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LECTUTE № 9 Theme: Chlorderivatives of benzene sulfonamide as drugs. Sulphamides with antidiabetic and diuretic effect. Sulfanilamide and its derivatives.

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Presentation on theme: "LECTUTE № 9 Theme: Chlorderivatives of benzene sulfonamide as drugs. Sulphamides with antidiabetic and diuretic effect. Sulfanilamide and its derivatives."— Presentation transcript:

1 LECTUTE № 9 Theme: Chlorderivatives of benzene sulfonamide as drugs. Sulphamides with antidiabetic and diuretic effect. Sulfanilamide and its derivatives with five- membered and six-membered heterocyclic substituents. Biseptol. Associate prof. Mosula L.M.

2  Derivatives of benzenesulphonic acid  Sulphatic acid – H2SO4 HO–SO2–OH HO–SO3H  Benzenesulphonic acid (sulphobenzoic acid) – product of substotution of one group in a molecule of sulphatic acid on benzene ring –С6Н5:  С6Н5–SO2–OHС6Н5–SO3H Graphic formula:  Introduction sulphonic group–SO3H in aromatic ring gives to substance of acid properties, promotes its solubility in water and lowers toxicity.  Benzenesulphonic acid forms series of derivatives, among which there are important drugs – derivatives of amides (chloramines, pentosept (pantocidum)) and alkyl ureides (chlorpropamide, tolbutamide (butamidum), carbutamide, glibenclamide).

3 Chlorderivatives of amides benzenesulphonic acid Amide of benzenesulphonic acid: С 6 Н 5 –SO 2 –NH 2 Chlorderivatives of amides benzenesulphonic acid have the general formula : Where R – H, COOH R 1 – Na, Cl

4  Substitution of one or two atoms of the Hydrogene in benzene sulphonamide group to Chlorine leads to formation of labile compounds – chloramines, which easily decay with allocation of "active chlorine” which shows oxidising properties. Therefore chloramine have antiseptic and disinfectant properties.  Are known various chloramine.  1. Chloramine and dichloramine (the letter B mean, that initial raw materials for

5  2. Chloramine Т and dichloramine Т (letter Т means, that initial raw materials for synthesis is toluene, it is developed abroad).   Chloramine Т dichloramine Т  Dichloramine have larger of active chlorine.

6  The essence of action chloramine consists that they in the water medium hydrolyze with formation HClO, which shows strong oxidising properties at the expense of oxygen disintegration:  HClO  HCl + O 2HClO  2HCl + O2  Or allocation of "active chlorine” Cl2:  2HOCl  Cl2 + Н2O2  Cl2 + Н2O + О  or  4HOCl  2Cl2 + 2Н2O + О2  Similar action have hypochlorites, for example, sodium hypochlorite NaClO which in water hydrolyzes to hypochlorite acid:  NaClO + НОН  NaОН + НСlO  But advantage chloramines before hypochlorites consists that they do not form some alkali NaОН, which corrodes a wound surface.

7  Chloramine T Chloramine; the sodium salt of N- chlorotoluene-p-sulphonamide; C7H7ClNNaO2S,3H2O =  General reagent grade of commerce.  Chloramine T SPU  Сhloraminum  C7H7ClNNaO2S, 3H20 М m. = 281,7 g/mol

8  The chemical name: sodium salt of N- chlorotoluene-p-sulphonamide, sodium N- chlor-4-methylbenzol-sulphoneimide trihydrate, N-chlorobenzene sulphonamide-sodium trihydrate.  Chloramine contains not less than 98,0 % and no more than 103,0 % of sodium salt of N- chlorotoluene-p-sulphonamide trihydrate.

9  Properties  The description. SPU. A crystal powder white або white colour with a yellowish shade.  Solubility. Freely soluble in water R, soluble in 96 % alcohol R, it is practically insoluble in ether R.  On air chloramine decays under the influence of carbonic gas СО2 and it is audible has begun to smell chlorine (І) oxide Cl2O: At fast heating chloramine decays with explosion and flash.

