SU1436874A3 - Method of producing derivatives of phenothiazine or additive salts thereof with lower dicarboxylic acids - Google Patents

Abstract

The invention relates to a process for the preparation of phenothiazine derivatives of the formula C, JU B-COOH TS A (N) RiR 2 where A is straight or branched C-C4 alkylene; B - straight or branched C, -C-alkylene; R and R C (-C4-alkyl, or their lower dicarboxylic acid additive salts that exhibit antihistaminic and antiallergic activity. Obtaining the desired compounds are from a compound of the formula where A, R and R2 are as indicated above and Z is a radical B-CN, where B is indicated above, or radical) to (0 where X is oxygen or sulfur, by hydrolysis with dilute mineral acid at the boiling point of the reaction mixture, followed by isolation of the desired product in free form or as an additive salt with lower dicarboxylic acid. 1 Table § W with 4 Sf fOti 00 hh 4;

Description

 s

11436874

The invention relates to a process for the preparation of new derivatives of phenothiazine or their additive salts with lower dicarboxylic acids, which exhibit antihistamine and antiallergic activity and can be used in medicine.

The aim of the invention is to obtain new biologically active derivatives of phenothiazine, showing antihistamine and antiallergic activity without side effects.

An example. Q - (- Dimethyl 10

The aqueous solution is washed with diethyl zester and then added with an excess of sodium hydroxide. The free amines are then extracted with dichloromethane, which is dried over magnesium sulphate and evaporated to give a red viscous oil-like product, which consists of a mixture of the compound ex-2b and its isomer: 2-acetyl-0- (2-dimethylamino-1- methylethyl) -phenothiazine. The compound ex-2b is dominant; it is obtained analytically pure.

aminopropyl) -phenothiazin-2-ylJ-ykcyc-j by obtaining acidic maleate-co

The aqueous solution is washed with diethyl zester and then added with an excess of sodium hydroxide. The free amines are then extracted with dichloromethane, which is dried over magnesium sulphate and evaporated to give a red viscous oil-like product, which consists of a mixture of the compound ex-2b and its isomer: 2-acetyl-0- (2-dimethylamino-1- methylethyl) -phenothiazine. The compound ex-2b is dominant; it is obtained analytically pure.

by producing acidic maleate -co

on acid.

2-Aceti. Phenothiazine ethylene ketal (compound ex-2a).

In a stream of nitrogen, 100 g of 2-apethylphenothiazine, 50 g of ethylene glycol and 2.0 g of p-toluenesulfonic acid hydrate in 900 MP of benzene are refluxed in a water separator (Dean-Stark trap) for 18 Thin layer chromatographic analysis (silica gel, a mixture of hexane with ethyl acetate in the ratio 4: 1) confirms the almost complete consumption of the starting compound, which is replaced by a compound with a higher Pvf (ex-4). After cooling, the benzene solution is washed with a 1% solution of sodium hydroxide, dried over a solid of potassium carbonate and evaporated. 115 g of a dark butter-like product are obtained, which solidifies to form a dark green crystalline solid when standing at room temperature.

temperature NMR spectrum data with hydrochloric acid (40t) ml of water

correspond to the structure. The product is subsequently used without purification in the next stage.

2-Acetyl-10- (2-dimethylamino-6-propyl) -phenothiazine (compound ex-2c).

A mixture of 47.5 g of crude ex-2a and 20.9 g of potassium t-butoxide in 250 ml of benzene is stirred in a stream of nitrogen for 15 minutes. 23 g of 2-dimethylamino-isopropyl chloride are added to this mixture and the resulting solution is maintained at reflux for 75 minutes. After cooling, the amines are extracted with a dilute aqueous solution of hydrochloric acid, and the resulting acidic solution is held for 2 () min over water vapor in order to hydrolyze the ketal. After oohy 16 ml of concentrated hydrochloric acid). The aqueous solution is taken up in diethyl ether, and then alkalinized with an excess of hydro., Sodium oxide. The resulting product was extracted with 400 ml of chloroform, which was washed with three portions of 600 ml of water each. Evaporation of the chloroform solution allows to obtain 16.4 viscous red oil-like products, a thin layer chromatographic analysis of which (silica gel, dichloromethane mixed with methane in a ratio of 25: 1) shows the presence of many components. The sample is separated by preparative thin-layer chromatographic analysis with high resolution using sequentially determined

50

55

or in a mixture of ethyl acetate with methanol and two recrystallizations from the same solvent. T, pl. 187-19 C, NMR data and CHN analysis

consistent with the indicated structure. The isomer is obtained pure from the mother solutions by chromatographic treatment of the free amine in a column on silica gel, gelled mixture of ethyl acetate and ethanol in a ratio of 20: 1.

