DE1168913B - Process for the preparation of new 10- [pyrrolidyl- (3 ') -methyl] -phenthiazines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C07d

German class: 12 ρ -4/05

Number: 1 168 913

File number: C 28797IV d / 12 ρ

Filing date: December 29, 1962

Opening day: April 30, 1964

It has been found that 10- [pyrrolidyl- (3 ') - methyl] -phenthiazines of the general formula

CH ₁

N-Ri-OR ₂

in which X is a hydrogen or chlorine atom, Ri is a Alkylene radical having 2 to 4 carbon atoms and R2 is a hydrogen atom or a lower one Acyl radical of the general formula R3CO represents, in which Rg is an alkyl radical or a mono- or is dialkylated amino group or a piperidino, morpholino or N'-alkylpiperazino group, and their acid addition salts and quaternary salts have valuable pharmacological properties exhibit.

The phenthiazines defined by the general formula I have not yet been derived from them described alcohols of the general formula

HO - CH ₂

II

N -Ri-O -R ₂

away. Among other things, they can be used as antihistamines, ganglioplegics, to potentiate analgesic or hypnotic substances are used.

They are particularly used in psychiatric practice as sedatives. she have a strong anti-inflammatory and temperature-lowering effect.

The new phenthiazines of the general formula I have the advantage of a powerful central analgesic effect compared with the 10- [l'-alkylpyrrolidyl- +0 (3 ') - methyl] -phenthiazines described in German patent specification 1 049 382. For example, the previously known 10- [l'-propylpyrrolidyl- (3 ') - methyl] -phenthiazine (A) with the process-obtainable 10- [r - (/ i-hydroxyethyl) -pyrroli- +5 dyl- (3' ) -methyl] -phenthiazine (B) and 10- [l '- (0-N ₅ N-Dimethylcarbamoyloxyäthyl) - pyrroliclyl - (3') - methylj-phenthiazine (C) and the 10- [l '- (j3- Morpholinocarbonyloxyäthyl) - pyrrolidyl - (3 ') - methyl] -phenthiazine (D) comparatively tested for toxicity and analgesic effect. The following numbers were obtained:

Process for the preparation of new 10- [pyrrolidyl- (3 ') - methylJ-phenthiazines

Applicant:

CILAG-CHEMIE Aktiengesellschaft, Schaffhausen (Switzerland)

Representative:

Dipl.-Chem. Dr. A. Ullrich

and Dipl.-Chem. Dr. T. Ullrich, patent attorneys, Heidelberg, Poststr. 30th

Named as inventor:

Dr. phil. Ernst Habicht,

Dipl.-Chem. Georg Feth, Schaffhausen (Switzerland)

Claimed priority:

Switzerland of February 1, 1962 (1230)

of September 25, 1962 (11 291)

toxicity

A. B. C. D. LD50 mg / kg
Mouse i. ν 49.5 35.5 43.6 44.5

analgesia
Mean increase in the stimulus threshold in%

mg / kg iv
Rabbit tooth

within 90 minutes 13.9 I 326 I 249 | 261

within 90 to 180 minutes

3.8

153

, 9 95

The process products (B), (C) and (D) thus show compared to the previously known product (A) a similar toxicity, but an incomparably stronger analgesic effect.

The new phenthiazine derivatives can be obtained in a manner known per se by

409 587/480

in a phenthiazine compound of the general formula

CH ₂

NO

in which R either a) a benzyl, benzhydryl or carboxybenzyl radical or b) the radical -Ri-O-Rj denotes, where R4 also represents a benzyl, benzhydryl or carboxybenzyl radical, the benzyl, Benzhydryl or carboxybenzyl radical is split off by hydrogenolysis and that the im Case a) obtained compound of the general formula

N-H

with a compound of the general formula

Y - Ri - O - R ₂ V

converts, where Y is a reactive cleavable radical, and that obtained in case b) Compound of the general formula

VI

Ri-OH

if desired with a reactive derivative of an acid of the general formula R3COOH or with a compound of the general formula RiNCO, in which R5 is an alkyl group and that the phenthiazine derivative of the general formula I obtained in this way, if appropriate by adding acid to its salt or by reaction with an alkyl halide, sulfate or sulfonic acid alkyl ester converted into a quaternary salt.

