Lecture №20
Current state and development of the
corticosteroids as chemical drugs.
Hormones of the adrenal glands cork
layer and some semi-synthetic
analogues. Relationship between
structure and biological activity.
Gestagene hormones and their
synthetic analogues.
prepared Kozachok S.S.
The hormones of the adrenal of cortical layer
(corticosteroids) and sex hormones belong to the steroid
hormones. Sex hormones can be divided into male sex
hormones (androgens), female sex hormones
(estrogen) and luteal hormones (progestogens, or
lutoid
hormones).
The structural base of the steroid hormones is a
cyclopentaneperhydrophenanthrene
hydrocarbon
chain. The general formula of steroid hormones is:
The chemical structure of the steroid hormones
Hormone’s
group
corticoste
roid
Substitute
Double bond
en-4
dien-1,4
Х1
=О
Х2
-Н
-ОН
=О
R
CH2OH
C
O
- - - -OH
gestogen
ен-4
=О
-Н
CH3
C
O
androgen
ен-4
=О
-Н
-ОН
estrogen
trien-1,3,5
(don’t have
С-19)
-ОН
-Н
-ОН
=О
Steroid hormones
Methyl groups attached to the steroid cycle in the 10-th
and 13-th position, are named angularly. Radical R and
the hydrogen atoms (in 8, 9, 14 positions) are oriented to
the space in a cis-or trans-position relative to the angularly
groups. Conventionally assumed that the angularly methyl
groups are located above the plane of the drawing (the
bond is indicated by solid (full) line). If the other
substituents are in cis-position, in the same plane as the
angularly groups (β-configuration), then their relationship
are denoted by the solid line, and if the trans-position (αconfiguration) - dotted line.
Because the structure of the steroid hormones have much in
common, a lot of their analysis method are common.
Steroid hormones - crystalline substances, so for them to
determine the melting point it is one of the method to
measure the purity and identity.
Steroid hormones and their analogues are an optically-active substances,
most of them are dexter isomers (methylandrostendiol - levogyrate). AND for
the identification and confirmation of purity recommends to determine the
angle of rotation of the plane of polarized light by the solution of the
compounds in organic solvents and to calculate the specific rotation.
General reaction for all steroid hormones and their synthetic analogues is
the reaction with concentrated H2SO4. When to dissolve in it and to heat the
substances give appearance a specific color, sometimes fluorescence, with
a further addition of water, chloroform, the color changes, there is a specific
fluorescence.
Steroid hormones possessi keto group in 3-d position, they give the addition
reaction Steroid hormones possessing keto group in position 3, given the
addition reaction with elimination of water with hydroxylamine,
phenylhydrazine, 2,4-dinitrophenylhydrazine, isoniazid and elimination of
water – observing the precipitation with a characteristic melting point, or
there is a characteristic color (yellow, orange) : with hydroxylamine,
phenylhydrazine, 2,4-dinitrophenylhydrazine, isoniazid - observing
precipitation with a characteristic melting point, or there is a characteristic
color (yellow, orange):
These reactions can be used for the quantity determination
of the steroid hormones and their analogues by the
gravimetry method ((mass of sediment formed) or
photometric (optical density of colored solutions).
For the hormone’s identification which have hydroxyl
groups in 3 or 17 position, often there is using the reaction
of the esters forming (acetate, benzoate), with a
characteristic melting point:
For the hormone’s identification and their synthetic analogues that are
used as esters (acetate, propanoate), apply the hydroxamic reaction:
For the identification and quantitative analysis of steroid
hormones and their analogues are widely used UV
spectroscopy of alcohol solutions. The identification is carried
out according to the location of the maximus and minimum on
a particular part of the spectrum, comparing with the
spectrum of standard sample, according to the relative
between the optical densities in the various absorption
maximus and calculate the spesific absorbtion valur. The
content of the active substance is determined by the specific
absorption rate or standard solution.
The substance’s indentification is confirmed by the IRspectropy, which is compared with the pharmacopeial
or standard semples.
For the identifying and determining the presence of impurities
there is widely used method of TLC.
