Phenothiazine, or thiodiphenylamine, was used in the past in medical practice as an anthelmintic drug for enterobiasis and as an antiseptic for inflammatory diseases of the urinary tract. Currently, due to the introduction of more effective and less toxic drugs into practice, it is no longer used in medicine. In veterinary medicine, phenothiazine is used for helminthic infestations in cattle, pigs, and horses. Technical (unpurified) phenothiazine is used to kill mosquito larvae. Phenothiazine derivatives include methylene blue. In 1945, it was found that by replacing the hydrogen at the nitrogen atom of the phenothiazine ring with alkylaminoalkyl radicals, compounds with strong antihistamine activity, anticholinergic and other important pharmacological properties can be obtained. The first in a series of phenothiazine alkylamino derivatives that found use as antihistamines was 10-(2-diethylaminoethyl)-phenothiazine hydrochloride, which was used under the name etiine. A diethyl analogue of ethizin, called dynesin, turned out to be a substance with n-cholinolytic activity and has found use as a treatment for parkinsonism. Further studies showed that 10-(2-dimethylaminopropyl)-phenothiazine hydrochloride, or dipraine, has very strong antihistamine activity. Upon closer examination of these and other similar phenothiazine derivatives, it was found that they have multifaceted effects on the central and peripheral nervous system. Diprazine, along with antihistamine activity, has sedative properties, enhances the effect of narcotics, hypnotics, analgesics and local anesthetics, causes a decrease in body temperature, has an antiemetic effect, and has adrenolytic activity. In search of substances that have a more active and more selective effect on the functions of the central nervous system, phenothiazine derivatives were synthesized by replacing the nucleus at the C2 position with a chlorine atom or other substitutes. One of the most active was 2-chloro-103-dimethyl-aminopropyl)-phenothiazine hydrochloride, or aminazine. Various other phenothiazine derivatives were subsequently synthesized. Many phenothiazine derivatives are antipsychotic drugs. However, in the series of phenothiazines, new antidepressants have also been obtained (see Fluoroacizin), coronary dilators (see Nonachlazine), antirhythmics (see Ethmozin, Etatsizin), antiemetics (see. Thiethylperazine) agents. Neuroleptics of the phenothiazine series, depending on the characteristics of their chemical structure, are usually divided into three groups: 1) compounds containing a dialkylaminoalkyl chain at the atom of the phenothiazine nucleus; these are the so-called aliphatic derivatives (aminazine, propazine, levomepromazine, etc.); 2) compounds containing a piperazine core in the side chain; these are the so-called piperazine derivatives (metherazine, etaperazine, triftazine, fluorophenazine, etc.); 3) compounds containing a piperiine core in the side chain (thioridazine, periciazine, etc.). The drugs included in each of these groups, along with the properties characteristic of each individual drug, have some common features. Thus, drugs of the first group (aliphatic derivatives), along with a pronounced antipsychotic effect, are distinguished by the presence of an inhibitory component, the ability to cause lethargy, intellectual and motor retardation, passivity, and apathetic state (hypnosedative effect). The sedative effect of these drugs is superior to other phenoioazine antipsychotic drugs. The picture of extrapyamidal disorders caused by them is also dominated by lethargy and hypokinesia (up to akinetic syndrome). Drugs of the second group (piperazine derivatives), along with an antipsychotic effect, are characterized by the presence of a stimulating, activating component, and the picture of extrapyramidal disorders is dominated by hyperkinetic and dyskinetic phenomena. Drugs of the third group (piperidine derivatives) have less strong antisychotic activity, do not have a hypnosedative effect, and rarely cause extrapyramidal disorders.

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Federal State Budgetary Educational Institution

Higher professional education

"Maikop State Technological University"

Faculty of Pharmacy

Department of Pharmacy

Coursework

in pharmaceutical chemistry

"Pharmaceutical and pharmacological analysis of phenothiazine derivatives"

Completed by: 4th year student

Faculty of Pharmacy

F-41 groups

Sizykh Yu.V.

Checked by: Velichko G.P.

Maykop, 2013

Introduction

Chapter I. Pharmaceutical analysis of drugs, phenothiazine derivatives

1.1 Classification

1.2 Relationship between chemical structure and pharmacological action

1.3 Physical properties

1. 4 Preparation of phenothiazine derivatives

1.5 Cleanliness

1.6 Identification

1.6.1 Chemical methods of analysis

1.6.2 Physico-chemical methods

1.7 Quantification

1.7.1 Chemical methods

1.7.2 Physico-chemical methods

1.8 Storage

Chapter II. Pharmacological characteristics of drugs, derivatives

phenothiazine

Conclusion

Literature

Introduction

Phenothiazine is a condensed heterocyclic system consisting of a six-membered thiazine heterocycle and two benzene nuclei, also including nitrogen and sulfur heteroatoms:

Thiazine Phenothiazine

Phenothiazine derivatives represent one of the most important and promising groups of medicinal substances in modern pharmacy and pharmacology. In world medical practice, about 40 neuroleptics of the phenothiazine series are used from more than 5000 synthesized compounds. The search for new drugs continues. The history of the creation of the first antipsychotic drug, chlorpromazine, dates back to the 30s. XX century, when antihistamines were sought among phenothiazine derivatives. At the same time, it was discovered that a number of them also exhibit neuroleptic and antipsychotic effects, and phenothiazine acyl derivatives have an antiarrhythmic effect.

In our country (M.N. Shchukina, A.P. Skoldinov, S.V. Zhuravlev, N.V. Savitskaya) and abroad in the 50s. A large number of phenothiazine derivatives have been synthesized, having the general formula:

According to IUPAC nomenclature, phenothiazines are numbered counterclockwise, starting with the carbon atom following the nitrogen atom.

ChapterI. Pharmaceutical analysis of drugs, phenothiazine derivatives

1.1 Classification

pharmacology phenothiazine derivative

According to the chemical structure and the nature of the pronounced pharmacological action, phenothiazine derivatives can be divided into two groups. The first of them includes 10-alkyl phenothiazine derivatives: promazine, levomepromazine, promethazine, chlorpromazine, trifluoperazine, which have neuroleptic and antihistamine effects, and the second includes 10-acyl phenothiazine derivatives: moracizine, etacizine, which are effective in the treatment of cardiovascular diseases.

10-alkyl derivatives of phenothiazine 10-acyl derivatives of phenothiazine.

Based on the structure of the substituent at N 10, neuroleptics of the phenothiazine series are divided into those containing:

aliphatic radical

piperidine fragment

piperazine fragment

According to pharmacological action:

psychotropic (propazine, aminazine)

antihistamines (diprazine)

· antiarrhythmic (ethmosin)

· antidepressants (fluoroacyzine)

1.2 Relationship between chemical structure and pharmacological action

The nature of the substituent at N 10 also affects the pharmacological effect. Phenothiazines with aliphatic side chains (eg, chlorpromazine) are generally low-potency compounds (i.e., higher doses of the drug must be used to achieve a therapeutic effect). Piperidine derivatives have anticholinergic properties and are less capable of causing the development of extrapyramidal disorders (for example, thioridazine). Piperazine phenothiazines (such as trifluoperazine) are the most potent antipsychotic compounds.

Phenothiazine drugs have versatile

pharmacological action, but depending on the structural characteristics, one of the manifestations of the biological action is predominant (for example, neuroleptic).

· For the manifestation of pharmacological action, a certain structure is required (certain substituents at C-2 and N-10).

· The optimal length of alkyl and acyl chains is 3.

· The movement of the dimethylamine radical from C-2 to C-3 (from diprazine to chlorpromazine) leads to a decrease in antihistamine activity and an increase in sedative effect.

· The introduction of a halogen at position C-2 (Cl, CF 3) leads to increased pharmacological action, but at the same time to increased toxicity. Replacing the methyl groups with ethyl and the propyl radical with propionyl leads to a change in the pharmacological action (chlorpromazine - to chloracyzine, a change from? neuroleptic? to? antiarrhythmic,? coronary dilator).

1.3 Physical properties

Phenothiazine derivatives are white (or with a slight yellowish, grayish, creamy tint) crystalline substances. They are easily oxidized (even by air oxygen) and darken. Salts of phenothiazine derivatives are highly soluble in water and ethanol, and practically insoluble in diethyl ether. The bases are a syrupy mass that is poorly soluble in water, but well soluble in ethanol, chloroform, diethyl ether, and ethyl acetate. Phenothiazine derivatives are substances of a basic nature, which is due to the presence in the structure of the molecule of a heterocyclic nitrogen atom and a tertiary nitrogen atom in the aliphatic radical. The pH values ​​of aqueous solutions are in the range of 3-4 (alkyl derivatives) and 4-6 (acyl derivatives). Characteristic T.pl. have the drugs themselves (most of them are hydrochlorides), their bases and base picrates.

1.4 Preparation of phenothiazine derivatives

Phenothiazine was first synthesized by Berntsen in 1883 by heating diphenylamine with sulfur.

Phenothiazine can be obtained by reacting sulfur with diphenylamine in the presence of a catalyst - iodine or aluminum chloride. Sulfur dichloride or thionyl chloride can also be used to add sulfur, but in this case a side chlorination reaction occurs. The reaction takes place at a temperature of 180--250°C. Using this reaction, it is also possible to obtain phenothiazine derivatives, however, some diphenylamines, especially 2-substituted ones, do not enter into it, and 3-substituted ones can give both 2- and 4-substituted phenothiazine derivatives.

A generalized method for the preparation of phenothiazine and its derivatives is the transformation of 2"-halogen or -nitro derivatives of 2-aminodiphenyl sulfide in the presence of strong bases (KNH 2, liquid ammonia) to form a heterocycle:

3-substituted phenothiazine derivatives are obtained by heating o-nitrodiphenyl sulfides with triethylphosphite:

The synthesis of phenothiazine derivatives consists of three stages: preparation of the phenothiazine ring, synthesis of an alkyl or acyl radical, addition of this radical to the phenothiazine ring (at position 10) and production of an organic base hydrochloride.

To synthesize chlorpromazine hydrochloride, 2-chlorophenothiazine is first prepared from 2,4-dichlorotoluene:

2,4-dichlorotoluene 2,4-dichlorobenzoic acid 3-chlorodiphenylamino-6-carboxylic acid

3-chlorodiphenylamine 2-chlorophenothiazine

Dialkylated compounds are pre-synthesized from simple organic substances. For example, 3-dimethylaminopropyl chloride is prepared according to the following scheme:

ethylene cyanohydrin

3-dimethylaminopropanol 3-dimethylaminopropyl chloride hydrochloride

The addition of dialkylaminoalkyl chlorides to the phenothiazine ring is carried out by replacing the hydrogen atom at position 10. First, an organic base is obtained, and then the hydrochloride. An example is the third stage of the synthesis of chlorpromazine hydrochloride from 2-chlorophenothiazine and 3-dimethylaminopropyl chloride hydrochloride:

Other 10-alkyl derivatives of phenothiazine are prepared using similar schemes.

The synthesis of 10-acyl derivatives of phenothiazine differs from the synthesis of 10-alkyl derivatives in that at the stage of substitution of the hydrogen atom in position 10 they act not with dialkylaminoalkyl chloride, but with the acid chloride of β-chloropropionic acid:

The chlorine atom is then replaced with the corresponding radical. According to this scheme, the synthesis of moracisine and etacizine was carried out.

1.5 Purity

Thin layer chromatography (TLC) is used to detect foreign impurities. For this method, as a rule, Silufol UV-254 plates are used. Chromatograph using the ascending method in parallel with solutions of witnesses in a solvent system of hexane-acetone-diethylamine (50:30:2) or chloroform-diethylamine (9:1). The chromatograms are detected under UV light at 254 nm. The permissible content of impurities is determined by the number, location, size, and intensity of spots on the chromatogram in comparison with witnesses. The total content of impurities (PC) should not exceed 1.5% for promethazine hydrochloride, 2% for chlorpromazine hydrochloride, and 1% for moracizine hydrochloride. Of the possible impurities in GF X preparations, sulfates, heavy metals and phenothiazine are allowed within the standards. The acidity limit is also determined.

1.6 Identification

1.6.1 Chemical identification reactions

Most medicinal substances of the phenothiazine group are salts of strong mineral acids and organic nitrogenous bases. Bases are isolated from drug solutions by the action of dilute solutions of alkalis, carbonates, and ammonia.

As salts of nitrogenous bases, they interact with general alkaloid precipitation reagents (Mayer, Dragendorff, Bushard, Wagner, tannin, picric acid, etc.). Some of the sediments crystallize well and have a certain T.pl. Since the bases of phenothiazine group drugs are not crystalline, but amorphous or oily, the determination of T.pl. complexes with general alkaloid reagents is significant in the analysis of their quality. The Global Fund recommends determining T.pl. triphthazine picrate.

Some complex compounds of drugs in this group with Dragendorff's reagent have a characteristic crystal shape, which is used in toxicological chemistry.

With palladium chloride (II), the studied drugs form blue complexes, which are also used for the quantitative determination of dosage forms by the FEC method.

The more specific of the listed reagents for the phenothiazine ring is bromine water (Table 1). This reagent is used (PS) to distinguish phenothiazine derivatives from each other (solutions of medicinal substances are heated to boiling with bromine water).

Table 1

Color reactions of phenothiazine derivatives with bromine water

The colored products obtained by heating phenothiazine derivatives with bromine water are due to the formation of perbromo derivatives of the phenothiazonium cation. Phenothiazine, when oxidized with bromine, forms red-colored perbromophenothiazonium:

Instead of the unstable and toxic reagent - bromine water, a 1% aqueous solution of potassium bromate in the presence of 0.15 ml of dilute hydrochloric acid was proposed to be included in the FS to test the authenticity of 10-alkyl derivatives of phenothiazine (promazine, promethazine, chlorpromazine, trifluoperazine hydrochlorides). Aqueous or aqueous-alcoholic 0.1% solutions of these medicinal substances acquire a pink or pink-orange color, gradually turning into crimson or brown. Unlike others, a cherry-red precipitate precipitates from a colored solution of promethazine hydrochloride.