The hydrogenolytic cleavage of the benzyl, benzhydryl or carboxybenzyl radical is advantageous in alcoholic solution in the presence of mineral acids with the help of catalytically excited Hydrogen. The catalysts used are advantageously palladium-carbon (5 to 10%). In the Usually the application of pressure is not necessary. But it can accelerate the reduction.

The radical Y in the general formula V preferably represents a halogen atom or the radical of a organic sulfonic acid, e.g. B. the tosoxy or mesoxy radical. The condensation of the compounds of the general formulas IV and V can be used in the presence or absence of solvents or diluents and of condensing agents ν jr. As a condensing agent, for example use: potassium carbonate, potassium bicarbonate, sodium oxide or tertiary bases such as Ethyldiisopropylamine. Solvents or diluents that are used are those containing hydroxyl groups or hydroxyl-free solvents in question, e.g. B. ethanol, isopropanol, dioxane, benzene, xylene, Toluene. When working in dioxane, particularly pure products are obtained and in good yields.

As already mentioned, the above-defined compound can be used in a compound of the general formula VI obtained Acyl radical RjCO are introduced. These

ίο Introduction can e.g. B. with the help of an acid chloride or acid anhydride of the acid of the general formula R3COOH. As such Acids can be used, for. B. use: acetic acid, propionic acid. Butyric acid, pivalic acid. The won Hydroxyalkyl compounds of the general formula VI can also be converted into carbamates be e.g. B. the mono- or disubstituted carbamates defined above. This transformation can with the help of carbamic acid halides or for monosubstituted derivatives with the help of isocyanates defined above. The production of N-methyl, N-ethyl, N-isopropyl, Ν, Ν-dimethyl and Ν, Ν-diethyl carbamates are preferred. The implementation of a 1-hydroxyalkyl compound with the carbamic acid halide is preferably carried out in the presence of tertiary bases, such as Pyridine, triethylamine, ethyldiisopropylamine.

The phenthiazine derivatives of the general formula III which are used as starting compounds are won one by reacting a phenthiazine or a chlorophenthiazine or an N-metal salt of a such phenthiazine with an inorganic or organic ester of a pyrrolidyl- (3) -carbinol of general formula II. (Protection is not sought for this.) The 10- [pyrrolidyl- (3 ') - methyl] -phenthiazines obtained in this way of the general formula I can be isolated in the form of their salts with inorganic or organic acids. Suitable for salt formation especially hydrochloric, hydrobromic, sulfuric, sulfamic or phosphoric acid or also organic acids such as methanesulfonic, fumaric, maleic, citric, ethane disulfonic, p-aminobenzoic. Salicylic or p-aminosalicylic acid.

The conversion of the process products of the general formula I into quaternary salts takes place with The help of alkyl halides, alkyl sulfates or alkyl sulfonic acid alkyl esters in inert solvents, z. B. in ether or ethyl acetate. Used as intermediates for manufacturing some of the phenthiazines of the general formula III used l- (RiORi -) - 3-hydroxymethylpyrrolidines of the general formula II can be obtained in the following manner, which is not claimed will:

Itaconic acid or an itaconic acid ester. preferably an alkyl ester. is made with an amine of general formula

H ₂ N - Ri - O - R ₄

Reacted in this way, whereby l- (R4ORi -) - 5-oxo-pyrrolidine- (3) -carboxylic acid or - ^ - carboxylic acid ester is formed. The reaction is preferably carried out in the heat, advantageously at temperatures between 100 and 18O ⁰ C. The one made in this way

s ₅ Pyrrolidoncarbonsäure or a corresponding ester is then with the help of lithium aluminum hydride or hydrogen in the presence of a copper chromium oxide under pressure to

corresponding 1 - (R4ORi -) - 3-hydroxymethylpyrrolidine reduced.