Corticosteroid and their synthetic analogues
Cortical layer of the human and animals adrenal
glands produces corticosteroids (Latin "cortex" crust).
Corticosteroids are the regulators of metabolic
processes and are divided into two groups:
mineralocorticoids (regulate the exchange of
electrolytes and water in the body) and steroids
(regulate the exchange of carbohydrates and
proteins).
They are used at the sharp adrenal insufficiency
(Addison's disease), as well as addisonizmi.
Natural hormones - hydrocortisone, cortisone,
desoxycorticosterone (Dox), etc.
The source of the more than 40 adrenal
corticosteroids is beef cattle.
The initial products for the synthesis of
corticosteroids can be natural substances of steroid
structure (diosgenin, stigmasterol) and cholesterol,
which is considered a precursor of corticosteroids
in the body.
Cortisone is isolated in 1936 from the adrenal cortex by Kendal and
Vintershteyner in USA and Reichstein in Switzerland.
The problem of its synthesis in the fact that in nature there are no
available steroidal compounds containing keto group in 11 position.
Synthesis such a group can be by biochemical oxidation (using
fungi, yeasts, actinomycetes, and various bacteria). This process
allows us to introduce the hydroxyl in 9, 11, 14, 15, 16, 17, 21
positions, in addition to the α- and β-configuration.
The total synthesis of cortisone was spent in 1951 by Woodward
(USA). It includes about 30 stages that’s why have only theoretical
interest.
In 1956, Suvorov M.M. (VNDHFI) used solasodin - aglycone of
glucoalkaloid of avian nightshade (Solanum aviculare) as the initial
product for the industrial production of cortisone. Scheme of its
synthesis consists of several stages.
Corticosteroids have very important side-effects and thus their use
as anti-inflammatory, desensitizing and anti-allergic means. In
addition, they have antishock and immunosuppressive activity and
therefore they are used at the transplantation of organs and tissues to
suppress the rejection reaction, as well as in various autoimmune
diseases.
Side effects of corticosteroids: a delay of sodium and water in the
body with the appearance of an edema, increased allocation of
potassium ions, increased blood pressure, hyperglycemia,
osteoporosis, etc.
At the long-term treatment they can suppress the cortical adrenal
function, so the treatment should not be suddenly stopped because it
may be the aggravation of the disease or condition of acute adrenal
insufficiency.
Corticosteroids in ointments and drops can not be used at the viral
diseases
of
the
eye
(can
form
the
ulcers).
All dosage forms of corticosteroids stored as potent tools in a dark
place.
All dosage forms of corticosteroids stored as potent tools in a dark
place.
Natural corticosteroids
CH3
COCH2OH
HO
CH3
O
OH
CH3
COCH2OH
OH
CH3
O
O
Hydrocortisone
CH3
CH3
O
Desoxycorticosterone (Dox),
COCH2OH
Cortisone
Chemical signs of corticosteroids
Derivatives of pregnane
1. In the 17-th position there is
oxyacetyl – СОСН2ОН
(reducing properties)
2. In the 17 α oxy (-ОН) group
(for glucocorticosteroids)
3. In the 11 oxo (=О) or оxy (-ОН)
group
4. In the 4 – double bond, in the
separate remedy there is also in
the 1-st position.
5. In the 3 position - oxo (=О)
group.
Characteristics and general identification reaction of the
corticosteroids
Adrenal cortex hormones and their synthetic analogs - a white
crystalline substance, which sometimes have a yellowish or cream
color, and odorless.
They are practicaly insoluble in water, soluble in the most organic
solvents. Desoxycorticosterone acetate and cortisone acetate readily
soluble in chloroform.
Corticosteroids and their analogues are dextergyrate isomers.
The steroid structure is confirmed by:
а) Boscot reaction: corticosteroids are dissolved in the mixture of 88%
Н3РО4 and concentrated СН3СООН, the solution heated 2 minutes
at 100ºС and leave for 1 hour at room temperature, and then it is
diluted by СН3СООН. Under the UV lamp (Bah lamp) fluorescence
occurs.
b) reaction with concentrated sulfuric acid.
