1. LECTURE 11- 12 Derivatives of pyrrolidine, pyrazolone and pyrazolidindione: its properties, analysis, storage, action and use. Derivatives of imidazole, imidazoline, triazole Associate prof. Mosula L.M.

2. The plan 1.Derivatives of pirolidine as drugs: piracetam (Nootropilum), polyvinylpyrrolidone. 2.Derivatives of pyrazolone-5 as drugs: phenazone (antipyrine), dipyrone (metamizole sodium), budirol (propiphenazonum). 3.Derivatives of pyrazolidine-3,5-dione as drugs: phenylbutazone, tribuzonum, kebuzone. 4.Derivatives of imidazole as drugs : thiamazole (mercazolil), metronidazole. 5.Derivatives of imidazoline as drugs: naphazoline nitrate 5.Derivatives of imidazoline as drugs: naphazoline nitrate, hylometazoline hydrochloride (halazolin), clonidine hydrochloride. 6. Derivatives of triazole as drugs: thiotriazolinum.

3.  A heterocycle or heterocyclic compound is an organic compound in which the carbon ring includes at least one atom in addition to carbon (S, O, N, etc.). Derivatives of pirolidine as drugs Pyrrole – not satureted pentatomic heterocycle with one heteroatom of Nitrogene: Pyrrolidine – satureted pentatomic heterocycle with one heteroatom of Nitrogene : Pyrrolidine – satureted pentatomic heterocycle with one heteroatom of Nitrogene : As drugs most often are used derivatives of 2-oxopyrrolidine (2- pyrrolidone) : Like drugs: piracetam, Like drugs: piracetam, polyvinylpyrrolidone and its combined preparations.

4.  Piracetam  General Notices  (Ph Eur monograph 1733)  Pyracetamum Nootropilum C6H10N2O2 142.2 DEFINITION 2-(2-Oxopyrrolidin-1-yl)acetamide. Content 98.0 per cent to 102.0 per cent (dried substance). CHARACTERS Appearance. White or almost white, powder. Solubility. Freely soluble in water, soluble in ethanol (96 per cent). It shows polymorphism.

5. IDENTIFICATION 1. (PhBr). Infrared absorption spectrophotometry. 2. (not pharmacopoeial reaction). Reaction with solution of alkaly at heating ; ammonia gas are formed, which identificated by waited red litmus paper – paper becames blue. TESTS Inadmisible impurities not present in the test substance. ASSAY 1. (BrPh). Liquid chromatography. 2. Modificated Keldal”s method. Test substance hydrolyzed by alkaly; Nitrogen deformed in the ammonia.

6. STORAGE Protected from light. Action and use Central nervous system stimulant. Ph Eur

7. Polyvinylpyrrolidone It is polymer of N-vinyl-2-oxopyrrolidine or N-vinyl- pyrrolidone. Synthesis from γ-butyrolactone

8. Action and use Detoxic agent, plasma substitute. It is a part of such preparations: 1.Haemodesum. 2. Neohaemodesum

9. Pyrazole (1,2-diazole) is pentatomic heterocycles with two heteroatoms of Nitrogene in the positions 1, 2: Pyrazoline is a partially hydrogenated cycle of pyrazole:

10. Completely hydrogenated cycle (saturated compound) of pyrazole names pyrazolidine: In the medical practice as antiseptic, anti-inflammatory and febrifuges agents are used derivatives of pirazolone-5 (pyrazyl ketone) (pyrazoline, containing in the position 5 ketogroup С=О): phenazone, metamizol sodium (analginum), propiphenazone.

11. To derivatives of pyrazolidine-3,5-dione concerns drugs: phenylbutazone, tribuzonum, kebuzon. Derivatives of pirazolone-5 (pyrazyl ketone) For phenylbutazone, dipyrone (metamizole sodium), propiphenazone is characteristic the general formula:

12. Phenazone General Notices (Ph Eur monograph 0421) Antipyrine Phenazonum Antipyrinum Analgesin Sedatin C 11 H 12 N 2 O 188.2 DEFINITION Phenazone contains not less than 99.0 per cent and not more than the equivalent of 100.5 per cent of 1,5-dimethyl-2-phenyl-1,2- dihydro-3H-pyrazol-3-one, calculated with reference to the dried substance.