To identify 10-acyl derivatives of phenothiazine (moracizine hydrochloride and etacizine), it is recommended to use a 1% solution of potassium bromate as a reagent, but after preliminary hydrolysis with diluted hydrochloric acid (when heated for 15 minutes). The subsequent procedure is the same as for 10-alkyl phenothiazine derivatives. This group of phenothiazine derivatives also forms colored oxidation products with an alkaline solution of hydroxylamine at pH 4.0. The color depends on the nature of the radical in position 2 (V.I. Prokofiev).

Levomepromazine, when exposed to concentrated sulfuric acid, acquires a lilac color. To identify phenothiazine derivatives, a reaction with concentrated sulfuric acid or with 50-60% solutions of this acid in the presence of other oxidizing agents can be used. For some phenothiazine derivatives, ammonium vanadate (Mandelin reagent) is added to the reaction mixture. When lead oxide powder is added to an aqueous solution of promethazine hydrochloride, there should be no red color in the top layer, but it slowly turns bluish. Other oxidation products are also formed, having absorption maxima in the UV and visible regions of the spectrum. The indicated chemical reactions give positive results when analyzing levomepromazine. When 1 ml of a 37% formaldehyde solution and a few drops of a 0.1 M cerium sulfate solution are added to a solution of levomepromazine, an intense purple color appears. These tests are based on the oxidation process of phenothiazine derivatives, which, depending on the chemical structure, occurs when heated or at room temperature.

When heated with copper, phenothiazine splits off a sulfur atom, transforming into carbazole:

When treated with butyllithium, phenothiazine gives a 1,10-dilithium derivative, upon carboxylation of which phenothiazine-1 carboxylic acid is formed:

The most important property of phenothiazine group drugs, which determines the analysis of their quality, is their extremely easy ability to oxidize. Oxidation processes are complex. They proceed in vitro and in vivo according to the following scheme:

When interacting with other oxidizing agents (sulfuric acid, Fe(III), Ce(IV)), C-oxidation occurs at positions 3 and 7:

Unlike other phenothiazine derivatives with trifluoperazine hydrochloride, concentrated sulfuric acid does not form a colored product, but a jelly-like precipitate. Under the influence of nitric acid, dark red-colored reaction products with promethazine and chlorpromazine hydrochloride are formed and become cloudy.

Being an aromatic compound, phenothiazine is an electron donor and readily undergoes electrophilic substitution reactions.

Chlorination of phenothiazine in acetic acid leads to the replacement of hydrogen atoms with chlorine, first in positions 3 and 7, and then 1 and 9. The final product of chlorination is 1,3,7,9-tetrachlorophenothiazine:

When chlorinated in a nitrobenzene medium, deep chlorination occurs with the addition of up to 11 chlorine atoms and the loss of aromaticity of one of the rings:

When heated to 180°C, this product splits off three chlorine atoms, resulting in the formation of a stable free radical, which partially dimerizes, resulting in the formation of 10,10"-bi-(octachlorophenothiazinyl).

The ratio of free radical and 10,10"-bi-(octachlorophenothiazinyl) at a temperature of 180°C is 30:70.

Solutions of moracizine hydrochloride and etacizine in diluted hydrochloric acid after boiling turn lilac, but the solution of etacizine becomes cloudy, and for moracizine hydrochloride, from the addition of sodium nitrite, the color turns green and then yellow (reaction to the morpholine cycle).

Dyes are also used as identification reagents. A common reagent for phenothiazine derivatives is methylene blue, which in the form of a 0.1% solution in the presence of concentrated sulfuric acid forms colored reactions. Chlorpromazine hydrochloride acquires a purple color, promazine hydrochloride - purple-brown, trifluoperazine hydrochloride - grayish-green.

An acetone solution of maleic anhydride is a group reagent for phenothiazine derivatives. The reaction products acquire a yellow-orange color, the light absorption maxima of the solutions are in the region of 336-360 nm.

Red-colored complex compounds with phenothiazine derivatives form iron (III), mercury (II), cobalt, palladium, and platinum ions. A solution of promethazine hydrochloride after adding silver nitrate in a 0.002 M sulfuric acid solution after heating in a water bath acquires a cherry-red color. White precipitates form with solutions of some phenothiazine derivatives: potassium thiocyanate, ammonium oxalate, potassium hexacyanoferrate (III), and sodium nitroprusside gives a red precipitate (promethazine and chlorpromazine hydrochlorides).

When phenothiazine is oxidized with iron (III) chloride in the presence of sodium p-toluenesulfonate, sodium nitrite or thiourea, 3-(p-toluenesulfonyl)phenothiazine and 3-nitrophenothiazine are formed, respectively, and after hydrolysis of the isothiuronium salt, 3-mercaptophenothiazine. In the presence of compounds containing active methylene groups, dyes with a quinoid structure are formed, for example, as a result of interaction with indanedione-1,3:

Electrophilic substitution in a phenothiazine can also be accompanied by oxidation. Thus, the final product of phenothiazine nitration with nitric acid is 3,7-dinitrophenothiazine oxide-5:

and nitration with nitrous acid leads to 3,7-dinitrophenothiazine:

Phenothiazine derivatives form colored precipitates when interacting with thiocyanatoacid complexes of iron, cobalt and nickel, and white precipitates with thiocyanatoacid complexes of zinc and cadmium. Precipitates dissolve in benzene, chloroform, dichloroethane.

Sodium cobaltinitrite (hexanitrocobaltate) in the presence of acetic anhydride forms substances with a red color when heated with phenothiazine derivatives. Trifluoperazine hydrochloride turns green under these conditions. A solution of iodine monochloride with promethazine, chlorpromazine hydrochlorides and trifluoperazine hydrochloride - violet color (A.I. Sichko).

The presence of a sulfur atom in the molecules of phenothiazine derivatives is determined after calcination with sodium carbonate and potassium nitrate. The resulting sulfate ion is detected in the filtrate using a barium chloride solution as a reagent. The nitrogen atom is confirmed using general alkaloid reagents, in particular a solution of iodine in potassium iodide (Wagner-Bouchard reagent).

Trifluoperazine hydrochloride with a solution of picric acid releases picrate, which has a stable decomposition temperature (240-243ºC). Picrates can also form other phenothiazine derivatives, incl. promethazine hydrochloride (160°C), chlorpromazine hydrochloride (177°C), etc. The carbethoxy group in the molecules of moracizine hydrochloride and ethacyzine is detected by the formation of iodoform after exposure to an iodine solution in an alkaline medium:

C 2 H 5 OH+4I 2 +6KOH>CHI 3 v+5KI+HCOOK+5H 2 O

A common test for phenothiazine derivatives is the precipitation of bases from their aqueous solutions when exposed to sodium hydroxide solution (the base precipitates as a white precipitate). The precipitate is filtered off and chlorides are detected in the filtrate by reaction with a solution of silver nitrate.

The fluorine atom in the molecules of fluorine-containing phenothiazine derivatives (trifluoperazine hydrochloride) is detected after combustion in oxygen to form a fluoride ion. It is then opened by reaction with alizarin red C in the presence of zirconium nitrate. The mixture of these reagents (alizarin zirconium) has a red-violet color. When fluoride ion is added, it turns yellow (free alizarin color).

The Friedel-Crafts acylation of a phenothiazine leads mainly to substitution at positions 2,10, but reaction products of unknown composition have also been isolated:

Phenothiazine is sulfonated with chlorosulfonic acid. Alkylation of a phenothiazine with alkenes in the presence of boron trifluoride leads to 3,7 dialkyl derivatives:

When phenothiazine reacts with chlorine-substituted tertiary and secondary amines in the presence of sodium amide, 10-substituted phenothiazine derivatives are formed. For example, alkylation of a phenothiazine with 2-dimethylamino-1-chloropropane or 1-dimethylamino-2-chloropropane produces 10-(2-dimethylaminopropyl)phenothiazine (promethazine):

Phenothiazine undergoes the Ullmann reaction; when heated with metallic copper and iodobenzene in nitrobenzene, toluene or DMF, the benzene ring is added to position 10 to form 10-phenylphenothiazine:

When phenothiazine interacts with phosgene, 10-chlorocarbonylphenothiazine is formed, which, when reacted with amino alcohols, forms esters, which, when heated in a vacuum with copper, remove carbon dioxide, which allows the introduction of alkali-sensitive groups:

1.6.2

UV spectrophotometry is used to test the authenticity of phenothiazine derivatives. FS recommends setting the specific absorption rate when testing trifluoperazine dihydrochloride (0.001% solution in 0.01 M hydrochloric acid solution at a wavelength of 256 nm). The UV spectrum of a solution of promazine hydrochloride in a 0.01 M solution of hydrochloric acid has two absorption maxima in the region of 230-380 nm - at 252 and 302 nm. The UV spectrum of a 0.0005% solution of promethazine hydrochloride under the same conditions has light absorption maxima at 249 and 300 nm, and chlorpromazine hydrochloride at 254 and 307 nm. The authenticity of levomepromazone hydrochloride is determined by the identity of the UV spectra of the test and standard solutions.

A.P. Arzamastsev et al. Systematized information on the use of UV and IR spectroscopy to assess the authenticity of 12 medicinal substances, phenothiazine derivatives. It has been established that the optimal solvent for UV spectroscopy is ethanol. The UV spectra of 10-alkyl derivatives of phenothiazine have two absorption maxima in the region of 290-330 nm; In 10-acyl derivatives, a hypsochromic shift in both maxima is observed. In the IR spectra of phenothiazine derivatives, certain characteristic frequencies are detected, reflecting the types of bonds and functional groups in the molecules. IR spectra taken after pressing potassium bromide tablets on a two-beam IR spectrophotometer in the region of 4000-250 cm -1 contain 20-25 absorption bands. The main distinguishing feature of the IR spectra of 10-acyl derivatives (from 10-alkyl derivatives) are absorption maxima in the region of 1680-1660 cm - 1 due to the presence of amide carbonyl in the molecule. Other absorption bands, associated with the characteristics of the chemical structure, make it possible to distinguish phenothiazine derivatives (PS) from each other.

Gas-liquid chromatography. Phenothiazine derivatives are separated using medium polarity phase OV-225 (3-5% on chromatone). Glass microcolumns 1-2 m long at 200-300°C. The detector is flameless nitrogen-phosphorus (NPD), its sensitivity is 0.006 μg/ml; for chlorine-containing phenothiazines, an electron capture detector is used, its sensitivity is 0.001 μg/ml. Detection of phenothiazine derivatives is carried out by retention parameters (retention time or volume or relative retention time). Imisine is used as an internal standard.

Thin layer chromatography (TLC) method. Phenothiazine derivatives can be differentiated using the TLC method on Silufol UV-254 plates in a solvent system of ethyl acetate-ethanol-diethylamine (17:2:0.5). After chromatography and development with iodine vapor, depending on the nature of the substituent in position 2, the adsorption zones acquire a blue-green (promazine, promethazine, chlorpromazine hydrochlorides) or pink-orange color (trifluoperazine hydrochloride, fluorophenazine). In addition, they can be identified by differing average Rf values. The TLC method was used in the ND to establish the authenticity of levomepromazine tablets. The main spots of the chromatograms of the test and standard solutions should be identical in size, color and Rf value (about 0.7).

High performance liquid chromatography (HPLC) method. The following conditions have been proposed for the detection of phenothiazine derivatives using HPLC: liquid chromatograph "Milichrome A-02" produced by JSC "EkoNova", chromatographic column 2×75 mm, reversed-phase sorbent - "Silasorb C18", mobile phase: eluent A-0.1% solution trichloroacetic acid, eluent B - acetonitrile, flow rate - 100 µl/min, analytical wavelengths - 210, 220, 240, 250, 280 nm, column thermostat temperature -35°C, gradient - from 10% of eluent B to 80% in 30 min , the volume of the injected sample is 2 µl. Alcohol solutions of the test substances are introduced into the chromatograph. Substances are identified by retention time and spectral ratios.

HPLC has proven promising for quality control of drug substances of 10-alkyl and 10-acyl phenothiazine derivatives. Four options have been developed for the selective separation of 16 derivatives of this group, which can be used for their identification, control of purity and quantitative determination in dosage forms (V.I. Prokofieva).

1. 7 Quantification methods

1.7.1 Chemical methods

Methods for the quantitative determination of phenothiazine drugs are varied and are based on the properties of the compounds. The pharmacopoeial method is the method of acid-base titration in non-aqueous media. The drug is dissolved in glacial acetic acid or acetone, mercuric oxide acetate is added and titrated with perchloric acid using a crystal violet or methyl orange indicator.

(PS) titration options in a non-aqueous medium without the addition of mercury (II) acetate are also used. For example, hydrochlorides of 10-acyl phenothiazine derivatives (moracizine hydrochloride, etacizine) can be titrated in a mixture of formic acid, acetic anhydride and benzene (1:30:20) with crystal violet indicator. The chemistry of this process is considered using the example of the determination of ephedrine hydrochloride. There is no need to add mercury acetate (II) when determining chlorpromazine hydrochloride in acetic anhydride, provided that malachite green is used as an indicator, when titrating promethazine hydrochloride with crystal violet indicator, but in a mixture of formic acid and acetic anhydride (1:20), and also promazine hydrochloride with the same indicator in a mixture of glacial acetic acid, acetic anhydride and benzene (1.5:20:5).

The content of phenothiazine derivatives can be determined using the alkalimetric method, titrating with a 0.1 M aqueous solution of sodium hydroxide (phenolphthalein indicator). To extract the released organic base, add chloroform:

The reducing properties of phenothiazine derivatives are the basis for cerimetric determination. The essence of the methods is to dissolve a sample (0.02-0.03) in 10 ml of methanol, heat to boiling, cool, add 10 ml of diluted sulfuric acid and titrate with a 0.1 M solution of cerium (IV) sulfate until the appearance after adding the first drops of staining titrant. Thus, titration is performed without using an indicator.