The following is an example of the preparation of one of the desired 3-hydroxymethylpyrrolidines described in more detail.

a) 316 g of itaconic acid and 367.5 g of benzyloxyethylamine are heated in a 1-1 flask with turbines in an air bath. After 2 hours of heating at 125 to 175 ⁰ C (internal temperature) is allowed to cool, and then 350 cc of chloroform. After standing for a long time, the whole thing is shaken again with 900 ecm chloroform in the separating funnel and then separated. The aqueous solution is washed again with chloroform and then the chloroform solution is extracted with 2η hydrochloric acid. The chloroform solution is dehydrated over sodium sulfate, filtered and concentrated. After a long time, the residue crystallizes to form reddish-colored needles which melt at 76 to 79 ° C. The yield is 589 g (92% of theory). (- Benzyloxyäthyl /? -) -5-oxo-pyrrolidine (3) -carboxylic acid in colorless, at 79 to 81 ⁰ C melting needles after recrystallization from benzene-ether to give the l.

b) A solution of 228 g of the carboxylic acid obtained according to a) in 350 ecm of absolute dioxane is added dropwise to a solution of 70 g of lithium aluminum hydride in 590 ecm of absolute dioxane and 260 ecm of absolute tetrahydrofuran. The reaction is carried out with stirring under a nitrogen atmosphere. The whole thing is then kept at 75 to 80 ° C. for a further 5 hours, then cooled, and 138 ecm of water and 65 ecm of concentrated sodium hydroxide solution are added. 165 g of calcined soda are then added, the whole thing is sucked through a frit and the residue is washed with dioxane. The filtrate is concentrated and the residue is distilled in a high vacuum. 182 g (89% of theory) of 1- (β-benzyloxyethyl) -3-hydroxymethylpyrrolidine, which boils ^{at 142 to 143 ° C. under a pressure of 0.2 mm Hg, are obtained.}

example 1

a) 215 g of l - (/ 3-benzyloxyethyl) -3-hydroxymethylpyrrolidine are dissolved in 230 ecm of absolute chloroform together with 111g of triethylamine. To this Solution is added dropwise with stirring and cooling a solution of 192 g of toluenesulfonic acid chloride in 160 ecm absolute chloroform. The mixture is then stirred for 2 hours at room temperature and then still 2 hours at 30 ° C. The reaction mixture is treated with ice water and ether and the organic Layer separated. This is then extracted with 2N acetic acid, and the aqueous acidic solution is separated off and mixed with concentrated potassium carbonate solution. The oil that separates out is in Ether absorbed, the ethereal solution drained over potassium carbonate and evaporated. Of the The residue is the toluenesulfonic acid ester of 3-hydroxymethylpyrrolidine. This is not further cleaned, but used immediately for further implementation.

b) 206 g of phenthiazine are taken with the aid of 21.2 g of lithium amide in 220 ecm of absolute pyridine Nitrogen converted into the lithium salt (stirring for 1 hour at boiling temperature). After cooling down 303 g of the tosyl ester obtained in accordance with a) are added dropwise to 100 ° C. without further supply of heat from 20 to 30 minutes too. The mixture is then heated to boiling for a further 1 hour and the mixture is cooled then off. The reaction mixture is mixed with 100 ecm of water and then in vacuo concentrated to remove most of the pyridine. The residue is with 500 ecm of water and 1500 ecm of ether displaced. The ether solution is separated and then several times with 200 ecm each 2 η-acetic acid extracted. The combined, aqueous acidic extracts are washed with

ίο ether mixed with concentrated sodium hydroxide solution. The oil that separates out is absorbed in ether, the ethereal solution is dried and evaporated. The residue is distilled in a high vacuum. This gives the hog mm under a pressure of 0.25 Hg at 255 to 26O ⁰ C for continuous 10 - [I '- (beta - Benzyloxyäthyl) - pyrrolidyl - (3') - methyl] -phenthiazine. The oxalate of the phenthiazine obtained in this way melts, recrystallized from dioxane, at 155 to 157 ° C.

c) 49.8 g of the starting compound obtained according to b) are hydrogenated in 450 ecm absolute butanol with the addition of 65 ecm 4 η-hydrochloric acid in the presence of 30 g palladium-charcoal (5%) in the shaking duck under normal pressure. Since the hydrogen uptake is usually a little slow towards the end, it is preferable to heat a little. The recording is usually over after 2 to 3 hours. The catalyst is filtered off with suction, the solution is filtered with a filter aid and then concentrated in vacuo. The oxalate is prepared from the residue in absolute acetone. Recrystallized from methanol, this melts at 155 to 158 ° C. 29.6 g (59% of theory) of oxalate of 10 - [I '- (ß - hydroxyaryl) - pyrrolidyl - (3') - me-

thyl] -phenthiazines. In the same way, as described, the 10- [l '- (/ S'-hydroxypropyl) -pyrrolidyl- (3') - methyl] -phenthiazine is obtained; its hydrobromide melts at 203 to 204 ⁰ C.

