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LECTURE № 1 5

LECTURE № 1 5 Theme: Fused five-, six- and seven-membered heterocycles : properties, analysis, storage, action and use. Associate prof . Mosula L.M. The plan The fused five-membered heterocycles: - derivative of indole as anti-inflammatory agent ( Indometacin ).

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LECTURE № 1 5

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  1. LECTURE № 15 Theme: Fused five-, six- and seven-membered heterocycles: properties, analysis, storage, action and use. Associate prof. Mosula L.M.

  2. The plan • The fused five-membered heterocycles: - derivative of indole as anti-inflammatory agent(Indometacin). • - derivative ofbenzimidazoleasantispasmodic and antihypertensive agent (Bendazolhydrochloride). 2. The fused six-membered heterocycles: - derivatives ofquinoline(Nitroxolineas antibacterial agent, Chloroquine Phosphate as antimalarial agent). - derivative of acridineas antiseptic agent (Ethacridine lactate monohydrate). - derivative of benzothiadiazineas diuretic agent (Hydrochlorothiazide) - derivatives of phenothiazineas neuroleptic antipsychotic, sedative, antihistaminic agents. 3. The fused seven-membered heterocycles: - derivatives of benzodiazepine( Oxazepam as anxiolytic agent, Nitrazepamas hypnotic agent, Diazepamas sedative, anticonvulsant agent).

  3. Derivatives of indole as drugs Indole (benzopyrrole, benzoimidol)– is condensed system, which consist of benzene and pyrrole (pentatomic heterocycle with heteroatom of Nitrogen): For indole are characteristic aromatic properties, reactions electrophilic substitution on positions 2, 3 and 6, most reactive is position 3 with max electronic density. Because in the molecule of indole is “pyrrole“ atom of Nitrogen group–NH has weak acid properties. To derivatives of indole concern many natural and synthetic drugs.

  4. IndometacinGeneral Notices(Ph Eur monograph 0092)Indometacinum C19H16ClNO4357.8 • DEFINITION • Indometacin contains not less than 98.5 per cent and not more than the equivalent of 100.5 per cent of [1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid, calculated with reference to the dried substance.

  5. CHARACTERS • A white or yellow, crystalline powder, practically insoluble in water, sparingly soluble in alcohol. • IDENTIFICATION • First identificationA, C. • Second identificationA, B, D, E. • A. Melting point (2.2.14): 158 °C to 162 °C. • B. UV-spectroscopy. • C. IR-absorption spectrophotometry. • D and E – chemical methods.

  6. The test substance is practically insoluble in water, therefore the first can make mineralization(for example, melting with mix K2CO3and KNO3), after that can make all reactions for chloride-iones. - Reaction with si1ver nitrate in the nitric-acid medium; white curdled precipitate is formed: Cl– + Ag+  AgCl  AgCl + 2NH4OH = [Ag(NH3)2]Cl + 2H2O - Reaction with oxidizer(for example, К2Cr2O7) in the sulphatic-acid medium; toxic gas Cl2is alocated: 6KCl + K2Cr2O7 + 7H2SO4 = 3Cl2 + Cr2(SO4)3 + 4K2SO4 + 7H2O Cr2O72– + 14H+ + 6е  2Cr3+ + 7Н2О 2Cl– – 2е  Cl2 MnO2 + 4HCl = MnCl2 + Cl2 + 2H2O MnO2 + 4H+ + 2е  Mn2+ + 2H2O 2Cl– – 2е  Cl2

  7. E. (BrPh). Reaction with dimethylaminobenzaldehyde solution • To 0.5 ml of the solution in alcohol prepared in identification test D, add 0.5 ml of dimethylaminobenzaldehyde solution R2. A precipitate is formed that dissolves on shaking.Heat on a water-bath. A bluish-green colour is produced. Continue to heat for 5 min and cool in iced water for 2 min. A precipitate is formed and the colour changes to light greyish-green. Add 3 ml of alcohol R. The solution is clearand violet-pink in colour. D.(BrPh). Reaction of alcoholic solution of test substance with solution of hydroxylamine hydrochloride (hydroxamic reaction) violet-pink colour

  8. ASSAY • (BrPh). Alkalimetry, direct titration • Dissolve 0.300 g in 75 ml of acetone R, through which nitrogen R, free from carbon dioxide, has been passed for 15 min. Maintain a constant stream of nitrogen through the solution. Add 0.1 ml of phenolphthalein solution R. Titrate with 0.1 M sodium hydroxide. Carry out a blank titration. • 1 ml of 0.1 M sodium hydroxide is equivalent to 35.78 mg of C19H16ClNO4. Em = М. m.