The iodometric determination of chlorpromazine hydrochloride is based on the formation of polyiodide. Its bromatometric determination is described, the essence of which is to titrate a sample solution in a 2 M solution of hydrochloric acid with a 0.1 M solution of potassium bromate in the presence of potassium bromide until the red color appears discolored. The iodometric determination of promazine and chlorpromazine hydrochlorides involves the isolation of an equivalent amount of iodine after separation and decomposition of the resulting adduct (RN)2 ICI:

(RN) 2 ICI+KI>2RN+KCI+I 2

Quantitative determination of levomepromazine is performed by a two-phase titration method using a titrant of 0.01 M sodium lauryl sulfate solution and dimethyl yellow indicator in the presence of chloroform.

1.7.2 Physico-chemical methods of analysis

There are also known methods for the photocolorimetric method of determination, which is based on the reaction with concentrated sulfuric acid, the reaction with Mandelin's reagent and the reaction with a mixture of solutions of 18% hydrochloric acid and 1M arsenic acid. Photometry is carried out at l = 508 nm in a cuvette 5.105; comparison standard - control of reagents. The drug content is calculated according to the calibration schedule.

1.8 Storage

All phenothiazine derivatives are stored according to list B, taking into account their hygroscopicity and ability to easily oxidize. They should be stored in orange glass jars, tightly sealed with paraffin-filled stoppers, in a dry place, since phenothiazine derivatives darken in the light.

ChapterII. Pharmacological characteristics

With the introduction of phenothiazine derivatives into medicine, a new era in pharmacology opened. Possessing a wide spectrum of action on various functions of the body, they are widely used in almost all areas of medicine.

Phenothiazine derivatives have the following pharmacological properties.

1. They have a sedative effect, which differs in its mechanism from the sedative effect that occurs as a result of the use of bromide drugs and hypnotics. Wanting to emphasize the special nature of the sedative effect, new terms are introduced to designate it, namely “tranquillizers” (from the Latin tran-quillns - quiet, calm, serene) or ataractics (from the Greek - calm, unshaken, not disturbed by any passion). What is common in the action of tranquilizers is their ability in therapeutic doses to eliminate pathological manifestations of anxiety and fear, reduce or completely remove emotional tension, eliminate mood disorders, delusions, hallucinations, reduce elements of asociality in the behavior of patients, reduce increased excitability, especially of a manic and hypmanic nature. With the advent of this group of means, the opportunity opened up to intervene in human mental processes. This branch of pharmacology is called neuro- or psychopharmacology. Regarding the mechanism of the sedative effect of phenothiazine derivatives, the overwhelming majority of researchers argue that it is associated with their influence on the reticular or reticular formation of the midbrain. A less probable point of view is when they try to connect its sedative effect with the influence on cortical processes. The reticular formation, receiving irritating impulses from afferent nerve pathways going to the cerebral cortex (specific projection system), itself is toned and turns into a battery, which has a powerful tonic (“charging” according to I. P. Pavlov) effect on the cerebral cortex (non-specific projection system). In the absence of the influence of the reticular formation on the cerebral cortex, the cortex loses its normal tone and falls into a state of rest. It becomes slightly irritable in relation to afferent impulses going directly to the cerebral cortex. It is believed that phenothiazine derivatives have a calming and inhibitory effect on the reticular formation. It therefore becomes unresponsive to afferent impulses, unable to charge itself and therefore exert an activating influence on the cortex.

The mechanism of action is that they block the stimulating effect of adrenaline on the reticular formation. The pituitary-adrenal cortex system plays an important role in the sedative effect of phenothiazine derivatives.

2. Phenothiazine derivatives have the property, even in small doses, of enhancing (potentiating) the effect of narcotic and hypnotic drugs (fatty derivatives), anticonvulsants, central and local anesthetics, etc. With the advent of phenothiazine derivatives, wide opportunities and prospects are opening up for further improvement of the analgesic properties of already existing and widely used means.

3. Hypothermic properties have already been widely used in hypothermia. Reduces temperature in warm-blooded animals below normal; enhances its decrease under the influence of cooling.

4. Phenothiazine derivatives have a strong antiemetic effect and in this respect are superior to all drugs known so far.

5. The antihistamine effect of some phenothiazine derivatives is very pronounced; it is widely used in medical practice along with other antihistamines.

6.? Phenothiazine derivatives inhibit or completely suppress interoreceptive reflexes from internal organs to breathing, blood circulation and other body functions.

Phenothiazine derivatives have anticholinergic properties (peripheral and central), antiarrhythmic, dilating effects on coronary vessels, ganglion blocking (mild), etc.

Table 2. Properties of phenothiazine derivatives

MedicinalVmore	Chemical structure	Description	Release form	Application
Promazine Hydrochloride - promazine hydrochloride (Propazine)	10-alkyl phenothiazine derivatives 10-(3?-dimethylaminopropyl) phenothiazine hydrochloride	White or white with a slight yellowish tint, crystalline powder, odorless. Hygroscopic. Melting point 177-181єС	Tablets and dragees of 0.025 and 0.05 g; 2.5% solution in ampoules of 2 ml.	In psychiatric practice it is used for maintenance therapy. In addition, it is prescribed for malignant hyperthermia and portphyria.
Promethazine Hydrochloride - promethazine hydrochloride (Diprazine)	10-(2?-dimethylaminopropyl) phenothiazine hydrochloride		Tablets of 0.005 and 0.01 g for children and 0.025 g; dragees 0.025 and 0.05 g; 2.5% solution in ampoules of 2 ml; lyophilized powder for injection solutions in ampoules of 0.05 g (50 mg	Prescribed for the treatment of allergic diseases. Diseases of the central nervous system. accompanied by increased vascular permeability
Chlorpromazine Hydrochloride - chlorpromazine hydrochloride (Aminazine)	2-chloro-10-(3?-dimethylaminopropyl) phenothiazine hydrochloride	White or off-white crystalline powder. Hygroscopic. T.pl. 195-198єС	Film-coated tablets of 0.01 g for children; dragee 0.025; 0.05; 0.1 and 0.25 g; 2.5% solution in ampoules of 1,2,5 and 10 ml	The main indications include schizophrenia and other psychoses. Used to potentiate anesthesia, with artificial hypothermia, to eliminate severe vomiting
Levomepromazine - levomepromazine (Tizercin)	2-methoxy-10-(3?-dimethylamino-2?-methylpropyl)phenothiazine hydrochloride	Yellowish-white, slightly hygroscopic powder. Unresistant to light and air	Tablets 0.025 g; 2.5% solution in ampoules of 1 ml (No. 5)	Used for psychoses with psychomotor agitation, trigeminal neuralgia, and itchy dermatoses.
Trifluoperazine Hydrochloride	2-trifluoromethyl-10-phenothiazine hydrochloride	White or slightly greenish-yellowish crystalline powder, odorless. T.pl. 232-240єС	Tablets 0.001; 0.005 and 0.01 g (No. 50); 0.2% solution in ampoules of 1 ml.	The main indications are schizophrenia and other psychoses. For neurotic disorders.
Moracizine Hydrochloride	10-acyl phenothiazine derivatives 2-carbethoxyamino-10-(3?-morpholylpropionyl) phenothiazine hydrochloride	White or off-white crystalline powder	Tablets of 0.025 and 0.1 g (No. 50); 2.5% solution for injection in ampoules of 2 ml.	Used to relieve life-threatening ventricular arrhythmias, including sustained ventricular tachycardia
Ethacizine	2-carbethoxyamino-10-(3?-diethylaminopropionyl) phenothiazine hydrochloride	White crystalline powder. T.pl. 199-208єС	Tablets of 0.05 g (No. 10, 50); 2.5% solution for injection in ampoules of 2 ml.	Used to relieve life-threatening ventricular arrhythmias.

Conclusion

Phenothiazine is a heterocyclic compound containing sulfur and nitrogen atoms in the ring. Phenothiazine derivatives are substances of a basic nature, which is due to the presence in the structure of the molecule of a heterocyclic nitrogen atom and a tertiary nitrogen atom in the aliphatic radical. According to the chemical structure and the nature of the pronounced pharmacological action, phenothiazine derivatives are divided into two groups: 10-alkyl derivatives and 10-acyl derivatives. The nature of the substituent at N10 also affects the pharmacological effect. They have neuroleptic (aminazine), antihistamine (diprazine) or antiarrhythmic (ethmozine) effects.

Phenothiazine can be obtained by reacting sulfur with diphenylamine in the presence of a catalyst - iodine or aluminum chloride. The synthesis of phenothiazine derivatives consists of three stages: obtaining a phenothiazine ring, synthesis of an alkyl or acyl radical, addition of this radical to the phenothiazine ring (at position 10) and obtaining an organic base hydrochloride.

Thin layer chromatography (TLC) is used to detect foreign impurities. The permissible content of impurities is determined by the number, location, size, and intensity of spots on the chromatogram in comparison with witnesses. Of the possible impurities in GF X preparations, sulfates, heavy metals and phenothiazine are allowed within the standards. Most medicinal substances of the phenothiazine group are salts of strong mineral acids and organic nitrogenous bases. Bases are isolated from drug solutions by the action of dilute solutions of alkalis, carbonates, and ammonia.

As salts of nitrogenous bases, they interact with general alkaloid precipitation reagents (Mayer, Dragendorff, Bushard, Wagner, tannin, picric acid, etc.). Some of the sediments crystallize well and have a certain T.pl. Since the bases of phenothiazine group drugs are not crystalline, but amorphous or oily, the determination of T.pl. complexes with general alkaloid reagents is significant in the analysis of their quality. The Global Fund recommends determining T.pl. triphthazine picrate.

The most important property of phenothiazine group drugs, which determines the analysis of their quality, is their extremely easy ability to oxidize. Coloring depends on the nature of the radical at C2 and does not depend on the nature of the oxidizing agent. National pharmacopoeias use various reagents as oxidizing agents.

UV spectrophotometry is used to test the authenticity of phenothiazine derivatives. Phenothiazine derivatives exhibit two light absorption maxima at 250-255 and 300-315 nm. The measurement is carried out in a 0.5 M sulfuric acid solution and the characteristic absorption bands are recorded.

In the IR spectra of phenothiazine derivatives, certain characteristic frequencies are detected, reflecting the types of bonds and functional groups in the molecules. The IR spectrum is compared with spectra available in special reference books.

Phenothiazine derivatives are also determined by gas-liquid chromatography. Detection is based on retention parameters (retention time or volume or relative retention time). Imisine is used as an internal standard.

Thin layer chromatography (TLC) method is used to identify the identity of phenothiazine derivatives. The main spots of the chromatograms of the test and standard solutions must be identical in size, color and Rf value.

HPLC has proven promising for quality control of drug substances of 10-alkyl and 10-acyl phenothiazine derivatives. Alcohol solutions of the test substances are introduced into the chromatograph. Substances are identified by retention time and spectral ratios.

The standard method for the quantitative determination of individual drugs is acid-base titration in a non-aqueous medium. The drug is dissolved in glacial acetic acid or acetone, mercuric oxide acetate is added and titrated with perchloric acid using a crystal violet or methyl orange indicator. (PS) titration options in a non-aqueous medium without the addition of mercury (II) acetate are also used. can be titrated in a mixture of formic acid, acetic anhydride and benzene (1:30:20) with crystal violet indicator.

The content of phenothiazine derivatives can be determined using the alkalimetric method, titrating with a 0.1 M aqueous solution of sodium hydroxide (phenolphthalein indicator).

The reducing properties of phenothiazine derivatives are the basis for cerimetric determination. The essence of the methods is to dissolve the sample in methanol, heat to boiling, add diluted sulfuric acid and titrate with a 0.1 M solution of cerium (IV) sulfate until the color that appears after adding the first drops of the titrant disappears. Thus, titration is performed without the use of an indicator.

Iodometric determination of phenothiazine derivatives consists of isolating an equivalent amount of iodine after separation and decomposition of the resulting adduct.

Bromatometric determination, the essence of which is to titrate a sample solution in a 2 M solution of hydrochloric acid with a 0.1 M solution of potassium bromate in the presence of potassium bromide until the red color appears discolored.

Quantitative determination of levomepromazine is performed by a two-phase titration method using a titrant of 0.01 M sodium lauryl sulfate solution and dimethyl yellow indicator in the presence of chloroform. Physicochemical methods are also used for quantitative determination. The spectrophotometric method is based on the quantitative assessment of the absorption of drug solutions in the ultraviolet region. Photometry is carried out at l=508 nm. The drug content is calculated according to the calibration schedule.

The sensitivity of phenothiazine group drugs to oxidation necessitates their storage in hermetically sealed dark glass bottles, in a dry place protected from light. Injection solutions are stabilized by the addition of antioxidants (sodium sulfite mixture, etc.).

Neuroleptic and sedatives, phenothiazine derivatives - promazine hydrochloride, chlorpromazine hydrochloride, trifluoperazine hydrochloride are prescribed for mental illness. Promethazine hydrochloride has more pronounced antihistamine activity. Therefore, it is used for allergic diseases. Levomepromazine is a neuroleptic and antiemetic agent that also has sedative and antihistamine activity. It is prescribed for psychoses, neuroses, neuritis of various etiologies. Moracizine hydrochloride and etacizine are used for cardiac arrhythmias.

Having completed this course work, we can conclude that phenothiazine derivatives are of great importance for medicine, since they are used independently, as well as as part of other medications in psychiatric and cardiological practices. They are also used to relieve vomiting, potentiate anesthesia, for various forms of allergies, treat seasickness and air sickness, etc. Phenothiazine and its derivatives are easily oxidized, exhibiting reducing properties, and enter into electrophilic substitution, being an aromatic compound. Which is very important for the production, identification and quantification of these substances.