10  Identification  A. Hydrolisis of chloramine and action of a water solution on indicators.  1 g of chloramine place in a conic flask with volume of 50 ml and dissolve in water, free from СО2, R and lead up volume of solution the same solvent to 20 ml. The received solution paints red litmus paper R in dark blue colour, and then gradually decolours it.  It is possible to confirm occurring processes with such equations. Water solutions of chloramine have alkaline reaction (рН = 8,0–10,0), because in water the chloramine partially hydrolyzes with formation of alkali NaOH:  H3C–С6Н4–SO–NСl–ONa + HOH  H3C–С6Н4–SO2–NH2 + NaСlO  NaClO + НОН  NaОН + НСlO  Therefore the litmus paper in water solution of chloramine is painted in dark blue colour, and phenolphthalein becames crimson colouring.  The further decolouration of litmus paper is possible explaines oxidising properties НСlO, in particular, its acid and chloric decay (disintegration):  2HClO  2HCl + O2   4HOCl  2Cl2 + 2Н2O + О2

11  B. To 10 ml of solution S (substance solution in water, free from СО2, R) add 10 ml solution of hydrogene peroxyde diluted R Н2О2; the white precipitate, which is dissolved at heating, is formed. The received hot solution filter, cool. The formed white crystals, which washed out and have been dried up at temperature from 100  C to 105  C, should have melting point 137  C  C.  C. Calcination of chloramine in crucible and revealing in filtrate of chlorides-ions.  1 g substance place in a porcelain crucible, calcinate, adhering to safety measures from fire. The rest dissolve in 10 ml of water R and filter. The received filtrate gives reaction (a) for chlorides-ions: reaction with solution of AgNO3 in the medium of diluted HNO3.  The received filtrate acidify by diluted HNO3 R and add some drops of solution AgNO3 R1; white curdled precipitate AgCl, which is insoluble in nitric acid, but freely soluble in ammonia solution R* is formed:  CL - + Ag + → AgCl ↓  white curdled precipitate  *For the salts of organic bases solubility test of formed precipitate AgCl spend after filterings and washings of precipitate by water.

12 AgCl + 2NH4OH = [Ag (NH3) 2] Cl + 2H2O At addition HNO3 white precipitate AgCl again drops out: [Ag (NH3) 2] Cl + 2HNO3 → AgCl ↓ + 2NH4NO3 D. Calcination of chloramine in crucible and revealing in filtrate of sulphates-ions: reaction with solution of barium chloride BaCl2 in the medium of diluted HCl. To 5 ml of the filtrate received in test C, add 1 ml of diluted HCl R and 1 ml solution of barium chloride R1; the white precipitate is formed: SO42– + Ba2+  BaSO4 white precipitate The precipitate is insoluble in mineral acids, alkalis.

13  E. Calcination of chloramine in crucible and revealing in filtrate of Sodium- ions (reaction b): interaction with methoxyphenylacetic acid reagent (solution of methoxyphenylacetic acid in solution of tetramethyl hydroxide and ethanol); form white crystalline precipitate, soluble in an ammonia solution:  white

14  Other reaction  1. Reaction with solution of potassium iodide in the presence of chloroform (identification of chlorine – product of chloric disintegration).  At acidifying of substance solution by means of diluted HCl - allocates chlorine Cl2 (chloric disintegration):  At interaction of Cl2 with solution KI in the presence of chloroform free iodine I2 is allocated and chloroformic layer becomes violet colouring:  Cl2 + 2KI = 2KCl + I2

15 Tests 1. A solution transparency. Solution S (substance solution in water, free from СО2, R) on degree turbidity should not exceed the standard ІІ. 2. Chromaticity of solution. Solution S should be transparent and colourless. 3. рН solution S. From 8,0 to 10,0. 4. Ortho-derivatives. 5. The rest, insoluble in ethanol. Weight of the dry rest should not exceed 20 mg (2 %).

16  Assay  Iodometry, substitute titration  Nearby 0,125 g (exact shot) substance place in conic flask with capacity of 250 ml with the ground in glass stopper, dissolve in 100 ml of water R, add 1 g of KI R and 5 ml of sulphatic acid diluted R H2SO4, maintain during 3 mines and titrate with 0,1 M solution of sodium thiosulphate Na2S2O3, using as the indicator 1 ml of starch solution R. Cl2 + 2KI → I2 + 2KCl; I2 + 2Na2S2O3 → 2NaI + Na2S4O6. Еm (C7H7ClNNaO2S, 3H20) = М m./2

17  Storage  In air-tight container, at protecting from light, a dry and cool place, at temperature 8  C-15  C.  Action and use. External antiseptic and deodorant.  Apply to treatment of the infected wounds (1,5–2 % solutions – washing of wounds, wetting of tampons and napkins), disinfection of hands (0,25–0,5 % solution), processings of nonmetallic toolkit, disinfecting of subjects of care by patients (1–3 % solution), at a tubercular infection (5 % solution).  For disinfection sometimes use the "activated" chloramine solutions: addition of ammonia NH3, sulphate ammonium (NH4) 2SO4 or ammonium chloride NH4Cl strengthens bactericidal properties of solutions.

