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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5467_Библиотеки_им_академика_М_И_Перельмана.pdf
332
Pharmaceutical Chemistry of Natural Products
Glucocorticoids used for the treatment of asthma and allergy
O
HO
OH
CH
3
O
CH
3
CH
3
CH
3
O
O
F
Triamcinolone acetate Beclomethasone dipropionate
O
CH
3
HO
CH
3
O
Cl
H
CH
3
OCOCH
2
CH
3
OCOCH
2
CH
3
H
HO
CH
3
CH
3
O
H
H
H
F
O
O
O
OH
CH
3
CH
3
Flunisolide
O
HO
CH
3
CH
3
H
H
H
O
O
O
O
O
Ciclesonide
HO
CH
3
H
F
CH
3
H
F
O
O
CH
3
OCOCH
2
CH
3
SCH
2
F
Fluticasone propionate
O
CH
3
HO
H
Cl
CH
3
Cl
O
O
O
CH
3
H
O
Mometasone furoate
Isolation: The procedure for isolation was established by Pfi ffner and Reichstein. The minced ad-
renal glands are extracted with ethanol to precipitate proteins, followed by fi ltration through
Permutit to remove (–)-adrenaline. The residue after evaporation is partitioned between pentane
and 30% methanol to remove fats. After several extractions, the steroid acetates are separated on
neutral aluminium trioxide followed by hydrolysis to the free hormones.
Steroids and Hormones
333
Corticosteroids of Pharmaceutical Importance
Cortisone (Cortogen, Cortone)
4
6
O
CH
2
OH
CO
OH
1
2
3
5
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
O
17-Hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,7,8,10,13,15,16,17-
octahydro-2 -cyclopenta[ ]phenanthrene-3,11(6 ,9 ,12 ,14 )-dioneH a HHHH
Synthesis
CH OCOCH
23
CO
O
H CCOO
3
HCN
3 :21-Diacetoxy pregnane-11:20-dione␣
H CCOO
3
C(OH)CN
O
CH OCOCH
23
(i) POCl –C H N( H O)⫺
355 2
(ii) KOH
(iii) Ac O
2
CH OCOCH
23
CCN
O
HO
H
OsO
4
CH OCOCH
23
C
CN
O
O
OsO
2
O
H
HO
(i) CrO
3
(ii) Na SO
23
334
Pharmaceutical Chemistry of Natural Products
CH OH
2
OH
O
O
H
(ii) Br
2
(i) Ac O
2
CH OCOCH
23
CO
OH
O
H
Br
O
(i) –HBr
(ii) Hydrolysis
(iii) Ac O
2
CO
OH
O
O
CH OR
2
(i) Cortisone (R=H)
(ii) Cortisone acetate (R=OCOCH )
3
Properties and Use: It is a white, crystalline powder that is soluble in water and alcohol and used as
an anti-infl ammatory agent.
Cortisol or hydrocortisone (Hydrocortone, Cortef)
HO
OH
CO
COHH
2
O
Steroids and Hormones
335
It is a glucocorticosteroid and is the most important adrenocortical hormone which is physiologically
more active than cortisone. Cortisol is poorly soluble in water and it was fi rst isolated by Kendall
in 1937.
Cortisol and corticosterone are secreted by the zona fasciculate of the adrenal cortex in
response to ACTH stimulation from the anterior pituitary. ACTH secretions are, in turn, controlled
by the hypothalamic secretion of a peptide in response to varying levels of these two steroids in
the blood.
Synthesis
Route 1: From progesterone
CH OH
2
CO
O
Rhizopus nigrican
Oxidation
Progesterone
CO
O
HO
CH
3
11- Hydroxyprogesterone␣
Oxidation
CH
3
CO
O
O
Ethyl oxalate
HC
CO
COR
O
O
⫺
O
Br
2
Br
H
C
O
CO
Br
O
CH COONa
3
Favorsky reaction
CH
O
O
HOC
3
C
2
336
Pharmaceutical Chemistry of Natural Products
HOC
3
C
2
CH
O
O
O
(i) LiAlH
4
(ii) Ac O
2
(iii) Hcl
(i) OSO /H O
422
(ii) NaOH
HO
OH
CO
CORH
2
O
R = H Hydrocortisone
R = Ac Hydrocortisoneacetate
O
CH
ACcOH
2
O
Route 2: From cortisone acetate
O
H
CO
OH
CH OAc
2
O
H
H
NH NHCONH .HCl
22
⫹
Aq.CH OH–NaHCO
33
CH OAc
2
C
OH
O
HCl.H NOCHN.N
2
H
H
H
N.NHCONH .HCl
2
KBH in THF
4
HCl and excess of NaNO
2
CH OH
2
C
N.NHCONH .HCl
2
OH
H
H
H
OH
HCl.H NOCHN.N
2
Cortisone acetate
CH OH
2
C
HO
H
O
O
OH
H
H
Cortisol
Steroids and Hormones
337
Properties and uses: It is a white, crystalline powder that is insoluble in water and soluble in alcohol.
