Title: Alkaloids indol
1Lecture ?25
- Alkaloids indols derivatives, purine alkaloids
and their salts some synthetic analogues
according to the biological action as substances
of the medical drugs and components of the dosage
forms. - Ass. Medvid I. I.
2Indole - condensed system of pyrrole and
benzene cycles which have two share
atomsIndole is a structural basis of
physostigmine, strychnine, reserpine alkaloids.
3Group reaction on indole derivatives Van-Urks
reaction
4- In the base of reaction is the process of
electrophyllic substitution. Reagent
p-dimethylaminobenzaldehyde. Reaction conducts at
the presence of conc. H2SO4 and FeCl3 as oxidant. - Derivatives of indole which have free 2 and 3
positions give this reaction. Reserpine gives
this reaction by the opening of ring C in the
presence of acids, as a result position 2 becomes
free. - Product of reaction can exist in 2 forms. Color
of the reaction product depends on the chemical
structure of primer compounds conditions of the
reaction. Van-Urks reaction can be hold with
another aldehyde. So, for reserpine solution of
vanillin in chloride acid is used.
5Physostigmine salicylate (Physostigmini
salicylas)Eserini salicylas
- Salicylate of ester of methylcarbaminic acid and
eseroline or 5-methylcarbaminoiloxy-1,3,1-trimeth
yl-2,3,2,3-tetrahydropyrrole indole
6Physostigmine the main alkaloid of calabaric
beans (Faba calabarica) poisonous seeds of West
African plant Physostigma venenosus , Fabaceae
7- Physical properties
- Physostigmine salicylate - brilliant
colorless or almost colourless prismatic
crystals. Soluble in water, easily soluble in
alcohol, practically insoluble in ether. Aqueous
solutions are unstable. It melts at about 182 C,
with decomposition Optic active compound. When
heated with water easy hydrolyze and therefore
its solutions for parenteral usage produce in
aseptic introductions. On the air and light
product paints in the red color pharmacological
inactive rubrezerine formed. - Pharmacological action cased by the
methylurethane group. - Proserine - white crystalline powder with
bitter taste. Very easily soluble in water,
easily soluble in alcohol and chloroform, ether.
Hygroscopic. Becomes pink on the light.
8- Identification of Physostigmine salicylate
- Melting point, the specific rotation.
- Substance gives reaction to salicylates (2
reactions in SPU). - Total Pharmacopeial reaction on alkaloids (with
Dragendorff's reagent) - After evaporation of the preparation with
ammonium forms blue residue (physostigmine base),
which is dissolved in ethanol with formation of a
blue solution which after the acidification by
??3???? becomes red. - Drug solution in H2SO4 conc. gradually becomes
yellow. - Erdman and Frede reagents with medication give
reddish-yellow color, with HNO3 conc. yellow
color.
9- 7. When heated with alkalis (and gradually when
heated with water) physostigmine salycilate
hydrolyzed and appears character odor
methylamine - 8. At the heating with 0,1 ninhydrine solution
in conc. H2SO4 on the water bath at 60 0? during
10 min. And than after cooling solution have
green fluorescence. Proserine gives blue
fluorescence at this conditions. - 9. At the gradually adding to the solution boric
acid, 0,1 ? solution of nitrate acid and sodium
nitrite, after 1 min. add sodium hydroxide
solution, violet color appears.
10Assay Physostigmine salicylate
- Alkalimetriya, direct titration . The drug is
dissolved in a mixture of ethanol and chloroform
and titrated by 0,1 ? N??? to the pink color
(indicator phenolphthalein). ? ?.m. - Acidimetry in non-aqueous medium. The drug is
dissolved in a mixture of chloroform and conc.
CH3COOH, titrated by 0,1 ? ?Cl?4. For
determination of the end-point use potentiometry.
Equivalent point is fixed by potentiometric
method. ? ?.m./2. - Complexonometry, reverse titration. As a stable
titrant acetic-acidic solution of bismuth nitrate
is used in the presence of potassium iodide.
Scheme of reaction - Product of the interaction is filtrated
and an excess of reagent is titrated by 0,1 ?
sodium EDTA solution. ? ?.m.
11- STORAGE and USAGE of Physostigmine salicylate
-
- In an airtight containers of dark
glass, protected from light. Poison compound. -
- Cholinesterase inhibitor, myotic
mean (atropine antagonist). Used for the
treatment of glaucoma as 0,25-1 eye drops.