13. Synthesis Synthesis of Phenazone (antipyrine) from phenylhydrazine and acetacetic ester* * Acetacetic ester are synthesed by means of Klyaizen reaction: condensation two molecules of ethylacetate СН3СООС2Н5 at heating in the presents of sodium ethylate С2Н5ОNa: Acetacetic ester

14. Synthesis of Phenazone consists of three stages. 1. Interaction Acetacetic ester with phenylhydrazine and formation phenylhydrazone acetacetic ester, and then 1- phenyl-3-methylpyrazolone-5:

15. 2. Methylation the received product by means of methyliodide CH3I or methyl ester of benzene sulphonic acid C 6 H 5 –SO 2 –O–CH 3 with formation of intermediate product – salts of quarternary base: 3. Formation of Phenazone at action of alkali NaOH on the received salt quarternary base:

16. CHARACTERS A white or almost white, crystalline powder or colourless crystals, very soluble in water, in alcohol and in methylene chloride.

17. IDENTIFICATION First identification A, B. Second identification A, C, D. A. Melting point (2.2.14): 109 °C to 113 °C. B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with phenazone CRS. Examine the substances prepared as discs using potassium bromide R. C. Reaction with sodium nitrite in the acid medium. To 1 ml of solution S (see Tests) add 4 ml of water R and 0.25 ml of dilute sulphuric acid R. Add 1 ml of sodium nitrite solution R. A green colour develops.

18. TESTS Inadmisible impurities not presents in the test substance ASSAY Iodometry, back titration. Dissolve 0.150 g in 20 ml of water R. Add 2 g of sodium acetate R and 25.0 ml of 0.05 M iodine. Allow to stand protected from light for 30 min. Add 25 ml of methylene chloride R and shake until the precipitate dissolves. Titrate with 0.1 M sodium thiosulphate, using 1 ml of starch solution R, added towards the end of the titration, as indicator. Carry out a blank titration. 1 ml of 0.05 M iodine is equivalent to 0,009411 g of C11H12N2O.

19. The formed precipitate of 4-iodoantipyrine (iodopyrine) can adsorb a quantity of iodine I2 on the surface, therefore for precipitate dissolution add methylene chloride (chloroform) (shake until the precipitate dissolves). Sodium acetate CH3COONa add for fixation formed iodide acid HI: HI + CH 3 COONa  NаI + CH 3 COOH; I 2 + 2Na 2 S 2 O 3  2NaI + Na 2 S 4 O 6. Е m = М. м./2 STORAGE Store protected from light (list of strong means!). Action and use Anaesthetic, antipyretic, resolvent. Release forms: a powder and tablets - 0,25 g.

20. Dipyrone General Notices ( Metamizole Sodium, Ph Eur monograph 1346) Metamizolum natricum Analginum Analgetin C 13 H 16 N 3 NaO 4 S,H 2 O 351.4 DEFINITION Metamizole sodium contains not less than 99.0 and not more than the equivalent of 100.5 per cent of sodium [(1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H-pyrazol-4-yl)-N- methylamino]methanesulphonate, calculated with reference to the dried substance. Synthesis Synthesis from 4-aminoantipyrine

21. Synthesis consists of 3 stages. 1. Interaction 4-aminoantipyrine with benzaldehyde С6Н5СНО with formation benzylidenaminoantipyrine: 2. Methylation benzylidenaminoantipyrine by means of dimethylsulphate (СН 3 ) 2 SO 4 with formation 4-methylaminoantipyrine:

22. 3. Interaction 4-methylaminoantipyrine with a mix of solutions of formaldehyde НСНО and sodium hydrogensulphyde NaHSO 3 (differently НО–СН 2 –SO 3 Na):

23. CHARACTERS A white or almost white, crystalline powder, very soluble in water, soluble in alcohol. IDENTIFICATION First identification A, D. Second identification B, C, D. A. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with metamizole sodium CRS. B. Oxidation of preparation by means of strong hydrogen peroxide solution Dissolve 50 mg in 1 ml of strong hydrogen peroxide solution R. A blue colour is produced which fades rapidly and turns to intense red in a few minutes.

24. Mechanism of oxidation Interaction of dipyrone with differents oxidaizers (chloramine, chlorinated lime, solution of iron(ІІІ) chloride, hydrogen peroxide and other) is bused on formation not stability colored tetraoxiderivative of pirazolone-5, which change the colour after same minutes, then dioxiderivative is formed:

25. C. Oxidation of preparation by means of potassium iodate with the next revealing of oxidation products (see mechanism of reaction B) Identification of oxidation products (SO 2 и HCHO): 5SO 2 + 2KIO 3  I 2 + 4SO 3 + K 2 SO 4

26. D. 0.5 ml of solution S (see Tests) gives reaction (a) of sodium (2.3.1):. Na + + [Sb(OH) 6 ] – → Na[Sb(OH) 6 ] ↓ white precipitate TESTS The inadmisible impurities are not presents in the test substance ASSAY Iodometry, direct titration Dissolve 0.200 g in 10 ml of 0.01 M hydrochloric acid previously cooled in iced water and titrate immediately, dropwise, with 0.05 M iodine. Before each addition of 0.05 M iodine dissolve the precipitate by swirling. At the end of the titration add 2 ml of starch solution R and titrate until the blue colour of the solution persists for at least 2 min. The temperature of the solution during the titration must not exceed 10 °C. 1 ml of 0.05 M iodine is equivalent to 16.67 mg of C13H16N3NaO4S.

27. Еm (C13H 16 N 3 NaO 4 S, H 2 O) = М m./2 STORAGE Store protected from light. Action and use Analgesic. Ph Eur

28. Propiphenazonum (latin name) (not pharmacopoeial drug) Budirol Causytin The chemical name: 1-phenyl-2,3-dimethyl-4-isopropyl- pyrazolone-5 (4-isopropylantipyrine). CHARACTERS Appearance. White or slightly yellowish crystal powder without a smell, bitter taste. Solubility. Slightly soluble in water, freely soluble in alcohol, methylenchloride, chloroform and ether.

29. Chemical properties Unlike antipyrine propiophenazonum shows the expressed reducing properties, because it is derivative partially hydrogenated pyrazoline and is presence alkyl radical at С4, interfering reactions, characteristic for antipyrine. Like analginum propiophenazonum is oxidised even slight oxidizers. Identification 1.IR-spectroscopy. 2. UV-spectroscopy.

30. 3. Reaction with solution of silver nitrate At action on solution of substance of solution silver nitrate AgNO3 there is a violet colour, and then precipitate of grayish-brown colour (precipitate of metal silver).

31. 4. Reaction with solution of iron (ІІІ) chloride At action on water-alcoholic solution of substance several drops of solution iron(ІІІ) chloride FeCl3 there is a red-brown colour, which is passed after addition chloride acid HCl to the yellow colour. 5. Reaction with generalalkaliodal reagents (on tertiary atom of Nitrogen) With generalalkaliodal reagents the preparation forms precipitates of complex salts.

32. Assay Acidimetry, non-aqueous titration Shot of substance dissolve in dioxane and titrate with standard solution of perchloric acid HClO4 in the presence of ice СН3СООН (indicator - crystal violet). Storage The list of strong substances. In densely corked container, in the place protected from light. Action and use Anaesthetic, antipyretic, resolvent. Is a part of the combined preparations.

33. Derivatives of pyrazolidine-3,5-dione Phenylbutazone General Notices Phenylbutazonum Butadion Butadionum Pyrazolidin C 19 H 20 N 2 O 2 308.4 DEFINITION 4-Butyl-1,2-diphenylpyrazolidine-3,5-dione. Content 99.0 per cent to 101.0 per cent (dried substance).

34. Synthesis Condensation of diethyl ester of butylmalonic acid with hydrazono-benzene: CHARACTERS Appearance White or almost white, crystalline powder. Solubility Practically insoluble in water, sparingly soluble in alcohol. It dissolves in alkaline solutions.

35. IDENTIFICATION First identification A, C. Second identification A, B, D. A. Melting point (2.2.14): 104 °C to 107 °C. B. Thin-layer chromatography (2.2.27). C. Infrared absorption spectrophotometry. D. Reaction of oxidation by sodium nitrite in the acetic medium Chemism. Reaction is based on splitting (decomposition) of butadiene molecule and oxidation of hydrazono-benzene С6Н5–NH–NH–C6H5 to painted azobenzene: С6Н5–N=N– C6H5 (A brownish-red to violet-red precipitate is formed):

36. TESTS The inadmisible impurities are not presents in the test substance ASSAY Alkalimetry, direct titration in the presence of acetone (acid properties of phenylbutazone) (indicator - bromothymol blue solution. Titrate until a blue colour is obtained). Em = М. м.

37. STORAGE Protected from light. Action and use Anti-inflammatory; analgesic. Ph Eur

38. Tribuzonum* The chemical name: 4 (4,4- dimethyl-3-oxopenthyl)- 1,2-diphenyl- pyrazolidindione-3,5  Kebuzone*  Ketophezon The chemical name: 1,2- diphenyl -4 (3 '- oxobutyl)- pyrazolidindione-3,5

39. Tribuzonum show anti-inflammatory, analgetic and febrifugal (antipyretic) action. The release form: tablets for 0,25 Kebuzone also show anti-inflammatory and analgetic action. The release forms: drage (0,25 g), ampoules (5 ml of 20 % of intravenously solution for injection).

40. Thanks for attention!