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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5726_Библиотеки_им_академика_М_И_Перельмана.pdf
Anticonvulsant Agents 115
7.9 IMINOSTILBENS AGENTS
1. Carbamazepine (Tegretol®): 5H-dibenz[b,f] azepine-5-carboxamide.
Carbamazepine is sodium ion channel blockers. Epoxide form of carbamazepine generates after
its metabolism (z) cis-stilben double bond. Carbamazepine is clinically useful in the treatment of
generalized tonic-clonic and partial seizures.
N
OC—NH
2
Fig. 7.10
Synthesis:
N
H
N
CO
NH
2
5H-dibenz[b,f] azepine
Carbamazepine
(i) C Cl (Phosgene)
(ii) NH
2
3
o
Fig. 7.11
C
HC
3
CH
25
R
1
O
R
2
+
CH
2
COOC H
25
NC
Ethylcyano acetate
C
O
HC
52
CN
HC
3
COOC H
25
HC—C—C
3
CN
COOC H
25
CH
25
CN
KCN
(i) NaOH
(ii) Hydrolysis
(iii) Decarboxylation
H C — C — CH — COOH
32
CH
25
COOH
C
NH
CH
25
HC
3
O
CO
Ethosuximide
C
NH
3
C
R=CH
R=CH
R=CH
R=CH
125
23
165
23
Ethosuximide
Phensuximide
Amination
2-butanone
Fig. 7.9
116 A Textbook of Medicinal Chemistry
2. Oxycarbazepine (Trileptal®): 10, 11-dihydro-10-oxo-dibenz [b, f] azepine-5-carboxamide
Oxycarbazepine is derivative of caramazepine. Epoxide generation after its metabolism of
carbamazepine. It attributes the side effect and may produce the condition aplastic anemia. This
side effect is reduced by the oxycarbazepine. The monohydroxy compound is the major active
metabolite of oxycarbazepine. Oxycarbazepine is used in the treatment of partial seizures.
N
OC—NH
2
O
Fig. 7.12
7.10 ALIPHATIC ACID AGENT
1. Valproic Acid (Depakene®): 2-prophylpentanoic acid. Valproic acid represents the anticonvulsant
action by blocking Na
++
channels and increases the level of GABA in the brain. Valproic acid is
employed in the treatment of myoclonic and generalized tonic-clonic seizures.
H
2
C
HC
2
HC
3
CH — COOH
HC
2
HC
2
HC
3
Fig. 7.13
Synthesis:
C
CHO
25
O
C
H
2
CN
+ 2 CH — CH — CH — Br
322
C H ONa
25
(Alkylation)
C
HC—HC—HC
322
COOC H
25
CN
HC—CH —CH
322
NaOH
(i) Hydrolysis
(ii) Decarboxylation
CH — C N
HC—HC—HC
322
HC—CH —CH
322
NaOH
Hydrolysis
CH — COOH
HC—HC—HC
322
HC— —
3
HC HC
22
Cyanoacetic ester
Propyl bromide
Dipropylacetonitrile
Valproic acid
Fig. 7.14
Anticonvulsant Agents 117
7.11 SECOND GENERATION ANTIEPILEPTIC DRUGS
O
OH
NH
2
NH
2
COOH
O
O
NH
2
O
C—NH
2
O
Vigabatrin
(Hexanoic acid derivative)
Gabapentin
(Cyclohexane derivative)
Felbamate
(Carbamate) derivative
N
N
N
Cl
Cl
HN
2
NH
2
N
O
S—NH
2
O
O
Lamotrigine
(Triazine Derivative)
Zonisamide
(Sulfonamide derivative)
S
N
H
COOH
S
CH
3
O
O
SNO
2
NH
2
O
O
CH
3
CH
3
OO
CH
3
HC
3
Tiagabine
(Nipecotic acid derivative)
Topiramate
(Sulfamate derivative)
O
HC
3
Second generation anticonvulsant are GABA analogues.
1. Vigabatrin (Sabril®): 4-amino-5-hexanoic acid. Vigabatrin is 4-amino-5-hexanoic acid. It is a
recemeate of R and S form of vigabatrin. Its isomer is an active component. Vigabatrin inhibits
GABA-transaminose enzyme therefore increases the level of GABA in the brain, hence it acts as
anticonvulsant agent.
Fig. 7.15: Second generation anticonvulsants.
118 A Textbook of Medicinal Chemistry
2. Gabapentin (Neurontin®): 1-(amino-methyl)-cyclohexane-acetic acid. Like vigabatrin gabapentin
increase the hydrophobic character, it is relative to GABA. It is identified that acts on the Ca
++
ion
channels by their inhibitory mechanism. Gabapentine is used in the therapy of partial seizures and
generalized tonic-clonic seizures.
