Lecture № 13
Condensed azines.
Quinoline. Isoquinoline.
Acridine. Diazines. Purine.
Ass. Medvid I.I.,
ass. Burmas N.I.
Outline
1. Receipt of quinoline and his derivatives. Synthesis of Skraupa and synthesis
of Debner—Miller. Physical and chemical properties of quinoline.
2. Receipt of isoquinoline. Synthesis of Bischler-Napieralski. Physical and
chemical properties of isoquinoline.
3. Structure, nomenclature, methods of getting and physical and chemical
properties of acridine.
4. Methods of getting of sixmember heterocyclic connections with two
heteroatoms
5. Structure, classification, nomenclature, physical and chemical properties of
pyridazine.
6. Structure, nomenclature, physical and chemical properties of pyrimidine.
7. Structure, nomenclature, physical and chemical properties of barbituric acid
8. Structure, nomenclature, physical and chemical properties of pyrazine.
9. Structure, nomenclature, physical and chemical properties of purine.
10. Structure, nomenclature, physical and chemical properties of uric acid.
11. Structure, nomenclature and properties of azepines.
Benzazepine.
12. Structure, nomenclature and properties of diazepine.
Benzodiazepine.
13. Oxazepam. Radedrol (nitrazepam). Seduxen (diazepam).
14.Classification of alkaloids.
15. Alkaloids group of pyridine and piperine (nicotine,
anabasine, lobeline).
16. Alkaloids group of quinoline (quinine).
17. Alkaloids of group of quinoline and
phenanthreneisoquinoline (papaverine, morphine, codeine).
18. Alkaloids group of purine (caffeine, theobromine,
theophylline).
19. Alkaloids group of tropane (atropine, scopolamine,
cocaine).
20. Alkaloids group of indole (reserpine, strychnine).
1. Obtaining of quinoline and his derivatives. Synthesis of
Skraup and synthesis of Debner—Miller. Physical and
chemical properties of quinoline.
The impotent condensed of sixmembered heterocycles
connections are with one heteroatom is:
quinoline
isoquinoline
acridine
Quinoline, also known as 1-azanaphthalene, 1-benzazine, or
benzo[b]pyridine, is a heterocyclic aromatic organic compound. It
has the formula C9H7N and is a colourless hygroscopic liquid with a
strong odour. Aged samples, if exposed to light, become yellow and
later brown.
Quinoline is only slightly soluble in cold water but dissolves
readily in hot water and most organic solvents. Quinoline is
mainly used as a building block to other specialty chemicals.
Approximately 4 tonnes are produced annually according to a
report published in 2005. Its principal use is as a precursor to
8-hydroxyquinoline, which is a versatile chelating agent and
precursor to pesticides. Its 2- and 4-methyl derivatives are
precursors to cyanine dyes. Oxidation of quinonline affords
quinolinic acid (pyridine-2,3-dicarboxylic acid), a precursor to
the herbicide sold under the name "Assert".
The Skraup synthesis is a chemical reaction used to synthesize
quinolines. It is named after the Czech chemist Zdenko Hans
Skraup (1850-1910). In the archetypal Skraup, aniline is heated
with sulphuric acid, glycerol, and an oxidizing agent, like
nitrobenzene to yield quinoline. The Skraup synthesis place is
taken in three stages.
On the first stage glycerin is under the action of
сoncentrated H2S04 to dehydration with formation of
akrolein:
On the second stage appearing akrolein enters into the reaction of
condensation with an aniline:
-H2O
On the third stage of reaction of 1,2dihydroquinoline oxidizes nitrobenzol in to
quinoline:
Synthesis of Debner —Miller.
The reaction is opened in 1881. On the first stage there is krothonic
condensation of two molecules of aldehyde .
Further there is cooperation of krothonic aldehyde with aniline.
2-methyl-1,2-dihydroquinoline
2-methyl-quinoline
Chemical properties:
1. Reactions of heteroatom.
quinoline chloride
N-methylquinoline iodide
N-acethylquinoline chloride
2. Reactions of electrophilic and nukleophilic substitutions .
Reactions of electrophilic substitution in the molecula of
quinoline is entered in position of 5 and 8.
6- quinoline sulphatic acid
Reactions of nukleophilic substitution (is entered in position of 2) .
2- aminoquinoline
2- hydroxyquinoline
3. Reactions of reduction and oxidization.
quinolinic acid
Derivatives of quinoline
8-Hydroxyquinoline is an organic compound with the
formula C9H7NO. It is a derivative of the heterocycle
quinoline by placement of an OH group on carbon
number 8. This colorless compound is widely used
commercially, although under a variety of names. It is
usually prepared from quinoline-8-sulfonic acid and
from the Skraup synthesis from 2-aminophenol.
NaOH
-Na2SO3
8-Hydroxyquinoline is a monoprotic bidentate
chelating agent. Related ligands are the Schiff bases
derived from salicylaldehyde, such as salicylaldoxime
and salen. The roots of the invasive plant Centaurea
diffusa release 8-hydroxyquinoline, which has a
negative effect on plants that have not co-evolved
with it. The complexes as well as the heterocycle
itself exhibit antiseptic, disinfectant, and pesticide
properties. Its solution in alcohol are used as liquid
bandages. It once was of interest as an anti-cancer
drug.
O
[H]
CH 2=CH-C
NO 2
OH
NH 2
OH
OH
H2SO4
2-
+
OH
SO4
N
N
OH
H
quinozol
2
H
2. Receipt of isoquinoline. Synthesis of Bischler-Napieralski.
Physical and chemical properties of isoquinoline.
Isoquinoline, also known as
benzo[c]pyridine or 2-benzanine, is a
heterocyclic aromatic organic compound. It
is a structural isomer of quinoline.
Isoquinoline and quinoline are benzopyridines, which are
composed of a benzene ring fused to a pyridine ring. In a
broader sense, the term isoquinoline is used to make reference to
isoquinoline derivatives. 1-Benzylisoquinoline is the structural
backbone in naturally occurring alkaloids including papaverine
and morphine. The isoquinoline ring in these natural compound
derives from the aromatic amino acid tyrosine. Isoquinoline is a
colourless hygroscopic liquid at room temperature with a
penetrating, unpleasant odour. Impure samples can appear
brownish, as is typical for nitrogen heterocycles. It crystallizes
platelets that have a low solubility in water but dissolve well in
ethanol, acetone, diethyl ether, carbon disulfide, and other
common organic solvents. It is also soluble in dilute acids as the
protonated derivative.
 In the Bischler-Napieralski reaction an β-phenylethylamine is acylated
and cyclodehydrated by a Lewis acid, such as phosphoryl chloride or
phosphorus pentoxide. The resulting 1-substituted-3,4-dihydroisoquinoline
can then be dehydrogenated using palladium. The following BischlerNapieralski reaction produces papaverine.
1-substituted-3,4dihydroisoquinoline
1-substituted isoquinoline
Chemical properties:
1. Reactions of electrophilic and nukleophilic substitutions .
Reactions of electrophilic substitution in the molecula of isoquinoline is
entered in position of 5 and 8. Reactions of nukleophilic substitutions tare
place in position of 1.
isoquinoline of chloride
N-methylisoquinoline of iodide
2. Reaction of reduction
1,2,3,4tetrahydroisoquinoline
3. Reaction of oxidization
3,4- pyridinedicarbonic acid
3. Structure, nomenclature, methods of getting and physical
and chemical properties of acridine.
Acridine was first isolated in 1871
by Carl Gräbe and Heinrich Caro.
Acridine occurs naturally in coal tar. It
is separated from coal tar by extracting
with dilute sulfuric acid; addition of potassium dichromate to this
solution precipitates acridine bichromate. The bichromate is
decomposed using ammonia. Many synthetic processes are known
