then refluxed for 4 hours. After extracting of the reaction product with dilute acid, the aqueous acidic solution is made alkaline, extracted with ether, dried with potassium carbonate and distilled. You get 116 g (corresponding to 50.5 01o of theory) 3-acetyl-10- [N'-methylpiperidyl - (4 ') - methyl] phenthiazine (b.p. 0.01 245-256 ° C).

Example 2 125 g of 3-propionylphenthiazine are mixed with 29 g of sodium amide boiled under reflux in 700 cc of toluene for 4 hours. 78 g are then added dropwise N-methylpiperidyl- (4) -methylchloride, dissolved in 100 ccm toluene, and allows more Cook for 5 hours. It is worked up as described in Example 1 and 108 is obtained g (corresponding to 600 per theory) of 3-propionyl-10- [N'-methylpiperidyl- (4 ') -methyl] -phenthiazine (Bp 0.8 290 to 310 ° C).

Example 3 51 g of 3-propionylphenthiazine are mixed with 300 cc of dioxane 10 g of sodium amide refluxed for 4 hours. Then 32g of ß- [N-methylpiperidyl- (2)] ethyl chloride are added dropwise, diluted with 50 cc of dioxane, and boiled for another 5 hours. Then the Dioxane removed by steam; the basic parts are taken up in ether and then extracted from the ethereal solution with dilute acetic acid. The acetic acid Solution is washed with ether and made alkaline. It is absorbed into ether evaporated and the residue distilled.

Yield: 40 g (corresponding to 52.6% of theory) 3-propionyl 10 -fß - [N '- methylpiperidyl - (2')] - ethyl} -phenthiazine (Kpeonol 270 to 275 ° C), whose naphthalene-1,5-disulfonate melts at 210 to 212 "C.

Example 4 72.3 g of 3-acetylphenthiazine are mixed with 600 ccm of dioxane and 49 g of ß- [N-methylpiperidyl- (2)] - ethyl chloride heated to boiling and a suspension of 15 g of sodium amide in 200 cc of dioxane gradually introduced.

The batch is worked up after boiling for half an hour and 65 g are obtained 3-acetyl-10-ffl- [N'-methylpiperidyl- (2 ')] -ethyl} -phenthiazine (boiling point 0.05 250 to 260 ° C), the fumarate of which melts at 138 to 140 "C.

Example 5 In a boiling solution of 70 g of 3-acetylphenthiazine and 47.1 g of N-methylpiperidyl- (3) -methyl chloride in 400 cc of dry dioxane are carried gradually a suspension of 14.5 g of sodium amide in 150 cc of dioxane. One works the batch after boiling for 3 to 5 hours and receives 49.3 g of 3-acetyl-10- [N'-methylpiperidyl- (3 ') -methyl] -phenthiazine from bp. ,,,,, 150 to 160 "C (retort flask with wide cross-sections), its oxalate melts at 196 to 1970 C.

Claims (1)

PATENT CLAIM: Process for the preparation of phenthiazine derivatives of the general formula acylated in the 3-position in which Ac denotes an optionally branched acyl group, A denotes an optionally branched alkylene radical and R denotes a low molecular weight alkyl group, characterized in that either a) 3-acylphenthiazines or their derivatives with protected carbonyl groups are converted into their metal compounds and these are converted with reactive esters of basic alcohols general formula in which A and R have the meanings given above, or b) that at least 2 equivalents of a suitable metal donating compound are used to convert a 3-acylphenthiazine or a functional derivative thereof into the metal compound and the basic alkylation with the equivalent amount of a salt the reactive esters of the basic alcohols mentioned or that c) 3-acylphenthiazines or their functional derivatives with reactive esters of the basic alcohols mentioned without additional acid-releasing agent at elevated temperature with or without a solvent and optionally under pressure and in the cases in where the basic alkylation is carried out on functional derivatives of 3-acylphenthiazines, the blocking radical is split off again after the basic alkylation has taken place. ~~~~~~~~ Publications taken into consideration: German patent application C 7333 IVc / 12p (published on September 9, 1954).