18  Pantocidum SP Х  Pantosept* Halazone C7H5Cl2NO4S М m. = 270,09 g/mol Not less than 50 % of active chlorine The chemical name: N-dichlor-p-carboxy-benzene- sulphonamide, p-dichlorsulphoaminebenzoic acid. Pantosept is derivative of dichloramine.

19  Properties  The description. A white powder with a weak smell of chlorine.  Solubility. Slightly soluble in water and the diluted acids, freely soluble in solutions of caustic and carbonic alkalis.  Sodium salt of pantocidum is freely soluble in water. Therefore tablets of pantocidum always contain 50 % of anhydrous sodium carbonate.

20  Identification  A. Hydrolisis of pantocidum and action of water solution on(with) indicators.  To 1 g of pantocidum 10 ml of water and 2 drops of alkaline solution of methyl red. The liquid is painted in red colour and further becomes colourless.  It is possible to confirm occurring processes with such equations. Water solutions of pantocidum have acid reaction because hydrolisis*: Therefore alkaline solution of methyl red is painted in red colour (acid medium). The further decolouration of methyl red is possible explaines oxidation properties of hypochlorite acid НСlO, in particular, its acid and chloric disintegration (decay): 2HClO  2HCl + O 2  4HOCl  2 Cl 2 + 2Н 2 O + О 2 *It is necessary to notice, that because of bad solubility of pantocidum in water hydrolysis goes slowly.

21  2. Reaction with solution of potassium iodide in the presence of chloroform (identification of chlorine – product of chloric disintegration).  At acidifying of substance solution by means of diluted HCl - allocates chlorine Cl2 (chloric disintegration): At interaction of Cl2 with solution KI in the presence of chloroform free iodine I2 is allocated and chloroformic layer becomes violet colouring: Cl2 + 2KI = 2KCl + I2

22  Tests  The general impurity of heavy metals, Arsenic – within standards.  Sulphatic ashes from 0,5 g of pantocidum should not exceed 0,5 %.  Assay. Iodometry, substitute titration  Nearby 0,2 г g (exact shot) substance dissolve in mix (80 ml of water and 10 ml solution of NaOH), add 15 ml solution of KI and 15 ml of diluted sulphatic acid H2SO4. Allocated iodine I2 titrate with 0,1 M solution of sodium thiosulphate Na2S2O3, using as indicator 1 ml of starch solution R. 4HOCl 2Cl2 + 2Н2O + О2 Cl2 + 2KI 2KCl + I2 I2 + 2Na2S2O3 → 2NaI + Na2S4O6 Em = М m. Cl2/2

23  Storage  In dense corked containers, at protecting from light, a dry and cool place (not to admit decomposition of drug and reduction of the maintenance of active chlorine).  Action and use. An active antiseptic.  Apply mainly to water disinfecting (the weak smell of chlorine) therefore is audible, using the tablets containing pantocidum 0,0082 g, sodium carbonate anhydrous Na2CO3 0,0036 g and sodium chloride NaCl 0,1082 g. One tablet contains 3 mg of active chlorine. To water disinfecting apply 1 tablet of pantocidum for 0,5– 0,75 l of water, and at strong water infection on the same volume of water use - 2 tablets. Disinfecting occurs within 15 minutes.  Use пантоцид also for disinfection of hands (1–1,5 % solutions), syringings and processing of wounds (0,1– 0,5 % solutions).

24 Alkyl ureides derivatives of benzenesulphonic acids   Benzenesulphonic acid – С6Н5– SO2OH Urea (carbamide) – amide of carbonate acid Н2СО3 Ureides – N-acyl-derivatives of urea: Alkyl ureides of benzenesulphonic acids:

25 Alkyl ureides of benzenesulphonic acid reduces of sugar level in blood and because used to diabetum treatment ІІ type (achrestic diabetes). It is known more than 15 thousand sulfamides with hypoglycemic action, among which the important place occupy sulfanilureas and their derivatives (Chlorpropamide, Tolbutamide, Carbutamide, Glibenclamide).