for the production of acridine and its derivatives. A. Bernthsen
condensed diphenylamine with carboxylic acids, in the presence of
zinc chloride in the Bernthsen acridine synthesis. With formic acid
as the carboxylic acid the reaction yields acridine it self, and with
the higher homologues the derivatives substituted at the meso
carbon atom are generated. Other older methods for the organic
synthesis of acridines include condensing diphenylamine with
chloroform in the presence of aluminium chloride, by passing the
vapours of orthoaminodiphenylmethane over heated litharge, by
heating salicylic aldehyde with aniline and zinc chloride to 260 °C
or by distilling acridone (9-position a carbonyl group) over zinc
dust.
A general method for acridine synthesis is the
cyclisation of N-phenylanthranilic acid or 2(phenylamino)benzoic acid with phosphoric acid. A
classic method for the synthesis of acridones is the
Lehmstedt-Tanasescu reaction.
Acridine and its homologues are stable
compounds of weakly basic character.It also shares
properties with quinoline which is the single fused
homologue. Acridine crystallizes in needles which
melt at 110 °C. It is characterized by its irritating
action on the skin, and by the blue fluorescence
shown by solutions of its salts.
Methods of getting:
1. Condensation of diphenylamine with carbonic
acids :
diphenylamine
acridine
2. Cyclization N-fenilanthranilic acid on the reaction of
Drozdov—Mahidson—Hrihorovsky:
N-fenilanthranilic acid
anhidride chloride
N-fenilanthranilic
acid
acridone-9
acridole-9
9,10-dihydroacridine
9-chloracridine
acridine
Chemical properties:
Acridine combines readily with alkyliodides to form alkyl
acridinium iodides, which are readily transformed by the action of
alkaline potassium ferricyanide to N-alkyl acridones. On oxidation
with potassium permanganate it yields acridinic acid
C9H5N(COOH)2 or quinoline-1,2-dicarboxylic acid. Acridine is
easily oxidized by peroxymonosulfuric acid to the acridine amine
oxide. The carbon 9-position of acridine is activated for addition
reactions. The compound is reduced to the 9,10-dehydroacridine
and reaction with potassium cyanide gives the 9-cyano-9,10dehydro derivative. Numerous derivatives of acridine are known
and may be prepared by methods analogous to those used for the
formation of the parent base. 9-Phenylacridine is the parent base of
chrysaniline or 3,6-diamino-9-phenylacridine, which is the chief
constituent of the dyestuff phosphine (not to be confused with
phosphine gas), a by-product in the manufacture of rosaniline.
Chrysaniline forms red-coloured salts, which dye silk and wool a
fine yellow; and the solutions of the salts are characterized by their
fine yellowish-green fluorescence. Chrysaniline was synthesized
by O. Fischer and G. Koerner by condensing orthonitrobenzaldehyde with aniline, the resulting ortho-nitro-paradiamino-triphenylmethane being reduced to the corresponding
orthoamino compound, which on oxidation yields chrysaniline.
1.
Reactions of heteroatom.
acridinium chloride
N-oxide of acridine
N-methylacridine iodide
2. Reactions of electrophilic and nukleophilic substitutions .
9-hydroxacridine,
acridole-9
9- oxoacridine,
acridone-9
3. Reactions of oxidization.
acridinic acid
4. Reactions of reduction.
9,10-dehydroacridine,
acridane
Derivatives of acridine
9- Aminoacridine is an antiseptic and disinfectant.
Acidylating flows on aminogroup:
9-N-acethylaminoacridine
9-aminoacridine chloride
arcihine
rivanol
medicinal preparations
COOH
O2N
Cl
OC2H5
COOH
H2N
O2N
NH
O
OH
O2N
OC2H5
POCl3
OC2H5
C
POCl3
-HCl
NH
NH2
OC2H5
N
N
O2N
Cl
O2N
OC2H5
OC2H5
NH3
-HCl
[H]
O2N
N
9-amino-2-ethoxy-6-nitroacridine
NH2
OC2H5
COOH
+
HC OH
N
H2N
CH3
NH2
OC2H5
H2N
N
.
COOH
HC OH
CH3
ethacridine lactate,
rivanol,
6,9 – diamimo-2-ethoxyacridine lactate
Sixmembered heterocycles connections are with two
heteroatoms
In addition to these three diazines, the
bicyclic tetraaza compound, purine,
is an important heterocyclic system.
These ring systems, particularly that of pyrimidine, occur commonly
in natural products. The pyrimidines, cytosine, thymine, and uracil
are especially important because they are components of nucleic
acids, as are the purine derivatives adenine and guanine.
The рininе nucleus also occurs in such
compounds as caffeine (coffee and tea) and
theobromine (cacao beans).
4. Methods of getting of sixmember heterocyclic connections with two
heteroatoms
CH
HC
C
H
C
H
NH 2 NH 2
O
O
N
- H 2O
N
maleinaldehide
pyridazine
O
O
H
C
CH
OC H
2
H N
5
+
2
C
OC H
2
C H ONa
2
5
2
C
Malene ephir
H
N
N
C
H
O
-C 2H 5O H
H N
O
N
2
HO
O
H
uric
O
5
барбітурова
barbituric acid
Cl
POCl 3
N
6H (Zn)
N
Cl
N
N
Cl
OH
pyrimidine
N
OH
These method use for obtaining pyridazine and his derivatives
NH2
CH2
H
O
C
to
C
- 2 H2O
+
CH2
O
NH2
H
NH2
NH2
N
N
- H2O
N
2,3- dihydropyrazine
pyrazine
O
+
N
O
hlioxal
ethylendiamine
N
N
C H
HO
N
N
- 2 H2O
N
N
H
purine
5. Structure, classification, nomenclature, physical
and chemical properties of pyridazine.
Pyridazine is a heteroaromatic organic compound
with the molecular formulaC4H4N2, sometimes
called 1,2-diazine. It contains a six-membered
ring with two adjacent nitrogen atoms. It is a
colorless liquid with a boiling point of 208 °C.
Pyridazine has no household use. It is mainly
used in research and industry as building block
for more complex compounds. The pyridazine
structure is found within a number of herbicides
such as credazine, pyridafol and pyridate. It is
also found within the structure of several
pharmaceutical drugs such as cefozopran,
cadralazine, minaprine, hydralazine, and
cilazapril.
Pyridazine
Other names
1,2-diazine, orthodiazine,
oizine
Properties
Molecular formula
C4H4N2
Molar mass
80.09 g mol−1
Appearance
colorless liquid
Density
1.107 g/cm3
Melting point
-8°C
Boiling point
208°C
+
N
N
I-
HCl (í àäë.)
CH3I
CH3
N-methulpyridazine iodide
N
+
N
N
CH3COOOH
+
N _
N O
N
ClH
Pyridazine chloride
N-oxide pyridazine
thethramethyleldiamine
Derivatives of pyridazine
6. Structure, nomenclature, physical and chemical
properties of pyrimidine.
Three nucleobases found in nucleic acids (cytosine,
thymine, and uracil) are pyrimidine derivatives: In DNA
and RNA, these bases form hydrogen bonds with their
complementary purines. Thus the purines adenine (A)
and guanine (G) pair up with the pyrimidines thymine (T)
and cytosine (C), respectively.
Pyrimidine
Properties
Molecular formula
C4H4N2
Molar mass
80.088
Melting point
20–22 °C
Boiling point
123–124 °C
Chemical properties
A pyrimidine has many properties in common with
pyridine, as the number of nitrogen atoms in the ring
increases the ring pi electrons become less energetic and
electrophilic aromatic substitution gets more difficult while
nucleophilic aromatic substitution gets easier. An example
of the last reaction type is the displacement of the amino
group in 2-aminopyrimidine by chlorine and its reverse.
Reduction in resonance stabilization of pyrimidines may
lead to addition and ring cleavage reactions rather than
substitutions. One such manifestation is observed in the
Dimroth rearrangement. Compared to pyridine, N-alkylation
and N-oxidation is more difficult, and pyrimidines are also
less basic.
+
N
N
HCl
H
_
ê. HNO3
N
Cl
N
NH2
NH2
N
HO
pyrimidine chloride
N
ê. H2SO4
N
HO
N
N
4-amino-2-hydroxypyridine
Br2
N
N
NH2
Br
N NaNH2
N
N
NH2
N
NO2
2- aminopyridine
N
N
N
NH2
Derivatives of pyrimidine
Barbituric acid (2,4,6-trihydroxypyrimidine)
Keto-enole and lactam-lactim tautomery
7. Structure, nomenclature, physical and chemical properties of
barbituric acid.