3. Felbamate (Felbatol®): 2-phenyl-1, 3-propandiol-dicarbamate. Felbamate is carbamate derivative.
Its action has been identified by its inhibitory action on voltage dependent Na
++
channels. NMDA
receptor is also a target of felbamate. Felbamate is widely used in the treatment of generalized tonic-
clonic and partial seizures.
4. Lamotrigine (Lamictal®): 3, 5-diamino-6-[2, 3-dichlorophenyl]-1, 2, 4-triazine. Lamotrigine is
triazine analogue and is believed to have primary action on sodium ion channels by their inhibitory
action. Apart from that, lamotriqine prevents the release of glutamate. Lamotrigine is clinically used
in the treatment of partial seizures.
Synthesis:
Cl
Cl
COOH
SOCl
2
(Thionyl chloride)
Cl
Cl
COCl
KCN
(Pot. cyanide)
Cl
Cl
COCN
Cl
Cl
C
HN— —C
2
HN
NH
NH
2
(Aminoguanidine)
N
NH
C
NH
NH
2
NC
NaOC H
25
Cl
Cl
N
N
N
NH
2
HN
2
2, 3-dichlorobenzoic acid
(Lamotrigine)
Imine
Fig. 7.17
Fig. 7.16
Cl
CH
2
CH
CH
CH
2
Cl
+
CH COO—CH
25 2
COOC H · NaOC H
2525
HC CH—C—C
2
CH
2
H H
COOC H
25
COOC H
25
NH
3
CH
NH
2
HC CH
2
HC
2
CH
2
COOH
1, 4-dichloro-2-butene
Vigabatrin
Dimethyl malonate
Synthesis:
Anticonvulsant Agents 119
5. Tiagabine (Gabitril®): (R)-(–)1-[4, 4-bis-(3-methyl-thienyl-3-butenyl]-3 piperidine carboxylic
acid.
Tiagabine is a nipecotic acid derivative. It is GABA-re-uptake inhibitor and increase the required
level of GABA in the brain. Tiagabine is used against partial seizures.
6. Sulfonamide and sulfamate derivatives: Zonisamide (Zonegran®): 1, 2-benzisoxazole-3-
methanesulfonamide.
Topiramate (Topamax®): 2, 3, 4, 5-bis-O-(1-methylethyl-idene)-β-D-fructopyranose sulfamate.
Both are sodium ion channel blockers. Zonisamide is calcium-T-channels blocker while Topiramate
inhibits the action of glutamate. Kainic acid thus increases the level of GABA. Both drugs are used
against partial seizures.
7.12 OTHER MISCELLANEOUS ANTIEPILEPTIC AGENTS
1. Primidone (Mysoline®): 5-ethyldihydro-5-phenyl-4, -6-(1H, 5H)-Pyrimidinedione
Primidone is 2-deoxyanalogue of Phenobarbital. Primidone shows a potent anticonvulsant agents
in conjunction with other antiepileptic drugs, it exhibits tremendous action against seizures. It is
clinically used in the treatment of psychomotor condition, grandmal and focal epileptic stages.
HC
2
NH
C
C
NH
C
CH
25
CH
65
O
O
Fig. 7.18
Synthesis:
C—NH
2
C—NH
2
O
O
C
HC
56
CH
25
+
C
H
HN
2
O
Cyclization
HC
2
NH
C
C
NH
C
CH
25
CH
65
O
O
Primidone
Formamide
Ethyl phenyl malonamide
D
Fig. 7.19
120 A Textbook of Medicinal Chemistry
7.13 MODELS REQUIREMENTS FOR ANTIEPILEPTIC AGENTS/SAR
N—H
N
C
H
O
O
X
Y
N
CO
O
N
H
H
N
HH
Y
N
N
N
N—H
H
Cl
Cl
Phenytoin
Carbamazepine
Lamotrigine
N
O
S—N
O
H
H
HAD
N
N
N
C
O
N
H
H
Y
O
Zonisamide
Rufinamide
C—N
HC
3
H
O
N—H
H
X
X
Y
HAD
Y
X
X
Y
X
HAD
HAD
F
Fig. 7.20: Remacemide.
Note
1. Dotted lines indicate essential structural elements
2. HAD → Hydrogen donor/acceptor unit
3. X represent hydrophobic unit (Aryl ring)
4. Y represents electron donor group
Salient Features of Models
1. All the pharmacophores are based on the structure-activity data of MES-receptors.
2. All the anticonvulsant classes of pharmacophores are concerned with distinguished anti-
MES activity in the testing animals studies. All the classes include benzodiazepines, barbiturates,
triazolines, semicarbazones and enaminones respectively.
3. All distinguished classes of anticonvulsants show similar anticonvulsant profiles.
Anticonvulsant Agents 121
4. The Unverferth model postulates the favourable representation towards anticonvulsant activity
and this model also favours suitable possible candidate among the derivatives.
5. The required features include the anticonvulsant properties.
(i) Pharmacophores must have at least one aryl ring I hydrophobic unit (X)
(ii) One electron donor (Y) serve as important role.