26  Chlorpropamide  (Ph Eur monograph 1087)  Chlorpropamidum C10H13ClN2O3S М m. = 276,74 g/mol The chemical name: N - (p-chlorobenzenesulphonyl)-N '-propylureas, 1-[(4-chlorophenyl)sulphonyl]-3-propylurea. DEFINITION Chlorpropamide contains not less than 99.0 per cent and not more than the equivalent of per cent of 1-[(4-chlorophenyl)sulphonyl]- 3-propylurea, calculated with reference to the dried substance.

27 CHARACTERS A white, crystalline powder, practically insoluble in water, freely soluble in acetone and in methylene chloride, soluble in alcohol. It dissolves in dilute solutions of alkali hydroxides. It shows polymorphism. IDENTIFICATION First identification C, D. Second identification A, B, D. A. Melting point (2.2.14): 126 °C to 130 °C. B. UV-spectroscopy. Dissolve 0.10 g in methanol R and dilute to 50.0 ml with the same solvent. Dilute 5.0 ml of the solution to ml with 0.01 M hydrochloric acid. Dilute 10.0 ml of the solution to ml with 0.01 M hydrochloric acid. Examined between 220 nm and 350 nm (2.2.25), the solution shows an absorption maximum at 232 nm. The specific absorption at the maximum is 570 to 630.

28 C. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with chlorpropamide CRS. Examine the substances prepared as discs. If the spectra obtained show differences, dissolve the substance to be examined and the reference substance in methylene chloride R, evaporate to dryness and record the new spectra using the residues. D. Mineralization of chlorpropamide and revealing Sulphur and Chloride. Heat 0.1 g with 2 g of anhydrous sodium carbonate R until a dull red colour appears for 10 min. Allow to cool, extract the residue with about 5 ml of water R, dilute to 10 ml with water R and filter. The solution gives the reaction (a) of chloride (2.3.1) and Sulphur:

29 a) Revealing in filtrate of chloride-ions: CL - + Ag + → AgCl ↓ white curdled precipitate AgCl + 2NH4OH = [Ag (NH3) 2] Cl + 2H2O [Ag (NH3) 2] Cl + 2HNO3 → AgCl ↓ + 2NH4NO3 (This reaction use for difference chlorpropamide from tolbutamide, which does not contain some Chlorine in molecule). b) Revealing in a filtrate of sulphate-ions: To 5 ml of filtrate add 5 ml of diluted HCl R and 1 ml solution of barium chloride R1; the white precipitate is formed: SO42– + Ba2+  BaSO4 white precipitate The precipitate is insoluble in mineral acids, alkalis

30  Other reactions of identification:  1. Alkaline hydrolysis of chlorpropamide and identification of hydrolysis products.  0,1g of chlorpropamide heat up with 3 drops of solution NaOH; allocated steams (NH3  ) paint the red litmus paper, moistened with water (bring near test tube aperture) in dark blue colour. 2. Acid hydrolysis of chlorpropamide and identification of hydrolysis products. To 0,5 g of chlorpropamide add 40 ml 50 % solution of sulphatic acid H2SO4 and heat up with a return refrigerator within 30 minutes. Cool in cooler with ice, crystals filter, wash out water before neutral reaction on methyl orange and dry at 100–105  C within 2 hours. Melting point of syntesed p-chlorobenzenesulphamide 143–144  C.

31  TESTS  Related substances  Examine by thin-layer chromatography (2.2.27), using a suitable silica gel as the coating substance. Heavy metals (2.4.8) Loss on drying (2.2.32) Not more than 0.5 per cent, determined on g by drying in an oven at 100 °C to 105 °C. Sulphated ash (2.4.14) Not more than 0.1 per cent, determined on 1.0 g.

32  ASSAY  Alkalimetry, direct titration of alcoholic solution  Dissolve g in 50 ml of alcohol R previously neutralised using phenolphthalein solution R1 as indicator and add 25 ml of water R. Titrate with 0.1 M sodium hydroxide until a pink colour is obtained.  The method is based on acid properties of a substance at the expense of presence in molecule sulphamide group –SO2–NH–: Em (C10H13ClN2O3S) = М m. 1 ml of 0.1 M sodium hydroxide is equivalent to mg of C10H13ClN2O3S. Other method of assay: Gravimetry After mineralization of chlorpropamide and reconducting (transistorizing) of Sulphur in sulphate-anions (chande S on SO42-), receive precipitate BaSO4 (weight or gravimetric form), which dry, calcinate to constant weight and weighing. By means of weight BaSO4 calculates maintenance of chlorpropamide in drug.