Literature

1. Arzamastsev A.P. Pharmaceutical chemistry: Textbook.-M: GEOTAR-MED.2004-640 p.

2. Belikov V.G. Pharmaceutical chemistry. Textbook ed.2. Moscow "Medpress inform" 2008.

3. Kartashov V.A., Chernova L.V. Physicochemical methods of analysis in pharmaceutical and toxicological chemistry. Educational and methodological manual for students of the Faculty of Pharmacy - Maykop: publisher A.A. Grigorenko, 2009.-58 p.

4. Krasnov E.A., Ermilova E.V. Course of lectures on pharmaceutical chemistry: textbook. In 2 parts. Part 1. Medicines of the heterocyclic series - Tomsk: Siberian State Medical University, 2010.-196 p.

5. Mashkovsky M.D. Medicines. A manual for doctors. 16th ed., revised, corrected. and additional - M.: New Wave: Publisher Umerenkov, 2010.-1216 p.

6. Samarenko V.Ya. Text of lectures on the course “Chemical technology of medicinal substances” St. Petersburg State Chemical-Pharmaceutical Academy (SPHFA)

7. Course of lectures on pharmaceutical chemistry

8. http://www.himhelp.ru/

9. http://medlib.tomsk.ru/fulltext/72374.pdf course of lectures

10. http://ru.wikipedia.org/wiki/%D4%E5%ED%EE%F2%E8%E0%E7% E8%ED

11. http://www.xumuk.ru/encyklopedia/2/4742.html

12. http://dosmed.ru/

13. Vergeichik T.Kh. Toxicological chemistry: textbook; edited by Prof. E.N. Vergeichik. - M.: MEDpress-inform, 2009. - 400 p.

14. Glushenko N.N., Pleteneva T.V. Pharmaceutical chemistry: Textbook for students. avg. prof. textbook institutions - M.: "Academy", 2004 - 384 p.

15. Loginova N.V. Polozov G.I. Introduction to pharmaceutical chemistry: Textbook. manual - Mn.: BSU, 2003 - 250 p.

16. Kukes V.G. Clinical pharmacology: Textbook. - M.: GEOTAR-Media, 2006 - 944 p.

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The phenothiazine ring is a condensed system of three rings - a thiazine and associated benzene rings, therefore phenothiazine can be called a dibenzo derivative of thiazine.

Although phenothiazine exhibits physiological activity (anthelmintic and local antiseptic), it has now lost its significance as a medicine.

Phenothiazine derivatives having a substituent (R) in positions 2 and 10 of the ring are much more important. More often R 10 represents the remainder of 3-dialkylaminopropanol

Similar phenothiazine derivatives unite a large group of drugs with psychotropic effects (neuroleptics).

In appearance, all these drugs are similar to each other. These are mostly white or white with a creamy tint crystalline powders, some have a greenish-yellowish color (triftazine, mepazine). Very easily soluble in water, easily soluble in 95% alcohol, chloroform; practically insoluble in ether and benzene.

Of the chemical properties of phenothiazine derivatives, the most characteristic is their ability to oxidize. Depending on the nature of the oxidizing agent (bromine water, nitric and sulfuric acids, ferric chloride, etc.), oxidation products of different colors are formed. Therefore, these reactions are used to identify phenothiazine drugs.

The place of greatest reactivity in the molecule of phenothiazine and its derivatives is the sulfur atom, which can be oxidized to $ 4+ and S 6 "h

Oxidation of phenothiazine or its derivatives with bromine in acetic acid or another oxidizing agent, such as hydrogen peroxide, leads to the formation of S-oxide (I) and dioxide-sulfone (II).

Due to the tertiary nitrogen in the molecule, phenothiazine derivatives can react with general alkaloid reagents (see “Alkaloids”).

All drugs of the phenothiazine series are used in the form of hydrochlorides, therefore, after isolating the base with alkali, a chlorine ion with a solution of silver nitrate is detected in the filtrate.

Of the possible impurities in GF X preparations, sulfates, heavy metals and phenothiazine are allowed within the standards. The acidity limit is also determined.

Methods for the quantitative determination of phenothiazine drugs are varied and are based on the properties of the compounds. The pharmacopoeial method is the method of acid-base titration in non-aqueous media. The drug is dissolved in glacial acetic acid or acetone, mercuric oxide acetate is added and titrated with perchloric acid using a crystal violet or methyl orange indicator.

The pharmacopoeial method is also the usual method of neutralization: lysis with differentiating solvents. GF X recommends this method for diprazine solutions and tablets. Determination of nitrogen using the Kjeldahl method is recommended by GPC for the quantitative determination of chlorpromazine in solution. Since phenothiazine derivatives darken in the light, which is associated with their ability to easily oxidize, and are hygroscopic, they should be stored in orange glass jars , tightly closed with paraffin-filled stoppers, in a dry place.

When working with phenothiazine derivatives, precautions should be taken to prevent the possibility of powder and solutions getting on the skin and mucous membranes, as they cause severe irritation, swelling of the skin of the eyelids, and a decrease in blood pressure.

The drugs belong to list B.

Pharmacopoeial drugs of the phenothiazine series are aminazine, digaraein, trnphthazine, chloracyzine.

Phenothiazine itself has neither psychotic nor neurotropic properties. Known as an anthelmintic and insecticidal drug. Psychotropic drugs are obtained by introducing various radicals into its molecule at positions 2 and 10.

All phenothiazine derivatives are hydrochlorides and are similar in appearance. These are white with reddish, some (triphthazine, mepazine) crystalline powders with a greenish-yellow tint. Easily soluble in water, 95% alcohol, chloroform, practically insoluble in ether and benzene. Easily oxidize and darken in light. Solutions without stabilizers deteriorate. In case of contact with skin or mucous membranes, they cause severe irritation (weigh or pour from one container to another with rubber gloves and a respirator!). With intramuscular injections, painful infiltrates are possible, and with rapid injection into a vein, damage to the epithelium is possible. Therefore, the drugs are diluted in solutions of novocaine, glucose, and isotonic sodium chloride solution.

Causes photosensitivity in animals; in addition to the neuroleptic effect - muscle relaxation, reduce body temperature; block the trigger zone of the vomiting center and prevent or relieve the development of the emetic effect mediated through this zone (for example, from apomorphine, arecoline, etc.), do not act antiemetic when irritating the vestibular apparatus and gastric mucosa; inhibit the cough center, eliminate hiccups.

Aminazine. White or off-white fine-crystalline powder, easily soluble in water; It is bactericidal, so solutions are prepared using boiled distilled water without subsequent sterilization.

Aminazine has a well-expressed central adrenolytic effect. It blocks impulses coming from extero- rather than from interoreceptors more strongly: it prevents neurogenic gastric ulcers that occur during immobilization and electrical stimulation of rats, but does not affect their development during trauma to the duodenum; reduces the time between the end of feed intake and the beginning of the ruminant period and prevents the cessation of ruminant cycles in sheep after severe electrical stimulation of the skin. Sensitivity to chlorpromazine is higher in horses than in cattle.

Used orally and intramuscularly: as an anti-stress agent for various manipulations with animals; for premedication and potentiation of the action of analgesics, anesthetics, hypnotics and anticonvulsants; before manipulations to remove blockage of the esophagus in ruminants (in emergency cases, it can be administered intravenously), to reduce dislocated joints; with self-gnawing and hypogalactia in fur-bearing animals; as an antiemetic when deworming dogs with arecoline.

After administration of chlorpromazine to slaughter animals, it is most often found in the lungs, kidneys and liver. Residual amounts remain in the muscles for 12-48 hours.

Levomepromazine (tizercin). It potentiates anesthetics and analgesics more strongly than aminazine, but acts weaker than it as an antiemetic. It acts more on norepinephrine than on dopamine receptors. Side effects are less pronounced.

Etaperazine. It is better tolerated and has a stronger antiemetic effect than aminazine, but is less suitable for premedication.

Triftazin. The most active antipsychotic. The sedative effect is stronger than aminazine, and the adrenolytic effect is weaker. Does not have antihistamine, anticonvulsant or antispasmodic effects. It inhibits gastrointestinal motility in ruminants more than in other species. The liver is less affected.

Fluorophenazine decanoate. A drug with a moderate sedative effect, it blocks dopamine receptors more than norepinephrine receptors. Its antipsychotic effect is combined with an activating one. It is of interest for testing on animals as a long-acting antipsychotic (a single injection is effective for 1-2 weeks or more).

Butyrophenone derivatives.

The peculiarity of the pharmacodynamics of drugs in this group is that they have highly pronounced antipsychotic and stimulating properties, while sedative and hypothermic properties are weaker. More specifically than other neuroleptics, they act on the cerebral cortex, enhancing inhibition processes in it. This is apparently explained by the great similarity of their chemical structure to GABA, the inhibitory transmitter of the cerebral cortex. The main disadvantage is the possibility of extrapyramidal disorders. However, these disorders occur from large doses. Studies have shown that butyrophenones (haloperidol) are promising for use in veterinary medicine as anti-stress and promoting the growth of young animals. The latter is apparently due to the well-pronounced energizing properties of butyrophenones.

Haloperidol. One of the most active antipsychotics (stronger even than triftazine), which is characterized by sedative and central adrenolytic effects (especially on dopamine receptors) in the absence of central and peripheral effects on cholinergic receptors, low toxicity.

Approximate doses (mg/kg body weight): 0.07-0.1 orally and 0.045-0.08 intramuscularly to prevent transport stress in calves.

Of other butyrophenones, it is of interest trifluperidol(more active in psychotic action than haloperidol), droperidol(acts strongly, quickly, but does not last long).

Rauwolfia alkaloids.

Extracts from the roots and leaves of the rauwolfia plant have long been used as sedatives and antihypertensives in Indian folk medicine. Rauwolfia is a perennial shrub of the Kutrov family, growing in South and Southeast Asia (India, Sri Lanka). The plant, especially in the roots, contains a large amount of alkaloids (reserpine, ajmalicine, serpine, etc.), which act sedatively, hypotensively (reserpine) or adrenolytically (ajmalicine, etc.).

Under the influence of rauwolfia alkaloids, especially reserpine, animals calm down, physiological sleep deepens, and interoreceptive reflexes are inhibited. The hypotensive effect is quite strong, and therefore the drugs are widely used in medicine for hypertension. The hypotensive effect develops gradually, maximally after a few days.

Unlike aminazine, reserpine (one of the main alkaloids of rauwolfia) does not have an adrenolytic effect and

along with this, it causes a number of cholinomimetic effects: a slowdown of cardiac activity, increased motility of the gastrointestinal tract, etc. It does not have a ganglion-blocking effect.

Of the mechanisms of action, disruption of the process of norepinephrine deposition is important; its release from the presynaptic endings of adrenergic nerves is accelerated. In this case, the mediator is quickly inactivated by monoamine oxidase and its effect on peripheral organs is weakened. Reserpine does not appear to affect the reuptake of norepinephrine. Reserpine reduces the content of norepinephrine, dopamine and serotonin in the central nervous system, since the transport of these substances from the cellular plasma is blocked and they are deaminated. As a result, reserpine has a depressant effect on the central nervous system. Animals become less active and react weaker to exogenous stimuli. The effect of sleeping pills and narcotic substances increases.

Under the influence of reserpine, the content of catecholamines in the heart, blood vessels and other organs decreases. As a result, cardiac output, total peripheral vascular resistance and arterial blood pressure decrease. Most authors deny the effect of reserpine on the vasomotor center. Along with a decrease in blood pressure, kidney function improves: blood flow increases and glomerular filtration increases.

Secretion and motility of the gastrointestinal tract increase. This is due to the predominant influence of the vagus nerve and local irritating effect, which manifests itself with prolonged use of the drug.

Reserpine reduces body temperature, which is apparently explained by a decrease in serotonin content in the hypothalamus. In dogs and cats it causes constriction of the pupils and relaxation of the nictitating membrane. There is also some information about the inhibitory effect on the gonads in animals.

Drugs in this group are used as sedatives and hypotensives for stress and other neuropsychiatric disorders, hypertension, mild forms of heart failure, and thyrotoxicosis.

Side effects usually occur with long-term use of drugs and are manifested by drowsiness, diarrhea, increased blood clotting, bradycardia, and fluid retention in the body. These phenomena are relieved by atropine.

Reserpine. The ester breaks down in the body into reserpic acid, which is an indole derivative, and other compounds. White or yellowish finely crystalline powder, very slightly soluble in water and alcohol, highly soluble in chloroform. The most active drug has a more pronounced local irritant effect.

Cattle are very sensitive to it, so when administered intravenously, the dose should not exceed 7 mg per animal. Horses are also sensitive to reserpine, and a dose of 5 mg parenterally causes severe colic. Dogs and cats tolerate higher doses of reserpine - 0.03-0.035 mg/kg live weight.

Used for prevention and treatment of stress, neuroses, hypertension, thyrotoxicosis. Contraindicated in severe cardiovascular diseases, insufficient renal function, gastric and duodenal ulcers,

Carbidine. Indole derivative. White crystalline powder, easily soluble in water, very slightly soluble in alcohol; pH of solutions is 2.0-2.5. It has neuroleptic, antipsychotic activity and moderate antidepressant effects. Possible side effects: stiffness, tremor, hyperkinesis, which can be relieved with cyclodol.

It is used for nervous disorders, it can be used to prevent stress, and in medicine for schizophrenia and alcoholic psychoses. Contraindicated in case of liver dysfunction, drug poisoning and analgesics.

Lithium salts.