Example-2

In a manner analogous to that described in Example 1, a) and b), 10 - [1 '- {ß- benzyloxyethyl) - pyrrolidyl - ( 3 ') - methyl] -3-chlorophenthiazine. From this, according to the process, 10- [r- (ß-hydroxyethyl) -pyrrolidyl- (3 ') -methyl] -3-chlorophenthiazine is produced by reduction. The yield is 41% of theory and the melting point of the oxalate is 141 to 143.degree.

B e i s ρ i e 1 3

a) 190 g of l-benzyl-3-hydroxymethylpyrrolidine are dissolved in 200 ecm of absolute chloroform together with 100 g of triethylamine. A solution of 200 g of p-toluenesulfonic acid chloride in 120 ecm of absolute chloroform is added dropwise to this solution with stirring and cooling. The mixture is then allowed to stir at room temperature for 2 hours and then at 30 ^{° C. for a further 2 hours.} The reaction mixture

is treated with ice water and ether and the organic layer is separated. This is done with 2N acetic acid pulled out, the aqueous acidic layer separated and washed with concentrated potassium carbonate solution offset. The oil that separates out is in

Ether absorbed, the ethereal solution drained over potassium carbonate and evaporated. Of the The residue is the toluenesulfonic acid ester of l-benzyl-3-hydroxymethylpyrrolidine. This is

not further cleaned, but used immediately for further implementation.

b) 180 g of phenthiazine are converted into the lithium salt with the aid of 23 g of lithium amide in 200 ecm of absolute pyridine under nitrogen (stirring for 1 to 2 hours at the boiling point). After cooling to 100 ⁰ C is allowed to a) obtained in accordance with tosyl ester within 30 to 40 minutes is added dropwise. The mixture is then heated to boiling for a further 3 hours and the mixture is then cooled. The reaction mixture is mixed with 100 ecm of water and then concentrated in vacuo to remove most of the pyridine. The residue is shaken well with 500 ecm of water and 1500 ecm of ether and the ether solution is separated off and extracted several times with 200 ecm 2 of η-acetic acid each time. After washing with ether, the combined aqueous acid extracts are mixed with concentrated sodium hydroxide solution. The oil that separates out is absorbed in ether, the ethereal solution is dried and evaporated. The residue is taken up in heptane, dehydrated over sodium sulfate, decanted and anhydrous hydrogen chloride is passed into the heptane solution. After recrystallization from acetone, Essigester or the Hydrochloriddesl0- [r-Benzylpyrrolidyl- (3 ') - methyl] -phenthiazins which melts at 208-209 ⁰ C.

c) 50 g of the starting compound obtained in this way are dissolved in 500 ecm of absolute butanol in the presence hydrogenated by about 30 g of 5% palladium-carbon in the shaking duck under normal pressure. if the If the hydrogen uptake becomes slower towards the end of the hydrogenation, it can also be warmed up somewhat. The catalyst is filtered off with suction, the solution is filtered with a filter aid and the filtrate is concentrated. This gives 22 g of 10- [pyrrolidyl- (3 ') -methyl] -phenthiazine.

d) 20 g of the phenthiazines obtained in this way are left to stand for 10 days with 7 g of ß-iodoethyl acetate in 100 ecm of dioxane. During this time, the hydroiodide of 10- [r - (/ 3-AcetoxyäthylpyrrolidylH3 ') - methyl] -phenthiazine separates. The whole thing is evaporated, the residue is shaken with saturated potassium carbonate solution and ether, the ethereal solution is dehydrated and ethereal hydrochloric acid is added. After recrystallisation of the precipitated amorphous mass from acetone-dioxane-ether to obtain 15 g of the melt at 164-165 ⁰ C pure hydrochlorides of the new ester.