α-Ketonic group – reducing propertiesі (oxidizing to
carboxilic group.
а) Felling reaction (copper-tartrate reagent). At the heating
of the mixture of the alcohol substance’s solution and
Felling reagent on the waterbathe Cu2O is settled down.
b) Except Felling reagent as a oxidizing agent Tollens
reagent can be used (ammonia solution of silver nitrate) –
reaction of “silver mirror”, Zonnenshten reagent Н3Р04 • 12Мо03 • 2Н20 ), Iron (III) salt.
c) Gorega reaction. At the oxidation of corticosteroids with
ethanolic solution of triphenyltetrazolium chloride in the
presence of a solution of tetrametylamine hydroxide, as a
reducing product there is formed red color of formazans:
HO
O
C
N
C
H
+
N
C6H5
Cl-
C6H5
O
N
HO
C
N
OH
+
+
C6H5
N
NH
C6H5
N
N
C6H5
C6H5
O
The reaction is used for the identification and quantification by a
spectrophotometry.
d) At the oxidation of potassium periodate there is released 17carboxylic acid, formaldehyde, which can be associated by
chromotropic acid (aurine dye).
Carbonyl (keto) group in the 3-d position: the reaction of
association with the elimination of water with
hydroxylamine, phenylhydrazine, 2,4dinitrophenylhydrazine, isoniazid - observed precipitation
with a characteristic melting point, or there is a
characteristic color.
Esteric group:
a) hydroxamic test
b) alkaline hydrolysis with subsequent identification of the
hydrolysis products.
Identification of the covalently bounded fluorite. In fluorine
continuing corticosteroids the present of fluorine is
identified after the mineralization (to burn with oxygen in
flask) with zirconium-alizarine complex.
(Desoxycorticosteroni acetas)
Desoxycorticosterone acetate*, DOXA
CH3
COCH2OCOCH3
CH3
O
Pregnane-4-оl-21-dione-3,20-21-acetate
or 21-acetoxypregnane-4-dion-3,20
Desoxycorticosterone is a natural mineral-corticosteroid, does not
contain -OH group in 11-th position. Extracted from cholesterol.
Identification of DOXA
1.
2.
On the steroid system – Boscot reaction. A violet color wiyh a
fluorescence.
With concentrated H2SO4 – cherry color with greenish-brown
fluorescence. After adding chloroform and shaking, the lower
layer is painted in yellow top - green (a steroid cycle).
On the oxyacetylic group, which is acetylated:
а) with Felling reagent – forming the red sediment Cu2O
b) With Tollens reagent – metallic silver settled down
4. On the ester group – hydroxamic reaction (red-brown color)
5. On the keto-group in 3-th position – the oxym formation,
phenylhydrazine, 2,4-dinitrophenylhydrazone.
6. Acetylic group after hydrolysis КОН is identified according to
the formation ethylacetate (specific smell):
3.
O
CH3
C
C
H2
O
C
CH3
O
CH3
KOH
O
CH3
O
C
C
H2
OH
CH3
+ CH3COOK
O
2CH3COOK + H2SO4 + 2C2H5OH
2CH3COOC2H5 + K2SO4 + 2H2O
Assay of DOXA
UV-spectrometry.
Photocolorimetric determination of the 0,5% oil
solution for injection after heating with
concentrated H3PO4.
Application
For the treatment of Addison's disease,
gipocortocyzm, myasthenia gravis, asthenia, etc.
Injected intramuscularly of the oily solution
of 5 mg 3 times a week, or in the severe cases of
10 mg daily.
Produced - amp. 1,0 - 0,5% oil solution, tab.
5 mg sublingual application.
Glucocorticoid
They regulate the body carbohydrate and protein metabolism they
have little effect on the exchange of electrolytes and water.
Their side effects are much more important as functional.
From natural glucocorticosteroids the practical value acquired
cortisone and hydrocortisone, which is produced from solasodinu
that is located in the bird nightshade (Solanum aviculare).