Barbituric acid or malonylurea or 4hydroxyuracil is an organic compound based
on a pyrimidine heterocyclic skeleton. It is an
odorless powder soluble in hot water. Barbituric
acid is the parent compound of a large class of
barbiturates that have central nervous system
depressant properties, although barbituric acid
itself is not pharmacologically active.
The compound was discovered by the German chemist
Adolf von Baeyer on 4. December 1864—the feast of St
Barbara and therefore the name given to the
compound—by combining urea and malonic acid in a
condensation reaction. Malonic acid has since been
replaced by diethyl malonate.
Bases of pyrimidine (important derivatives )
These bases are present in nucleinic acids

Vitamin B1 (thiamine) contain pyrimidine and thyazole ring connect
through methyl group.
Physiological active form of vitamin B1 in living organisms is cocarboxilaza,
which take part in enzyme processes, in hydrocarbon exchange
Orotic acid is primary compound in biosynthesis of pyrimidine bases
8. Structure, nomenclature, physical and
chemical properties of pyrazine.
Pyrazine is a heterocyclic aromatic organic compound.
It is found in folic acid in the form of pterin. Derivatives
like Phenazine are well known for their antitumor,
antibiotic and diuretic activity. Pyrazine is less basic in
nature than pyridine, pyridazine and pyrimidine.
Tetramethylpyrazine (also known as ligustrazine) is
reported to scavenge superoxide anion and decrease
nitric oxide production in human polymorphonuclear
leukocytes. Tetramethylpyrazine is also a component of
some herbs in Traditional Chinese Medicine.
Pyrazine
Other names
1,4-Diazabenzene, p-Diazine, 1,4Diazine, Paradiazine, Piazine, UN
1325
Properties
Molecular formula
C4H4N2
Molar mass
80.09 g/mol
Appearance
White crystals
Density
1.031 g/cm3
Melting point
52 °C
Boiling point
115 °C
Solubility in water
Soluble
Synthesis of pyrazine
Many methods exist for the organic synthesis of
pyrazine and derivatives and some of them very
old. Staedel-Rugheimer pyrazine synthesis
(1876) is the condensation of 1,2-diamine with
1,2-dicarbonil compounds and then oxidation to
a pyrazine. A variation is the Gutknecht
Pyrazine Synthesis (1879) also based on this
selfcondensation but differing in the way that
alpha-ketoamine is synthesised (the chlorine
compound in the above method is a
lachrymatory agent).
The Gastaldi synthesis (1921) is another variation:
Chemical properties of pyrazine
N
N
N
H
N
H
pyperazine
(Na + CH3CH2OH)
NaNH2, NH3
N
H
N
2-aminopyrazine
N
N
NH2
N
N
N
CH3COOOH
+
N
_
O
N- oxide pyrazine
9. Structure,
nomenclature, physical and chemical
properties of purine.
Purine is a heterocyclic aromatic organic
compound, consisting of a pyrimidine ring
fused to an imidazole ring. Purines,
including substituted purines and their
tautomers, are the most widely distributed
kind of nitrogen-containing heterocycle in
nature. Purines and pyrimidines make up
the two groups of nitrogenous bases,
including the two groups of nucleotide
bases. Notable purines
Purine
Properties
Molecular formula C5H4N4
Molar mass
120.112
Melting point
214 °C
History
The name 'purine' (purum uricum) was coined by the German
chemist Emil Fischer in 1884. He synthesized it for the first
time in 1899.
Laboratory synthesis
In addition to in vivo synthesis of purines in purine metabolism,
purine can also be created artificially.
Purine (1) is obtained in good yield when formamide is heated
in an open vessel at 170 oC for 28 hours.
Procedure: Formamide (45 gram) was heated in an open
vessel with a condenser for 28 hours in an oil bath at 170-190
oC. After removing excess formamide (32.1 gram) by vacuum
distillation, the residue was refluxed with methanol. The
methanol solvent was filtered, the solvent removed from the
filtrate by vacuum distillation, and almost pure purine obtained;
yield 4.93 gram (71 % yield from formamide consumed).
Crystallization from acetone afforded purine as colorless
crystals; melting point 218 oC.
Synthesis of purine
Traube method: condnsation 4,5diaminopyrimidines with carbonic acids
The Traube purine synthesis (1900) is a classic
reaction (named after Wilhelm Traube) between an
amine substutited pyrimidine and formic acid
Chemical properties of purine.
For purine is characteristic of azole tautomery
:
NH
Cl
NH
N
N
NH
Cl
Cl
NH
N
(1:1)
2
N
3
Cl
Cl
adenine
KOH
N
NH
Cl
Cl
N
OH
OH
OH
N
NH
N
NH
N
N
N
H
N
2
NH
(1:1)
H 2N
H
N
N
3
Cl
N
NH
N
N
H 2N
NH
N
guanine
H
HNO
O
O
N
HN
N
N
H
hypoxanthine
N
HN
O
N
H
N
H
xanthine
2
Purine is an amphoteric compound
Derivatives of purine
Main derivatives of purine are oxopurines:
Uric acid is colorless crystal compound, bad soluble in water, ethanol and
ether, soluble in dilute base solutions and glycerin. Uric acid is dibases acid.
Thauthomeric forms
O
HN
N
N
O
N
H
N
H
O
OH
H
N
HO
OH
N
H
N
uric acid
O
OH
N
HN
N
H
N
H
O
N
N
HO
N
H
N
xanthine
O
OH
N
HN
N
N
N
N
H
hypoxanthine
N
N
H
10. Structure, nomenclature, physical and
chemical properties of uric acid.


Uric acid (or urate) is an organic compound of carbon, nitrogen,
oxygen and hydrogen with the formula C5H4N4O3. Uric acid is
produced by xanthine oxidase from xanthine and hypoxanthine,
which in turn are produced from purine. Uric acid is more toxic to
tissues than either xanthine or hypoxanthine.
In humans and higher primates, uric acid is the final oxidation
(breakdown) product of purine metabolism and is excreted in urine.
In most other mammals, the enzyme uricase further oxidizes uric
acid to allantoin. The loss of uricase in higher primates parallels the
similar loss of the ability to synthesize ascorbic acid. Both uric acid
and ascorbic acid are strong reducing agents (electron donors) and
potent antioxidants. In humans, over half the antioxidant capacity of
blood plasma comes from uric acid.

Salts of uric acid called urats. Urats is bad soluble
in water, except salts with litium (Li).
 In hydroxyform uric acid gives reactions of
nucleophilic substitutions.
Chemical properties
O
H
O
N
H
N
O
2NaOH
O
N
H
H
N
N
H
+
NaO
HO
N
N
H
disodium salt of uric acid
Cl
N
OH
N
_ +
ONa
_
OH
N
H
N
N
H
POCl3
N
N
Cl
Cl
N
NH
2,6,8-threechlorpurine
Reactions of oxidation
aloxane
urea
alantoine
Murexidne’s reaction is the qualitative
reaction on uric acid

By heating uric acid with nitrate acid and next
adding of ammonium observe purpur-violet color
purpure acid
(enole form)
murexide
Reactions of reduction
xanthine
 Hypoxantine
and xantine have the same
chemical properties as uric acid
N-methyl derivatives of hypoxantine and xantine widely used in
pharmacy
Aminopurines
aminoderivatives of purine –
adenine and guanine present in nucleinic
acids as purine’s bases.
 Maine
Sources of uric acid






In many instances, people have elevated uric acid levels for
hereditary reasons. Diet may also be a factor.
Purines are found in high amounts in animal internal organ food
products, such as liver. A moderate amount of purine is also
contained in beef, pork, poultry, fish and seafood, asparagus,
cauliflower, spinach, mushrooms, green peas, lentils, dried peas,
beans, oatmeal, wheat bran and wheat germ.
Examples of high purine sources include: sweetbreads, anchovies,
sardines, liver, beef kidneys, brains, meat extracts (e.g Oxo, Bovril),
herring, mackerel, scallops, game meats, and gravy.
Moderate intake of purine-containing food is not associated with an
increased risk of gout.
Serum uric acid can be elevated due to high fructose intake ,
reduced excretion by the kidneys, and or high intake of dietary
purine.
Added fructose can be found in processed foods and soda
beverages as sucrose, or in some countries, as high fructose corn
syrup.
Phenothiazine

