Download Dopamine Agonist

항 파킨슨씨 약물
Anti-Parkinson Drug
파킨슨씨병 의 날
4월 11일
Substansia Nigra
(흑질)
History of Parkinson’s Disease
Parkinon’s small but famous publication, "Essay on the Shaking
Palsy", appeared in 1817, 7 years before his death in 1824.
Epidemiology
 Average incidence is 20 per 100,000 in North
America
 1 Million affected in the United States
 50,000 new cases per year
 Cost estimated to exceed $5.6 Billion annually
Diagnostic Features
Typical
Signs of Parkinsonism
•Four
Four
Cardinal
Signs
–
–
–
–
Tremor
Rigidity
Akinesia and bradykinesia
Postural instability
Parkinson’s Disease
Reduction
of
inhibitory
Dopamine
rgic
Neron
Imbalance
of Ach &
DA
Pakinson
Syndrome
Positron-Emission Tomography
Antiparkinson’s Drug
Treatment for Parkinson’s disease
DA Synthesis
MAO-B
inhibitor
Dopamine
Anti-
receptor
Muscarinic
agonist
Pakinson
syndrome
agent
Parkinson’s disease 예방
담배와 파킨슨씨병
Drug Interaction
Structure of Drug for Parkinson’s Disease
16
Why L-Dopa instead of DA?
• If dopamine is too polar to cross the BBB, how can
L-DOPA cross it?
NH3+
HO
NH3+
HO
Polar groups
HO
Dopamine
NH3+
HO
HO
O
O
H
L-DOPA
(In Blood)
Polar groups
Mostly protonated
to the corresponding
ammonium salt
HO
L-DOPA
O
O
Mostly protonated
to the corresponding
ammonium salt
H
Polar group
Active Transport
HO
(crosses BBB)
HO
NH3+
O
O
H
L-DOPA
(In Brain)
Dopamine Decarboxylase
(DDC)
(In Brain)
NH3+
HO
HO
Dopamine
Trojan horse Approach for Carrier Protein
Recognized as amino acid
by carrier protein
19
20
The Effect of Carbidopa on the metabolism of L-Dopa
CH3
CO2H
HN
HO
OH
Carbidopa
NH2
The Action of Selegiline in the metabolism of Dopamine
CH3
H3C
N
Selegiline
The mechanism of Entacaone as Anti-parkinsonism
CH3
CO2H
HN
HO
OH
Carbidopa
NH2
O
O2N
NEt2
CN
HO
OH
Entacapone
Muscarine Antagonist
☞ Chemical Name:
3-(1-Piperidyl)-1-cyclohexyl-1-phenyl-1-propanol HCl
a-Cyclphexyl-a-phenyl-1-piperidinepropanol HCl
☞ Trade Name:
트리헥산 정 (태극), 염산트리헥시딜 정 (장우), Artane® (Lederle)
24
Retrosynthesis of Trihexylphenidyl
N
O
a 
N
HO
MgBr
+
Trihexylphenidyl
Mannich rx
O
a
HCHO
HN
Muscarine Antagonist
☞ Chemical Name:
:1-(Bicyclo[2.2.1]hept-5-en-2-yl-1-phenyl-3-phenyl-3-(piperidin1-yl)propan-1-ol HCl
:a-(2-Norbonenyl)-a-pheny-1-piperidinepropanol HCl
☞ Trade Name:
아톨 정 (유나이티드), 염산비페리덴 정 (풍림), Akineton® (Abbot)
Muscarine Antagonist
27
Mannich Reaction
Dopamine Agonist
☞ Chemical Name:
:(S)-2-Amino-3-(3,4-dihydroxyphenyl)propanic acid
☞ Trade Name:
레보다 서방정 (산도스), 스다레보 필름코팅 정 (노바티스), 씨네메트/씨알정
(MSD), 콤비도파 서방정(노바티스)
Stalevo® (a mixture of L-DOPA, carbidopa, entacapone, Orion
29
Side Effect of levodopa
Drug Interactions
34
Why L-Dopa, not Dopamine ?