Introduce subcutaneous 0,1 -1,0 solution the
neuromuscular diseases (Alzheimer's disease). H.
d. 0,0005 g, H. d. d. 0,001 g.
12Synthetic substitute of physostigmine Proserine
(Proserinum) Neostigmine methylsulfate
- N-(m-dimethylcarbamoiloxiphenyl)-N,N,N-trimethylam
monium methylsulfate
13- Identification of proserine
- Reaction to methylsulfate-ion. If after heating
the drug with HNO3 conc. add solution of BaCl2,
white precipitate falls (BaSO4). - With a solution of iodine preparation forms brown
sediment of periodide. - At the heating of drug with alkali dissolution
of urethane group takes place (m-dimethylaminophen
ol formed, which is detected by the condensation
with diazotative sulfanylic acid cherry-red
color (azo-dyes))
14(No Transcript)
15- Assay
- The modified K'yeldal method. The drug is boiled
in a K'yeldal flask with NaOH. Dimethylamine,
which evaporates, distilled with water vapor in
the receiver with a solution of boric acid.
Metaborate and tetraborate of dimethylamine
formed, which are titrated by 0,1 ? solution of
HCl (mixed indicator). ? ?.m.
16- STORAGE and USAGE of proserine
- In an airtight containers of dark glass,
protected from light. Poison compound. - Substitute of physostigmine.
Anticholinesterase, antimyasthenic mean. Curare
antagonist drugs. Used for treatment of
myasthenia, paralysis, neuritis, atony of
intestine and urinary bladder, glaucoma, for
stimulating labor activity as 0,25-1 as eye
drops. - Issue tablets 0,015 g, amp. 0,05-1,0.
- H. d., internally 0,015 g, H. d. d.,
internally 0,05 g H. d. subcutaneous 0,002
g, H. d. d. s/c 0,006 g.
17Strychnine nitrate (Strychnini nitras)
- Cycles ??, BD, ED derivatives of indole.
- Cycle ? aromatic and strychnine can be
nitrated and halogenated. - N19 tertiary atom, has a base character and
gives salts with acids. - N9 is in the lactam group, which may be
disclosed by the interaction with alcohol
solution of KOH with formation of carboxyl and
secondary amino-groups.
18Strychnine can be found with brucine in the seeds
of tropical plant Strychnos Nux Vomica (emetic
nut)
19Reserpine (Reserpinum)
11,17-dimethoxy-16-carbmethoxy-18(3,4,5,-trimet
hoxibenzoyloxy)-alloyohimban
20- Reserpine molecule contains indole (??),
dihydroquinolysidine (?D), - partially hydrogenated 3-carbolynic (???),
hydrogenated isoquinoline (ED) cycles.
Alloyohiban
21Reserpine contains in the roots of the plant
Rauwolfia serpentina Benth
22- Physical properties
-
- Strychnine nitrate - a colorless brilliant
crystals with very bitter taste. Difficultly
soluble in water and alcohol, easily soluble in
boiling water, practically insoluble in ether. - Reserpine - colorless, white or slightly
yellow, small crystals or crystalline powder with
melting point 261-265?. Insoluble in water,
soluble in chloroform, acetone, pyridine and
ether, darkening slowly on the exposure to - light. Optic active compound. At the heating with
acids or alkalis hydrolysis takes place
(reserpinic acid, methanol, trimethoxybenzoic
acid form).
23- Identification of strychnine nitrate
- Pharmacopeial reaction on alkaloids.
- Solution of the drug in H2SO4 conc. crystal of
K2Cr2O7 formed the blue-violet strips which
pass into the red and lilac-green. - Vitali-Morens reaction. At the interaction with
HNO3 conc. drug becomes yellow (as opposed to
brucine, which becomes blood-red) by nitration of
benzene cycle ? after the evaporation of
reaction product the residue gives with alcohol
solution of ??? formed red-violet color. - Van-Urks reaction (on indole cycles). With 1
vanillin in glycerol in the presence of H2SO4
dil. Pink-violet color appears.