The synthetic analogues are widely used - prednisolone,
dexamethasone and their derivatives, which active in smaller
doses
and
have
less
side
effects.
Divided
into
three
groups:
1. Glucocorticosteroids which do not contain halogen atoms in
molecules;
2.
Fluorine
compounds;
3. Compounds with the atoms of chlorine and fluorine or only with
chlorine atoms in the molecules.
(Cortisoni acetas)
Cortisone acetate*
CH3
O
COCH2OCOCH3
OH
CH3
O
Pregnane-4-diol-17α,21-trion-3,11,20-21-аcetate
or 21-acetoxy- 17α-oxypregnane-4-trion-3,11,20
It is a semisynthetic substance, natural hormone cortisone. It
was first identified in 1937 as a drug first used in the late 40's,
when obtained synthetically from solasodyne.
Identification of Cortisone acetate
Boscot reaction. A violet fluorescence.
Basic hydrolysis (heating with КОН solution). At the
addition of the concentrated H2SO4 appearance the fruit
smell of ethyl acetate.
3. On the oxyacetylic group, which is acetylated here:
а) With Felling reagent – formation red sediment Cu2O
b) With Tollns reagent – metallic silver settled down
5. On ester group – hydroxamic reaction (darkred color)
4. On keto group in 3-th position – formation of
phenylhydrazone
(bright-yellow
color),
2,4dinitrophenylhydrazone (melting temperature 240ºС).
5. Remedy solution in the concentrated H2SO4 in UV-ligt gives
intensive yellow fluorescence.
1.
2.
Assay of of Cortisone acetate
UV- spectrophotometry in alcohol solution at λ=238 nm
in the comparing with the standard solution.
Application
When Addison's disease, rheumatism, rheumatoid
arthritis, asthma, and leukemia, mononucleosis, in
the dermatology - at neurodermatitis, eczema and
other allergic diseases.
Taking inside firstly by 0,1-0,2 g, and then by 25 mg
per day in pill or injected intramuscularly at 25-50 mg
as
a
suspension.
Produced: Table. 25-50 mg; vials on 10 ml
suspension (1 ml - 25 mg cortisone acetate).
Hydrocortisone acetate
(Hydrocortisonum)
11,17α,21-trioxypregnane-4-dion-3,20
Natural primary hormone more active than cortisone.
Applied in the form of microcrystalline suspension (Suspensio
Hydrocortisoni 25%) for the injection in the joint cavity of 0,2-1 ml at
rheumatoid arthritis, bursitis, etc. tendovaginitah 1 time per week.
Available in 5 ml vials.
For the treatment of inflammatory and allergic skin diseases, eczema,
neurodermatitis - hydrocortisone cream 1% (Unguentum
Hydrocortisoni
1%).
Produced
in
tubes
of
10
g.
Aerosol "oxycort - oxytetracycline g / x 0,3 g, hydrocortisone, 0,1 g.
Ointment "Locoida", "Latycort - 0.1% hydrocortisone 17-N-butyrate,
tube 15 g.
Ointment "Pimafucort - hydrocortisone, neomycin, natamycin.
Hydrocortisone acetate (Hydrocortisoni
acetas) (SPhU) Hydrocortisonе acetate
CH3
HO
COCH2OCOCH3
OH
CH3
O
11β,17α-dihydroxy-3,20-dioxypregn-4-en-21-yl аcetate
Characteristics. Crystalline powder of white or nearly white.
Practically insoluble in water, slightly soluble in ethanol and
methylene chloride. Melts at about 220 º C with
decomposition.
Identification of Hydrocortisone acetate
1.
2.
3.
4.
Using physical-chemical constant: IR-spectroscopy, ТLC.
Remedy solution in ethanol with H2SO4 gives an intense
brownish-red color with a green fluorescence. The resulting
solution is added to water and stirred, the solution
decolorized, and the fluorescence disappears (a steroid
cycle).
Substance gives a characteristic response to acetyl.
Not
pharmacopeial
reaction:
a)
Boscot
reaction.