Example 4

75 ecm of 96% ethanol and 24.3 g of calcined potash are placed in a flask. Afterward 24.8 g of OH-pyrrolidyl-ßO-methyl] -phenthiazine are added and 12.1 g of ethylene bromohydrin. The whole is slowly heated to the boil while stirring and then at this temperature for 9 hours leave with stirring. Formed potassium bromide and unreacted potassium carbonate are suctioned off and the filtrate evaporated in vacuo. The residue is taken up in isopropanol and a solution of 20 g of anhydrous oxalic acid in 70 ecm of acetonitrile is added. You cook the whole thing with a little charcoal, filtered and evaporated to half. After standing in the refrigerator for several days is the oxalate of 10- [l '- (/ 3-hydroxyethyl) -pyrrolidyl- (3') - methyl] -phenthiazine crystallized out.

Recrystallization from methanol gives 25 g of the pure product at 158 to 159 ° C. with decomposition melting oxalate.

Example 5

11.5 g of 10- [r - (/ i-hydroxyethyl) -pyrrolidyl- (3 ') - methylj-phenthiazine are dissolved together with 7.4 g of triethylamine in 75 ecm of chloroform. In addition a solution of 5.5 g is added with a turbine

ίο Acetyl chloride in 25 ecm absolute chloroform. The whole thing heats up by itself to about 54 ° C. Then another 1 hour at 56 ° C stirred and then left to stand overnight. Now you shake the whole thing twice with 40 ecm each concentrated potassium carbonate solution and then with 60 ecm of water and ice. The organic solution is dehydrated over anhydrous sodium carbonate and then concentrated in vacuo. The residue is dissolved in 80 ecm of ether, little that is not dissolved

filtered, the filtrate made up to about 400 ecm with ether and with 12.5 ecm 2.68 normal ethereal Hydrochloric acid added. After a few hours, the crystals formed are filtered off with suction and crystallized out Acetone — ether around. 9 g of the at 164 bis are obtained 10- [r - (/? - acetoxyethyl) -pyrrolidyl- (3 ') - methyl] -phenthiazine melting at 165 ° C. The new ester dissolves well in cold water, cold ethanol and cold chloroform, but little in benzene, ether and petroleum ether.

Examples

In the same way as described in Example 5, 15 g of 10- [r - (/? - hydroxyethyl) -pyrrolidyl- (3 ') -methyl] -phenthiazine are obtained and 11.1 g of pivalic acid chloride in the presence of 10 g of triethylamine 11 g of 10- [r- (β-pivaloyloxyethyl) -pyrrolidyl- (3 ') -methyl] -phenthiazine. The oxalate can be produced from this in acetone, which is produced at 145 to 148 ° C melts. The oxalate can be obtained from a mixture

₄ “Recrystallize from acetone — dioxane — ether. The new salt dissolves well in the heat in water, ethanol and dioxane, but little in benzene, ether and petroleum ether. The same compound can also be prepared according to Example 1 by reacting 10- [pyrrolidyl- (3 ') -methylj-phenthiazine with pivalic acid-JS-bromoethyl or / 3-iodoethyl ester.

Example 7

₅ “In the same way as described in Example 5, obtained from 15 g of 10- [l '- {/? - Hydroxyethyl) pyrrolidyl- (3') - methyl] -phenthiazine and 8.5 g of propionic acid chloride in the presence of 10 g of triethylamine 10- [l '- (^ - propionyloxyethyl) -pyrrolidyl- (3') - methylj-phenthiazine (weight: 9 g). The oxalate is produced from this in acetone solution with the help of oxalic acid. This melts, recrystallized from a mixture of acetone-ether-ethanol, at 139 to 141 ^° C. The new salt is in the

6,) Heat readily soluble in water and ethanol, in acetone very little soluble in cold, readily soluble in hot; Little soluble in benzene, ether and petroleum ether.

The ester mentioned here can also be prepared according to Example 1, for example by reaction of 10- [pyrrolidyl- (3 ') - methyl] -phenthiazine with propionic acid / I-iodoethyl ester in isopropanol as a solvent. The conversion in dioxane gives better yields and a purer product.