24- 5. Reaction on nitrate ions NO3-
- ?) SPU. The interaction with nitrobenzene in the
presence of sulfate acid - Quantity of substance, listed in a separate
article, add to the mixture of 0,1 ml of
nitrobenzol R and 0,2 ml of sulfate acid R and
after 5 min. cooled in ice water. Continuing to
cool slowly and while stirring add 5 ml of water
R, 5 ml of sodium hydroxide concentrated solution
R NaOH, 5 ml of acetone R, shake and put for
standing the apper layer becomes dark purple. - b) SPU, N. Not discolors potassium permanganate
- The solution of the substance,
acidified by acid sulfate diluted R H2SO4, not
discolors solution of 1 g/l potassium
permanganate R (difference of nitrite ). - ?) Not pharmacopeial reaction. Interaction with
iron (??) sulfate FeSO4 in the medium of conc.
H2SO4 brown ring is formed (FeSO4?NO) (on the
clock glass ) - 2 Strychnine?NO3 6FeSO4 4H2SO4 2NO
3Fe2(SO4)3 (Strychnine)2?2SO4 4H2O - NO Fe2 SO42 ? Fe(NO)SO4
25- d) Unpharmacopeial reaction. Interaction with
diphenylamine in acidic medium. (conc. H2SO4),
formed an bright blue organic dye -
- diphenylbenzidine
- Sulfimmonium salt of diphenylbenzidine (blue dye)
26- Identification of reserpine
- Specific optical rotation (6 assymetric carbon
atoms). - UV-spectroscopy (chromophor groups indole and
trimethoxybenzoatic acid 2 maximum of
absorption on UV-spectrum). - Reactions of indole cycle. With chloric water
purple, with KMnO4 dark lilac, with vanillin
in the presence of HCl - pink, with ?2?2
yellow-lilac color. - Water solutions of reserpine in UV-light blue
fluorescence. - Alcohol solution of the preparation H2SO4
NaNO2 green fluorescence.
27- With Frede reagent red color, which goes to the
blue. - On ester groups
- ?) alkali hydrolysis
- ?) hydroxame sample.
- Van-Urks reaction. With p- dimethylaminobenzaldeh
yde H2SO4 ??3???? green coloring that goes
into the red. With vanillin in chloride acid
pink color.
28Assay
- Strychnine nitrate Alkalimetry, direct
titration. Titration of the drug in
alcohol-chloroform solution of 0,1 ? NaOH
(phenolphthalein indicator). - ? ?.m.
- Specific additive - brucine.
- Reserpine Acidimetry in non-aqueous medium.
Hatch is titrated in the medium of anhydrous
??3???? by 0,1 ? solution HClO4 (indicator
crystal violet) to the appearance of green color.
? ?.m.
29Storage, usage
- Reserpine
- In airtight containers, in a dark place. Powder
- poisonous substance. - Neuroleptic , treatment of hypertension.
Included in tablets Adelphane (0.1 mg of
reserpine,10 mg of dihydralasine), Adelphan
esidrex (Triresid) (Adelfane 10 mg of
dichlorothiazide), Adelphane esidrex -?
(Triresid ?)(0,6 g of ??l), Crystepin,
Neocrystepin. Raunatinethe amount of Rauwolfia
alkaloids.
- Strychnine nitrate
- In airtight containers. Poison compound.
- CNS stimulant, tonic mean.
- Issue - amp. 0,1-1,0.
- H. d. s/c 0,002 g H. d. d. s/c 0,005 g.
30Alkaloids, purine derivatives Purine condensed
system of pyrimidine and imidazol
If in the core of purine hydrogen atoms in the
pyrimidine nucleus replaced by hydroxyl groups,
we will get xantine
31 Caffeine is contained in coffee beans (Coffea
arabica), tea leaves (Thea sinensis), cola (Cola
acuminata)
32- Pharmacology
- Caffeine stimulates the central nervous system
first at the higher levels, resulting in
increased alertness and wakefulness, faster and
clearer flow of thought, increased focus, and
better general body coordination, and later at
the spinal cord level at higher doses. Once
inside the body, it has a complex chemistry, and
acts through several mechanisms as described
below. - Metabolism and half-life
33- Theophylline first was isolated from tea leaves
(Thea sinensis)
- Theobromine is extracted from cocoa beans
(Theobroma cacao)
34Three natural alkaloids, derivatives xantine
caffeine, theophylline, theobromine
- Extracted from semi-synthetic uric acid, guanine
and urea.