Phenothiazine (dibenzo-1,4-thiazine) – colorless crystal compound,
insoluble in water, diethyl ether, well soluble in hat ethanol.
Method of getting
Chemical properties
1. Alkylation and acylation
2. Oxidation
3. Reaction of electrophilic sybstitution go in location 3 and 7
with oxidation of sulphur
Derivatives of phenothiazine
Pteridine (pyrazino[2,3-d]pyrimidine)
Method of getting: condensation of 4,5diaminopyrimidins with 1,2-dicarbonile compounds
Pteridine is light yellow crystal compound, soluble in water, ethanol, less soluble in
diethyl ether and benzole. Pteridine is stable to oxidation, by acting of acids and
bases pteridine cycle decompose. Gives reaction of electrophilic substitution,
protonate on nitrogen atom in 1 location.
Derivatives of pteridine
 Folic
acid (vitamin Bc)
Aloxasine and isoaloxasine
 These
compounds include benzyl,
pyrazine and hydrate pyriidine cycles
Flavine is a primery compound of riboflavin:
11. Structure, nomenclature and properties of
azepines. Benzazepine.
Sevenmember heterocyclic ring compounds
have received much attention in the past few
years owing to its wide range of biological
activity.
Azepines are heterocycles
of seven atoms, with a
nitrogen replacing a carbon
at one position.
A well known azepine is
caprolactam
 Skeletal
formula of caprolactam.
Sevenmember heterocycles which
containing nitrogen
Benzazepine: bicyclic structure consisting of
fused benzene and azepine rings; many
compounds with this structure react with
biogenicamine receptors, and so are psychotropic
and neurotropic.
Examples of benzazepine include fenoldopam and
galantamine.
fenoldopam
galantamine
12. Structure, nomenclature and properties
of diazepine. Benzodiazepine.
Diazepine is a sevenmember
heterocyclic compound with two
nitrogen atoms (e.g., in ring
positions 1 and 2) and three
double bonds.
When diazepine combined with a benzene ring, these is
the basis of the benzodiazepine family . In these
compounds the nitrogen atoms are at the 1 and 4
positions as, for example, in clobazam (depending on
the position of the fused benzene ring, the nitrogen
atoms are also in positions number 1 and 4).
5-Phenyl-1,3-dihydro-2H-1,4benzodiazepin-2-on
forms the skeleton on many of
the most common benzodiazepine
pharmaceuticals, such as diazepam
(chloro-substituted).


The benzodiazepines are a class of psychoactive drugs with
varying hypnotic, sedative, anxiolytic (anti-anxiety), anticonvulsant,
muscle relaxant and amnesic properties, which are mediated by
slowing down the central nervous system. Benzodiazepines are
useful in treating anxiety, insomnia, agitation, seizures, and muscle
spasms, as well as alcohol withdrawal. They can also be used
before certain medical procedures such as endoscopies or dental
work where tension and anxiety are present, and prior to some
unpleasant medical procedures in order to induce sedation and
amnesia for the procedure. Benzodiazepines are also used to treat
the panic that can be caused by hallucinogen intoxication.
Benzodiazepines can cause a physical dependence and a
benzodiazepine addiction to develop and upon cessation of long
term use a benzodiazepine withdrawal syndrome can occur.
Benzodiazepine receptors also appear in a
number of non nervous-system tissues and are
mainly of the peripheral benzodiazepine
receptor (PBRs) type. These receptors are found
in various tissues such as heart, liver, adrenal,
and testis. In lymphatic tissues, they modulate
apoptosis of thymocytes via reduction of
mitochondrial transmembrane potential. PBRs
have many other actions on immune cells
including modulation of oxidative bursts by
neutrophils and macrophages, and inhibition of
macrophage secretion of cytokines inhibition of
the proliferation of lymphoid cells and secretion
of cytokines by macrophages.
13. Oxazepam. Radedrol (nitrazepam). Seduxen
O
(diazepam).
N
Oxazepam (marketed in English speaking
N
countries under the following brand names
Alepam, Medopam, Murelax, Noripam,
Ox-Pam, Purata, Serax and Serepax), is a
drug which is a benzodiazepine derivative.
Oxazepam
Oxazepam has moderate amnesic,
anxiolytic, anticonvulsant, hypnotic,
7-clorine-3-hydroxysedative and skeletal muscle relaxant
5-phenil-1,3-dihydro2H-1,4-benzodiazepin-2-on properties compared to other
benzodiazepines.
OH
Cl