  9. STORAGE • Store protected from light. • Action and use • Anti-inflammatory; analgesic. • Preparations • Indometacin Capsules • Indometacin Suppositories • Ph Eur

  10. Derivative of benzimidazole Bendazolihydrochloridum SP Х Dibazolum 2-benzylbenzimidazole hydrochloride or 2-(phenylmethyl)-1H-benzimidazole hydrochloride

  11. CHARACTERS A white or grayish-white or yellowish-white crystalline powder, hygroscopic, melting point 182–186 С; slightly soluble in water, acetone and chloroform, freely soluble in alcohol,practically insoluble in ether

  12. Identification 1. SP Х. Reaction with solution of iodine in the hydrochloric-acid medium (reaction for heterocyclic atoms of Nitrogen) Dissolve0,02 g in 5 ml of water, add 3 drops ofdilute hydrochloric acidHCl, 2–3 drops of0,05 М solution of iodine I2and shakes; reddish-silvery precipitate(dibazol periodide) is formed: At temperaturenot more then 25 С.

  13. 2. SP Х. Reaction for chloride-iones after precipitation of dibasol-base by means of solution of ammonia DibasolHCl + NH4OH Dibasol + NH4Cl + H2O base AgNO3 + NH4Cl = AgCl↓ + NH4NO3 white AgCl + 2NH4OH = [Ag(NH3)2]Cl + 2H2O [Ag(NH3)2]Cl + 2HNO3 → AgCl↓ + 2NH4NO3

  14. 3. Reaction with solution of alkali DibasolHCl + NаOH Dibasol + NаCl + H2O base Tests 1. Specific impurity -о-phenylendiamine.Reagent - iron(ІІІ) chloride FeCl3in the hydrochloric-acid medium; any pink colour not can be.

  15. ASSAY • SP Х. Acidimetry, non-aqueous titration • Dissolve0,15 g in10 ml of anhydrous acetic acid,add5 mlof mercury acetate solution and titrate with 0,1 М perchloric acid (as indicator – solution of crystalline violet). Ttitrate to occurrence bluish-green colour of solution. • Carry out a blank titration. • Em = М. m.

  16. 2. Alkalimetry in the presence of organic solvent (titration of bonded HCl). DibasolHCl + NаOH Dibasol + NаCl + H2O Em = М. м. 3. Argentometry, direct titration in the presence of acetone and solution of sodium acetate (Morh method) T – AgNO3; Ind – solution ofK2CrO4 (titrate to occurrence red-orange colour - Ag2CrO4). Acetone add for dibasol-base fixation, solution of sodium acetate add for nitric acid fixation. DibasolHCl + 2AgNO3Dibasol-Ag + AgCl + HNO3 2AgNO3 + K2CrO4 = Ag2CrO4 + 2KNO3 CH3COONa + HNO3 NaNO3 + CH3COOH Em = М.m. /2

  17. 4. Thiocyanatometry, substitute titration To alcoholic solution of test substanse add solution of concentrated AgNO3in the presence NH4OH; white precipitate of Ag-salt of dibasol is formed. Filtrate and precipitate dilute with HNO3. Equivalent quantity of AgNO3titrate with standard solution of NH4SCN (as indicator – iron ammonium sulphate FeNH4(SO4)2). Titrate to occurrence pink colour. AgNO3 + NH4SCN = AgSCN↓ + NH4NO3 3NH4SCN + FeNH4(SO4)2 = Fe(SCN)3 + 2(NH4)2SO4

  18. STORAGE Store protected from light. Action and use Antispasmodic and antihypertensive agent

  19. Derivatived of quinoline as drugs Quinoline – is condensed dicyclic compound, which consists of benzene and pyridinecycles(benzopyridine)

  20. Quinoline was discovered in1834 in coal. Quinolineis bactericidal, antiseptic and antipyretic agent, but quinoline is vetry toxic(nerve toxine!), therefore asdrug quinoline not use. The introduction different substituents to quinoline ring can lower its toxicity. Derivatives of quinoline have different pharmacological activity: 1. Antimalarial agents: derivatives of4-aminoquinoline, derivatives of 8-aminoquinoline. 2. Antiseptic and antibacterial agents: derivatives of8-hydroxyquinoline. 3. Anesthetic agent: derivative of 4-quinolincarboxylic acid.

  21. Derivatives of 8-hydroxyquinoline The non-substituted derivatives of 8-hydroxyquinoline (chinosolum), and substituted derivatives with haloid substituents on the5and7 positions of quinoline cycle (Chiniofonum, Enteroseptol) and substituted derivatives withnitro-group on 5 position of the ring(Nitroxolinum) have antibacterial, antiparasitic and antimicotic activity. Chemical properties Derivatives of 8-hydroxyquinolineis ampholytes.But their acid properties are strongest (influence of heteroatom of Nitrogen on mobility atom of Hydrogen from phenolic hydroxyl (–ОН) unlike phenols. Therefore 8-hydroxyquinoline is soluble in carbonates (this property is used at identification). The second property this derivatives – formation of chelate complexes with cations of metals.

  22. Chinosolum SP X 8-hydroxyquinoline sulphate

  23. CHARACTERS A yellow fine-crystalline powder, melting point 175–178С; freely in water, slightly soluble in alcohol,practically insoluble in ether and chloroform .