35Very convenient is the method of extraction of
caffeine and theobromine from xantine, which can
be extracted from uric acid (waste poultry farms)
and guanine (fish flakes, waste of paper)
36Synthesis of caffeine and theophyllin by method
Hmelevskiy - Abramova( firs was synthesed by
Traube in1900 year).
37Caffeine Medications
- Caffeine (??ff??nu?) , Caffeine monohydrate
(??ff??nu? monohydricum) (SPhU) -
- 1,3,7-Trimethyl-3,7-dihydro- 1H-purine-2,6-dione
- 1,3,7-trimethylxantine
- Caffeine-sodium benzoate (Coffeinum-natrii
benzoas) -
38Physical properties
- Caffeine - White or almost white, crystalline
powder or silky crystals, sublimes readily.
Moderately soluble - in water, freely soluble in boiling water,
slightly soluble in ethanol and ether. Soluble in
the concentrated solutions of alkali benzoate or
salicylates. Very weak base, forms unstable salts
with acids by nitrogen in position 9.
- Caffeine-sodiume benzoate white powder,
odorless, bitter taste. - Easily soluble in water, slightly soluble in
ethanol. Contains 38-40 caffeine. - Extracted by the mixing and evaporation to the
dry state of aqueous solutions containing
equimolar quantity of caffeine and sodium
benzoate.
39General Pharmacopeial reaction - a reaction on
xantines (Murexide reaction or reaction on purine
alkaloids)
40Identification of caffeine
- By the physico-chemical constants melting point,
IR-spectroscopy. - With potassium iodide in iodine in the presence
of HCl dil.- brown precipitate formed(periodide
?8?10N4?2J2HJ), which dissolves in NaOH dil.
solution at the neutralization. - Murexide sample.
- Unpharmacopoeial reaction - with 1 solution of
tannin white precipitate dissolved in excess of
reagent. - With HgCl2 white crystalline sediment, which is
a complex compound with the following content
C5H10N4O2 HgCl2. - With acetylacetone and dimethylaminobenzaldehyde.
Solution of the substance in a mixture of
acetylacetone and dil. NaOH heated in a water
bath, cooled, than add solution of
dimethylaminobenzaldehyde and heat again, cool
and add water - appears an intense blue color
41Caffeine monohydrate gives all reactions on
caffeine after a preliminary drying at 100-105
C.
42Identification of caffeine-sodium benzoate
- 1. Caffeine identify by
- a) melting temperature (234-237 C) after
extraction by chloroform from alkaline solution - b) Murexide sample
- c) reaction with 1 solution of tannin
- d) reaction with iodine solution
- 2. Sodium benzoate identify by
- e) the reaction with solution of iron (III)
chloride - pink-yellow sediment - f) the sodium cation paints the flame in yellow
color.
43Assay
- Caffeine
- Acidimetry in non-aqueous medium in a mixture of
acetic acid anhydrous, acetic anhydride and
toluene, a direct titration. Potentiometric
indication, the control experiment (??.m). - Iodometry, reverse titration, indicator - starch
(??.m/4). - Cerimetry, reverce titration, with iodometric
ending. An excess of cerium is neutralized by
potassium iodide solution. Sodium thiosulfate
used as titrant. (??.m/4).
- Caffeine-sodium benzoate
- Caffeine content is determined by iodometric
method (??.m/4). ). In the dry matter it should
be 38,0 - 40,0 . - Sodium is determined in the presence of mixed
indicator (methyl orange solution and methylene
blue at a ratio of 11) and ether (for the
extraction of benzoic acid, available in the
titration) (??.m). Sodium benzoate in the dry
matter must be not less than 58,0 and not more
than 62,0 .
44(No Transcript)
45Cerimetric determination of caffeine
- 2 Ce(SO4)2 2 KI ? I2 K2SO4 Ce2(SO4)3
- I2 2 Na2S2O3 ? 2 NaI Na2S4O6
46Storage, Usage
- Caffeine-sodium benzoate
- In a dry, dark place.
- Central nervous system stimulant, cardiotonic
mean. Thanks to the solubility in water used in
the form of injection solutions. Issue - powder,
tablets 0,1 and 0,2 g, 0,075 g (for children)
10 ? 20 solutions in amp. by 1,0-2,0 ml.
