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LECTURE LECTURE № 1№ 155
Theme: Theme: Fused Fused five-, six- and seven-membered five-, six- and seven-membered heterocyclesheterocycles: properties, analysis, storage, : properties, analysis, storage,
action and use.action and use.
Associate profAssociate prof. . Mosula L.M.Mosula L.M.
The planThe plan1.1. The fused five-membered heterocycles:The fused five-membered heterocycles: - - derivative of indolederivative of indole as anti-inflammatory agent as anti-inflammatory agent ((IndometacinIndometacin).). - - derivative ofderivative of benzimidazolebenzimidazole asas antispasmodic and antispasmodic and
2. The fused six-membered heterocycles:2. The fused six-membered heterocycles: - - derivatives ofderivatives of quinolinequinoline ((NitroxolineNitroxoline as antibacterial agentas antibacterial agent, ,
Chloroquine Phosphate as antimalarial agent).). - - derivative of acridinederivative of acridine as antiseptic agent as antiseptic agent (Ethacridine lactate (Ethacridine lactate
monohydrate)monohydrate).. - - derivative of bderivative of benzothiadiazineenzothiadiazine as diuretic agent as diuretic agent
((Hydrochlorothiazide)Hydrochlorothiazide) - - derivatives of pderivatives of phenothiazinehenothiazine as as neurolepticneuroleptic antipsychotic antipsychotic, ,
3. 3. The fused seven-membered heterocycles:The fused seven-membered heterocycles: - - derivatives of bderivatives of benzodiazepineenzodiazepine ( Oxazepam( Oxazepam as a as anxiolytic nxiolytic
agent, agent, NitrazepamNitrazepam as as hypnotichypnotic agent, agent, DiazepamDiazepam as as sedativesedative, , anticonvulsantanticonvulsant agent). agent).
Derivatives of indole as drugsDerivatives of indole as drugs
IndoleIndole ( (benzopyrrole, benzoimidolbenzopyrrole, benzoimidol)) – – is condensed is condensed systemsystem, , which consist of which consist of benzene and pyrrolebenzene and pyrrole ( (pentatomic pentatomic heterocycle with heteroatom of Nitrogenheterocycle with heteroatom of Nitrogen):):
For indole are characteristic aromatic properties, For indole are characteristic aromatic properties, reactions electrophilic substitution on positions reactions electrophilic substitution on positions 2, 3 2, 3 andand 6, 6, most reactive is positionmost reactive is position 3 3 with max electronic densitywith max electronic density..
Because in the molecule of indole is Because in the molecule of indole is ““pyrrolepyrrole“ “ atom atom of Nitrogen groupof Nitrogen group–NH –NH has weak acid propertieshas weak acid properties..
To derivatives of indole concern many natural and To derivatives of indole concern many natural and synthetic drugs. synthetic drugs.
C19H16ClNO4C19H16ClNO4 357.8357.8 DEFINITIONDEFINITION Indometacin contains not Indometacin contains not
less than 98.5 per cent and less than 98.5 per cent and not more than the not more than the equivalent of 100.5 per equivalent of 100.5 per cent of cent of [1-(4-chlorobenzoyl)-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-5-methoxy-2-methylindol-3-yl]acetic acidyl]acetic acid, calculated , calculated with reference to the dried with reference to the dried
substance.substance.
N
C
1
2
3
4
5
6
7CH3
CH2COOHH3CO
O
Cl
CHARACTERSCHARACTERS A white or yellow, crystalline powder, practically insoluble in A white or yellow, crystalline powder, practically insoluble in
water, sparingly soluble in alcohol. water, sparingly soluble in alcohol.
IDENTIFICATIONIDENTIFICATION First identificationFirst identification A, CA, C. . Second identificationSecond identification A, B, D, EA, B, D, E. .
A. Melting point A. Melting point (2.2.14)(2.2.14): 158 °C to 162 °C. : 158 °C to 162 °C. B. UV-spectroscopy. C. IR-absorption spectrophotometry.
D and E – chemical methods.
The test substance is practically insoluble in water, therefore the first The test substance is practically insoluble in water, therefore the first can make can make mineralizationmineralization ((for examplefor example, , melting with mixmelting with mix K K22COCO33 andand
KNOKNO33), ), after that can make all reactions for chloride-ionesafter that can make all reactions for chloride-iones..
- Reaction with si- Reaction with si11ver nitrate in the nitric-acid mediumver nitrate in the nitric-acid medium; ; white curdled white curdled precipitate is formedprecipitate is formed::
E. (BrPh). Reaction with dimethylaminobenzaldehyde solutionE. (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 clear and violet-pink in colour.
