MEDICINAL CHEMISTRY

Hydralazine is a direct relaxant of vascular smooth muscle for the treatment of moderate
to severe hypertension. It causes reflex tachycardia and fluid retention; therefore, it
should always be given in combination with a β-adrenergic receptor blocker and a
diuretic. Nitric oxide can be generated from hydralazine; therefore, its action is similar in
mechanism to sodium nitroprusside and organic nitrites. Headache, palpitations, and GI
disturbances are the most frequent adverse effects. The major metabolite is hydralazine
pyruvic acid hydrazone. Dose: 25 to 100 mg oral twice daily; 20 to 40 mg i. v. in
emergency.
Minoxidil (Loniten): 6-(1-Piperidinyl)-2, 4-pyrimidine diamine 3-oxide (91)
Synthesis: It can be prepared starting from ethylcyano acetate in the following way:
C N
CH 2
O C OC2H5 H 2N
+ C NH
H 2N
C 2H 5ONa
H 2N N
N NH 2
POCl 3
N NH2 Ethylcyno acetate (124) (125) (126)
OH
OH
O
Cl
H 2N
CO 3H
(127)
O
N NH 2
Cl
N
H
N
H 2N
H 2N
N NH 2
N
N
Minoxidil (91)
It occurs as a white, crystalline solid soluble in water. Minoxidil (91), a piperidino
pyrimidine derivative directly relaxes arterial smooth muscle and is indicated for patients
with severe hypertension who do not respond to other drugs. It causes considerable Na +
retention and tachycardia, which necessitate concomitant use of diuretic and β-adrenergic
blocking agents. It is biotransformed to an active metabolite, minoxidil N→O sulfate,
which releases vascular smooth muscles and increases the permeability of the cell
membrane to K + , resultant hyperpolarization. Minoxidil (91) also causes hirusutism, a
side effect that has prompted its development as a treatment (Rogaine 2% solution) for
baldness. Dose: Initial 5 mg; can be increased to 40 mg/ day.
Diazoxide (Hyperstat):7-Chloro-3-methyl-2H-1, 2, 4-benzothiadiazine- 1, 1 –dioxide
(90).
Synthesis: It can be prepared by condensing 2, 4- dichloro nitrobenzene (128) and
benzylthiol in the following way:
N