Included in the tablets Anaprylline, Pentalgin.
- Caffeine
- In a dry, dark place.
- Central nervous system stimulant, cardiotonic
mean, at the angiospasms enuresis in children
stimulant of mental and physical disability,
poisoning with drugs. Produced as powder. - Caffeine monohydrate is part of the tablets
Theophedrine, Cytramone, Cytropak, Askofene,
Cofficyll, Cophetamine, Benalgin, Coldrex,
Solpadein, Panadol-??????. Apply in doses by
0,05-0,1 g as CNS stimulant.
47- Theobromine Theobrominum (SPhU)
-
- 3,7-Dimethyl-3,7- dihydro-1?-purine-2,6-dione, or
3,7- dimethylxantine
- Theophylline monohydrate Theophyllinum
monohydricum (SPhU) -
- 1,3-Dimethyl-3,7- dihydro-1?-purine-2,6-dione
monohydrate, or monohydrate of 1,3-
dimethylxantine -
48Properties
- Theobromine
- White crystalline powder, with bitter taste.
very slightly soluble in water, ethanol ,ether
and chloroform slightly soluble in hot water
easily in dil. Solutions of alkalis and acids.
- Theophylline
- White crystalline powder. Sightly soluble in
water, ethanol and chloroform easily soluble in
hot water soluble in dil. Solutions of acids and
alkalis.
Theobromine and theophylline - amphoteric
compounds with a predominance of acidic
properties (by moving the hydrogen atom at the
nitrogen atom in position 1 or 7).
49Identification of theobromine
- IR-spectrophotometry.
- Dissolve the substance in ammonium solution at
the heating. After cooling add silver nitrate
solution solution must still be colorless.
After the boiling during few minutes white
precipitate formed. - Reaction on xantines (murexide sample). At the
oxidation of theobromine 3-methylalloxane and
methylurea formed. Ammonium salt of
dimethylpuepuric acid formed as a result of
murexide reaction
50- Unpharmacopoeial reactions
- Reaction of the sodium salt of theobromine,
obtained by the interaction of alkali with an
excess of preparation, with cobalt (II)chloride
solution intense violet color appears, which
quickly disappears, grey-blue precipitate
51- The reaction of theobromine sodium salt with
silver nitrate - formed a dense gelatin mass
(silver salt), which is thinning by heating to
80 ? and solidifies again at the cooling. - With HgCl2 white crystalline precipitate.
52Identification of theophylline
- Determination of the melting temperature alter
the drying. - IR spectrophotometry.
- Theophylline in the alkali medium decomposes to
teophyllidine, which can be identified by the
reaction of azojoining with diazonium salts, red
color azo-dye formed.
53- Determination of the water by semimicromethod (?.
Fisher) (8-9,5 ). - Reaction on xantines (murexide sample). At the
oxidation of theophylline 1,3-dimethylalloxane
and urea. Ammonium salt of tetramethylpuepuric
acid forme as a result of murexide reaction
54- The reaction of theobromine sodium salt obtained
by the interaction of alkali with an excess of
drug, with a solution of cobalt (II) chloride -
formed white with pink tinge precipitate of
cobalt salt. - With HgCl2 white crystalline precipitate.
- With alkali solution of sodium nitroprusside
green color formed dissappears at the adding an
excess of acid.
55- The reaction of theobromine sodium salt with
silver nirate - formed a dense gelatin mass. - Theophylline with 2,6-dichloroqiunonechloroimide
in borate - buffer solution
- (?? 8,5) gives intense blue
- merocyanic dye
56AssayTheophylline and TheobromineAlkalimetry by
the substituent (indirect alkalimetry).Indicator
phenolphthalein (theobromine) or Bromothymol
blue (theophylline). ? ?.m.
57Storage, usage
- Theophylline
- In airtight containers, place protected
from light. - Non-selective phosphodiesterase inhibitor
(xanthine) treatment of reversible airways
obstruction. Broncholitic, cardiotonic and
diuretic mean with moderate influence on the
stagnation phenomena in the cardiac and renal
origin organs. Issue powder and tablets by 0,1
and 0,3 g amp. 2-5,0 candles by 0,2 g. Teopek,
Theotard, Neophylline, Euphylline. Included in
tablets Theoephedrine.