D.D. ((BBrrPhPh)). . Reaction of alcoholic solution of test substance with solution of Reaction of alcoholic solution of test substance with solution of hydroxylamine hydrochloride (hydroxamic reaction)hydroxylamine hydrochloride (hydroxamic reaction)
N
C
CH3
CH2COOHH3CO
O
Cl
NH2OH . HCl
N CH3
CH2COOHH3CO
H
+ Cl C
O
N
OH
H
FeCl3 Cl C
O
N
O
H
Fe3
violet-pink colour
ASSAYASSAY (BrPh). Alkalimetry, direct titration(BrPh). Alkalimetry, direct titration Dissolve 0.300 g in 75 ml of Dissolve 0.300 g in 75 ml of acetone Racetone R, through which , through which nitrogen Rnitrogen R, free from carbon , free from carbon
dioxide, has been passed for 15 min. Maintain a constant stream of nitrogen through dioxide, has been passed for 15 min. Maintain a constant stream of nitrogen through the solution. Add 0.1 ml of the solution. Add 0.1 ml of phenolphthalein solution Rphenolphthalein solution R. . Titrate with Titrate with 0.1 M sodium 0.1 M sodium hydroxidehydroxide. Carry out a blank titration. . Carry out a blank titration.
1 ml of 1 ml of 0.1 M sodium hydroxide0.1 M sodium hydroxide is equivalent to 35.78 mg of C19H16ClNO4. is equivalent to 35.78 mg of C19H16ClNO4.
EEm = М. m = М. mm..
N
C
CH3
CH2COOHH3CO
O
Cl
+ NaOHN
C
CH3
CH2COONaH3CO
O
Cl
+ H2O
STORAGESTORAGE Store protected from light. Store protected from light.
Action and use Action and use Anti-inflammatory; analgesic. Anti-inflammatory; analgesic. PreparationsPreparations Indometacin Capsules Indometacin Capsules Indometacin Suppositories Indometacin Suppositories Ph EurPh Eur
Derivative of benzimidazole Bendazoli hydrochloridum
SP ХDibazolum
N
N
H
CH2. HCl
2-benzylbenzimidazole hydrochloride or 2-(phenylmethyl)-1H-benzimidazole hydrochloride
CHARACTERSCHARACTERS A white or grayish-white or yellowish-white crystalline powder, A white or grayish-white or yellowish-white crystalline powder, hygroscopic, melting point hygroscopic, melting point 182–186 С;
slightly soluble in water, acetone and chloroform, freely soluble in alcohol, practically insoluble in etherpractically insoluble in ether
Identification 1. SP Х. Reaction with solution of iodine in the hydrochloric-acid medium (reaction for heterocyclic atoms of Nitrogen)
Dissolve 0,02 g in 5 ml of water, add 3 drops of dilute
hydrochloric acid HCl, 2–3 drops of 0,05 М solution of iodine I2 and shakes; reddish-silvery precipitate (dibazol periodide) is formed:
N
N
H
CH2
2 + 3J2 + 2H+
N
N
H
CH2
. J2. HJ
2HCl
At temperature not more then 25 С.
2. SP Х. Reaction for chloride-iones after precipitation of dibasol-base by means of solution of ammonia
3. Reaction with solution of alkaliDibasolHCl + NаOH Dibasol + NаCl + H2O
base
Tests
1. Specific impurity - о-phenylendiamine. Reagent - iron(ІІІ) chloride FeCl3 in the hydrochloric-acid medium; any pink colour not can be.
ASSAY1. SP Х. Acidimetry, non-aqueous titration Dissolve 0,15 g in 10 ml of anhydrous acetic acid, add 5 ml of
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.
N
N
H
CH2. HCl
2 + 2HClO4 + Hg(CH3COO)2CH3COOH
N
N
H
CH2.
2H
+
_ClO4 + HgCl2 + 2CH3COOH
2. Alkalimetry in the presence of organic solvent (titration of bonded HCl).
DibasolHCl + 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 of K2CrO4 (titrate to occurrence red-orange colour - Ag2CrO4). Acetone add for dibasol-base fixation, solution of sodium acetate add for nitric acid fixation.
DibasolHCl + 2AgNO3 Dibasol-Ag + AgCl + HNO3
2AgNO3 + K2CrO4 = Ag2CrO4 + 2KNO3
CH3COONa + HNO3 NaNO3 + CH3COOH
Em = М.m. /2
4. Thiocyanatometry, substitute titrationTo alcoholic solution of test substanse add solution of
concentrated AgNO3 in the presence NH4OH; white precipitate of Ag-salt of dibasol is formed. Filtrate and precipitate dilute with HNO3. Equivalent quantity of AgNO3 titrate 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
AgNO3
NH4OHN
N
CH2
H
C6H5 N
N
CH2
Ag
C6H5
+ NH4NO3+ H2O
N
N
CH2
Ag
C6H5
HNO3
N
N
CH2
H
C6H5
AgNO3
STORAGESTORAGE
Store protected from light. Store protected from light.