Not cross the BBB
In Brain
NH3+
HO
HO
O
O
H
L-DOPA
(In Blood)
Cross the BBB
Active Transport
HO
(crosses BBB)
HO
NH3+
O
O
H
L-DOPA
(In Brain)
Dopamine Decarboxylase
(DDC)
(In Brain)
NH3+
HO
HO
Dopamine
Retro synthesis of L-DOPA
NH2
HO
CO2H
CO2H
CO2H
NH2
HO
O
OH
NH2
HO
O
Bayer-Villiger Ox
O
L-Tyrosine
S
CO2H
F,C Reaction
HO
NH2
L-Tyrosine
O
Cl
L-DOPA
37
38
Regiochemistry of Bayer-Villiger-Oxidation
Retrosyntheis of L-DOPA(II)
CO2H
CO2H
NH2
HO
OH
NHAc
AcO
OAc
CO2H
O
+
HO
OH
NHAc
L-DOPA (Dopamine Agonist)
41
Carbidopa
☞ Chemical Name:
:(S)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid
☞ Trade Name:
: Stalevo® (a mixture of L-DOPA, carbidopa, entacapone, Orion
Levodopa & Carbidopa
Nausea and Vomiting
Retrosynthesis of Carbidopa
KCN + NH2NH2
CO2H
CN
HN
HO
NH2
HN
HO
OH
NH2
O
HO
OMe
OMe
Carbidopa
NH
HO
OMe
OMe
O
HO
OMe
NH2
HO
NO2
NO2
HO
OMe
Dopamine Agonist
Dopamine Agonist
46
Dopamine Agonist
47
Dopamine Agonist
Ropinirole
☞ Chemical Name:
4-[2-(Dipropylamino)ethyl-1,3-dihydro-2H-indol-2-one
☞ Trade Name:
: RopiniroleHCl: 뉴큅 정 (유한), 로큅 정 (대웅), 로피맥스 전 (고려), 파로킨 정 (현대),
도파로핀(일동), 로킨스 정(신풍). 리큅피디 정 (글라고스미스클라인)
: Ropinirole: 리큅 정 (글락소스미스클라인, ropinirole), Requip (GSK)
Retrosynthesis of ropinirole
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
OH
N
H
OH
O
NO2
OH
O
NH2
O
Ropinirole•HCl
N(n-Pr)2
HO2C
O
NO2
EtO
CO2Et
O
NO2
CO2H
O
NO2
Dopamine Agonist
Synthesis of Ropinirole
N(n-Pr)2
HO2C
SOCl2
NO2
EtO
CO2Et
then
(n-Pr)2NH
toluene/H2O
rt, 1 h, 90%
reflux, 1 h
83%
NO2
N(n-Pr)2
N(n-Pr)2
30% H2O2
CO2H 2% NaOH
O
KOEt, EtOH
rt, 8 h
52%
O
O
NO2
N(n-Pr)2
BH3
THF
rt, 1 h
80%
CO2H
NO2
CH3
Highly Acidic Proton
NO2 Why???
H2 (50 psi)
Pd/C
EtOH
rt, 5 h
78%
N(n-Pr)2
N
H
O
Ropinirole•HCl
selegiline
CH3
H3C
N
Selegiline
(R)-N-methyl-N-(1-phenylpropan-2-yn)-1-amine
유멕스 정(사노피-아벤티스 코리아), 아오비 정(초당), Eldepryl(Somerset)
Retrosynthesis of Selegiline
CH3
H3C
N
Selegiline
CH3
Br
H3 C
N
H3C
NH
Metamphetamine
OH
CH3
H3C
NH
Ephedrine
CH3
H3C
N
CH3
O
Dopamine Agonist
Synthesis of Selegiline
Dopamine Agonist
Asymmetric Synthesis of Selegiline
Dopamine Agonist
Entacapone
☞ Chemical Name:
(E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)-propenamide
☞ Trade Name:
: 콤탄 정 (노바티스), 스타레보 필름코팅 정 (L-DOPA 및 Carbidopa 와 복합제, 노바티
스), Comtan® (Orion)
Retrosynthesis of Entacapone
O
O2N
NEt2
CN
HO
OH
Entacapone
O2N
O
O
NEt2
+
HO
OH
CN
Knoevenagel Condensation
Dopamine Agonist
Synthesis of Entacapone