Violet
fluorescence.
b) On the oxyacetylic group which is acetylated, the reaction:
with triphenyltetrazolium chloride in alkaline medium - red
color
(formazan
formation);
with
Felling
and
Tollens
reagents.
c) On the ester group - hydroxamic reaction (dark cherry
color)
d)
On the
keto
group
in the 3-d
position:
the formation of phenylhydrazone (yellow color);
with isoniazid in the presence of HCl - yellow in color (this
reaction prednisolone and dexamethasone don’t give).
Assay of Hydrocortisone acetate
UV spectrophotometry. The content of active ingredient
calculated by the using of the specific absorption index.
Application
Apply at the same diseases that hydrocortisone. For the
injection in the joint cavity at rheumatoid arthritis, bursitis there is
used hydrocortisone suspension for injection 2,5%
(Suspensio
Hydrocortisoni
acetatis
2,5%
pro
injectionibus)
in
the
amp.
2
ml.
For the treatment of inflammatory and allergic skin
diseases, eczema, neurodermatitis apply ointment 1%,
which is produced in tubes of 5 g ointment Gioxyson "together
with
oxytetracycline
h/ch.
In ophthalmic practice using 0,5% eye ointment, which
can not be used for viral and fungal diseases of the eye.
Prednisolone (Prednisolonum) (SPhU 1.2)
CH3
HO
COCH2OH
OH
CH3
O
11β,17,21-trihydropregn-1,4-dien-3,20-dion
or 1,2-dehydrohydrocortisone
Characteristics. Crystalline powder of white or nearly white color.
Hygroscopic. Very slightly soluble in water, soluble in ethanol
and methylene chloride. It has polymorphism.
Identification of Prednisolone
1.
2.
3.
4.
5.
6.
Pharmacopeial reaction : IR-spectroscopy, ТLC.
Remedy solution in ethanol with a concentrated H2SO4 forming the
pink color (steroid cycle).
With diphenylamine at the present of H2SO4 and СН3СООН it
forms green color.
Boscot reaction. A violet fluorescence.
On the oxyacetylic group which is acetylated, the reaction:
with triphenyltetrazolium chloride in alkaline medium - red
color
(formazan
formation);
with Felling and Tollens reagents.
On
the
keto
group
in
the
3-d
position:
the formation of phenylhydrazone at the present of H2SO4
(yellow
color);
with isoniazid in the presence of HCl – solution doesn’t
change.
Assay of Prednisolone
UV
spectrophotometry.
Method
of
specific
absorption.
Application
It was the first received by Hercoh in 1955
The introduction of the double bond in the first position in molecule of
hydrocortisone
enhances
the
action
by
3-5
times.
It is used for rheumatism, infectious nonspecific arthritis, asthma,
eczema, neurodermatitis, etc.
They are produced in table. By 5 mg and solution for injection. 30 mg
amp. 1ml number 3.
For the treatment of inflammatory and allergic skin diseases, eczema,
neurodermatitis applying ointment 0.5%, which is produced in tubes
by 10 and 20 g.
Ointment Prednicarb-Darnica - prednisolone 0.5%, urea 10%, Trilon B
1%.
Ointment "dermozolon" contains 0.5% prednisolone, and 3%
clioquinone.
Ointment "aurobin" - contains 20 grams of 0,04 g prednisolone and 0,4 g
lidocaine. In ophthalmic practice using 0.5% eye drops which contains
prednisolone acetate solution.
Prednisolone sodium phosphate
(Prednisolonі natrii phosphas) (SPhU)
O
CH3
HO
C
O
C
H2
OH
O
P
ONa
ONa
CH3
11β,17α,-dihydroxi-3,20-dioxopregnaO
1,4-dien-21-yl disodium phosphate
Characteristics. Crystalline powder of white or nearly white.
Hygroscopic. Easily soluble in water, very slightly soluble in
ethanol.
Identification Prednisolone sodium phosphate
Pharmacopeial reaction :
1. UV- and IR-spectroscopy, TLC.
2. Solution of the drug in ethanol with the conc. H2SO4 forms a red
color (a steroid cycle), in UV light - a red-brown fluorescence. After
adding water, the solution becomes colorless, and in UV light yellow-green fluorescence.