Oxazepam is an intermediate acting benzodiazepine.
Oxazepam acts as inhibitor on the central nervous system. The halflife of oxazepam is 4-15 hours. Oxazepam has been shown to
suppress cortisol levels.
Oxazepam is an active metabolite formed during the
breakdown of diazepam, nordazepam, and certain
similar drugs. Oxazepam may be safer than many other
benzodiazepines in patients with impaired liver function
because it does not require hepatic oxidation, but rather
it is simply metabolized via glucuronidation. Such means
as oxazepam is less likely to accumulate and cause
adverse reactions in the elderly or people with liver
disease. Oxazepam is similar to lorazepam in this
respect. There is preferential storage of oxazepam in
some organs including the heart of the neonate.
Absorption by any administered route and the risk of
accumulation is significantly increased in the neonate
and it is recommended to withdraw oxazepam during
pregnancy and breast feeding as oxazepam is excreted
in breast milk.
H
O
N
O 2N
N
Nitrazepam is a nitrobenzodiazepine It
is a 1,4 benzodiazepine, with the
chemical name 7-nitro-5-phenyl-1,3dihydro-2H-1,4- benzodiazepin-2-on.
Nitrazepam
Nitrazepam is a type of benzodiazepine
drug and is marketed in English speaking
countries under the following brand names Alodorm, Arem, Insoma, Mogadon,
Nitrados, Nitrazadon, Ormodon, Paxadorm,
Remnos and Somnite.
It is a hypnotic drug with sedative and motor impairing
properties, anxiolytic, anticonvulsant and skeletal muscle relaxant
properties. It is long acting drug, has lipophilic and hepatometabolitic
properties via oxidative pathways. It acts on benzodiazepine receptors
in the brain which are associated with the GABA receptors (gammaaminobutyric acid). GABA is a major inhibitor neurotransmitter in the
brain, involved in inducing sleepiness, muscular relaxation and control
of anxiety and seizures, and slows down the central nervous system.
In sleep laboratory studies, nitrazepam
decreased sleep onset latency. In
psychogeriatric in-patients nitrazepam was
found to be no more effective than placebo
tablets in increasing total time spent asleep.
Nitrazepam is most often used to treat shortterm sleeping problems (insomnia), namely
difficulty falling asleep, frequent awakening,
early awakenings or a combination of theme.
Nitrazepam is long acting and is sometimes
used in patients who have difficulty in
maintaining sleep. Nitrazepam shortens the time
required to fall asleep and lengthens the
duration of sleep. It is also useful for the
treatment of myoclonic seizures and has been
used in the treating of seizure disorders in
children and also for infantile spasms .
H 3C
O
N
N
Cl
O
diazepam
(4N-oxide 7-chlorine-1-methyl-
Diazepam first marketed as Valium by
Hoffmann-La Roche, is a benzodiazepine
derivative drug. It possesses anxiolytic,
anticonvulsant, hypnotic, sedative, skeletal
muscle relaxant and amnestic properties. It is
commonly used for treating anxiety, insomnia,
seizures, muscle spasms, alcohol withdrawal
and benzodiazepine withdrawal.
5-phenil-1,3-dihydro-2Н1,4-benzodiazepin-2-оne )
Diazepam occurs as solid white or yellow
crystals and has a melting point of 131.5 to 134.5 °C.
It is odorless, and has a slightly bitter taste. The British
Pharmacopoeia lists diazepam as being very slightly
soluble in water, soluble in alcohol and freely soluble
in chloroform. The United States Pharmacopoeia lists
diazepam as soluble 1:16 in ethyl alcohol, 1:2 in
chloroform, 1:39 in ether, and practically insoluble in
water.
The pH of diazepam is neutral (i.e., pH = 7).
Diazepam has a shelf-life of 5 years for oral
tablets and 3 years for IV/IM solution. Diazepam
should be stored at room temperature (15°30°C). The solution for parenteral injection
should be protected from light and kept from
freezing. The oral forms should be stored in airtight containers and protected from light. If
diazepam is to be administered concomitantly
with other drugs, attention should be paid to the
possible pharmacological interactions. Particular
care should be taken with drugs that enhance
the effects of diazepam, such as barbiturates,
phenothiazines, narcotics and antidepressants.
Qualitative reactions on benzodiazepines
1. With concentrated acids (H2SO4, HCl, HClO4)
derivatives of benzodiazepines form color salts.
2. Heterocyclic nitrogen atom gives positive reaction with
common alkaloids precipitate reagents.
3. Specific reaction on benzodiazepines derivatives is
formation of green color after pyrolisis.
4. Formation of azodays after primary hydrolysis:
Nozepam
5. Belshteine probe use for determination of halogens.
6. Noozepam by heating with conc. H2SO4 hydrolyzed with
formation of formaldehyde, which forms violet color with
fuxinsulfite acid.
14.Classification of alkaloids.
Alkaloids are naturally occurring chemical compounds
containing basic nitrogen atoms. The name derives from the word
alkaline and was used to describe any nitrogen-containing base.
Alkaloids are produced by a large variety of organisms, including
bacteria, fungi, plants, and animals and are part of the group of
natural products (also called secondary metabolites). Many alkaloids
can be purified from crude extracts by acid-base extraction. Many
alkaloids are toxic to other organisms. They often have
pharmacological effects and use as medications and recreational
drugs. Examples are the local anesthetic and stimulant cocaine, the
stimulant caffeine, nicotine, the analgesic morphine, or the
antimalarial drug quinine. Some alkaloids have a bitter taste.
Alkaloids are usually classified by their common molecular
precursors, based on the metabolic pathway used to construct the
molecule. When not much was known about the biosynthesis of
alkaloids, they were grouped under the names of known
compounds, even some non-nitrogenous ones (since those
molecules' structures appear in the finished product; the opium
alkaloids are sometimes called "phenanthrenes", for example), or by
the plants or animals they were isolated from. When more is learned
about a certain alkaloid, the grouping is changed to reflect the new
knowledge, usually taking the name of a biologically-important
amine that stands out in the synthesis process.
Methods of extraction
1.
2.
Extraction as salts: to raw material add water
or ethanol with few drops of tartaric acid. All
alkaloids forms salts with tartaric acid. For
purification to this extract add base and all
alkaloids form bases, which obtained by
organic solutions. Operation of purification
repeat few times. Then solvent separated from
alkaloids. Sum of alkaloids is separated on
individual compounds.
Extraction as bases: to raw material add alkali
solution (ammonium, sodium hydrocarbonate
or carbonate). Alkaloids bases are extracted
by organic solutions. Purification realize by
transferring alkaloids to salts and then to
bases. Operation of purification repeat few
times.
Common precipitate reagents on alkaloids
1.Lyugol, Vagner, Bushard reagents (I2 in KI
in different concentraions).
2. Dragendorph reagent (K[BiI4]).
3. Maier reagent (K2[HgI4]).
4. Marme reagent (CdI3 in KI).
5. Zonnenshten reagent
(H3PO4·12MoO3·2H2O).
6. Sheibler reagent (H3PO4·12WO3·2H2O).
7. Berthran reagent (SiO2·12WO3·2H2O).
8. 5% Tannin solution.
9. Saturated solution of picric acid.
Special reagents on alkaloids
1. Conc. H2SO4.
2. Conc. HNO3.
3. Erdman reagent (H2SO4 conc.+HNO3
conc.).
4. Phrede reagent ((NH4)2MoO4+H2SO4
conc.).
5. Marki reagent (HCOH+H2SO4 conc.).
6. Mandelin reagent (NH4VO3+H2SO4
conc.).
7. Sodium nithroprusid
(Na2[Fe(CN5)No]·2H2O).

Pyridine and piperidine group: piperine, coniine, trigonelline, arecoline,
arecaidine, guvacine, cytisine, lobeline, nicotine, anabasine, sparteine,
pelletierine.
N
N
H

Pyrrolidine and pyrolisidine group: hygrine, cuscohygrine, platyphylline,
nicotine.
N
N
H

Tropane group: atropine, cocaine, ecgonine, scopolamine, catuabine.
N CH 3

Quinoline group: quinine, quinidine, dihydroquinine, dihydroquinidine,
strychnine, brucine, veratrine, cevadine.
N

Isoquinoline group: opium alkaloids (papaverine, narcotine, narceine),
sanguinarine, hydrastine, berberine, emetine, berbamine, oxyacanthine.
N

Phenanthrene alkaloids: opium alkaloids (morphine, codeine,
thebaine)
Phenethylamine group: mescaline, ephedrine, dopamine

Indole group:

N
H
Tryptamines: serotonin, bufotenine, psilocybin

Ergolines (the ergot alkaloids): ergine, ergotamine, lysergic acid

Beta-carbolines: harmine, harmaline, tetrahydroharmine

Yohimbans: reserpine, yohimbine

Vinca alkaloids: vinblastine, vincristine

Kratom (Mitragyna speciosa) alkaloids: mitragynine, 7hydroxymitragynine

Tabernanthe iboga alkaloids: ibogaine, voacangine, coronaridine

Strychnos nux-vomica alkaloids: strychnine, brucine
Purine group:
N
N
H


N

N
Xanthines: caffeine, theobromine, theophylline
15. Alkaloids group of pyridine and piperine
(nicotine, anabasine, lobeline).
CH3
Systematic (IUPAC) name
Nicotine is an alkaloid found in the
nightshade family of plants (Solanaceae)
which constitutes approximately 0.6–3.0%
of dry weight of tobacco, with biosynthesis
taking place in the roots, and accumulating
in the leaves.
3-[2’-(N-methylpyrrolidil)]pyridine
It functions as an antiherbivore chemical with particular
specificity to insects; therefore nicotine was widely used as an
insecticide in the past, and currently nicotine analogs such as
imidacloprid continue to be widely used.
Chemistry
Nicotine is a hygroscopic, oily liquid that is miscible with water in its
base form. As a nitrogenous base, nicotine forms salts with acids that are
usually solid and water soluble. Nicotine easily penetrates the skin. As
shown by the physical data, free base nicotine will burn at a temperature
below its boiling point, and its vapors will combust at 308 K (35 °C; 95 °F) in
air despite a low vapor pressure. Because of this, most of the nicotine is
burned when a cigarette is smoked; however, enough is inhaled to provide
the desired effects. The amount of nicotine inhaled with tobacco smoke is a
fraction of the amount contained in the tobacco leaves.
Pharmacology
Pharmacokinetics
As nicotine enters the body, it is distributed quickly through the
bloodstream and can cross the blood-brain barrier. On average it
takes about seven seconds for the substance to reach the brain
when inhaled. The half life of nicotine in the body is around two
hours. The amount of nicotine absorbed by the body from smoking
depends on many factors, including the type of tobacco, whether the
smoke is inhaled, and whether a filter is used. For chewing tobacco,
dipping tobacco and snuff, which are held in the mouth between the
lip and gum, or taken in the nose, the amount released into the body
tends to be much greater than smoked tobacco. Nicotine is
metabolized in the liver by cytochrome P450 enzymes (mostly
CYP2A6, and also by CYP2B6). A major metabolite is cotinine.
Pharmacodynamics
Nicotine acts on the nicotinic acetylcholine
receptors, specifically the ganglion type nicotinic
receptor and one CNS nicotinic receptor. In
small concentrations, nicotine increases the
activity of these receptors. Nicotine also has
effects on a variety of other neurotransmitters
through less direct mechanisms.
In adrenal medulla
By binding to ganglion type nicotinic
receptors in the adrenal medulla nicotine
increases flow of adrenaline (epinephrine), a
stimulating hormone. By binding to the
receptors, it causes cell depolarization and an
influx of calcium through voltage-gated calcium
channels.
Anabasine is a pyridine alkaloid found in the Tree Tobacco
(Nicotiana glauca) plant, a close relative of the common
tobacco plant (Nicotiana tabacum). It is similar to nicotine. Its
principal (historical) industrial use is as an insecticide.
Anabasine is present in trace amounts in tobacco smoke, and
can be used as an indicator of a person's exposure to tobacco
smoke.
β-(α’-pyperidile)pyridine
Pharmacology
Anabasine is a nicotinic acetylcholine receptor
agonist. In high doses, it produces a depolarizing
block of nerve transmission, which can cause
symptoms similar to those of nicotine poisoning
and, ultimately, death by asystole. In larger
amounts it is thought to be teratogenic in swine.
Lobeline is a natural alkaloid found in
"Indian tobacco" (Lobelia inflata), "Devil's
tobacco" (Lobelia tupa), "cardinal flower"
(Lobelia cardinalis), "great lobelia"
(Lobelia siphilitica), and Hippobroma
CH3
longiflora. In its pure form it is a white
amorphous powder which is freely
Systematic (IUPAC) name
soluble in water. Lobeline has been used
L-(-)-2benzoilmethyle-6-(2’-hydroxy- as a smoking cessation aid, and may
2’-phenylethyl)-1-methylpyperidine have application in the treatment of other
drug addictions such as addiction to
amphetamines or cocaine.
Lobeline has multiple mechanisms of action, acting as
a VMAT2 ligand, which stimulates dopamine release to a
moderate extent when administered alone, but reduces the
dopamine release caused by methamphetamine.
16. Alkaloids group of quinoline (quinine).
Quinine
Systematic (IUPAC) name (R)-(6methoxyquinolin-4-yl)- (8’vinylquinuclidin-2’-yl)methanol
Quinine is a natural white crystalline alkaloid having
antipyretic (fever-reducing), antimalarial, analgesic (painkilling), and
anti-inflammatory properties and a bitter taste. It is a stereoisomer of
quinidine.
Quinine was the first effective treatment for malaria caused by
Plasmodium falciparum, appearing in therapeutics in the 17th century.
Since then, many effective antimalarials have been introduced,
although quinine is still used to treat the disease in certain critical
situations. Quinine is available with a prescription in the United
States. Quinine is also used to treat nocturnal leg cramps and
arthritis.
Chemical structure
Quinine contains two major fused-ring systems: The aromatic quinoline and
the bicyclic quinuclidine .
Qualitative reaction on quinine
Thaleyoquine test: emerald-green color
– with conc. H2SO4 – blue fluorescence;
– with sodium nitroprusside - yellow sediment.
Because of its relatively constant and
well-known fluorescence quantum yield,
quinine is also used in photochemistry as
a common fluorescence standard. Quinine
(and quinidine) are used as the chiral
moiety for the ligands used in Sharpless
asymmetric dihydroxylation. Quinine is
sometimes added to the recreational drugs
cocaine, heroin and others in order to "cut"
the product and make more profit.
17. Alkaloids of group of quinoline and phenanthreneisoquinoline
(papaverine, morphine, codeine).
Papaverine is an opium alkaloid used
primarily in the treatment of visceral
spasm, vasospasm (especially those
involving the heart and the brain), and
occasionally in the treatment of erectile
dysfunction. While it is found in the
opium poppy, papaverine differs in both
structure and pharmacological action
from the other opium alkaloids
(opiates).
Papaverine
Systematic (IUPAC) name
1-(3’,4’-dimethoxybenzyl)6,7-dimethoxyisoquinoline
Qualitative reactions on papaverine
1. With conc. H2SO4 by heating – violet color after heating.
2. With conc. HNO3 – yellow color, that after heating becomes orange.
H3CO
H3CO
H3CO
N
N
HNO3
H3CO
N
HNO3
H3CO
0
CH2
t C
CH2
H3CO
O2N
NO2
H3CO
OCH3
H3CO
OCH3
жовте забарвлення
Yellow
3. With bromine water – yellow precipitate.
CH2
NO2
H3CO
OCH3
оранжеве забарвлення
Orange
4. With Erdman reagent (H2SO4 conc.+HNO3 conc.) – red color.
5. With Phrede reagent ((NH4)2MoO4+H2SO4 conc.) – violet color after heating.
6. With Mandelin reagent (NH4VO3+H2SO4 conc.) – blue-green color becomes
blue.
7. With Marci reagent (HCOH+H2SO4 conc.) – at first forms red color,
then yellow and at the end orange. By adding bromine water and
ammonium appears violet precipitate, which dissolves in alcohols.
H3CO
OCH3
C
H2
H3CO
H3CO
OCH3
OCH3
C
H2
OCH3
+
N+
N
H
H
C
H2
2-
OCH3 SO4
Uses
Papaverine is approved to treat spasms of
the gastrointestinal tract, bile ducts and ureter
and for use as a cerebral and coronary
vasodilator in subarachnoid hemorrhage
(combined with balloon angioplasty) and
coronary artery bypass surgery. Papaverine may
also be used as a smooth muscle relaxant in
microsurgery where it is applied directly to blood
vessels. It is also commonly used in
cryopreservation of blood vessels along with the
other glycosaminoglycans and protein
suspensions. Functions as a vasodilator during
cryopreservation when used in conjunction with
verapamil, phentolamine, nifedipine, tolazoline
or nitroprusside.
Systematic (IUPAC) name
3,6-dihydroxy-N-methyl- 4,5epoxymorphinene-7
Morphine is a highly potent opiate analgesic
drug, is the principal active agent in opium, and
is considered to be the prototypical opioid.
Morphine was in 1803 the first alkaloid isolated
from a plant source. Like other opioids, e.g.
oxycodone, hydromorphone, and
diacetylmorphine (heroin), morphine acts
directly on the central nervous system (CNS)
to relieve pain, particularly at the synapses of
the nucleus accumbens. Morphine has a high
potential for addiction; tolerance and both
physical and psychological dependence
develop rapidly.
Chemistry
Chemical structure of morphine in correct 3D configuration. The
benzylisoquinoline backbone is shown in blue. Morphine is a benzylisoquinoline
alkaloid with two additional ring closures. Most of the licit morphine produced is used
to make codeine by methylation. It is also a precursor for many drugs including
heroin (diacetylmorphine), hydromorphone, and oxymorphone. Replacement of the
N-methyl group of morphine with an N-phenylethyl group results in a product that is
18 times more powerful than morphine in its opiate agonist potency.
Morphinene
Qualitative reactions on morphine
1. With Marci reagent – purpur color quickly becomes blue-violet
(distinctive reaction between morphine and codeine).
2. With ammonium – white crystal precipitate dissolves in NaOH.
3. With Phrede reagent – at first forms violet color, that changes to blue
and by standing – to green.
4. With FeCl3 – blue color.
6. Oxidation reaction with K3[Fe(CN)6] and FeCl3 – blue color:
7. With Mandelin reagent – violet color.
8. With Erdmane reagent – intense red color:
9. With conc. HNO3 – red-orange complex compound:
10. With diazonium salts – azoday (red color).
Obtaining derivatives of morphine
Both morphine and its hydrated form are sparingly
soluble in water. In five litters of water, only one gram of
the hydrate will dissolve. For this reason, pharmaceutical
companies produce sulphate and hydrochloride salts of
the drug, both of which are over 300 times more watersoluble than their parent molecule. Whereas the pH of a
saturated morphine hydrate solution is 8.5, the salts are
acidic. Since they derive from a strong acid but weak
base, they are both at about pH = 5; as a consequence,
the morphine salts are mixed with small amounts of
NaOH to make them suitable for injection. A number of
salts of morphine are used, and the opioids Morphine-NOxide (Genomorphine) which is a pharmaceutical which
is no longer in common use; and Pseudomorphine, an
alkaloid which exists in opium, form as degradation
products of morphine.
Most semi-synthetic opioids, both of the morphine and
codeine subgroups, are created by modifying one or
more of the following:
1. Saturating, opening, or other changes to the bond betwixt positions 7
and 8 on the morphine carbon skeleton, as well as adding,
removing, or modifying functional groups to these positions;
saturating, reducing, eliminating, or otherwise modifying the 7-8
bond and attaching a functional group at 14 yields hydromorphinol;
the oxidation of the hydroxyl group to a carbonyl and changing the
7-8 bond to single from double changes codeine into oxycodone.
2. Attachment, reduction or modification of functional groups to
positions 3 and/or 6 (dihydrocodeine and related, hydrocodone,
nicomorphine); in the case of moving the methyl functional group
from position 3 to 6, codeine becomes heterocodeine which is 72
times stronger, and therefore six times stronger than morphine
3. Attachment of functional groups or other modification at position 14
(oxymorphone, oxycodone, naloxone)
4. Modifications at positions 2, 4, 5 or 17, usually along with other
changes to the molecule elsewhere on the morphine skeleton.
Morphine can be used:







as an analgesic in hospital settings to relieve

pain at myocardial infarction

pain at sickle cell crisis

pain associated with surgical conditions, pre- and
postoperatively

pain associated with trauma
in the relief of severe chronic pain, e.g.,

cancer

pain from kidney stones (renal colic, ureterolithiasis)

severe back pain
as an adjunct to general anesthesia
in epidural anesthesia or intrathecal analgesia
as an antitussive for severe cough
in nebulized form, for treatment of dyspnea, although the evidence
for efficacy is slim. Evidence is better for other routes.
as an antidiarrheal in chronic conditions (e.g., for diarrhea
associated with AIDS, although loperamide (a non-absorbed opioid
acting only on the gut) is the most commonly used opioid for
diarrhea).
Codeine
Systematic (IUPAC) name
6-hydroxy-N-methyl-3-methoxy4,5-epoxymorphinen-7
Codeine (INN) or methylmorphine
is an opiate used for its analgesic, antitussive
and antidiarrheal properties. It is by far the
most widely used opiate in the world and
probably the most commonly used drug
overall according to numerous reports over
the years by organizations such as the World
Health Organization and its League of Nations
predecessor agency and others.
It is one of the most effective orally-administered opioid analgesics and has a wide
safety margin. It is from 8 to 12 percent of the strength of morphine in most people;
differences in metabolism can change this figure as can other medications.
Pharmacology
Codeine is considered a prodrug, since it is metabolised in vivo to the primary
active compounds morphine and codeine-6-glucuronide. Roughly 5-10% of codeine will be
converted to morphine, with the remainder either free, conjugated to form codeine-6glucuronide (~70%), or converted to norcodeine (~10%) and hydromorphone (~1%). It is less
potent than morphine and has a correspondingly lower dependence-liability than morphine.
Like all opioids, continued use of codeine induces physical dependence and can be
psychologically addictive. However, the withdrawal symptoms are relatively mild and as a
consequence codeine is considerably less addictive than the other opiates.
Qualitative reactions on codeine
1. With Marci reagent – blue-violet color.
2. Formation of apomorphine. After heating with
conc. H2SO4 and FeCl3 appears blue color that
becomes red after adding 1 drop of dilute HNO3.
3. With conc. HNO3 – red color becomes yellow.
4. With AgNO3 – orange precipitate Ag3PO4.
5. With Erdman reagent (H2SO4 conc.+HNO3
conc.) -blue color after heating.
6. With Phrede reagent ((NH4)2MoO4+H2SO4
conc.) - green color becomes blue.
7. With Mandelin reagent (NH4VO3+H2SO4 conc.)
- green color becomes blue.
8. With sodium nithropruside– yellow sediment.
18. Alkaloids group of purine (caffeine, theobromine,
theophylline).
1,3,7-trimethylxanthine,
trimethylxanthine,
Caffeine is a bitter, white crystalline xanthine
alkaloid that acts as a psychoactive stimulant
drug and a mild diuretic. Caffeine was
discovered by a German chemist, Friedrich
Ferdinand Runge, in 1819. He coined the
term "kaffein", a chemical compound in
coffee, which in English became caffeine.
Caffeine is also part of the chemical mixtures and insoluble complexes
guaranine found in guarana, mateine found in mate, and theine found in tea; all
of which contain additional alkaloids such as the cardiac stimulants theophylline
and theobromine, and often other chemicals such as polyphenols which can form
insoluble complexes with caffeine. Caffeine is found in varying quantities in the
beans, leaves, and fruit of some plants, where it acts as a natural pesticide that
paralyzes and kills certain insects feeding on the plants. It is most commonly
consumed by humans in infusions extracted from the cherries of the coffee plant
and the leaves of the tea bush, as well as from various foods and drinks
containing products derived from the kola nut.
Caffeine present in sugh plants:Coffea
arabica, Thea sinensis and Cola acuminata
Thea sinensis
Theobroma cacao
In humans, caffeine is a central
nervous system (CNS) stimulant.
Beverages containing caffeine, such as
coffee, tea, soft drinks and energy drinks
enjoy great popularity. Caffeine is the
world's most widely consumed
psychoactive substance, but unlike many
other psychoactive substances it is legal
and unregulated in nearly all jurisdictions.
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
Common reaction on caffeine, theobromine
and theophylline – Murexyde reaction
Specific reactions on caffeine
– with 1% solution of tannin – white precipitate dissolved in
excess of reagent;
– with 0,1M solution of I2 by the present of HCl – brown
precipitate dissolved in excess of alkali;
– with HgCl3 - white precipitate;
– with sodium nithropruside – yellow sediment;
– with acetylacetone and dimethylamnobenzaldehyde:
solution of the substance with acetylacetone and
NaOH heat on water bath and then cooling. Add
solution of dimethylamnobenzaldehyde and heat ones
more, then cooling and add water. Appears intense
blue color:
Theobromine
Systematic (IUPAC) name 3,7-dimethyl2,3,6,7-tetrahydro-1H-purine-2,6-dione
Theobromine, also known as xantheose, is a bitter alkaloid of the
cacao plant, found in chocolate, as well as in a number of chocolate-free
foods made from theobromine sources including the leaves of the tea
plant, the kola or cola nut, and acai berries. It is in the methylxanthine class
of chemical compounds, which also includes the similar compounds
theophylline and caffeine. Theobromine is a water insoluble, crystalline,
bitter powder; the colour has been listed as either white or colourless. It
has a similar, but lesser, effect as caffeine, making it a lesser homologue.
Theobromine is an isomer of theophylline as well as paraxanthine.
Theobromine is categorized as a dimethylxanthine, which means it is a
xanthine with two methyl groups.
Specific reactions on theobromine
– theobromine reacts with NaOH and CoCl2, appears evanescent
violet color and separates gray-blue precipitate of cobalt salt.
Theophylline in these conditions forms cobalt salt - white
sediment with pink tinge:
– with HgCl3 - white crystal precipitate;
– sodium salt of theobromine reacts with AgNO3 –
forms gelatins mass (silver salt):
A chocolate bar and melted chocolate.
Chocolate is made from the cacao bean, which is a
natural source of theobromine.
The mean theobromine concentrations in cocoa and carob products are:
Item
Mean theobromine
content (mg/g)
Cocoa
20.3
Cocoa cereals
0.695
Chocolate
bakery
products
1.47
Chocolate
toppings
1.95
Cocoa beverages
2.66
Chocolate ice
creams
0.621
Chocolate milks
0.226
Carob products
0-0.504
Theophylline
Systematic (IUPAC) name 1,3dimethyl-7H-purine-2,6-dione
Synthesis
Theophylline can be prepared synthetically from
dimethylurea and ethyl 2-cyanoacetate.
Specific reactions on theophylline
– theophylline forms with CoCl2 salt - white sediment with pink tinge (look at the
previous slide);
– with alkali solution of sodium nitropruside – green color dissolved in excess of acid;
– with HgCl3 - white crystal precipitate;
– sodium salt of theophylline reacts with AgNO3 – forms gelatins mass (silver salt):
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