Lithium is an element from the group of alkali metals, widely distributed in nature, found in small quantities in the blood, organs and muscles of animals. Lithium salts have long been used in medicine to treat gout and dissolve kidney stones. In the early 50s, it was found that lithium drugs have a sedative effect on mental patients and prevent attacks of schizophrenia. In this regard, lithium preparations belong to a new group of substances with a calming effect - mood stabilizers. They are able to normalize the functions of the central nervous system and are active in both depression and agitation.

The pharmacodynamics of the drugs is simple. They are quickly absorbed after oral administration and distributed depending on the blood supply to organs and tissues. In the body they dissociate into ions, which can be detected in various organs and tissues 2-3 hours after administration of the drug. Lithium is excreted primarily by the kidneys, and excretion depends on the content of sodium and potassium ions in the blood. With a lack of sodium chloride, lithium retention occurs, and with increased administration, lithium excretion increases. Lithium can cross the placenta and be excreted in milk.

The mechanism of the psychotropic action of lithium is explained by two theories: electrolyte and neurotransmitter. According to the first, lithium ions affect the transport of sodium and potassium ions in the nervous and

muscle cells, and lithium is a sodium antagonist. According to the second, lithium increases the intracellular deamination of norepinephrine, reducing its content in brain tissue. In large doses, it reduces the amount of serotonin. In addition, the brain's sensitivity to neurotransmitters changes. The effect of lithium on healthy and sick people is different, so there is conflicting information in the literature.

The pharmacodynamics of lithium have been studied in laboratory animals and humans.

Compared to aminazine, lithium has a milder and longer-lasting effect on the nervous system, but is weaker. Lithium does not increase the sensitivity threshold and does not suppress the defensive reflex, reduces motor activity and research activity. Lithium hydroxybutyrate inhibits the transmission of excitation from the afferent pathways of the brain, while blocking the flow of pain impulses from the periphery to the central nervous system. The drugs prevent the manifestation of the stimulating effect of various stimulants on the central nervous system and at the same time reduce depression.

[Lithium potentiates the action of haloperidol, benzodiazepines and analgesics.

The drugs suppress the function of the thyroid gland, inhibiting the stimulating effect of thyrotropin, i.e., they inhibit the pituitary gland, but increase the content of luteinizing, parathyroid hormones and insulin. The latter changes the metabolism of carbohydrates and fats. Lithium also affects nitric acid metabolism, improves the absorption of amino acids, reduces the ammonia content in the body and increases the amount of urea in the urine. Lithium salts increase urination, inhibiting the secretion of antidiuretic hormone.

The main drug is lithium carbonate. It is used for the prevention and treatment of psychosis and depression in medicine, in veterinary medicine for the prevention of stress in poultry farming and during the transportation of calves, as well as before vaccination of animals, including poultry.

Side effects: thirst, drowsiness, depression, cardiac dysfunction.

Contraindicated in case of impaired renal function and cardiovascular system.

Lithium carbonate. White light powder, difficult to dissolve in water, alkaline solutions, insoluble in alcohol.

Reduces the aggressiveness of birds and other animals, but the ranking struggle among piglets remains. Reduces motor activity, improves adaptation to new conditions, improves animal resistance and live weight gain.

Used for stress before and after transportation, animal transplantation and poultry vaccination.

Lithium hydroxybutyrate. White crystalline powder, easily soluble in water, difficult in alcohol. It is a lithium analogue of sodium hydroxybutyrate. The action is associated with the presence of lithium ion, and the sedative effect characteristic of sodium hydroxybutyrate is pronounced. The drug is more active and less toxic. Prescribed for the same indications orally and intramuscularly in the same doses.

TRANQUILIZERS

The name of the group comes from the Latin tranquillare - to make calm, serene. These are substances that have a calming effect on the central nervous system. Unlike neuroleptics, tranquilizers do not have a pronounced antipsychotic effect; they reduce emotional tension, anxiety and fear, mainly of neurotic origin. Therefore, tranquilizers only affect minor dysfunctions of the nervous system. Most drugs, along with a sedative effect, have a weak muscle relaxation and anticonvulsant effect, which is associated with their effect on the central nervous system. The tranquilizing effect of certain drugs is accompanied by an activating or sedative effect.

Based on their chemical structure, tranquilizers are divided into several groups:

1) benzodiazepine derivatives (chlozepid, sibazone, phenazepam, nozepam);

2) propanediol derivatives (meprotane);

3) diphenylmethane derivatives (amizil).

Most drugs are absorbed quickly when taken orally, the highest concentration in the blood plasma is observed after 2-4 hours. A decrease in concentration by 50% occurs after 8-10 hours. In the body, substances undergo biotransformation. In the form of metabolites, conjugates and partly unchanged, they are excreted mainly by the kidneys, less - by the gastrointestinal tract.

Under the influence of tranquilizers, the excitability of the subcortical areas of the brain (limbic system, thalamus, hypothalamus) is reduced and interactions between them and the cerebral cortex are inhibited. In addition, these substances inhibit spinal polysynaptic reflexes. As a result, a sedative effect develops and skeletal muscle tone decreases. Thanks to this, an anticonvulsant effect is possible. They potentiate the inhibitory effect on the central nervous system of drugs, hypnotics and analgesics. They have virtually no effect on autonomic innervation, although certain drugs (amizil) block the cholinergic systems of the brain. A decrease in heart rate and breathing is associated with a decrease in feelings of fear and muscle tension.

With prolonged use of drugs, addiction develops and side effects are possible (drowsiness, nausea, etc.).

Tranquilizers are used in medicine in psychiatric practice, in veterinary medicine for neuroses, stress, for premedication before surgery, for skin diseases accompanied by itching.

Benzodiazepine derivatives. The drug molecule is based on a benzodiazepine core. When hydrogen atoms are replaced with halogens or oxygen, compounds with a pronounced tranquilizing effect are obtained.

All preparations are white crystalline powders with a yellowish tint, insoluble in water and sparingly soluble in alcohol. Under the influence of light they quickly collapse.

In the mechanism of action, the main link is the weakening of the formation and action of dopamine and norepinephrine in the brain and the enhancement, like bromides, of inhibition processes, where the neurotransmitter is gamma-aminobutyric acid (GABA). Benzodiazepines also interact with their specific receptors. The main effect for this group is sedative. Anticonvulsant activity and potentiation of the action of hypnotics and analgesics are also expressed. Large doses may have a hypnotic effect.

Chlozepid (chlordiazepoxide, elenium). This is the first representative of benzodiazepine derivatives. Pharmacodynamics are typical for this group. It has a calming effect on the nervous system, relaxes muscles, stops cramps, and can induce sleep. It is quickly absorbed and acts for 8-10 hours. It is used for neuroses, nervous system excitation, spastic conditions, myositis, arthritis and skin diseases accompanied by muscle tension. Administer orally after feeding. Treatment begins with a small dose.

Contraindicated during pregnancy, as it penetrates the placental barrier, acute liver and kidney diseases.

Sibazon (diazepam, seduxen). In terms of chemical structure and pharmacological action, it is close to chlozepid, but more active than it. The tranquilizing effect is more pronounced, reduces feelings of fear, anxiety, tension, and normalizes sleep. Anticonvulsant activity is expressed and has an antiarrhythmic effect.

Used for the same indications, as well as for convulsions in combination with other anticonvulsants and gastric ulcers. Contraindications are the same as for chlozepid.

Phenazepam. It has the most powerful tranquilizing effect, its activity is close to that of neuroleptics. It also causes pronounced anticonvulsant, muscle relaxant and hypnotic effects. Strengthens the effect of sleeping pills and narcotics.

Indicated for neuroses, psychosomatic stress, accompanied by anxiety, fear, increased irritability, as an anticonvulsant and hypnotic; to prevent stress and improve adaptation. Complications and contraindications are the same as for chlozepid.

Nozepam (tazepam, oxazepam). Compared to previous drugs, the effect is weaker, but less toxic and better tolerated. Muscle relaxant and anticonvulsant effects are less pronounced.

Used for mild dysfunctions of the nervous system (neuroses and neurosis-like conditions). The contraindications are the same; allergic and dyspeptic symptoms are possible.

Propanediol derivatives.

Propanediol derivatives have similar pharmacological properties to benzodiazepines. They inhibit the transmission of excitation in the area of ​​interneurons of the spinal cord, inhibit the thalamus and hypothalamus, resulting in a calming effect. The drugs relax muscles and have an anticonvulsant effect, enhance the effect of substances that depress the nervous system. The autonomic system is not affected.

Meprotan (meprobamate, andaxin). White crystalline powder, slightly soluble in water, soluble in alcohol. Easily absorbed from the gastrointestinal tract, slowly decomposes, and is excreted mainly by the kidneys. It has a pronounced sedative and anticonvulsant effect, and slightly lowers body temperature. Causes the induction of microsomal liver enzymes. It is weaker than benzodiazepines and less toxic.

Used for neuroses arising from fear, anxiety, increased muscle tone, in surgery - in preparation for operations. Prescribed orally after feeding. Addiction may develop, drowsiness and muscle weakness may occur.

Diphenylmethane derivatives.

Substances of this group, along with the general action of tranquilizers, have a strong blocking effect on the cholinergic systems of the brain, which is why they are called central anticholinergic blockers. In addition, a peripheral anticholinergic effect is also expressed.

Amizil (benactnzii). White crystalline powder, soluble in water, difficult in alcohol. It has central and peripheral anticholinergic effects, has a sedative and anticonvulsant effect, and suppresses the cough reflex. It has a moderate antispasmodic, antihistamine, antiserotonin and local anesthetic effect. Weakens the influence of the vagus nerve, as a result of which the pupils dilate, the secretion of glands decreases, and the tone of smooth muscles decreases.

Used for neurotic conditions, extrapyramidal disorders, preparation for anesthesia and in the postoperative period, for smooth muscle spasms, to dilate the pupil for diagnostic purposes, as an antitussive. Prescribed orally 1-3 times a day. To dilate the pupil, 1-3 drops of a 1-2% solution are injected into the conjunctival sac.

Side effects: dry mouth, tachycardia, dilated pupils. Contraindicated in glaucoma.

Nootropic drugs.

The first information about nootropic substances appeared in the 70s. The name of the group comes from the Greek. noos - thinking, reason and tropos - aspiration, affinity. In the 80s, they took a prominent place among psychotropic drugs, as they activate the integrative mechanisms of the brain, improve memory and mental activity, and increase the brain’s resistance to harmful influences. The first and main drug in this group is piracetam.

Nootropics, unlike other psychotropic drugs, do not significantly affect motor reactions, the activity of these substances, do not have a hypnotic or analgesic effect, and do not change the function of the peripheral nervous system. At the same time, they characteristically influence a number of functions of the central nervous system: they facilitate communication between the hemispheres of the brain and increase its resistance to hypoxia.

The mechanism of action has not been studied precisely enough, but it has been found that nootropics enhance ATP synthesis, glucose utilization, and activate phospholipase. The chemical structure of piracetam is similar to gamma-aminobutyric acid (GABA) and has many similarities in action. GABAergic substances (aminalone, sodium hydroxybutyrate, etc.) are combined into one group with nootropics, since they have much in common in their effect on the central nervous system. They improve metabolic processes in the brain, stimulate learning, and correct disorders due to stress, hypoxia, intoxication, and aging. Nootropic drugs are considered as a means of metabolic therapy, because they are based on substances of biogenic origin and affect metabolic processes.

Nootropics improve redox reactions, other metabolic processes and blood circulation in the brain. They increase tissue resistance to hypoxia and various toxic effects, restore blood flow and impaired brain functions, relieve lethargy and lethargy.

The drugs are used in medicine for depression, lethargy, treatment of poisoning, memory and cerebral circulation disorders, hypoxia, in gerontology and in the complex treatment of various mental illnesses.

Due to their positive and versatile effects on the functions of the brain and blood circulation in it, nootropics are a promising group of substances. It is necessary to study their effects on animals for use in veterinary medicine.

Piracetam (nootropil). List B. White crystalline powder, highly soluble in water and alcohol. Easily absorbed, penetrates the blood-brain barrier, and is excreted by the kidneys without changes.

Increases adenylate cyclase activity and energy potential, inhibits nucleotide phosphatase, improves memory, learning, and resistance to hypoxia. Reduces inhibition, eliminates vegetative and neurotic disorders. Indicated for hypoxia, cerebrovascular accidents, depression, etc. Used orally and intramuscularly, the course of treatment is 2-3 weeks. Approximate doses for dogs are 0.1-0.4 g.

Contraindicated in pregnancy and acute renal failure.

Aminalon (gammalon, ganevrin). Gamma-aminobutyric acid (GABA). List B. White powder, easily soluble in water, slightly soluble in alcohol.

GABA is found in the central nervous system and is involved in inhibition processes by interacting with specific receptors. Improves blood supply to the brain, breathing, thinking, restores movement, weakens vestibular disorders. Prescribed for vascular diseases of the brain, after brain injuries, polyneuritis, developmental delays. Use orally before feeding 3 times a day. The approximate dose for dogs is 0.25 g.

Phenibut. Gamma-amino-beta-phenylbutyric acid hydrochloride. White powder, easily soluble in water, less so in alcohol.

Reduces tension, fear, anxiety, prolongs and enhances the effect of substances that depress the central nervous system; the effect is similar to tranquilizers. Does not eliminate cramps. Indicated for neuroses and before surgery. Used orally before feeding 3 times a day in the same doses as aminalon.

ANTICONVULSANTS

In some animal diseases, the tone of the skeletal muscles increases and fibrillary contractions appear, sometimes then convulsions develop. Anticonvulsants are used to relieve this tension and to prevent or reduce seizures. For this purpose, all substances that depress the central nervous system can be used, but they also affect other organs and systems. Therefore, as anticonvulsants, it is advisable to use drugs that selectively suppress convulsive reactions and do not have a general inhibitory effect on the central nervous system. The most effective are diphenine, hexamidine, benzonal and trimethine. Based on their chemical structure, these compounds belong to different groups. Some barbituric acid derivatives (phenobarbital, benzonal) also have anticonvulsant activity.

