Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5987_Библиотеки_им_академика_М_И_Перельмана.pdf
322
Pharmaceutical Chemistry of Natural Products
Progesterone derivatives
O
C
CH
3
R
1
O
R
1
19
11
14
18
17
Name
Progesterone
Hydroxy progesterone caproate
Hydroxy progesterone acetate
R
–H
–H
–CH
3
R
1
–H
–OCO(CH ) CH
24 3
–OCOCH
3
Hydroxy progesterone caproate
O
CO
CH
3
OCO
(CH
2
)
4
CH
3
HO
22
HO
O
HBr
Pregnenolone
CO
CH
3
HO
CO
CH
3
Steroids and Hormones
323
AcO
CO
CH
3
OCO
(CH
2
)
4
CH
3
CO—(CH ) CH
24 3
CO—(CH ) CH
24 3
O
(i) CH OH
3
(ii) Oppenauer oxidation
AcO
CO
CH
3
OH
AC O
2
HO
CO
CH
3
OH
Br
17- -Hydroxypregnenolonea
HO
CO
CH
3
OH
H /CH COONH
23 4
O
CO
CH
3
OCO
(CH
2
)
4
CH
3
17- -Hydroxyprogesterone
caproate)
a
Properties and uses: It is a white, crystalline powder insoluble in water. It is more potent than
progesterone, with longer duration of action with short onset of action.
324
Pharmaceutical Chemistry of Natural Products
SAR of Progesterones
Presence of steroid nucleus (cyclopentanophenanthrene ring) is compulsory for pharmacological
activity of progestins.
CH
3
CH
3
AB
CD
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Steroid nucleus
19
O
CH
3
CH
3
H
H
O
H
3
C
H
Progesterone
1. Ketone group at C-3 is not essential for the activity of progesterone, because even its removal
retains the progesterone activity (e.g. desogestrel).
HC
3
OH
H
H
H
H
H
Desogestrel
O
2. Presence of ethyl or ethinyl or diethyl group at C-17 in α-confi guration increases bioavailability
through oral route, but decreases by subcutaneous route (e.g. ethisterone).
CH
3
OH
H
H
H
H
Ethisterone
CH
3
O
3. The L-enantiomer of the compound resulting from the substitution of ethyl group at C-ring
juncture is found to be active.
4. Derivatives of the progestins such as 3-oxime-17-ester decrease androgenic side effect, while
retaining the progestin activity.
Steroids and Hormones
325
5. Introduction of halogen or CH
3
at C-6 or C-7 atoms in α-confi guration increases hormonal
activity of progestins (e.g. medroxy progesterone acetate).
O
CH
3
CH
3
CH
3
H
H
O
O
O
H
3
C
H
Medroxyprogesterone acetate
6. Presence of methyl at C-19 is not essential for activity because its removal leads to formation
of compound with increased activity (e.g. norethindrone).
CH
3
OH
H
H
H
H
Norethindrone
H
O
7. Addition of Cl or F at C-21 prevents metabolic hydroxylation and also enhances oral
effectiveness.
8. Unsaturation at rings A and B enhances activity of 19-norethindrone (e.g. trimegestone).
9. Addition of methyl at eighteenth position increases the activity.
10. In ring D at C-17 position, acetylation of 17α-hydroxyl group increases the duration of action
(e.g. norethindrone acetate).
O
H
CH
3
H
H
OCOCH
3
H
Norethindrone acetate
H
326
Pharmaceutical Chemistry of Natural Products
HORMONAL CONTRACEPTIVES
Because of our alarming population trends, antifertility drugs are the need of the day. These are
hormonal preparations used for reversible suppression of fertility. In 1955, successful use of an
oral progestin for contraception was found, and soon it was discovered that addition of a small
quantity of an oestrogen enhances their effi cacy.
Oral Contraceptives
A variety of oral preparations are now available (Table 6.6) as per individual choices.
1. Combined pill: It contains an oestrogen and a progestin, while both oestrogens and progestins
synergistically inhibit ovulation, the progestin ensures prompt bleeding at the end of a cycle
and blocks the risk of developing endometrial carcinoma because of oestrogen. This is the
most popular and most effi cacious method.
2. Phased regimens: This is recommended for women over 35 years of age or when other risk
factors are present. These have been introduced to reduce steroid dose without compromising
effi cacy. It may be biphasic or triphasic. The oestrogen dose is kept constant while the
amount of progestin is low in the fi rst phase and progressively higher in the second and third
phases.
3. Mini pill (progestin-only pill): A low-dose progestin-only pill taken daily continuously without
any gap. It has been devised to eliminate oestrogen, mainly because of the long-term risks.
4. Postcoital (emergency) contraception: Currently three regimens are available:
Table 6.6 Oral contraceptives
Trade name Progestin (dose) Oestrogen (dose)
Combined pills
Mala-D (21 tabs + 7 ferrous sulphate
(60 mg) tabs)
Norgestrel (0.3 mg)
Ethinyl oestradiol (30 μg)
Ovral-G Norgestrel (0.5 mg) Ethinyl oestradiol (50 μg)
Ovral-L, Bandhan Levonorgestrel (0.15 mg) Ethinyl oestradiol (30 μg)
NOVELON Desogestrel (0.15 mg) Ethinyl oestradiol (30 μg)
FEMILON Desogestrel (0.15 mg) Ethinyl oestradiol (20 μg)
Phased pills
TRIQUILAR (6 + 5 + 10 tabs) Levonorgestrel (50–75–125 μg) Ethinyl oestradiol (30–40–30 μg)
Ortho-Novum
(7 + 7 + 7 tabs)
Norethindrone (0.5–0.75–1.0 mg) Ethinyl oestradiol (35–35–35 μg)
Postcoital pills
Ovral, DUOLUTON-L (2 + 2 tabs) Levonorgestrel (0.25 mg) Ethinyl oestradiol (50 μg)
NorLevo, Ecee2 (1 + 1 tab) Levonorgestrel (0.75 mg ) Nil
Mini pills
Micronor Norethindrone (0.35 mg) Nil
Steroids and Hormones
327
The regimen called Yuzpe method has been the most popular. It is estimated to prevent three
out of four possible pregnancies.
