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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
312
Pharmaceutical Chemistry of Natural Products
Method 3:
HO
OH
COC H
25
CHCH
3
C
CH
25
OH
C
OH
CH
25
OH
Na/Hg
(i) C H COCl
65
(ii) CH COCl–Ac O
32
C
C
CHCH
3
COOC H
65
CH
65
OOC
OH
CHCH
3
CHCH
3
C
C
HO
4-Hydroxy propiophenone
Dienoestrol
Dienoestrol dibenzoate
Alc. KOH
Properties and Uses: These are white needle-like crystals, insoluble in water and soluble in
alcohol. They are used topically only for the treatment of atrophic vaginitis and kraurosis vulvae.
Benzoestrol
It is an example of synthetic oestrogen that can be derived from hexoestrol by lengthening the
carbon chain between the phenyl groups.
HO
CH
25
CH
25
CH
3
CCC
HHH
OH
Benzoestrol
Synthesis
HCO
3
CH
2
CH
25
OHC
OCH
3
O
C
⫹
HCO
3
O
C
C
CH
25
C
H
OCH
3
C H MgBr
25
HCO
3
O
C
CH
25
C
H
C
H
OCH
3
CH MgBr
3
CH
25
Steroids and Hormones
313
HCO
3
CH
25
CH
25
CCC
HH
OH
CH
3
OCH
3
Dehydration/
Reduction
HCO
3
CH
25
CH
25
CH
3
CCC
HHH
Demethylation
OCH
3
HO
CH
25
CH
25
CH
3
CCC
HHH
OH
Benzoestrol
Structure–Activity Relationship (SAR) of Oestrogens
Presence of steroid nucleus (cyclopentanoperhydrophenanthrene ring) is essential for
pharmacological activity of oestrogens.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
A
B
C
D
CH
3
CH
3
Steroid nucleus
Modification of Ring A
1. Ring A is aromatic in nature in all the oestrogens which is essential for oestrogenic activity.
2. –OH group at C-3 is also essential for oestrogenic activity. Removal of this –OH group leads
to great loss of activity.
3. Substitution at C-1 reduces the activity.
4. Smaller groups can be substituted at positions C-2 and C-3 (e.g. 2-hydroxy ethinyl
oestradiol).
314
Pharmaceutical Chemistry of Natural Products
HO
H
O
H
H
Oestrone
OH
OH
HO
H
H
H
Oestriol
OH
HO
H
H
H
Oestradiol
Modification of Ring B
1. Presence of unsaturation at positions C-6 and C-7 increases the potency of drug. Similarly,
additional double bond between positions C-8 and C-9 further increases the activity (e.g.
equilin and equilenin).
2. 7α-Substituents show increased oestrogenic activity.
CH
3
O
H
HO
H
O
CH
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Equilenin Equilin
Modification of Ring C
1. Substitution of –OH groups at positions C-6, C-7 and C-11 reduces the activity.
2. Substituting with alkyl group or alkoxy groups which has 17-ethinyl group at C-11 β-position
greatly increases the affi nity for the oestrogenic receptor compared to oestradiol (e.g. 11β-
methoxy or 11β-ethyl oestradiol).
3. –CH
2
Cl group at C-11 with β-confi guration shows more potent activity.
4. N,N-dialkyl undecylamides (an example of larger substituent) show antagonistic activity.
Modification of Ring D
1. 17β-OH is essential for oestrogenic activity.
2. Epimerization of 17β-OH to α-confi guration results in the formation of less active
analogues.
Steroids and Hormones
315
3. 17α-Ethinyl or 17α-vinyl groups provide greatest activity due to increase in polarity (e.g.
ethinyl oestradiol).
HO
OH
CCH
17 -Ethinyl oestradiola
4. Reversal of C-2 confi guration or replacement of ‘H’ for ethinyl in ring D leads to loss of
oestrogenic activity or increase in androgenic activity.
5. The distance between C-3 and C-17 –OH groups should be 10–12 Å; presence of this
hydrophobic scaffolding helps to optimize oestrogenic activity (e.g. as seen in all oestrogens
and diethylstilbestrol).
HO
CH
25
CC
CH
25
OH HO
CH
3
CCC
HHH
CH
25
CH
25
OH
BenzoestrolDiethylstilbestrol
CORPUS LUTEUM HORMONES OR GESTOGENS OR PROGESTINS
Progestin means favouring pregnancy. These are substances secreted in the corpus luteum which
convert the oestrogen-primed endometrium to secretory endometrium and maintain pregnancy
in animals spayed after conception.
The key endogenous steroid hormone that acts at the progesterone receptors is progesterone. It
is one of the most important members of gestagens. All other endogenous steroids lack signifi cant
progestational action.
For biosynthesis of progesterones refer to Biosynthesis of Sex Steroid Hormones on
pages 284–285.