(2-Dimethylaminopropyl) -phenothiazin-2-yl3-acetic acid (compound B),

A mixture of 15.4 g of compound ex-2c,

3.2 g of sulfur and 10 ml of morpholine are maintained at reflux in a stream of nitrogen for 5 h. Then the warm reaction mixture is taken up in 300 ml of ethyl acetate in a mixture with 100 ml of diethyl ether, after which the mixture is stirred and filtered. A small amount of undissolved material is discarded. Amines are extracted with a dilute solution of hydrochloric acid (40t) ml of water

and 16 ml of concentrated hydrochloric acid). The aqueous solution is washed with diethyl ether, and then alkalinized with an excess of sodium hydroxide. The resulting product is extracted with 400 ml of chloroform, which is washed with three portions of 600 ml of water each. Evaporation of the chloroform solution allows to obtain 16.4 g of a viscous red oil-like product, a thin layer chromatographic analysis of which (silica gel, dichloromethane mixed with methane in a ratio of 25: 1) shows the presence of many components. The sample was separated by preparative high-resolution thin-layer chromatography analysis using sequentially established

3

silica columns eluted with a mixture of dichloromethane and methanol in a ratio of 97: 3. After evaporation of the main fractions, a total of 9.2 g of viscous orange oily-like products are obtained, the NMR spectrum and thin layer chromatographic analyzes show that they represent imperfectly separated mixtures of the expected thiomorfol and (obviously) the product of its partial hydrolysis of oxymorpholide. Since both products are satisfactory intermediate products for hydrolysis to obtain the desired acid (compound B), they are further purified and jointly dissolved in 4 g of hydrochloric acid (225 ml) and heated under reflux for 6 hours. after which all traces of the starting materials are removed by thin layer chromatographic analysis.

The reaction mixture is evaporated to give a viscous green residue, which is dissolved in 70 ml of water and the solution is washed with ethyl acetate. Then the solution is made alkaline by adding a slight excess (with litmus) of the solid sodium hydroxide and dichloromethane. Partial evaporation of the aqueous solution results in precipitation of the sodium salt of compound B. The precipitation process is intensified by diluting with an equal volume of saturated sodium chloride solution. The solid that forms is filtered off and recrystallized from a mixture of water with a saturated sodium chloride solution in a 4: 1 ratio. Filtration and vacuum drying of the product at 70 ° C overnight gives characterized by appropriate data analysis for CHN and Karl Fischer analysis for compound B, sodium salt, including 5.5 mol. water.

It also gives acidic acid salt with m. Pl. 115-120 s, the data of the NMR spectrum and elemental analysis correspond to the specified structure.

Example 2. (2-Dimethyl-aminopropyl) -phenothiazin-2-yl-propionic acid.

0

five

 O- (2-Dimethylaminopropyl) -phenothiazin-2-mp-propionitrile (compound ex-Za).

With a stream of nitrogen, 4.0 g of tolylmethyl isocyanate in 15 ml of DMSO and 4 ml of THF are stirred in an ice bath and then 5.8 g of potassium t-butoxide are added to the mixture. After 5 minutes, 0.68 g of methanol is added. A solution of 3.4 g of ex-2b in 3 ml of DMSO and 1 ml of THF is then added dropwise over 3 minutes. The solution is then allowed to warm to room temperature and stirred over 5 hours for 20 hours. The reaction mixture is poured into diethyl ether and washed with water. The amines are extracted with dilute hydrochloric acid, washed with diethyl ether, and then alkalinized with an excess of 5% sodium hydroxide. The free amines are then extracted with diethyl ether, dried over magnesium sulphate and evaporated to give 2.5 g of an oil-like product, the thin layer chromatographic analysis of which (silica, dichloromethane / methanol in a 24: 1 ratio) shows the presence of components The target component, compound Ex-Za, was isolated in pure form by preparative thin-layer chromatographic analysis with high resolution, eluting with a mixture of dichloromethane and methanol in a ratio of 97: 3. Compound е-х-За was an oil-like product identified by IR and NMR spectra, the data of which agree with the structure indicated,

2- t 0- (2-Dimethylaminopropyl) -phenothiazin-2-yl3-propionic acid (compound C).

Ex-Over compound (1.7 g) was dissolved in 50 ml of 4N. hydrochloric acid and boiling at reflux for 20 hours. The solution is evaporated under reduced pressure to obtain a viscous oil-like product, which is then redissolved in 30 ml of water, rinsed with diethyl ether and then adjusted to pH alkaline. (litmus) by careful addition of sodium hydroxide. The resulting solution is washed with diethyl ether and then mixed to half the original volume. Hydrochloride

0

five

0

five

0

five

51

The salt of compound C is precipitated by the addition of an excess of concentrated hydrochloric acid. This oil-like product is redissolved in water and precipitated (again as an oil-like product) by adding excess hydrochloric acid, and then dissolved in diethyl

on the air, which causes solidification of the tests of the control animal oil-like product. This salt of the foam undergoes depressions on average recrystallized from a mixture of methane in as little as 33 seconds. The values were reduced with ethyl acetate, as a result of which colorless crystals were obtained with m.p.

Example 3. Antihistamine action.

A. Antihistamine activity in vitro. From the intact podzdona of the guinea pig (Hartley breed, male weighing 250-400 g), the longitudinal muscle was removed and placed in a bath for organs with a tension of 300 mg. After 1 h of equilibrium, cumulative concentration curves of the reaction to histamine were determined. After washing tk4ni subjected

baking protection against the action of histamine, calculating with the help of probit15 analysis, In this test, ET) indicates that, at this particular dosage, 50% of the animals provided complete protection against the action of histamine during the test.