It is used in the treatment of rheumatoid arthritis, rheumatic fever, severe shock, allergic condition
and chronic lymphatic leukaemia.
Metabolism of hydrocortisone
5 -Reductase
OH
CH
3
O
HO
O
OH
Hydrocortisone
(Cortisol)
5 -Hydroxysteroid
dehydrogenase
O
O
O
OH
OH
Cortisone
(inactive metabolite)
3 -Hydroxysteroid␣
dehydrogenase
HO
HO
OH
OH
O
Urocortisol (inactive metabolite)
3 -Hydroxy-5 -tetrahydrocortisol␣
OH
OH
O
HO
O
H
5 -Dihydroxycortisol
(inactive metabolite)

Aldosterone
19
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
20
21
COCH
2
OH
OH
O
O
338
Pharmaceutical Chemistry of Natural Products
It is a mineralocorticoid which was fi rst isolated in a crystalline form by Mason et al. in 1953.
It was named as electrocortin but this name was later on changed to aldosterone because of its
aldehydic and ketonic groups. Aldosterone in solution exists as an equilibrium mixture of the 18-
aldehyde and 11,18-hemiacetal forms.
Prednisolone (Prelone, Emsolone)
4
6
O
HO
CH
2
OH
CO
OH
1
2
3
5
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Prednisolone or (17R)-11,17-dihydroxy-17-(2-hydroxyacetyl)-
10,13-dimethyl-7,8,11,12,13,15,16,17-octahydro-6 -cyclopenta
[ ]phenanthren-3(9 ,10 ,14 )-one
H
a HHH
Synthesis
O
HO
CH
2
OH
CO
OH
Hydrocortisone
Prednisolone
Corynebacterium simplex
Selective dehydrogenation
at 1 and 2 position
Properties: It is a white, crystalline powder that is sparingly soluble in alcohol. It is four times as
potent as hydrocortisone.
Steroids and Hormones
339
Metabolism of prednisolone
Prednisone
(inactive metabolite)
O
OH
O
O
OH
11 -Hydroxysteroid Dehydrogenase
OH
O
HO
OH
O
CYP 450
CYP 450
O
OH
HO
O
OH
OH
6 -Hydroxyprednisolone
(active metabolite)

O
OH
HO
O
OH
OH
17 -Hydroxyprednisolone
(active metabolism)
␣
O
HO
OH
OH
HO
Prednisolone
20 / -Hydroxysteroid
dehydrogenase
␣
20 / -Hydroxyprednisolone
(inactive metabolite)
␣
340
Pharmaceutical Chemistry of Natural Products
Dexamethasone (Dalalone)
4
6
O
HO
CH
2
OH
CO
OH
1
2
3
5
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
F
CH
3
Dexamethazone or 9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-
trimethyl-7,8,11,12,13,15,16,17-octahydro-6 -cyclopenta[ ]phenanthren-
3(9 ,10 ,14 )-one
Ha
HHH
Synthesis
O
AcO
CO
CH
3
CH MgI
3
O
HO
CO
CH
3
CH
3
O
HO
C-OAc
CH
3
CH
3
(i) Peracid
(ii) H O
2
O
HO
CO
CH
3
CH
3
OH
Br
2
O
HO
CO
CH
2
Br
CH
3
OH
CH
3
COONa
O
HO
CO
CH
2
OAc
CH
3
OH
Oxidation
Steroids and Hormones
341
Br
2
KOH
O
O
CO
CH
2
OAc
CH
3
OH
O
O
CO
CH
2
OAc
CH
3
OH
(i) Ketalization
(ii) LiA1H
4
HO
O
CO
CH
2
OAc
CH
3
OH
POCl
3
Pyridine
O
CO
CH
2
OAc
CH
3
OH
HO
O
CO
CH
2
OH
CH
3
OH
F
HO
O
CO
CH
2
OH
CH
3
OH
F
Dexamethasone
SeO
2
HO
⫹
3
(i) HOBr
(ii) Peracid
(iii) HF
Properties and uses: It is a white, crystalline powder that is soluble in alcohol and insoluble in
water. It is used as an anti-infl ammatory and antiallergic drug.
SAR of Corticosteroids
Hydrocortisone (Cortisol) is the naturally occurring glucocorticoid with mineralocorticoid activity.
The aim of medicinal chemists is to modify this structure to increase glucocorticoid potency and
decrease sodium retention capacity. The SAR studies are described herein:
Hydrocortisone
4
6
O
HO
CH
2
OH
CO
OH
CH
3
CH
3
A
B
C
D
1
2
3
5
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21