The mechanism of action of anticonvulsants is different, but they all inhibit the transmission of excitation in the synapses of certain areas of the brain, increase the threshold of excitability of these areas of the brain and slow down the motor reaction time. Some drugs affect electrolyte metabolism and increase the content of GABA in brain cells, which is involved in the processes of central inhibition.

The preparations are white crystalline powders, very little or insoluble in water, sparingly soluble in alcohol; are destroyed when exposed to light. Well absorbed from the gastrointestinal tract. Biotransformation occurs mainly in the liver, metabolites and some substances are excreted unchanged by the kidneys. Since the substances are persistent, minor accumulation is possible (diphenin). With prolonged use, addiction is possible (barbiturates).

Difenin. A mixture of diphenylhydantoin and sodium bicarbonate (85:15). Promotes the release of sodium ions from nerve cells, which reduces the excitability of neurons and the transmission of excitation in the central nervous system. Relieves all types of cramps and skeletal muscle tension.

Prescribed for seizures of various origins, some forms of cardiac arrhythmias and vestibular disorders. Use internally after feeding.

Side effects: nausea, vomiting, difficulty breathing, ataxia. Contraindicated for diseases of the liver, kidneys, heart, cachexia.

Hexamidine. A pyrimidine derivative, chemically similar to phenobarbital, but less active and toxic. It has a longer lasting effect than diphenine and is used for the same purposes as a therapeutic and prophylactic agent. The side effects and contraindications are the same.

Bezonal. A derivative of barbituric acid, therefore, it has a similar effect to phenobarbital, providing an anticonvulsant effect, but without causing drowsiness, lethargy, or lethargy. Prescribed for the treatment of seizures of various origins, used orally after feeding. Treatment begins with a small dose, gradually increasing it to the optimal dose. Discontinuation of the drug and replacement of the previously used one are also carried out gradually (3-5 days).

The contraindications are the same.

Trimethine. Oxazolidinedione derivative. It has a weaker effect than previous drugs, therefore it is active in minor attacks of convulsions, in mental and vascular-vegetative disorders. Combined use in small doses with other anticonvulsants is advisable.

Prescribed orally after feeding 2-3 times a day.

Phenothiazine derivatives, as well as other psychotropic, antihistamine and cardiovascular drugs, in addition to their own therapeutic effect, exhibit side and toxic effects. Particular attention is drawn to the pronounced photosensitizing effect of phenothiazine derivatives. Poisoning with phenothiazine derivatives (domestic and suicidal, medical errors) often leads to death.

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Analysis of phenothiazine derivatives
TABLE OF CONTENTS

INTRODUCTION

After the discovery of the pharmacological activity of N-substituted phenothiazine derivatives (PNT), a large number of substances with antipsychotic, antihistamine, anticholinergic, sedative and antiarrhythmic effects were synthesized.

The following drugs are actively used in pharmaceutical practice: alimemazine (Theralen, France); levomepromazine (tizercin, Hungary); promazin (propazin, Russia); chlorpromazine (aminazine, Russia); methophenazine (frenolone, Hungary); perphenazine (etaperazine, Russia); prochlorpenazine (meterazine, Russia); thioproperazine (mazeptyl, France); trifluoperazine (stelazine, UK); flupenthixol (fluanxol, Denmark); fluphenazine (mirenil, Poland; moditene, UK); prolinate, India; pericyazine (neuleptil, France, India); Pipothiazine (Piportil, France); thioridazine (Melleril, Switzerland, Türkiye); Sonapax, Poland; Thiodazine and Thioryl, India.

Phenothiazine derivatives, as well as other psychotropic, antihistamine and cardiovascular drugs, in addition to their own therapeutic effect, exhibit side and toxic effects. Particular attention is drawn to the pronounced photosensitizing effect of phenothiazine derivatives. Poisoning with phenothiazine derivatives (domestic and suicidal, medical errors) often leads to death.

A large number of poisonings with these compounds have been described, often in combination with other medicinal substances (barbiturates, isonicotinic acid derivatives, imizin, antibiotics, insulin, etc.).

That is why the study of phenothiazine derivatives is a relevant and timely topic.

The goal and objectives of the work are to consolidate and generalize theoretical knowledge on the analysis of phenothiazine derivatives.

Chapter 1 THEORETICAL BASIS FOR THE ANALYSIS OF PHENOTHIAZINE DERIVATIVES

1.1 Classification of phenothiazine derivatives

Phenothiazine is a fused heterocyclic system consisting of a six-membered heterocyclathiazine and two benzene rings (Fig. 1.1).

Rice. 1.1 General formula of phenothiazine

Phenothiazine is one of the most important and promising groups of medicinal substances in modern pharmacy and pharmacology.

As medicines, phenothiazine derivatives in which the hydrogen atom at “N” is replaced by alkylaminoalkyl or alkylaminoacyl radicals are of greatest interest.

They are antipsychotics with a sedative effect, enhancing the effect of hypnotics, analgesics and local anesthetics.

In addition, they have antihistamine activity, anticholinergic effects and other pharmacological properties (cardiovascular, antiarrhythmic).

By the 60s of the 20th century, foreign and domestic scientists (M.N. Shchukina, A.P. Skoldinov, S.V. Zhuravlev, N.V. Savitskaya) synthesized many substituted phenothiazine derivatives, a number of which found application in medical practice as effective agents that act on sharply agitated patients, reducing their feelings of anxiety, fear, and absent-mindedness (aminazine, propazine, etc.). These were the so-called major tranquilizers and antipsychotic drugs.

The use of these drugs has opened a new era in the treatment of mental illness.

Thus, according to the chemical structure and the nature of the pronounced pharmacological action, phenothiazine derivatives can be divided into two groups. The first of them includes 10 alky derivatives of phenothiazine: promazine, levomepromazine, promethazine, chlorpromazine, trifluoperazine, which have neuroleptic and antihistamine effects, and the second 10 acyl derivatives of phenothiazine: moracizine, etacizine, which are effective in the treatment of cardiovascular diseases.

N-substituted aminoalkyl derivatives can be divided into the following groups:

1. Dialkylaminoalkyl phenothiazine derivatives (propazine, aminazine, diprazine, etc.)

2. Drugs containing a piperazine ring in the side chain (triftazine, frenolone, etapyrazine, fluorophenazine, etc.).

3. Drugs containing a piperidine ring in the side chain (thioridazine, etc.).

1.2 Medicines group

Properties of drugs N 10 -alkyl derivatives of phenothiazine are presented in table. 1.1.

Table 1.1

Properties N 10 -alkyl phenothiazine derivatives

Chemical structure	Description
	Aminazinum. Aminazine. 2-Chloro-10-(3-dimethylaminopropyl)-phenothiazine hydrochloride White or white with a faint creamy tint, finely crystalline powder. Slightly hygroscopic, darkens in light. Very soluble in water, easily soluble in alcohol and chloroform, practically insoluble in ether and benzene. Dosage forms: dragees, solutions for injections.
	Propazinum. Propazin. 10-(3-dimethylaminopropyl)-phenothiazine hydrochloride. White or white with a slight yellowish tint, crystalline powder, odorless. When exposed to light, the drug and its solutions acquire a bluish-green color. Hygroscopic. Dosage forms: dragees, tablets, solutions for injections.
	Diprazinum. Diprazine. 10-(2-Dimethylaminopropyl)-phenothiazine hydrochloride. Very easily soluble in water, easily soluble in alcohol and chloroform, practically insoluble in ether.
	Triphthazinum. Triftazin. 2-Trifluoromethyl-10-phenothiazine dihydrochloride. White or slightly greenish-yellowish crystalline powder, odorless. Easily soluble in water, soluble in alcohol, practically insoluble in ether and benzene. It's getting dark in the light. Dosage forms: film-coated tablets, solution for injection.

The properties of medicinal substances of 10-acylphenothiazine derivatives are presented in table. 1.2.

Table 1.2

Properties of medicinal substances derived from 10-acylphenothiazine

Chemical structure	Description
	Aethacizinum. Ethacizin. 10-(3-Diethylaminopropionyl)-2-(ethoxycarbonylamino)phenothiazine hydrochloride. White crystalline powder. Slowly soluble in water, soluble in alcohol. Dosage forms: tablets, injection solution.
	Aethmozinum. Ethmozin. 2-Carboethoxyamino-10-(3-morpholyl-propionyl)phenothiazine hydrochloride. White or off-white crystalline powder. Soluble in water, slightly soluble in alcohol. It's getting dark in the light. Dosage forms: film-coated tablets, solution for injection.
	Nonachlazinum. Nonachlazine. 2-Chloro-10-[β-(1,4-diazabicyclo(4,3,0) nonanyl-4)propionyl]-phenothiazine hydrochloride. Grayish-yellowish crystalline powder. Let's dissolve well in water. Dosage forms: tablets, drops.

1.3 Pharmacological properties of drugs of the group

Phenothiazine drugs with antipsychotic (neuroleptic) properties have been used clinically for about 50 years to treat schizophrenia, psychosis and other agitated conditions. The pharmacological effect of phenothiazine derivatives is associated with blockade of dopamine receptors.

Based on the structure of the substituent at N10, neuroleptics of the phenothiazine series are divided into those containing:

• aliphatic radical (aminazine, propazine, tizercin, etc.);
  • piperidine fragment (neuleptil, sonapax, etc.);
  • containing a piperazine fragment (triftazine, fluorophenazine, etaprazine, etc.).

The nature of the substituent at N10 also affects the pharmacological effect.

In world medical practice, about 40 neuroleptics of the phenothiazine series are used from more than 5000 synthesized compounds. The search for new drugs in this series continues.

Pharmacokinetics of 10-alkyl-

FNT derivatives are quite complex. The maximum level of the drug in the blood plasma after oral administration is observed on average 2-4 hours after oral administration. When administered parenterally, absorption of FNT derivatives occurs faster and more completely. When administered intramuscularly, the therapeutic effect is observed after 15-20 minutes, and the maximum effect after 30-60 minutes. When administered intravenously, the therapeutic effect is observed after 56 minutes, and the maximum therapeutic effect is observed after 20-30 minutes.

FNT derivatives bind to blood plasma proteins to a high degree (85-90%). As a rule, they are quickly cleared from the circulatory system and accumulate unevenly in various organs. They easily penetrate the blood-brain barrier and can reach high concentrations in brain tissue. The concentration of FNT in the brain is higher than in the blood plasma. Intensively metabolized in the liver. Some metabolites are active. Excreted by the kidneys and bile. The half-life of typical FNT derivatives ranges from 18 to 40 hours.

Most FNT derivatives are metabolized in the liver to demethylated and hydroxylated forms. They are more water soluble than the parent compounds and are more easily excreted from the body by the kidneys. Hydroxylated compounds are further metabolized primarily through conjugation with glucuronic acid. Many of the hydroxylated and demethylated metabolites of phenothiazines have the ability to block dopamine receptors.

The metabolism of chlorpromazine is quite complex. During its biotransformation, about 150 metabolites are formed, of which only 20 have been identified. During metabolism, hydroxylation, sulfoxidation, N-

demethylation, side chain cleavage and other changes in chlorpromazine molecules. According to the literature, about 20 metabolites of chlorpromazine have been isolated to date. The main metabolites of aminazine in humans are: 7-hydroxy derivative, desmonomethylaminazine and the corresponding sulfoxides of these metabolites. The metabolites listed above are excreted in the urine. Some of them are excreted in the urine in the form of conjugates with sulfates and glucuronic acid. About 20% of the taken dose of chlorpromazine is excreted per day. Part of the unchanged chlorpromazine (1-6%) is also excreted in the urine. A number of metabolites were found in the urine, which have not yet been identified. Traces of chlorpromazine metabolites can be detected in urine 12 months or more after stopping treatment.

Antiarrhythmic drugs of the phenothiazine group (ethmozine, etacizine, nonachlazine) are N10-acyl derivatives. Ethmosin and etacizin also contain a urea (as part of a urethane) group.

Along with the psychotropic and antiarrhythmic pharmacological effect, drugs of the phenothiazine group also have other types of activity: antihistamine, anticholinergic, hypothermic, etc.

The pharmacological effect depends mainly on the structure of the radical at N10. Thus, neuroleptics (aminazine, propazine, triftazine, etc.) contain three carbon atoms in the main chain of the aliphatic fragment; diprazine, which has an antihistamine effect, has two carbon atoms; Antiarrhythmic drugs (ethmozin, etacizin, nonachlazine) have a carbamide group at N10. Radicals at C2 potentiate pharmacological activity.

Chapter 2 EXPERIMENTAL ANALYSIS OF PHENOTHIAZINE DERIVATIVES

2.1 Physical properties

In appearance, drugs of the phenothiazine series are white crystalline powders with shades, odorless, soluble in water, some drugs are also soluble in chloroform; pH values ​​of aqueous solutions are in the range of 3 4 (alkyl derivatives) and 4 6 (acyl derivatives).

The drugs themselves (most of them are hydrochlorides), their bases and base picrates have a characteristic melting point.

All drugs have certain UV and IR absorption spectra. Other physicochemical methods (NMR spectroscopy, HPLC, TLC, etc.) are also used in the analysis of drugs in this group.

2.2 Chemical properties and authenticity reactions

Most medicinal substances of the phenothiazine group are salts of strong mineral acids and organic nitrogenous bases. Bases are isolated from drug solutions by the action of dilute solutions of alkalis, carbonates, and ammonia.

As salts of nitrogenous bases, they interact with general alkaloid precipitation reagents (Mayer, Dragendorff, Bushard, Wagner, tannin, picric acid, etc.). Some of the sediments crystallize well and have a certain melting point. Since the bases of phenothiazine group drugs are not crystalline, but amorphous or oily, determining the melting temperature of complexes with general alkaloid reagents is of certain importance in the analysis of their quality. The Global Fund recommends the definition of to pl. triphthazine picrate.