20 (after h after dosing). Full protection was determined by the complete absence of symptoms of a reaction to histamine for 6 minutes in an aerosol chamber (approximately ten times as compared with the onset of depression in control animals).

The test results on antihistamine action: compound EDjj ,,

Test results for antihistamine action: compound EDjj

incubating for 1 h together zo mg / kg through the mouth; triprolidine 5.77;

with the test compound, and then determined repeated concentration curves - reactions to histamine. Shifts to the right relative to the concentration curve of the agonist reaction obtained using antagonists were used to plot Schild's graphs. Reducing the value of log (ch-1) by log (B) j where ch is the equivalent reaction in the presence and absence of

the antagonist, and (B) the molar concentration of the antagonist, allowed us to calculate the pA value, i.e. negative logarithm of antagonist concentration, which shifts the 2X control curve of the reaction to histamine concentration to the right.

Test results: Promethazine compound 8.9; C 8.1

B. Antihistamine activity in-vivo. Guinea pigs (Hart Lee breed, males weighing 300-350 g) were not fed for 20 hours, and then the dosage of the test compounds was administered orally or intraperitoneally. After 1 h after dosing, on an individual basis, the guinea pigs were placed in a transparent plastic chamber, which

0.30 (4 hours later after dosing),

Anaphylactoid test procedure.

35 Rats who were not given feed (a Wistar variety, weight 280-300 g) were intraperitoneally or administered ro administered dosages of the tested compounds two hours before exposure.

40 on them with the help of the provocative product 48/80. One hour before the call of the reaction, 5 mg / kg of propanol was intrabryuzhalno injected into the organism of experimental animals. Anaphylactomy

The 45 action of the agent, compound 48 / was administered intravenously at a dosage of 2 mg / kg and then the animals were observed to detect symptoms of respiratory failure.

50 The data were analyzed using probit determinations, and the reaction was quantified by determining the dosage of the test compound, which provided protection

55 50% of animals from death at this time interval.

The experimental plan described above does not give positive results for selective antihistams and the aerosol diluent was overpowered and constantly gassed 0.25% of histamine. Guinea pigs were monitored for signs of histamine anaphylaxis (for example, coughing, sneezing, sudden movements in the peritoneum of the th region, cyanosis, and loss of direction), which provided protection against the action of histamine, and was assayed with this vitanoalysis. the ET) test indicates that at this particular dosage, 50% of the animals were fully protected against the effects of histamine during the test.

(after h after dosing). Full protection was determined by the complete absence of symptoms of a reaction to histamine for 6 minutes in an aerosol chamber (approximately ten times the period compared to the onset of depression in control animals).

The test results on antihistamine action: compound EDjj ,,

mg / kg by mouth; triprolidine 5.77;

 0.30 (4 hours later after the introduction of ozering),

Anaphylactoid test procedure.

Rats that were not given food (Wistar variety, weight 280-300 g) were intraperitoneally or orally administered doses of the tested compounds two hours before exposure.

on them with the help of the provoking drug 48/80. One hour before the reaction was triggered, 5 mg / kg of propanol was administered intraperitoneally in experimental animals. The anaphylactoid effect of the agent, compound 48/80, was administered intravenously at a dosage of 2 mg / kg and then the animals were observed to detect symptoms of respiratory failure.

The data were analyzed by probit determinations, and the reaction was quantified by determining the dosage of the test compound, which provided protection

50% of animals from death at a given period of time.

The described experimental design does not give positive results for selective antihists.7 .1

new In addition, rats did not respond to the intravenous administration of gnetamine with symptoms of anaphylaxis. Agents that block the action of compound 48/80 are usually classified as inhibitors of anaphylactic mediators or inhibitors of the release of anaphylactic mediators.

The results of the inhibition of the anaphylatoid reaction induced by the action of compound 48/80 are presented in the table.

Compound

.one

ED

-50

The dosage of the compound (intraperitoneal), providing 50% protection against death, caused by the action of the compound 48/80 (the compound was administered 2 hours before the test). EDyo when administered by mouth.

Claims (1)

For compound B, the approximate dosage of EDjg when tested on rats was 210 mg / kg (intraperitoneally) and exceeded 500 mg / kg when I was administered orally. Invention Formula The method of obtaining phenothiazine derivatives of the general formula v-soon where A is my pr or branched C, -C-alkylene; B is straight or branched C (-C | -alkylene; P, and H is. -Alkyl, or their lower dicarboxylic acid addition salts thereof, characterized in that the compound of the general formula  s 25 where a  have the indicated meanings; Z - radical - B - CN, where B has the indicated value, or Z is a radical 35 Ohhhh where X is oxygen or sulfur, is subjected to hydrolysis with dilute mineral acid at the boiling point of the reaction mixture, followed by isolation of the target product. that in free form or in an additive salt with a lower dicarboxylic acid.