3. On
the
keto
group
in
the
3-d
position:
the formation of phenylhydrazone at the present of H2SO4 (yellow
color);
4. After mineralization – reaction A on Sodium (with potassium
hydroxoantimonate – white sediment) and reaction B on phosphate
(with molibdenovanadium reagent – yrllow color).
ASSAY: UV spectrophotometry. Method of specific absorption.
Application: solution for injection 30 mg/ml amp. 1 ml, № 3 (1 ml
solution contains 40,32 mg prednisolone sodium phosphate on the
account of 30 mg [rednisolone.
Hydro corticosteroid with
fluorine
atom
Corticosteroids - the first drugs which proved the possibility of
increasing the efficiency according to the replacement of nitrogen to
fluorine atoms in their molecules. Fluorine atom is minimal and
more relative to the nitrogen atom (Van der Waals radius for these
atoms are respectively 1.35 and 2.1 angstroms) and have more
stronger electron acceptor and lipophilic properties. Therefore, the
introduction of fluorite atoms does not cause significant spatial
complications that would change the conformation of molecules and
also doesn’t interfere on their interaction with the active sites and
receptor
of
substrates.
Important the energy of the C-F is greater than the energy of the CH (470 and 410 kJ / mol, respectively). This leads to thermal and
chemical stability of the fluorine derivatives, in many cases, it
causes slowing of the metabolism and leads to the unchanged
extraction from the body. This contributes to their high lipophilicity,
which increases the solubility of fluorine derivatives in lipids and
facilitate
their
transport
to
biological
systems.
The introduction of fluorite atom in a molecule
increases the activity of prednisolone, enhances the
anti-inflammatory and antiallergic actions when
administered orally (dexamethasone, triamcinolone).
The introduction in corticosteroids molecules of two
fluorine atoms reduces the absorption and such
compounds are used as local anti-inflammatory,
antiallergic
and
funds
against
itch
(floucynoloneacetonide,
flumetasonpivalate,
halometason)
As a local anti-inflammatory, antiallergic means and
means that are used against itching and
prednisolone derivatives with one atom of fluorine,
which are difficult absorbed (triamcinoloneacetonide,
betametazon,
fluoocortolone,
ingacort)
Dexamethasone ( Dexamethasonum)
Dexona, Dexasone
CH3
HO
COCH2OH
OH
CH3
CH3
F
O
9α-Fluoro-16α-methylprednisolone or 11,17α,21-trioxy-16α-methyl9α-fluoropregnadien-1,4-dione-3,20
It is synthesized from dihydropregnenolone, which is one of the
intermediate transformation products of solasodine in progesterone.
Identification of Dexamethasone
1.
2.
3.
4.
5.
IR-, UV-spectroscopy, ТLC.
Remedy solution in the concentrated H2SO4 stays coloeless and at
the action of UV lights the fluorescence is not observed.
On
the
oxyacetylic
group,
the
reaction:
with triphenyltetrazolium chloride and KOH solution - red color
(formazan
formation);
with Felling and Tollens reagents.
On
the
keto
group
in
the
3-d
position:
at the heating of the remedy in the alcohol solution with
phenylhydrazine hydrochloride and sulfuric acid solution during 5
minutes
there
is
apparent
yellow
color;
with isoniazid in the presence of HCl – solution is staying
colorless.
Organically connected Fluorine is converted into fluoride ions by
the mineralization , fluoride ions have the ability decolorize the
alizarin red lacquer (alizarinate zirconium). Alizarin red lacquer is a
complex compound of zirconium with alizarin. At interacting with
the F- ions Alizarin red is decolorized to a pale yellow color, due to
formation of a stable colorlessing complex Na2 [ZrF6].
ASSAY of Dexamethasone
UV-spectroscopy
Application
It has a strong anti-inflammatory and antiallergic actions. It is
good tolerated, does not delay water in the body. Its efficiency
the 0.5 mg of dexamethasone corresponds to 3.5 mg of
prednisolone, 15 mg of hydrocortisone, 17.5 mg of cortisone.