316
Pharmaceutical Chemistry of Natural Products
Metabolism of Progesterone
O
O
Progesterone
O
OH
20 -Hydroxy progesteronea/b
HO
OH
5 -Pregnanediolb 6 -Hydroxy progesteronea
O
O
OH
Biological Activities of Progestins
Progesterone has various pharmacological actions, with the main target tissues being the uterus,
breast and brain. Progesterone in the uterus helps in the development of secretory endometrium.
It also acts to thicken cervical secretions, decreasing cervical penetration by sperm. Progesterone is
important for the maintenance of pregnancy by suppressing menstruation and decreasing uterine
contractility. During pregnancy, progesterone acts in conjunction with oestrogens to prepare the
breast for lactation.
Therapeutic Uses of Progestins
Therapeutic uses of progestins are as follows:
1. A signifi cant use of the progestins, as of the oestrogens, is inhibition of ovulation.
2. The combination of progestin with oestrogens may signifi cantly reduce the risk of endometrial
cancer in women taking postmenopausal oestrogens.
Steroids and Hormones
317
3. Progestins have been used very effectively to treat primary and secondary amenorrhoea,
functional uterine bleeding and related menstrual disorders caused by hormonal defi ciency
or imbalance.
4. Progestins can be used for palliative treatment of advanced carcinoma of the breast or
endometrium.
Classification of Progesterones
1. Derivatives of progesterone
O
CH
3
HC
3
CH
3
O
H
H
H
Progesterone
H
O
O
O
O
HC
3
CH
3
CH
3
H
H
Hydroxyprogesterone caproate
O
CH
3
H
H
H
CH
3
HC
3
O
O
O
CH
3
Megesterol acetate
O
HC
3
CH
3
CH
3
CH
3
H
H
H
O
O
O
Medroxyprogesterone acetate
2. Synthetic progesterones
CH
3
H
O
CH
3
OH
H
H
H
Ethisterone
OH
CH
3
H
H
H
H
H
O
Norethindrone
318
Pharmaceutical Chemistry of Natural Products
CH
3
CH
3
OH
H
H
H
CH
3
CH
3
O
Dimethisterone
CH
3
OH
H
H
H
H
O
Norethynodrel
H
H
H
H
CH
3
H
OAc
AcO
Ethynodiol diacetate
OH
H
O
H
H
H
H
H
3
C
Desogestrel
O
H
H
H
H
OH
H
3
C
H
Etonogestrel
Norgestromin
H
H
H
H
H
3
C
OH
H
HON
O
H
3
C
H
H
H
H
OH
H
Norgestrel
HON
H
H
H
H
H
3
C
OAc
H
Norgestimate
O
Progestins of Pharmaceutical Importance
Progesterone
Progesterone is a stable white crystalline solid with two polymorphic forms, i.e. prism and needle
form. Progesterone was isolated from the corpus luteum, the adrenal cortex, the placenta and the
testes. During the period of full corpus luteum activity, the human ovary produces about 1000 mg
of progesterone daily.
Isolation: After mincing, the ovaries are treated with CH
3
OH. The methanolic extract is diluted
with water and then fi ltered to remove the impurities (fatty matter). The fi ltrate is treated with
petroleum ether when progesterone is extracted into the petroleum ether. The solvent (petroleum
ether) is evaporated and the residue is treated with ethanol followed by addition of water, and again
Steroids and Hormones
319
progesterone is extracted from this by petroleum ether while oestrone remains in the alcoholic
phase. The petroleum ether extract when chilled to 20°C yields crystalline progesterone.
Synthesis
From cholesterol:
HO
H
H
H
AcO
H
H
H
Br
Br
Cholesterol
(i) Ac O
(ii) Br
2
2
(i) CrO –CH COOH
(ii) Zn–CH COOH
33
3
O
HO
H
H
H
AcO
H
H
H
HO
CN
AcO
H
H
H
CN
AcO
H
H
H
CO
CH
3
HO
H
H
H
CO
CH
3
Pregnenolone
O
H
H
H
CO
CH
3
Progesterone
(i) Ac O
(ii) HCN
2
POCl in pyridine at 150°C
3
Dehydroepiandrosterone
CH MgBr
3
(i) H –Raney Ni
(ii) Hydrolysis
2
Oppenauer
oxidation
320
Pharmaceutical Chemistry of Natural Products
From diosgenin:
O
O
CH
3
Diosgenin
HO
O
CO
CH
3
Ac O
2
200°C
CrO
3
CH
3
COOH
O
O
COCH
3
CH
3
CH
3
CO
H
3
COOC
CH
3
CO
HO
(i) H –Pd
2
(ii) Hydrolysis
Oppenauer oxidation
CH
3
C O
H
H
O
Progesterone
Steroids and Hormones
321
From ergosterol:
HCO
3
HCl
Heat
Isoergosterone
O
H /Pd–C
2
O
3
CHO
O
O
HN
CH
N
O
AcOH
Na Cr O
227
O
H
H
CH
3
CO
Progesterone
Oppenauer oxidation
O
Ergosterone
HCl in CH OH
3
Ergosterol
HO
Properties: White crystalline powder, insoluble in water and alcohol.