Levonorgestrel 0.5 mg + ethinylestradiol 0.1 mg (two Ovral tablets) taken as early as possible
but within 72 h of unprotected intercourse and repeated after 12 h.
Emergency postcoital contraception should be used for unexpected or accidental exposure
(rape, condom rupture) only, as it has higher failure rate and side effects than regular low-dose–
combined pill.
Side effects: The signs and symptoms are similar to those usually occurring during pregnancy.
Women using oral contraceptives experience undesirable side effects such as nausea, vomiting,
breast fullness, mastalgia, headache, dizziness, depression, apathy, fatigue, pelvic pain and
chloasma. Fluid retention and weight gain are also observed. This is due to the mild increase
in aldosterone secretion by the adrenals or because of some anabolic activity inherent in the
steroid.
CORTICOSTEROIDS (ADRENAL CORTICAL HORMONES)
The adrenal glands located in the superior part of kidney consist of two distinct parts, namely the
medulla and the cortex. The medulla synthesizes catecholamines (adrenaline), while the cortex
synthesizes a number of steroid hormones. The production of these adrenocortical hormones has
been controlled by adrenocorticotrophic hormone (ACTH) which is produced in the anterior lobe
of the pituitary.
Glucocorticoids or mineralocorticoids are labelled as per the type of actions found among
corticoids, which includes natural gluco- and mineralo-corticoids and their synthetic analogues.
Their main function is to maintain fl uid–electrolyte, cardiovascular and energy substrate
homeostasis and functional status of skeletal muscles and nervous system. They also prepare the
body to withstand effects of all kinds of noxious stimuli and stress.
Mineralocorticoids enhance Na
+
resbsorption in the distal convoluted tubule in kidney and
maintain Na
+
, K
+
and fl uid balance in body. Hence, they control blood volume and blood pressure
by maintaining proper electrolyte balance (e.g. aldosterone and 11-deoxycorticosterone).
Biological Effects of Glucocorticoids
1. They act on carbohydrate and protein metabolism and promote glycogen deposition in the
liver.
2. They promote lipolysis due to glucagon, growth hormone, adrenaline and thyroxine.
3. They inhibit intestinal absorption and enhance renal excretion of Ca
2+
.
4. They restrict capillary permeability, maintain tone of arterioles and myocardial contractility.
5. They suppress the attending infl ammatory response, irrespective of the type of injury or
insult.
328
Pharmaceutical Chemistry of Natural Products
Biosynthesis of the Adrenocorticoids from Cholesterol
HO
Cholesterol
O
HO
Pregnenolone
O
HO
OH
17 -Hydroxy pregnenolone␣
O
O
Progesterone
OH
O
O
17 -Hydroxy progesterone␣
HO
O
O
21-Hydroxy progesterone
Steroids and Hormones
329
HO
O
OH
O
11-Deoxycortisol
O
HO
HO
O
Corticosterone
Aldosterone
HO
O
CHO
COCH OH
2
HO
OH
O
O
HO
Hydrocortisone
Therapeutic Uses of Glucocorticoids
Therapeutically they are used in the following conditions:
1. Acute adrenal insuffi ciency
2. Chronic adrenal insuffi ciency (Addison’s disease)
3. Congenital adrenal hyperplasia (adrenogenital syndrome)
4. Rheumatoid arthritis
5. Severe allergic reactions
6. Autoimmune diseases
7. Bronchial asthma
8. Eye diseases
9. Skin diseases
330
Pharmaceutical Chemistry of Natural Products
Classification of Corticosteroids
1. Mineralocarticoids with high salt retention
OH
O
CH
3
H
OH
O
O
H
H
Aldosterone
O
O
CH
3
CH
3
H
H
H
OH
11-Deoxycorticosterone
O
CH
3
CH
3
CH
3
O
O
O
OH
HO
F
H
H
Fludrocortisone acetate
2. Glucocorticoids with moderate-to-low salt retention
CH
3
O
CH
3
H
H
H
CH
3
O
O
O
O
OH
Cortisone acetate
HO
O
CH
3
CH
3
H
H
H
O
OH
OH
Hydrocortisone
(Cortisol)
O
O
O
OH
CH
3
CH
3
H
H
H
OH
Prednisone
O
O
OH
OH
CH
3
CH
3
HO
H
H
H
Prednisolone
Steroids and Hormones
331
O
O
OH
CH
3
CH
3
OH
H
H
H
HO
H
CH
3
Methylprednisolone Betamethasone
O
CH
3
CH
3
O
OH
OH
CH
3
HO
H
H
H
F
Dexamethasone
O
O
OH
OH
CH
3
CH
3
CH
3
HO
H
H
H
F
Ophthalmic glucocorticoids
Medrysone
O
CH
3
HO
H
O
CH
3
H
H
CH
3
CH
3
OH
O
F
HO
CH
3
CH
3
CH
3
CH
3
H
H
O
Fluorometholone
O
CH
3
HO
H
O
CH
3
CH
3
CH
3
CH
3
H
H
Rimexolone
CH
3
CH
3
CH
2
Cl
O
O
O
O
O
O
HO
H
H
H
Loteprednol etabonate