Theophylline, also known as dimethylxanthine, is a
methylxanthine drug used in therapy for respiratory diseases such
as COPD or asthma under a variety of brand names. Due to its
numerous side-effects, these drugs are now rarely administered for
clinical use. As a member of the xanthine family, it bears structural
and pharmacological similarity to caffeine. It is naturally found in tea,
although in trace quantities (~1 mg/L), significantly less than
therapeutic doses.
The main actions of theophylline involve:
relaxing bronchial smooth muscle
increasing heart muscle contractility and efficiency: positive inotropic
effect
increasing heart rate: positive chronotropic effect
increasing blood pressure
increasing renal blood flow
some anti-inflammatory effects
central nervous system stimulatory effect mainly on the medullary
respiratory center.
19. Alkaloids group of tropane (atropine, scopolamine,
cocaine).
Atropine is a tropane alkaloid extracted from
Systematic (IUPAC) name (8methyl-8-azabicyclo[3.2.1]oct-3yl) 3-hydroxy-2phenylpropanoate; tropinic ester
of tropic acid
deadly nightshade (Atropa belladonna),
jimsonweed (Datura stramonium), mandrake
(Mandragora officinarum) and other plants of the
Solanaceae family.
Atropine
Derivatives of tropane
Tropine
Scopine
Echonine
It is a secondary metabolite of these plants
and
serves as a drug with a wide variety of
effects. It is a competitive antagonist for
the muscarinic acetylcholine receptor. It
is classified as an anticholinergic drug.
Being potentially deadly, it derives its
name from Atropos.
Physiological effects and uses
Increases firing of the sinoatrial node (SA) and conduction
through the atrioventricular node (AV) of the heart, opposes the
actions of the vagus nerve, blocks acetylcholine receptor sites, and
decreases bronchiole secretions. Generally, atropine lowers the
parasympathetic activity of all muscles and glands regulated by the
parasympathetic nervous system. Therefore, it may cause
swallowing difficulties and reduced secretions.
Chemistry and pharmacology
Atropine is a racemic mixture of D-hyoscyamine and Lhyoscyamine, with most of its physiological effects due to Lhyoscyamine. Its pharmacological effects are due to the binding with
muscarinic acetylcholine receptors. It is an antimuscarinic agent.
The most common atropine compound used in medicine is atropine
sulfate (C17H23NO3)2·H2SO4·H2O.
Common reaction on tropane alkaloids – rection of
Vitaly-Moren
In a porcelain cup to atropine add conc. HNO3
and heat to dry state – forms yellow polinitrocompound, dissolve this compound in
acetone, addo, 0,5M alcohol solution of KOH. Appears violet color disappears by
standing.
Qualitative reactions on atropine
– with picric acid – yellow precipitate;
– with Marci reagent – yellow color;
– formation of benzaldehyde:
Scopolamine
Systematic (IUPAC) name
(-)-(S)-3-hydroxy-2-phenyl-propionic acid
(1R,2R,4S,7S,9S)9-methyl-3-oxa9-aza-tricyclo[3.3.1.02,4]non-7-yl ester;
Scopinic ester of tropic acid
Scopolamine, known by the names
levo-duboisine and hyoscine, is a
tropane alkaloid drug with muscarinic
antagonist effects. It is obtained from
plants of the Solanaceae family
(nightshades), such as Datura
Stramonium.
It is among the secondary metabolites of these plants.
Therefore, scopolamine is one of three main active components of
belladonna and stramonium tinctures and powders used medicinally
along with atropine and hyoscyamine. Scopolamine has anticholinergic
properties and has legitimate medical applications in very small doses.
An overdose can cause delirium, delusions, dangerous elevations of
body temperature, stupor and death.
History
Scopolamine was one of the earlier alkaloids
isolated from plant sources, purified forms such as
free base and various salts, especially
hydrochloride, hydrobromide, hydroiodide and
sulphate, since its isolation by German chemists in
1881 and in the form of plant-based preparations
since antiquity and perhaps pre-historic times.
Physiology
Scopolamine acts as a competitive antagonist at
muscarinic acetylcholine receptors, specifically M1
receptors; it is thus classified as an anticholinergic,antimuscarinic drug.
Cocaine
Systematic (IUPAC) name
methyl (1R,2R,3S,5S)-3(benzoyloxy)-8-methyl-8azabicyclo[3.2.1] octane-2carboxylate; methylester of
benzoilechonine
The coca plant,
Erythroxylon coca.
Cocaine (benzoylmethyl ecgonine) is a
crystalline tropane alkaloid that is obtained from
the leaves of the coca plant. The name comes
from "coca" in addition to the alkaloid suffix -ine,
forming cocaine. It is both a stimulant of the
central nervous system and an appetite
suppressant.
Specifically, it is a dopamine reuptake
inhibitor, a norepinephrine reuptake inhibitor
and a serotonin reuptake inhibitor. Its
possession, cultivation, and distribution are
illegal for non-medicinal and non-government
sanctioned purposes in virtually all parts of the
world. Although its free commercialization is
illegal and has been severely penalized in
virtually all countries.
Qualitative reactions on cocaine
– with KMnO4 – violet crystal precipitate:
– heating with conc. H2SO4 (specific smell of
methylbenzoate, by standing forms crystals of benzoic acid)
20. Alkaloids group of indole (reserpine,
strychnine).
Systematic (IUPAC) name
11,17-dimethoxy-16carbmethoxy-18-(3’,4’,5’trimethoxybenzoyloxy)aloyohimbane
N
H3CO
N
H
OCH3
H3COOC
O C
OCH3
OCH3
O
OCH3
Reserpine is an indole alkaloid
antipsychotic and antihypertensive drug that
has been used for the control of high blood
pressure and for the relief of psychotic
behaviors, although because of the
development of better drugs for these
purposes and because of its numerous sideeffects, it is rarely used today. The
antihypertensive actions of Reserpine are a
result of its ability to deplete catecholamines
(among the others) from peripheral
sympathetic nerve endings. These substances
are normally involved in controlling heart rate,
force of cardiac contraction and peripheral
resistance.
Rauwolfia
serpentina
Aloyohimbane
6
9
10
8
A
11
12
B
13
5
7
1
C
2
N
H
3
4
N
21
D
14
20
19
15
E
Àë î é î õ³ì áàí
16
18
17
Reserpine can cause: nasal congestion, nausea,
vomiting, weight gain, gastric intolerance, gastric
ulceration (due to increased cholinergic activity in gastric
tissue and impaired mucosal quality), stomach cramps
and diarrhea are noted. The drug causes hypotension
and bradycardia and may worsen asthma. Depression
can occur at any dose and may be severe enough to
lead to suicide. Other central effects are a high incidence
of drowsiness, dizziness, and nightmares. Parkinsonism
occurs in a dose dependent manner. High doses of
reserpine cause fibroadenoma of the breast and
malignant tumors of the seminal vesicles among others.
Early suggestions that reserpine causes breast cancer in
women (risk approximately doubled) were not confirmed.
It may also cause hyperprolactinemia.
17
1
2
4
B
7
10
O
F
D
8
5
19
15
14
N 9
Strychnine
N
16
6
A
3
18
E
20
13
C
21
G
12
11
O
22
23
* HNO3
Strychnine is a very toxic (LD50 = 10 mg approx.), colorless
crystalline alkaloid used as a pesticide, particularly for killing small vertebrates
such as birds and rodents. Strychnine causes muscular convulsions and
eventually death through asphyxia or sheer exhaustion. The most common
source is from the seeds of the Strychnos nux vomica tree. Strychnine is one of
the most bitter substances known. Its taste is detectable in concentrations as
low as 1 ppm.
Pharmacology
Strychnine acts as a blocker or antagonist at the inhibitory or
strychnine-sensitive glycine receptor (GlyR), a ligand-gated chloride channel in
the spinal cord and the brain. Although it is best known as a poison, small doses
of strychnine were once used in medications as a stimulant, a laxative and as a
treatment for other stomach ailments. Because of its high toxicity and tendency
to cause convulsions, the use of strychnine in medicine was eventually
abandoned once safer alternatives became available.
Strychnos Nux
Vomica
Thank you for attention!