Using inside on 2-3 mg, the treatment is stopped step by
step, as with other glucocorticosteroids.
Producing tablets on 0.5 mg, Eye drops 0.1%, solution for
injection 0,4% in Amp. 1 and 2 ml № 5.
Triamcinolone (Triamcinolonum)
Polcortolone, Ketalong
CH3
HO
COCH2OH
OH
CH3
OH
F
O
9α-Fluoro-16α- methylprednisolone оr 11,16α 17α,21- trioxy- 9αfluoropregnadien -1,4-dione-3,20
Applying in the same cases that dexamethasone. IT is tolerated better
than other glucocorticoids. Using inside of 4-8-16 mg on a day.
Producing tablets on 4 mg; 0.1% ointment (ftorocort).
Triamcinolone acetonide (Triamcinoloni
acetonidum) Kenaloge 40
CH3
HO
COCH2OH
CH3
O
CH3
C
O
CH3
F
O
Triamcinolone 16α,17α-acetonide
Producing: suspension for injection 40 mg/ml in amp. 1 ml №5; 0,1
% ointment (“Fokort-Darnycya); “TrimistineDarnycya” ointment
contains 0,025 % triamcinolone acetonide , 0,5 % miramistine.
Fluocinoline acetonide (Fluocinoloni
acetonidum) Synaflan
CH3
HO
COCH2OH
CH3
O
CH3
C
O
CH3
F
O
F
6α,9α-difluoro-16α-oxyprednisolone- 16α,17α-acetonide оr 6αfluortriamcinolonacetonide
Applied externally as 0,025% ointment of Sinaflan or Flucynar, tube
on 15g. Ointment “Flucynar N "- Fluocinoline acetonide 0,25 mg/g and
neomycin sulfate 5 mg/g, tube on 15g.
Flumethasone pivalate
(Flumethasoni pivalas)
CH3
HO
COCH2OCOC(CH3)3
OH
CH3
CH3
F
O
F
6α,9α-difluoro-16α- methylprednisolone - 21-trimethylacetate (pivalate)
оr 6α-fluorodexametasone-21-pivalate
It is included in the ointment of "Lorinden A" (with salicylic acid) and
Lorinden C "(with clioquinol).
CH3
HO
COCH2OH
CH3
OH
CH3
HO
OCOC2H5
CH3
Cl
COCH2OCOC2H5
CH3
CH3
F
F
O
O
F
Halomethasone
Betamethasone dipropionate (SPhU)
CH3
HO
COCH2OCOC2H5
OCOC2H5
CH3
CH3
Cl
O
Beclomethasone dippropionate
Halomethasone (Sicorten) is used as 0,5% ointment.
Betamethasone dipropionate is used as suspension for
injection in amp. 1 ml №1 and №5 (Diprospan, Flosteron,
Celeston) and tabl. 0,5 mg №30 (Celeston).
Betamethasone is in the following complex ointment
“Celestoderm-В” (0,1%), “Celestoderm with garamycin”
and “Celestoderm” (with gentamicin), “Betasalik” and
“Diprosalik” (with salicylic acid), “Тriderm” (with
hentamicin sulfate and clotrimazol).
Betamethasone dipropionate is used as aerosol for
inhalation at asthma (Aldecyn, Beconazol, Beclazon).
Ointment “Canderm” (with gentamicin sulfate and
clotrimazole).
Progestin hormones
Pregnancy hormones are called progestins (Latin for "gestatio"
- pregnancy). These hormones are produced in the yellow
body. During pregnancy woman's body begins to operate a
new endocrine gland - the corpus luteum. The corpus luteum is
formed in ovary at the place of the follicle rupture, if the
pragnancy starts the corpus luteum is till the end of it, but if
the pragnancy does not start , it does not develop.
Corpus luteum secretes progesterone hormone, which helps to
create conditions for the implantation of a fertilized egg and
the correct development of pregnancy (lowers the excitability
of the muscles of the uterus).