Some complex compounds of drugs in this group with Dragendorff's reagent have a characteristic crystal shape, which is used in toxicological chemistry.

With palladium chloride (II), the studied drugs form blue complexes, which are also used for the quantitative determination of dosage forms by photoelectrocolorimetry.

The most important property of phenothiazine group drugs, which determines the analysis of their quality, is their extremely easy ability to oxidize. Oxidation processes are complex. They occur in vitro and in vivo according to the following scheme (Fig. 2.1).

Rice. 2.1 Scheme of oxidation processes

Coloring depends on the nature of the radical at C2 and does not depend on the nature of the oxidizing agent. National pharmacopoeias use various reagents as oxidizing agents: bromine water, potassium bromate solution in an acidic medium (PS), concentrated sulfuric acid (British Pharmacopoeia), iron (III) chloride in an acidic medium and cerium (IV) sulfate (Japanese Pharmacopoeia), etc.

In hydrochloride preparations, the chloride ion is determined. In this case, the drug solution is treated with an alkali solution to precipitate the base, and in the filtrate, acidified with nitric acid, the chloride ion is determined by reaction with silver nitrate. It is impossible to act directly on the drug with silver nitrate, since the latter will oxidize the phenothiazine system, and some nitrates (for example, aminazine) are insoluble in water.

Ethmosin and etacizin, containing a urethane group, undergo hydrolytic decomposition. An iodoform test can be carried out on the ethanol residue of urethane. The amide group of these same drugs at N10 makes it possible to carry out a hydroxamic test, as well as hydrolysis with the subsequent determination of its products.

2.3 Quantification methods

The standard method for the quantitative determination of individual drugs is acid-base titration in a non-aqueous medium.

In addition, other methods of quantitative determination are possible:

• alkalimetry based on a bound hydrochloric acid residue;
  • gravimetry (the weight form can be the base of the drug, or the product of interaction with general alkaloid precipitation reagents);
  • Kjeldahl method;
  • nephelometry (based on interaction with general alkaloid precipitation reagents);
  • extraction photometry (based on the interaction of drugs as weak bases with acidic indicators, for example, methyl orange, bromothymol blue, bromophenol blue, etc.);
  • other physicochemical methods (spectrophotometry, HPLC).

Quantitative determination of drugs in dosage forms (dragées, tablets, injection solutions) is carried out using various physicochemical methods (UV spectrophotometry, photoelectrocolorimetry), as well as the Kjeldahl method and cerimetrically.

To test the authenticity of phenothiazine derivatives, spectrophotometry in the UV region is used. FS recommends setting the specific absorption rate when testing trifluoperazine dihydrochloride (0.001% solution in 0.01 M hydrochloric acid solution at a wavelength of 256 nm). The UV spectrum of a solution of promazine hydrochloride in a 0.01 M solution of hydrochloric acid has two absorption maxima at 252 and 302 nm in the region of 230 380 nm. The UV spectrum of a 0.0005% solution of promethazine shidrochloride under the same conditions has light absorption maxima at 249 and 300 nm, and chlorpromazine hydrochloride at 254 and 307 nm. The authenticity of levomepromazine hydrochloride is determined by the identity of the UV spectra of the test and standard solutions.

A.P. Arzamastsev and his colleagues systematized information on the use of UV and IR spectroscopy to assess the authenticity of 12 medicinal substances, phenothiazine derivatives. It has been established that the optimal solvent for UV spectroscopy is ethanol. UV spectra of 10 alkyl derivatives of phenothiazine have two absorption maxima in the region of 290-330 nm; 10 acyl derivatives exhibit a hypsochromic shift of both maxima. IR spectra taken after pressing potassium bromide tablets on a dual-beam IR spectrophotometer in the region of 4000-250 cm-1 contain 20-25 absorption bands. The main distinguishing feature of the IR spectra of 10 alyl derivatives (from 10 alkyl derivatives) are absorption maxima in the region of 1680-1660 cm-1, due to the presence of amide carbonyl in the molecule. Other absorption bands, associated with the characteristics of the chemical structure, make it possible to distinguish phenothiazine derivatives (PS) from each other.

HPLC has proven promising for quality control of 10 alkyl and 10 acyl phenothiazine drug substances. Four options have been developed for the selective separation of 16 derivatives of this group, which can be used for identification, purity control and quantification in dosage forms [ 2 ].

Chromatographic methods for analyzing biological objects, as a rule, require sample preparation. Sample preparation for analysis is carried out in various ways (liquid - liquid-liquid extraction, solid-phase extraction).

The authors isolated 83% of chlorpromazine from the liver and kidneys by alkaline ether extraction. 90% of promazine can be isolated from human plasma by liquid-liquid extraction with a mixture of pentane: 2-propanol (98:2). In the work, 13 phenothiazine derivatives were extracted from homogenized brain tissue with tetrahydrofuran; after centrifugation and evaporation, the residue was dissolved in water. With this method of sample preparation, 85% of phenothiazine derivatives are recovered. Chlorpromazine from blood and promethazine from brain tissue are extracted with a mixture of heptane and isoamyl alcohol (99:1). It is proposed to carry out sample preparation in the work using the method of extraction with heptane. Tissues (liver, brain) were pre-homogenized. In whole blood and plasma, after precipitation with 10% sodium hydroxide, a 1.5% solution of amyl alcohol in heptane was added, after centrifugation, the organic phase was washed with an acetate buffer solution (pH 5.6), a solution of 0.1 mol/l hydrochloric acid was added, and after repeated centrifugation and chromatography. A method for isolating chlorpromazine by extraction with chloroform has been proposed. The resulting chloroform layer is filtered, dried, and the dry residue is dissolved in a small amount of the mobile phase.

The disadvantage of liquid extraction is that it is labor intensive and involves a large number of lengthy stages.

An alternative for liquid-liquid extraction of analytes from solid samples is supercritical fluid extraction.

When working with liquid samples and initial extracts, classical sample preparation methods can be replaced by the much more convenient method of solid phase extraction (SPE) - a sorption method of sample preparation in which analytes are transferred from a liquid sample to the solid phase of a concentrating sorbent.

The analytes are washed off from the adsorbent by a relatively small volume of solvent (within ten milliliters), which makes it possible to either immediately use the resulting concentrate for analysis, or additionally concentrate the sample through the stage of obtaining a dry residue by evaporating the solvent in a flow of inert gas, without resorting to the use of a rotary evaporator (as with liquid-liquid extraction).

The Sep-Pak C 18 concentrating cartridge is often used to isolate phenothiazine derivatives and their active metabolites. In this work it is proposed to use a concentrating cartridge with Amberlite XAD-2 sorbent. The authors used a cartridge with cyanopril to isolate chlorpromazine and its sulfoxide.

In the SPE methods described above, the stages of sample preparation and identification of analytes are instrumentally separated, so the prepared sample can be stored and later analyzed by several different analytical methods.

In some cases, a concentrating sorbent cartridge is directly connected to the analytical column of a liquid chromatograph; in this case, the sample is not isolated, but is immediately analyzed by HPLC.

Due to its undeniable advantages over liquid-liquid extraction, the solid-phase extraction method has been the object of intensive research in the field of adsorption technologies for more than two decades and is also used in the analysis of phenothiazine derivatives.

A well-known alternative to careful sample preparation is the use of a precolumn, which protects the main column from contamination. Polyvinyl resins, TSK Gel HW-65, dimethylsilane (RP-2), Inersil ODS-SP are used as a pre-column sorbent.

Sometimes it is advisable not to carry out sample preparation, but to add a filter and a precolumn to the hardware circuit in front of the main column. The advantages of this scheme are the simplicity and rapidity of analysis with less labor and reagents.

10-alkyl phenothiazine derivatives are easily oxidized in air, especially in the presence of light, so samples are stored at low temperatures.

The quantitative content of chlorpromazine, promethazine, prophenamine, levomepromazine, perazine, prochlorperazine, trifluoperazine, thioproperazine, perphenazine, fluphenazine, propericiain and thioridazine remained unchanged when plasma samples were stored for 3 months at -20°C.

A comparative study of the concentrations of chlorpromazine and six of its metabolites in plasma was carried out, samples of which were stored at a temperature of - 20°C for 24 hours, at - 20°C for a week, at - 70°C for 4 weeks and at - 70 °C - for 3 and 12 months. No significant differences in the concentrations of the studied phenothiazine derivatives were found when stored in an atmosphere of liquid nitrogen.

The authors recommend sampling and sample preparation of biomaterial containing phenothiazine derivatives in dark-colored test tubes.

The main HPLC chromatographic parameters for the determination of 10-alkyl derivatives of phenothiazine are listed in Table 1. To determine the content of most phenothiazine derivatives, reverse-phase chromatography is used, and normal-phase chromatography is less commonly used. The analysis is usually performed at room temperature. The speed of the mobile phase is 1.0 - 1.5 ml/min.

Typically, spectrophotometric or fluorimetric detectors are used, operating in the range 250 - 254 nm or at 1ex = 250 - 340 nm and 1em = 280 - 525, respectively. Electrochemical detectors are used (conductometric, voltammetric, coulometric). Electrochemical detectors are most widely used in reverse-phase HPLC, which uses polar eluents. In normal phase HPLC, electrochemical detection can also be used if an electrolyte or suitable high dielectric constant solvent is added after the separation column to the non-polar mobile phase. Highly sensitive mass spectrometric detectors began to be used for serial analyzes to control the quality of chemical production products and medicines, as well as traces of phenothiazine derivatives and metabolites in a wide variety of objects.

An important parameter is the pH of the mobile phase, which, as a rule, is created by a buffer solution (acetate, phosphate, formate). The pH values ​​vary from 3.0 to 5.6, which is consistent with the pKBH+ value of the studied phenothiazine or its metabolites. B gives the pKBH+ value of the protonated nitrogen atom in the phenothiazine ring for aminazine and other PNTs, approximately equal to 4.

The classic adsorption material for both normal- and reverse-phase chromatographic studies of phenothiazine derivatives is silica gel (the names of silica gel phases include the label Silica or Sil).

According to the type of stationary phases used, chromatographic methods for the analysis of nitrogen-containing substances can be classified as follows.

When chromatography on reverse phases of the “old” type (Silasorb C18, Separon C18, LiChrosorb RP-18), compounds of the group of phenothiazine derivatives elute in the form of broadened asymmetric peaks. This effect is explained by the interaction of the main adsorbates with the silica gel matrix containing “active silanols” and metal impurities. To block the surface of silica gel, it is necessary to dynamically modify the adsorbent, which is achieved by adding 0.1-1% aliphatic amine, for example, triethylamine, to the aqueous-organic mobile phase. To regulate pH in the range from 3.0 to 5.0, phosphoric, formic, acetic acids, as well as various buffer solutions (acetate, formate, phosphate) are used.

The use of dynamic modification will, in most cases, increase the separation efficiency to an acceptable level. However, such systems have a number of disadvantages. The use of aliphatic amines can lead to the appearance of a number of systemic peaks in the chromatogram. This negative effect is especially pronounced when detecting in the short-wave UV region. To correctly interpret the chromatogram, it is enough to carry out a control elution before analysis and identify all system peaks - both positive and negative.

The modern direction is analysis on reverse phases of a “new” type, obtained on the basis of a salt-gel (sol-gel), followed by intensive endcapping (Wakosil II C18RS, Zorbax Eclipse XDB C18, Hypersil BDS C18), modified with ligands with a polar group (Discovery Amide C16, Symmetry Shield C18), as well as based on “hybrid” type silica gel obtained by polymerization of alkylsiloxanes (XTerra).

In addition to physical and chemical methods, chemical reactions of oxidation, salt and complex formation, detection of nitrogen atoms, sulfur, and chloride ions are used to test phenothiazine derivatives. Most authentication tests utilize the ability of phenothiazine derivatives to readily oxidize to form colored products. Thus, when exposed to a 10% solution of chloramine T, a violet or red-violet color appears, turning into a layer of chloroform. Bromine water, nitric acid, iron (III) chloride, hydrogen peroxide, and concentrated sulfuric acid can be used as oxidizing agents. These reactions are mostly unspecific, because mixtures of oxidation products are formed that have a red, cherry red, red orange, and crimson coloration.

The more specific of the listed reagents for the phenothiazine ring is bromine water. This reagent is used to distinguish phenothiazine derivatives from each other (solutions of medicinal substances are heated to boiling with bromine water) (Table 2.1).

Table 2.1

Color reactions of phenothiazine derivatives with bromine water

Medicinal substance	Reaction result
Promazine hydrochloride Promethazine hydrochloride Chlorpromazine hydrochloride Trifluoperazine hydrochloride Moracizine hydrochloride and etacizine	Transparent brownish-red solution Cloudy dark cherry solution with suspended sediment. Transparent light raspberry solution Initially brown, and then pale pink solution. First, a light lilac, and then a bright purple solution.

The colored products obtained by heating phenothiazine derivatives with bromine water are due to the formation of perbromo derivatives of the phenothiazonium cation. Phenothiazine, when oxidized with bromine, forms red-colored perbromophenothiazonium (Fig. 2.2):

Rice. 2.2 Color reactions of phenothiazine derivatives with bromine water

Instead of the unstable and toxic reagent bromine water, a 1% solution of potassium bromate in the presence of 0.15 ml of dilute hydrochloric acid was proposed and included in the FS for the authenticity of 10 alkyl derivatives of phenothiazine (promazine, promethazine, chlorpromazine, trifluoperazine hydrochlorides). Aqueous or aqueous-alcoholic 0.1% solutions of these medicinal substances acquire a pink or pink-orange color, gradually turning into crimson or brown. Unlike others, a cherry red precipitate precipitates from a colored solution of promethazine hydrochloride.