33  STORAGE   Store protected from light.  Action and use   Hypoglycaemic.   Preparation   Chlorpropamide Tablets   Ph Eur

34  (Ph Eur monograph 0718) Glibenclamide  Glibenclamidum  Maninil*  Daonil* C23H28ClN3O5S М m. = 494,0 g/mol DEFINITION 1-[[4-[2-[(5-Chloro-2-methoxybenzoyl)amino]ethyl]phenyl]sulphonyl]-3-cyclohexylurea. Content 99.0 per cent to per cent (dried substance). CHARACTERS Appearance White or almost white, crystalline powder. Solubility Practically insoluble in water, sparingly soluble in methylene chloride, slightly soluble in alcohol and in methanol.

35  IDENTIFICATION   First identification A, C.   Second identification A, B, D, E.   A. Melting point (2.2.14): 169 °C to 174 °C.   B. UV-spectroscopy. Dissolve 50.0 mg in methanol R, with the aid of ultrasound if necessary, and dilute to 50.0 ml with the same solvent. To 10.0 ml of the solution add 1.0 ml of a 103 g/l solution of hydrochloric acid R and dilute to ml with methanol R. Examined between 230 nm and 350 nm (2.2.25), the solution shows an absorption maximum at 300 nm and a less intense maximum at 275 nm. The specific absorbances at the maxima are 61 to 65 and 27 to 32, respectively.   C. Infrared absorption spectrophotometry (2.2.24).   Preparation Discs of potassium bromide R.   Comparison glibenclamide CRS.   If the spectra obtained show differences, moisten separately the substance to be examined and the reference substance with methanol R, triturate, dry at °C and record the spectra again.

36  D. Thin-layer chromatography(2.2.27).   Test solution Dissolve 10 mg of the substance to be examined in a mixture of equal volumes of methanol R and methylene chloride R and dilute to 10 ml with the same mixture of solvents.   Reference solution Dissolve 10 mg of glibenclamide CRS in a mixture of equal volumes of methanol R and methylene chloride R and dilute to 10 ml with the same mixture of solvents.   Plate TLC silica gel GF254plate R.   Mobile phase alcohol R, glacial acetic acid R, cyclohexane R, methylene chloride R (5:5:45:45 V/V/V/V).   Application 10 µl.   Development Over a path of 10 cm.   Drying In air.   Detection Examine in ultraviolet light at 254 nm.   Results The principal spot in the chromatogram obtained with the test solution is similar in position and size to the principal spot in the chromatogram obtained with the reference solution.   E. Fluorescence of test substance solution in sulphatic acid. Dissolve 20 mg in 2 ml of sulphuric acid R. The solution is colourless and shows blue fluorescence in ultraviolet light at 365 nm. Dissolve 0.1 g of chloral hydrate R in the solution. Within about 5 min, the colour changes to deep yellow and, after about 20 min, develops a brownish tinge.

37  Heavy metals (2.4.8)   Maximum 20 ppm.   1.0 g complies with limit test D. Prepare the standard using 2 ml of lead standard solution (10 ppm Pb) R.   Loss on drying (2.2.32)   Maximum 1.0 per cent, determined on g by drying in an oven at °C.   Sulphated ash (2.4.14)   Maximum 0.1 per cent, determined on 1.0 g. TESTS Related substances

38  ASSAY  Alkalimetry, direct titration alcoholic solution  Dissolve g with heating in 100 ml of alcohol R. Titrate with 0.1 M sodium hydroxide, using 1.0 ml of phenolphthalein solution R as indicator, until a pink colour is obtained. Еm (C23H28ClN3O5S) = М m. 1 ml of 0.1 M sodium hydroxide is equivalent to mg of C23H28ClN3O5S

39 STORAGE Store protected from light. Action and use Hypoglycaemic. Preparation Glibenclamide Tablets Ph Eur

40  Dichlothiazidum  The chemical name: 6-хлор-7-sulfamoyl-3,4-dihydro-2Н-1,2,4-benzothiazine- 1,1-dioxide.  CHARACTERS  A white or white with yellowish shade, crystalline powder, very slightly soluble in water, slightly soluble in alcohol, very soluble in solutions of alkalis.  STORAGE   Store protected from light.   Action and use  Diuretic.  Preparations

41   Thanks for attention!


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