Progestins are needed in woman's body for pregnancy
maintenance.
As drugs progestins are used at the cases of insufficient of the
corpus luteum function at the prevention and treatment of
threatened abortive and interrupt them at amenorrhea,
infertility, bleeding associated with ovarian dysfunction, etc.
Chemical feature of Progestin
1. Derivatives of
pregnane
2. Oxogroup (=О) or
tribond in the 20-th
position
3. Double bond in the 4th position;
4. Oxogroup (=О) in the
3-d position
Progesterone (Progesteronum)
CH3
COCH3
CH3
O
Pregnen – 4 - dion-3,20
Characters. White crystalline powder. Practically insoluble in
water, soluble in ethanol and ether, readily soluble in
chloroform.
Extracted from solasodine or cholesterol.
Identification of Progesterone
1.
IR- and UV-spectroscopy, TLC.
2.
A solution of progesterone in H2SO4 conc. after
water addition becomes yellow with a green
fluorescence. After adding chloroform color
disappears (a steroid cycle).
3.
At the heating of the alcohol solution of progesterone with mdinitrobenzene and NaOH appearance pink color that transfers to redbrown.
Fro the identification to determine the composition temperature 2,4dinitrophenylhydrazone, obtaining at the quatitation detarmination (keto
group the 3-d position).
Boscot reaction – a blue fluorescence.
At the heating progesterone with NH2OH*HCl and CH3COONa settled
down oxime’s sediment which is identified by the melting point.
The double bond id identified by the interaction of the remedy solution in
СН3СООН with bromine water or with KMnO4 (colorless).
4.
5.
6.
7.
ASSAY of Progesterone
Gravimetry by the interaction products with 2,4dinitrophenylhydrazine or spectrophotometry in
ethanol
solution
at
λ
=
241
nm.
Storage and application
In the tightly stoppered container, protecting from light.
Progestin
drug.
Injecting by 5-25 mg intravenous. They don’t apply
at disorders of liver function, hepatitis, cancer of the
breast and genital organs, tendency to thrombosis.
Applied in the form of oil solutions for injection 1%
and 2,5% 1,0 ml № 5; caps "Utrogestan" 100 mg №
30 and 1% gel, "Progestogel" tube on 80 g.
Pregnine (Praegninum)
Ethisterone*
CH3
C
CH
OH
CH3
O
Pregnen-4-іn-20-оl-17β-оn-3 оr 17α-ethynyltestosterone
Characters. White or almost yellowish crystalline powder, odorless.
Practically insoluble in water, very slightly soluble in ethanol and
ether, slightly soluble in chloroform.
Identification of Pregnine
1. IR-spectroscopy, TLC.
2. At the dissolving of pregnine in H2SO4 conc. and
the addition of water appears crimson color with a
green fluorescence. After adding chloroform and
mixing of the lower layer is painted in orange, the
top - almost colorless (steroid cycle).
3. Determine the oxime’s melting point (keto group in
position 3).
4. At the Boscot reaction there is a green-purple color
of the solution, which after 60 minutes changes to
red, and after the addition of CH3COOH observed
an intense yellow-pink fluorescence.
ASSAY of Pregnine
Alkalimetry by the substitution. To a solution of the substance in
tetrahydrofuran, to add a solution of AgNO3 HNO3 is liberated it is titrated by
a NaOH solution . Indicator is a bromocresol green or potentiometrically, Ем=
М:
1.
Spectrophotometry in ethanol solution at λ = 241 nm in
comparison with the standard.
Storage and application
In the tightly stoppered container, protecting from light.
2.
Progestin agent. 5-6 times less active than progesterone, but
remains the activity at the using sublingual tablets.
Producing table. 10 mg.
CH3
COCH3
CH3
C
OCO(CH2)4CH3
CH
OH
CH3
O
Oxyprogesterone capronate
CH3
O
Norethisterone
CH2CH=CH2
H3C
CH2
Allylestrenol
CH
OH
OH
O
C
Norgestrel
Thanks for attention!