(iii) A second donor atom in close proximity to the N-H group required for generation of
hydrogen bond acceptor/donor (HAD) unit.
D
H—A
4.2–8.5 A°
3.2–5.1 A°
H—D
HAD
2.4–2.6 A°
3.9–5.5 A°
R
Fig. 7.21: Unverferth model.
Salient Features of Unverferth Model
(i) This model is suggested for pharmacophore model for anticonvulsants in respect of voltage
dependent sodium-ion channels on the basis of molecular dynamic simulation of classes of
anticonvulsant agents.
Upcoming model of semicarbazones
The extensive series of semicarbazones postulate the lead compound among the (Aryloxy) Aryl
semicarbazones found by the several studies, is the potent Na
++
channels blockers and in future it
would be developed for the treatment of neuroleptic pain. The model is shown in figure.
O
N—C—N—N C
H
H
O
H H
F
Van der
Waals
bonds
Hydrogen
bonds
Hydrogen
bonding
area
Proximal
ring bonding
area
Distal ring
bonding
area
Fig. 7.22: 4-(4’-Fluorophenoxy) Benzaldehyde semicarbazone.
7.14 NEWER DRUGS DEVELOPMENT
(1) Harkose ride: (R)-2-Acetamido-N-benzyl-3-methoxy propionamide.
122 A Textbook of Medicinal Chemistry
Harkoseride is an amino acid derivative. Studies postulated its excellent anticonvulsant activity.
N
H
O
O
H
N
HC
3
Fig. 7.23
(2) Pregabelin (C1-1008): S-(+)-3-aminomethyl hexanoic acid.
Pregabelin acts indirectly as Ca
++
and Na
++
channel blockers. Several studies confirm that it
increases the level of GABA content in neuronal tissue. Pregabalin is used clinically in the treatment
of partial seizures and also useful to pediatric patient profile.
(3) Remacemide: (±)-2-amino-N-(1-methyl-1, 2-diphenyl-ethyl) acetamide.
Remacemide is NMDA and Na
++
channel blockers. It is a potent anticonvulsant agent due to its
ability of its neuroprotective potential. It is also indicative to Parkinson’s disease.
NH
2
CH
3
Fig. 7.24
4. Retigabine (D-23129): ethyl-N-(2-amino-4-(4-fluorobenzalamino)-phenyl carbamate. Retigabine
shows the anticonvulsant action by increasing K
+
conductance in neuronal cells. It is an active
antiepileptic agent.
N
H
H
N
NH
2
O
O
CH
3
F
Fig. 7.25
EXERCISE
1. Classify anticonvulsant agents with their various structures.
2. Differentiate between antiepileptic and anticonvulsant drugs.
3. Explain hydantoins as anticonvulsant agents.
Anticonvulsant Agents 123
4. Write the synthetic approaches, mode of action and uses of the following.
(A) Hydantoins
(B) Trimethdione
(C) Ethosuximide
(D) Valproic acid
5. What are iminostilbent? Write the synthesis of carbamazepine.
6. Give a note on second generation antiepileptic drugs.
7. Give a note on model requirements for antiepileptic drugs. (SAR of antiepileptic drugs).
124 A Textbook of Medicinal Chemistry
8
Antiparkinsonism Agents
8.1 INTRODUCTION
Parkinsonism or Parkinson’s disease (PD) is the most common form of progressive
neurodegenerative disorders. About 1 million individuals in United States (over 55 years) are affected
by the PD. However, it has been studied that its peak age of its onset 60s of affected person’s life.
The clinical features of Parkinson’s disease include bradykinesia (slowness of cognitive activities),
impairment of movement, rest tremor (85% of patients), muscular rigidity, shuffling gait and flexed
posture, etc. Parkinson’s disease is postulated by a variety of non-motor symptoms like autonomic,
sensory, sleep, cognitive and psychiatric disturbances. All types of Parkinson’s diseases result from
a dramatic reduction of dopaminergic stimulation within the basal ganglia of brain. PD affects about
1% of the general population.
Parkinson’s disorders generally characterized by an earlier age of onset (before age 45 years)
and a longer course than cases of “sporadic PD. This type of Parkinson’s disorder is generally
represented by genetic form LLRK-2 in the same age range. There are also a number of factors
which cause PD like family history, gender, head injury, exposure of pesticides, consumption of
well water, rural living factors. Other factors include coffee drinking, smoking, NSAIDS, estrogen
replacement therapy.
8.2 ETIOLOGY OF PARKINSON
Exact etiology of PD is still not known. The most likely cause of the aforementioned motor stimulation
problems may be a lack of dopamine neurotransmitter (inhibitory action on spinal cord). On the
other hand, cholinergic neurons act in regulating the extrapyramidal system. Various alkaloid drugs
like belladonna, which have characteristics of cholinergic action (reduce the sensitivity to Ach)
have been used in the treatment of Parkinson’s disorders.