  24. IDENTIFICATION 1. SP Х. Reaction with iron(ІІІ) chloride(for phenolic hydroxyl) bluish-green colour

  25. 2. SP Х. Reaction with solution of sodium carbonate To1 ml of test solution add solution of Na2CO3; precipitate is formed, soluble in excess of reagent. 3. SP Х. Reaction for sulphate-iones: а) with solution ofВаCl2 in the medium of HCl: SO42– + Ва2+ ВаSO4 white

  26. ASSAY 1. SP Х. Alkalimetry in the presence of chloroform Disolve 0,5 g in50 ml of water, add 20 ml of chloroform (for extraction and dilution of 8-hydroxyquinoline) and titrate with0,1 М NaOH(as indicator – phenolphthalein). Titrate to occurrence pink colour. водного шару. Еm = М. m./2

  27. STORAGE Store protected from light. Action and use Antiseptic

  28. Derivatives of acridine Acridineis the condensed heterocyclic system, which consist of pyridine and two benzene cycles (or quinoline and benzene): In the medical practice as drugs are used such derivatives of acridine: quinacrine (antimalarial agent), aminoquinacrine (antimecotic agent), ethacridine lactate monohydrate (antiseptic agent).

  29. 2. ГФ Х. Реакция с раствором барий хлорида (наличие NaHCO3) К 10 мл раствора препарата (1:100) прибавляют 5 млраствора барий хлорида BaCl2; выпадает желтый осадок, растворимый в 2 млразбавленной хлоридной кислоты. В осадок выпадает белый осадок ВаСО3, цвет которого (желтый) обусловлен наличием в нем примеси 8-окси-7-йод-5-сульфохинолина. Ва2+ + СО32– ВаСО3 3. ГФ Х. Реакция с раствором феррум(ІІІ) хлорида (на фенольный гидроксил) К 10 мл того же раствора прибавляют 1 каплюраствора феррум(ІІІ) хлорида FeCl3; появляется зеленое окрашивание.

  30. Ethacridine lactate monohydrate General Notices (Ph Eur monograph 1591) Rivanolum Aethacridini lactas C18H21N3O4,H2O361.4 DEFINITION 7-Ethoxyacridine-3,9-diamine (2RS)-2-hydroxypropanoate. Content 99.0 per cent to 101.0 per cent (dried substance).

  31. CHARACTERS Appearance Yellow crystalline powder. Solubility Sparingly soluble in water, very slightly soluble in alcohol, practically insoluble in methylene chloride. IDENTIFICATION First identificationA. Second identificationB, C, D. A. Infrared absorption spectrophotometry(2.2.24). B.Mix 0.1 ml of solution S (see Tests) and 100 ml of water R. The solution is greenish-yellow and shows a strong green fluorescence in ultraviolet light at 365 nm. Add 5 ml of 1 M hydrochloric acid. The fluorescence remains. C.To 0.5 ml of solution S add 1.0 ml of water R, 0.1 ml of a 10 g/l solution of cobalt chloride R and 0.1 ml of a 50 g/l solution of potassium ferrocyanide R. The solution is green.

  32. D.Alkalizing of test solution with the subsequent revealing lactate-ions in the filtrate To 50 ml of solution S add 10 ml of dilute sodium hydroxide solution R. Filter. To 5 ml of the filtrate, add 1 ml of dilute sulphuric acid R. 5 ml of the solution obtained gives the reaction of lactates(2.3.1) (add some drops of 0,05 M solution KMnO4 and heat up; violet colouring of solution disappears). Alkali precipitates from ethacridine lactate solution a yellow precipitate of ethacridine-base: Ethacridine  lactate + NaOH =Ethacridine  + Na-lactate + Н2О yellow In filtrate lactate-ions reveales by means of solution KMnO4 in the sulphatic acid medium - decolouration of solution KMnO4 is observed : decolouration of solution

  33. Other reaction: 1. Reaction diazotization (for primary aromatic amino group) 5 ml of solution acidify diluted HCl and add 1 ml of sodium nitritesolution NaNO2; there is dark-red colouring (diazonium salt). dark red colour of diazonium salt 2. Reaction with solution of iodine To 5 ml of the same solution add 3 dropsof 0,05 M iodinesolution I2; the blue-green precipitate, soluble in 95 % alcohol, is formed. 2. Reaction with iodine solution blue-green precipitate

  34. ASSAY (BrPh). Acidimetry, non-aqueous titration (see phthivazid) Dissolve 0.270 g in 5.0 ml of anhydrous formic acid R. Add 60.0 ml of acetic anhydride R and titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20). 1 ml of 0.1 M perchloric acid is equivalent to 34.34 mg of C18H21N3O4.

  35. Other method: Iodochlorometry, back titration ICl + KI = I2 + KCl I2 + 2Na2S2O3 = 2NaI + Na2S4O6 Em(С15Н15N3OС3Н6O3) = М m./4

  36. STORAGE • Protected from light. • Action and use • Antiseptic. • Ph Eur

  37. Thanks for attention!

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