To identify 10 acyl derivatives of the phenothiazine moracizine hydrochloride and etacizine, it is recommended to use a 1% solution of potassium bromate as a reagent, but after preliminary hydrolysis with dilute hydrochloric acid (when heated for 15 minutes). The subsequent procedure is the same as for 10 alkyl derivatives of phenothiazine. This group of phenothiazine derivatives also forms colored oxidation products with an alkaline solution of hydroxylamine at pH 4.0. The color depends on the nature of the radical at position 2 [ 3 ].

Levomepromazine, when exposed to concentrated sulfuric acid, acquires a lilac color. To identify phenothiazine derivatives, a reaction with concentrated sulfuric acid or with 50-60% solutions of this acid in the presence of other oxidizing agents can be used. For some phenothiazine derivatives, ammonium vanadate (Mandelin reagent) is added to the reaction mixture. When lead oxide powder is added to an aqueous solution of promethazine hydrochloride, there should be no red color in the top layer, but it slowly turns bluish. Other oxidation products are also formed, which have absorption maxima in the UV and visible regions of the spectrum. The indicated chemical reactions give positive results when analyzing levomepromazine. When 1 ml of a 37% formaldehyde solution and a few drops of a 0.1 M cerium sulfate solution are added to a solution of levomepromazine, an intense purple color appears. These tests are based on the oxidation process of phenothiazine derivatives, which, depending on the chemical structure, occurs when heated or at room temperature.

The greatest reactivity in the molecules of phenothiazine derivatives is the sulfur atom, which is capable of oxidizing to form various substances. The oxidation products of 10-substituted phenothiazines are paramagnetic phenothiazonium radical cations (I), which upon subsequent oxidation are converted into diamagnetic phenazthionium (II) ions. The latter, when interacting with water, form sulfoxides (III), sulfones and 3 onium products (Fig. 2.3):

Rice. 2.3 Reactivity in molecules of phenothiazine derivatives

Thus, the final oxidation products can be 9 S oxide, 9.9 dioxide (sulfone), 3-hydroxy -, 3.7 dioxy -, 3 one -, 3 oxy -7-one phenothiazines.

Unlike other phenothiazine derivatives with trifluoperazine hydrochloride, concentrated sulfuric acid does not form a colored product, but a jelly-like precipitate. Under the influence of nitric acid, dark red-colored products of interaction with promethazine and chlorpromazine hydrochlorides are formed. The color turns yellow, and the chlorpromazine hydrochloride solution becomes cloudy. Solutions of moracizine hydrochloride and etacizine in diluted hydrochloric acid after boiling turn lilac, but the solution of etacizine becomes cloudy, and for moracizine hydrochloride, the addition of sodium nitrate turns the color green and then yellow (reaction to the morpholine cycle).

Dyes are also used as identification reagents. A common reagent for phenothiazine derivatives is methylene blue, which in the form of a 0.1% solution in the presence of concentrated sulfuric acid forms colored reaction products. Chlorpromazine hydrochloride acquires a purple color, promazine hydrochloride is light brown, promethazine hydrochloride is purple and brown, trifluoperazine hydrochloride is grayish green.

An acetone solution of maleic anhydride is a group reagent for phenothiazine derivatives. The reaction products acquire a yellow-orange color, the light absorption maxima of the solutions are in the region of 336-360 nm.

Red-colored complex compounds with phenothiazine derivatives form iron (III), mercury (II), cobalt, palladium, and platinum ions. A solution of promethazine hydrochloride after adding silver nitrate in a 0.002 M sulfuric acid solution after heating in a water bath acquires a cherry red color. White precipitates form with solutions of some phenothiazine derivatives: potassium thiocyanate, ammonium oxalate, potassium hexacyanoferrate (III), and sodium nitroprusside gives a red precipitate (promethazine and chlorpromazine hydrochlorides). Phenothiazine derivatives form colored precipitates when interacting with thiocyanatoacid complexes of iron, cobalt and nickel, and white precipitates with thiocyanatoacid complexes of zinc and cadmium. Precipitates dissolve in benzene, chloroform, and dichloroethane.

Sodium cobaltinitrite (hexanitrocobaltate) in the presence of acetic anhydride forms substances with a red color when heated with phenothiazine derivatives. Trifluoperazine hydrochloride turns green under these conditions. A solution of iodine monochloride with promethazine, chlorpromazine hydrochlorides and trifluoperazine hydrochloride forms brown precipitates. With the subsequent addition of a saturated aqueous solution of sulfanilic acid and ethanol, promethazine hydrochloride becomes green, and chlorpromazine hydrochloride and trifluoperazine hydrochloride become purple.

The presence of a sulfur atom in the molecules of phenothiazine derivatives is determined after calcination with sodium carbonate and potassium nitrate. The resulting sulfate ion is detected in the filtrate using a barium chloride solution as a reagent. The nitrogen atom is confirmed using general alkaloid reagents, in particular a solution of iodine in potassium iodide (Wagner-Bouchard reagent).

Trifluoperazine hydrochloride with a solution of picric acid releases picrate, which has a stable decomposition temperature (240-243 0 WITH). Picrates can also form other phenothiazine derivatives, incl. promethazine hydrochloride (160 0 C), chlorpromazine hydrochloride (177 0 C) and others. The carbethoxy group in the molecules of moracizine hydrochloride and etacizine is detected by the formation of iodoform after exposure to iodine solution in an alkaline medium:

A common test for phenothiazine derivatives is the precipitation of bases from aqueous solutions when exposed to sodium hydroxide solution (the base precipitates as a white precipitate). The precipitate is filtered off and chlorides are detected in the filtrate by reaction with a solution of silver nitrate.

The fluorine atom in the molecules of fluorine-containing phenothiazine derivatives (trifluoperazine hydrochloride) is detected after combustion in oxygen to form fluoride ion. It is then opened by a color reaction with alizarin red C in the presence of zirconium nitrate. The mixture of these reagents (zirconium alizarinate) has a red and violet color. When fluoride ion is added, it turns yellow (free alizarin color).

Phenothiazine derivatives can be differentiated using the TLC method on Silufol UV 254 plates in a solvent system of ethyl acetate ethanol diethylamine (17:2:0.5). After chromatography and development with iodine vapor, depending on the nature of the substituent in position 2, the adsorption zones acquire blue and green (promazine, promethazine, chlorpromazine hydrochlorides). In addition, it is possible to identify by different average values ​​of R f . The TLC method was used in the ND to establish the authenticity of levomepromazine tablets. The main spots of the chromatograms of the test and standard solutions must be identical in size, color and R value f (about 0.7). The same method is used to detect foreign impurities when testing the purity of phenothiazine derivatives. To identify impurities, as a rule, Silufol UV 254 plates are used. Chromatography is carried out using the ascending method in parallel with solutions of witnesses in the solvent system hexane acetone diethylamine (50:20:2) or chloroform diethylamine (9:1). Chromatograms are detected in UV light at 254 nm. The permissible content of impurities is established by the number, location, size and intensity of spots on the chromatogram in comparison with witnesses. The total content of impurities (PC) should not exceed 1.5% for promethazine hydrochloride, 2% for chlorpromazine hydrochloride, and 1% for moracizine hydrochloride.

Quantitative determination of phenothiazine derivatives is performed using various titration methods in non-aqueous media. The titrant in all cases is a solution of perchloric acid. using acetone and methyl orange indicator (in acetone) as a solvent, titrate promazine, promethazine, chlorpromazine hydrochlorides. In other cases, the solvent is glacial acetic acid (trifluoperazine hydrochloride) and the indicator is crystal violet. The indicated titration conditions are possible in the presence of mercury(II) acetate.

For hydrochlorides of 10 alkyl derivatives of phenothiazine, the process of non-aqueous titration occurs according to the following scheme (rsi.2.4):

Rice. 2.4 Non-aqueous titration process

They also use (PS) titration options in a non-aqueous medium without the addition of mercury (II) acetate. For example, hydrochlorides of 10 alkyl derivatives of phenothiazine (moracizine hydrochloride, etacizine) can be titrated in a mixture of formic acid, acetic anhydride and benzene (1:30:20) with a crystal violet indicator. The chemistry of this process is also considered using the example of the determination of ephedrine hydrochloride. The addition of mercury acetate (II) is not required when determining chlorpromazine hydrochloride in acetic anhydride, provided that malachite green is used as an indicator, when titrating promethazine hydrochloride with crystal violet indicator, but in a mixture of formic acid and acetic anhydride (1:20), and also promazine hydrochloride with the same indicator in a mixture of glacial acetic acid, acetic anhydride and benzene (1.5:20:5).

The content of phenothiazine derivatives can be determined by the alkalimetric method, titrating with a 0.1 M aqueous solution of sodium hydroxide (phenolphthalein indicator). To extract the released organic base, chloroform is added (Fig. 2.5):

Rice. 2.5 Alkalimetric method

The reducing properties of phenothiazine derivatives are the basis for cerimetric determination. The essence of the methods is to dissolve a sample (0.02-0.03 g) in 10 ml of methanol, heat to boiling, cool, add 10 ml of diluted sulfuric acid and staining titrant. Thus, titration is performed without the use of an indicator.

The iodometric determination of chlorpromazine hydrochloride is based on the formation of polyiodide. Its bromatometric determination is described, the essence of which is to titrate a sample solution in a 2 M solution of hydrochloric acid with a 0.1 M solution of potassium bromate in the presence of potassium bromide until the red color appears discolored. Iodochlorometric determination of promazine and chlorpromazine hydrochlorides consists of isolating an equivalent amount of iodine after separation and decomposition of the resulting addition product (RN) 2 ICI:

Quantitative determination of levomepromazine is performed by a two-phase titration method using a titrant of 0.01 M sodium lauryl sulfate solution and dimethyl yellow indicator in the presence of chloroform.

Methods for indirect complexometric titration of phenothiazine derivatives are also known. Quantitative determination of phenothiazine derivatives in dosage forms is carried out by the spectrophotometric method (promazine, chlorpromazine hydrochlorides, levomepromazine, etc.) at the above absorption maxima. Color reactions based on oxidation and complexation are widely used for photocolorimetric determination. Accuracy comparable to titrimetric methods allows one to achieve differential spectrophotometric and extraction photometric determination with cobalt thiocyanate acid complex [ 2 ].

CONCLUSIONS

In 1945, it was established that by replacing the hydrogen at the nitrogen atom of the phenothiazine ring with alkylaminoalkyl radicals, it is possible to obtain compounds with strong antihistamine activity, anticholinergic and other important pharmacological properties.

The first in a series of phenothiazine alkylamino derivatives to find use as antihistamines was 10-(2-dimethylaminoethyl)-phenothiazine hydrochloride, known as “ethizine”. A diethyl analogue of ethizin, called “dynesin,” turned out to be a substance with anticholinergic activity and began to be used as a treatment for parkinsonism. Further studies showed that 10-(2-dimethylaminopropyl)-phenothiazine hydrochloride, or diprazine, has very strong antihistamine activity. A more detailed study of these and other similar phenothiazine derivatives revealed their multifaceted effects on the central and peripheral nervous systems. Diprazine is characterized not only by antihistamine, but also by adrenolytic activity, has sedative properties, enhances the effect of narcotics, hypnotics, analgesics and local anesthetics, causes a decrease in body temperature, and exhibits an antiemetic effect.

In search of substances that are more active and more selectively affect the functions of the central nervous system, phenothiazine derivatives were synthesized by replacing the nucleus at the C2 position with a chlorine atom or other substituents. One of the most active was 2chloro-10-(3-dimethylaminopropyl)-phenothiazine hydrochloride, or aminazine. Subsequently, other phenothiazine derivatives were obtained.

Many phenothiazine derivatives are antipsychotic drugs. However, among the phenothiazines, new antidepressants, coronary dilators, antiarrhythmics, and antiemetics have also been synthesized.

Neuroleptics of the phenothiazine series are usually divided depending on the characteristics of their chemical structure into three groups:

1) compounds containing a dialkylaminoalkyl chain at the nitrogen atom of the phenothiazine nucleus, the so-called aliphatic derivatives (aminazine, propazine, levomepromazine, etc.);

2) compounds containing a piperazine core in the side chain, the so-called piperazine derivatives (meterazine, etaprazine, triftazine, fluphenazine, etc.);

3) compounds containing a piperidine core in the side chain (thioridazine, periciazine, etc.) piperidine derivatives.

The drugs included in any of these groups, along with the properties characteristic of each of them, have some common features. Thus, drugs of the first group (aliphatic derivatives) have a pronounced antipsychotic effect and at the same time the presence of an inhibitory component - the ability to cause lethargy, intellectual and motor retardation, passivity, and apathetic state (hypnosedative effect). They are superior to other phenothiazine antipsychotic drugs in terms of their sedative effect. The picture of the relatively moderate extrapyramidal disorders they cause is also dominated by lethargy and hypokinesia (up to akinetic syndrome). Drugs of the second group (piperazine derivatives), along with an antipsychotic effect, are characterized by the presence of a stimulating component, and hyperkinetic and dyskinetic phenomena prevail in the picture of pronounced extrapyramidal disorders. Drugs of the third group (piperidine derivatives) have less strong antipsychotic activity, do not have a hypnosedative effect, and rarely cause extrapyramidal disorders.

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4267.		Spectral analysis	3.49 KB
	Spectral analysis is used both for noise suppression and to solve other data processing problems. The spectrum of a data set хх is a certain function of another coordinate or coordinates Fw obtained in accordance with a certain algorithm. Each of the integral transformations is effective for solving its own range of data analysis problems.
21780.		Film Running analysis	10.84 KB
	The film Two Comrades, in my opinion, cannot give any interesting and truthful picture of the era that unfolds in these films. These two films were shot in different historical eras by different directors with completely different approaches to the formation of the cast; on the one hand, they reveal vivid images of people; on the other hand, they comprehensively show the historical upheavals in Russia of those years that terribly break the destinies of people. The appearance of the film Running itself, filmed in 1970 under Soviet rule...