- Theobromine
- In airtight containers, place protected from
light. - Stimulates the activity of the heart, somewhat
expands the coronary vessels and bronchi, shows
diuretic effect. Issue - powder and tablets by
0,25 g. - Included in tablets Theminal (with amidopyrine
and Phenobarbital), Theodibaverine (with
papaverine and dibazole), Theoephedrine.
58Pentoxifylline (Pentoxifyllinium)Agapurine,
Pentyline, Trental A synthetic analogue of
theobromine
- 3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-7?-purine
-2,6-dion or 1-(5-oxohexyl)-theobromine
59Identification of pentoxifylline
- Temperature of melting
- IR-spectroscopy
- TLC
- Reaction on xantines
- Formation of azo-dye (look theophylline)
- Assay
- pentoxifylline
- Acidimetry in non-aqueous media in a mixture of
anhydrous acetic acid and acetic anhydride,
direct titration. Potentiometric indication.
(??.m).
60Usage of pentoxifylline
- Has a vasodilator effect, improves tissue oxygen
supply, decreases thrombosis aggregation and
reduces blood viscosity. Apply at the peripheral
circulatory disorders, atherosclerotic disorders,
ischemic condition after heart attack, in
ophthalmology, at the hearing disorders. Issue
tablets of 0,1 g, ampoules of 2-5,0. Adopt
inside by 0,2 g 3 times daily after meals. In
the acute disorders of peripheral or cerebral
circulation injected 0,1 g intravenous in 250-500
ml of NaCl or 5 glucose solution.
61Synthetic analogues of theophylline
- Theophylline-ethylenediamine (Theophyllinum et
ethylenediaminum) (SPhU), - Euphylline (Euphyllinum), Aminophilline
-
Theophylline
with 1,2-ethylenediamine White, sometimes with
yellowish crystalline powder with slight ammonia
odor. On the air absorbs carbon dioxide, thus
decreasing its solubility. Soluble in water,
aqueous solutions have an alkaline reaction.
62Identification of euphylline
- 1. Theophylline is identified after the
separation by HCl of ethylenediamine according
to SPhU - ?) By the melting temperature of theophylline
(269 - 274?) after HCl acidification to ?? 4-5 - b) IR-spectroscopy
- c) Reaction of azojoining (look theophylline)
- d) murexide sample.
63- 2. Ethylenediamine can be confirmed by the
following reactions - ?) determination of the melting temperature of
the product of reaction with benzoyl in alkali
medium (dibenzoylethylenediamine) (SPhU) - b) with a solution of copper (II) sulfate a
bright purple color forms - c) with 2,4-dinitrochlorobenzene yellow
precipitate falls.
64AssayEuphylline
- Ethylenediamine can be determined by acidimetry,
indicator methyl orange. ? ?.m./2. - Ethylenediamine in euphylline should be 13,515
in the dry matter. - 2. Theophylline can be determined by
alkalimetry by substituent 1 after drying in a
drying cabinet at 25-130 ? to the disappearance
of amine odor. - The content of waterless theophylline in
euphylline should be 84- 87,4 .
65Storage, usage of euphylline
- Given the ability to absorb carbon dioxide,
stored in a well corked filled to the end
container, protected from the effects of light
and moisture. - Antispasmodic, bronchodilatin, diuretic mean. At
the bronchial asthma and bronchospasm,
hypertension, cardiac asthma, to improve blood
circulation to the brain, decreasing the
intraperitoneal pressure and brain edema in
ischemic stroke. - Used oral by 0,15g after food, i/v (2,4
solutions by 5,0) and i/m (24 solution by 1
ml). -
66Diprophylline (Diprophyllinum)
- 7-(2',3'-Dioxipropyl)-theophylline
- Less toxic than theophylline. Used for treatment
of coronary spasm, cardiac and bronchial asthma,
hypertension. Issue tablets by 0,2 g amp.
10-5,0 candles by 0,5 g.
67Xantinole nicotinate (Xantinoli nicotinas)
Complamine, Theonicol
- Used to improve peripheral and cerebral
circulation - Issue tablets by 0,15 g amp. 15-2,0 ?
10,0.
- 7-2-oxi-3-(N'-methyl-ß-oxiethylamino)-propyl-t
heophylline nicotinate
68Thank you for attention!