Example 8

15 g of 10 - [I'- (β - hydroxyethyl) - pyrrolidyl - (3> methyl] -phenthiazine are dissolved together with 10 g of triethylamine in 90 ecm of absolute chloroform j. A solution of 9 is added dropwise to this solution with vigorous turbination. 9 g Dimethylcarbaminsäurechlorid in 25 cc of absolute chloroform. the mixture is stirred P / 4 hours at 55 to 6O ⁰ C internal temperature. After standing overnight, is treated with 40 cc of concentrated potassium carbonate solution and ice, shaken well and the layers separated. the organic The layer is dehydrated over silica gel and concentrated, and the residue is dissolved in acetone. A solution of 3.05 g of anhydrous oxalic acid in 15 ml of acetone is added to this solution. The precipitated crystals are recrystallized from absolute dioxane. This gives 12 g of the oxalate of 10- [l '- (| 8-N, N-dimethylcarbamoyloxyäthyli-pyrrolidyl-iSO-methylJ-phenthiazine, which melts at 155 to 157 ° C. The salt of the new ester dissolves moderately in water and ethanol in the cold , in the Heat good. Little in dioxane in the cold, very good in the heat; the salt is practically insoluble in ether and petroleum ether.

Example 9

From 15.4 g of 10- [l '- (/ 5-hydroxyethyl) pyrrolidyl _: (3') - methyl] -phenthiazine fumarate, the base is set free in ether with the aid of dilute ammonia. After distilling off the ether, the base in a Rundkölbchen under vacuum at 100 ⁰ C is dried. After 2 hours, 7.2 g of morpholino-N-carbonyl chloride are added and the whole is heated in a reflux condenser on a water bath. An exothermic reaction occurs immediately and the temperature rises to 127 ° C. After heating for 2 hours on the water bath, the reaction mixture is stirred with ether, sharply suctioned off and dissolved in 500 ecm of water. Then add ice and solid potassium carbonate and extract a few times with ether. The combined ethereal solutions are washed with water, dehydrated over potassium carbonate and then the ether evaporated. The residue weighs 17 g and is a pale yellow, sticky resin. The 10- [r - (/ 9-morpholinocarbonyloxyethyl) -pyrrolidyl- (3 ') -methyl] -phenthiazine obtained in this way is advantageously isolated in the form of a salt.

The oxalate can be prepared from the base in acetone as the solvent. This melts, recrystallized from methanol, at 186 to 187 ^° C. with decomposition.

The fumarate is produced in butanol as a solvent with the help of fumaric acid dissolved in butanol. After recrystallization from isopropanol, the fumarate melts at 144 to 145 ^° C.

Claims (1)

Claim: Process for the preparation of new 10- [pyrrolidyl- (3 ') -methyl] -phenthiazines the general formula / v ^s v \ 30th 35 40 in which X is a hydrogen or chlorine atom, Ri has 2 to 4 carbon atoms Alkylene radical and Ra a hydrogen atom or represents a lower acyl radical of the general formula R3CO, in which R3 is an alkyl radical or a mono- or dialkylated amino group or a piperidino, morpholino or N'-alkylpiperazino group is, as well as their acid addition salts and quaternary salts, thereby characterized in that in a manner known per se in a phenthiazine compound the general formula III in which R either a) a benzyl, benzhydryl or carboxybenzyl radical or b) the radical - Ri - O - R ₄ means, where R4 is also a benzyl, Represents benzhydryl or carboxybenzyl radical, the benzyl, benzhydryl or carboxybenzyl radical split off by hydrogenolysis and that the compound obtained in case a) of the general formula A / ^S \ A with a compound of the general formula Y Ri 'O R2 V converts, where Y denotes a reactive cleavable radical, or the one obtained in case b) Compound of the general formula VI CH ₂ N - OH if desired with a reactive derivative of an acid of the general formula R3COOH or with a compound of the general formula R5NCO, in which R _{5 is} a hydrogen atom or an alkyl group, and that the phenthiazine derivative of the general formula I obtained in this way is converted into its salt or by adding an acid, if necessary Conversion with an alkyl halide, sulfate or alkyl sulfonate converted into a quaternary salt. Ri-O -R ₂ 409 587/480 4.64 © Bundesdruckerei Berlin Considered publications:
German interpretative document No. 1 049 382.