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

antihypertensive agent antihypertensive agent ((Bendazol hydrochloride).

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, ,

ssedativeedative, , antihistaminicantihistaminic agents. agents.

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.

N

H

1

2

3

4

5

6

7

IndometacinIndometacinGeneral NoticesGeneral Notices

(Ph Eur monograph 0092)(Ph Eur monograph 0092)

IndometacinumIndometacinum

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::

Cl– + Ag+ Cl– + Ag+ AgCl AgCl AgCl + 2NHAgCl + 2NH44OH = [Ag(NHOH = [Ag(NH33))22]Cl + 2H]Cl + 2H22OO

- Reaction with oxidizer- Reaction with oxidizer ((for example,for example, К К22CrCr22OO77)) in the sulphatic-acid in the sulphatic-acid

mediummedium; ; toxic gastoxic gas Cl Cl22 is alocatedis alocated::

6KCl + K6KCl + K22CrCr22OO77 + 7H + 7H22SOSO44 = 3Cl = 3Cl22 + Cr + Cr22(SO(SO44))33 + 4K + 4K22SOSO44 + 7H + 7H22OO

CrCr22OO772–2– + 14H + 14H++ + 6е + 6е 2Cr 2Cr3+3+ + 7Н + 7Н22ОО

2Cl2Cl–– – 2е – 2е Cl Cl22

MnOMnO22 + 4HCl = MnCl + 4HCl = MnCl22 + Cl + Cl22 + 2H + 2H22OO

MnOMnO22 + 4H + 4H++ + 2е + 2е Mn Mn2+2+ + 2H + 2H22OO

2Cl2Cl–– – 2е – 2е Cl Cl22

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

DibasolHCl + NH4OH Dibasol + NH4Cl + H2O base

AgNO3 + NH4Cl = AgCl↓ + NH4NO3

white

AgCl + 2NH4OH = [Ag(NH3)2]Cl + 2H2O[Ag(NH3)2]Cl + 2HNO3 → AgCl↓ + 2NH4NO3

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.

N

OH

+ FeCl33

N

O

Fe

+ 3HCl

I

SO3H SO3H

I

3

Ethacridine lactate monohydrateGeneral Notices (Ph Eur monograph 1591 )

Rivanolum Aethacridini lactas

C18H21N3O4,H2O  361.4   DEFINITION

7-Ethoxyacridine-3,9-diamine (2RS)-2-hydroxypropanoate.

Content

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:

Ethacridine lactate + NaOH = Ethacridine + Na-lactate + Н2О

yellowIn filtrate lactate-ions reveales by means of solution KMnO4 in the sulphatic

acid medium - decolouration of solution KMnO4 is observed :H3C

HC

OH

C

O

ONa

H3CHC

OH

C

O

OH

H3C C

O

H

H3CHC

OH

C

O

OH

2 + H2SO4 2 + Na2SO4

5 + 2KMnO4 + H2SO4 = 5 + 5CO2 + 2MnSO4 + K2SO4 + 8H2O

decolouration of solution

Other reaction: 1. Reaction diazotization (for primary aromatic amino group)

5 ml of solution acidify diluted HCl and add 1 ml of sodium nitrite solution NaNO2; there is dark-red colouring (diazonium

salt).

H2N N

NH2

OC2H5

NaNO2,HCl

N N

NH2

OC2H5

N+

Cl-

dark red colour of diazonium salt

2. Reaction with iodine solution

H2N N

NH2

OC2H5

H3CHC

OH

C

O

OH

.

H

H

+ 2I2

H2N N

NH2

OC2H5

H3CHC

OH

C

O

OH

.

I

I

+ 2HI

2. Reaction with solution of iodineTo 5 ml of the same solution add 3 drops of 0,05 M iodine

solution I2; the blue-green precipitate, soluble in 95 % alcohol, is

formed.

blue-green precipitate

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.

Other method: Iodochlorometry, back titration

H2N N

NH2

OC2H5

H3CHC

OH

C

O

OH

.

H

H

+ 2ICl

H2N N

NH2

OC2H5

H3CHC

OH

C

O

OH

I

I

+

+ 2HCl

ICl + KI = I2 + KCl

I2 + 2Na2S2O3 = 2NaI + Na2S4O6

Em (С15Н15N3OС3Н6O3) = М m./4

STORAGESTORAGE

Protected from light. Protected from light.

Action and use Action and use

Antiseptic.Antiseptic.

Ph EurPh Eur

Thanks for attention!