Action and use Action and use
AAntispasmodic and antihypertensive agentntispasmodic and antihypertensive agent
Derivatived of quinoline as drugsDerivatived of quinoline as drugs
QuinolineQuinoline – – is condensed dicyclic compoundis condensed dicyclic compound, , which which consists of consists of benzenebenzene and and pyridinepyridine cyclescycles ((benzopyridinebenzopyridine))
N1
2
345
6
78
Quinoline Quinoline was discovered inwas discovered in 1834 1834 in coalin coal. . QuinolineQuinoline is is bactericidalbactericidal, , antiseptic and antipyretic agentantiseptic and antipyretic agent, , but quinoline but quinoline is vetry toxicis vetry toxic ((nerve toxinenerve toxine!)!), therefore asdrug quinoline , therefore asdrug quinoline not usenot use. . The introduction different substituents to quinoline The introduction different substituents to quinoline ring can lower its toxicityring can lower its toxicity..
Derivatives of quinoline have different Derivatives of quinoline have different pharmacological pharmacological activityactivity::
1. 1. Antimalarial agentsAntimalarial agents: : derivatives ofderivatives of 4-4-aminoquinolineaminoquinoline, , derivatives of derivatives of 8-8-aminoquinolineaminoquinoline. .
2. 2. Antiseptic and antibacterial agentsAntiseptic and antibacterial agents: : derivatives ofderivatives of 8-8-hydroxyquinolinehydroxyquinoline..
3. 3. Anesthetic agentAnesthetic agent: : derivative of derivative of 4-4-quinolincarboxylic quinolincarboxylic acidacid..
Derivatives of 8-hydroxyquinoline
The non-substituted derivatives of 8-hydroxyquinoline (chinosolum), and substituted derivatives with haloid substituents on the 5 and 7 positions of quinoline cycle (Chiniofonum, Enteroseptol) and
substituted derivatives with nitro-group on 5 position of the ring (Nitroxolinum) have antibacterial, antiparasitic and antimicotic activity.
Chemical properties
Derivatives of 8-hydroxyquinoline is 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.
Chinosolum SP X
N
OH
H2SO4
2
8-hydroxyquinoline sulphate
CHARACTERSCHARACTERS
A yellow fine-crystalline powder, melting point A yellow fine-crystalline powder, melting point 175–178 С;
freely in water, slightly soluble in alcohol, practically insoluble in ether and practically insoluble in ether and chloroform
.
IDENTIFICATION
1. SP Х. Reaction with iron(ІІІ) chloride (for phenolic hydroxyl)
N
OH
+ FeCl33
N
O
Fe3
+ 3HCl
bluish-green colour
2. SP Х. Reaction with solution of sodium carbonateTo 1 ml of test solution add solution of Na2CO3;
precipitate is formed, soluble in excess of reagent.
N
OH 2
H2SO4 + Na2CO3
N
OH
+ Na2SO4 + H2O + CO2
N
OH
+ Na2CO32
N
ONa
2 + H2O + CO2
3. SP Х. Reaction for sulphate-iones: а) with solution of ВаCl2 in the medium of HCl:
SO42– + Ва2+ ВаSO4 white
ASSAY
1. SP Х. Alkalimetry in the presence of chloroformDisolve 0,5 g in 50 ml of water, add 20 ml of
chloroform (for extraction and dilution of 8-hydroxyquinoline) and titrate with 0,1 М NaOH (as indicator – phenolphthalein). Titrate to occurrence pink colour.
N
OH 2
H2SO4 + 2NaOH
N
OH
+ Na2SO4 + 2H2O2
Еm = М. m./2
STORAGESTORAGE
Store protected from light. Store protected from light.
Action and use Action and use
AAntisepticntiseptic
Derivatives of acridine
Acridine is 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).
N
1
2
3
41056
78 9
2. ГФ Х. Реакция с раствором барий хлорида (наличие NaHCO3)
К 10 мл раствора препарата (1:100) прибавляют 5 мл раствора барий хлорида BaCl2; выпадает желтый осадок, растворимый в 2 мл разбавленной 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 каплю раствора феррум(ІІІ) хлорида FeCl3; появляется зеленое окрашивание.
99.0 per cent to 101.0 per cent (dried substance).
CHARACTERSAppearance Yellow crystalline powder. Solubility Sparingly soluble in water, very slightly soluble in alcohol, practically insoluble in methylene chloride.
IDENTIFICATION
First identification A. Second identification B, 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.
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: