决奈达隆 抗心律失常药物
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6
Multichannel blocking agent
Singh D. Dronedarone for Atrial Fibrillation :Have We Expanded the Antiarrhythmic Armamentarium? 2010
Potential Role for Dronedarone in AF
left ventricular hypertrophy +
left ventricular hypertrophy -
dofetilide sotalol
advanced or recently decompensated heart failure
less advanced and without recently decompensated heart failure
Samples
1.healthy humans (plasma）、 2.goats (plasma and myocardium)
mobile phase
acetonitrile,isopropanol, water and ammonia (80/10/10/0.025, v/v/v/v)
flow-rate Sample preparation
dronedarone
7
Singh D. Dronedarone for Atrial Fibrillation :Have We Expanded the Antiarrhythmic Armamentarium? 2010
Synthesis
scheme1
DCE=Dichloroethane MEK= Methyl Ethyl Ketone
(13)
(14)
aq,HCl,-H2O
one pot
(8) (15)
aq,HCl,-H2O
(16)
(7)
91.0%
(17)
10
US.Pat.20050049302
Key Intermediates
Cl
O n-Bu NO2
(1)
.
HCl N
O O
(8)
2-(n-butyl)-5-nitrobenzofunan
It needs further studies!!!
16
17
DMF=N,N-Dimethylformamide
US5223510 WO2008139056A1 WO2008152217A2
(20) (18) (19)
(1) (22)
NaH,DMF
(23)
(25) (21) (24)
Байду номын сангаас12
盐酸决奈达隆合成路线图解、WO2008152217
Synthesis of (8)
amiodarone dofetilide dronedarone
amiodarone dronedarone
Flecainide propafenone sotalol
amiodarone dofetilide
amiodarone dofetilide
amiodarone dofetilide dronedarone
14
Robert W. Boldermana ，Journal of Chromatography B.2009
Conclusion
Plasma
Calibration curves ：0.01–5 µg/ml Lower limit of quantification (LLOQ) ：0.04 µg/ml
1.deproteinization with acetonitrile 2.extraction with a mixture of heptane and dichloromethane 1 ml/min
column
a Pathfinder PS polymeric C18 column (50 mm × 4.6 mm, 2.5 µm)
决奈达隆
DRONEDARONE
——一种治疗房颤的抗心律失常药物 ——一种治疗房颤的抗心律失常药物
1
CONTENTS
Intruduction
Synthesis
Determination
2
Antiarrhythmic Drug
Cardiac Arrhythmia——a condition in which the heart beats with an irregular or abnormal rhythm
Myocardium
linear curves ：0.02–500 µg/g LLOQ：0.08 µg/g.
All
Within- and between-day precision：<18%, Accuracy ：97.5 - 109.7%, Recovery ：67.6 - 79.9%.
The present method is sensitive and specific!
DRONEDARONE
Sanofi-Aventis,
N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5benzofuranyl]methylsulfonamide
N-(2-丁基-3-(4-(3-二丁基氨基丙氧基)苯甲酰基) -5苯并呋喃基)甲磺酰胺
tachycardia
classification
bradycardia Class I Na+channel blocker ：flecainide氟卡胺
Class II β-blocker：propranolol普萘洛尔
drugs
Class III K+channel blocker ：amiodarone胺碘达隆 Class IV Ca2+channel blocker ：diltiazem地尔硫卓 3 3
AF Efficacy
Class III antiarrhythmic drug Delay in recurrences of AF or maintenance of sinus rhythm Rate control：the ability to control both rhythm and rate Safty：as second-line agents for lowintermediate risk stable patients
11
4-(3-dibutylaminopropoxy)benzoyl chloride hydrochloride
4-(3-二正丁基氨基丙氧基 苯甲酰氯 二正丁基氨基丙氧基)苯甲酰氯 二正丁基氨基丙氧基 盐酸盐
11
2-正丁基 硝基苯并呋喃 正丁基-5-硝基苯并呋喃 正丁基
Synthesis of (1)
Atrial Fibrillation（房颤） （房颤）
Atrial fibrillation (AF) is the most common of the serious cardiac rhythm disturbances
AF AF
P wave
Conduction
ECG
Common drugs amiodarone 胺碘达隆、dofetilide多非利特、sotalol索他洛尔 flecainide氟卡胺、propafenone丙胺苯丙酮 4
15
Dronedarone may be best viewed only as half a step forward in our efforts to expand the antiarrhythmic armamentarium.
Uncertainties remain in the clinical effectiveness and cost-effectiveness of dronedarone
dronedarone
Dronedarone is a noniodinated benzofuran derivative that is pharmacologically related to amiodarone
amiodarone
5
JEAN-YVES LE HEUZEY. M.D. Study to Evaluate the Efficacy and Safety of Dronedarone versus Amiodarone.2010
H
aq,HCl aq HCl
HOOC
(30)
O(CH2)3N(n-Bu)2.HCl SOCl2
75.5-90%
O Cl Cl O
(28)
(8)
O(CH2)3N(n-Bu)2.HCl
13
CN101153012 B
Determination
The determination of dronedarone and its metabolite in both plasma and myocardial tissue by HPLCcoupled with uv-detection.
Drug therapy for maintenance of sinus rhythm
No(or minimal) heart disease
Hypertension
Coronary artery disease
Heart failure
Flecainide propafenone sotalol
Cl N
K2CO3/DMF COOCH3 COOCH3
H3COOC
(29)
O(CH2)3N(n-Bu)2
COOCH3
tol ue ne
(27)
Cl K2CO3/MEK Br
O(CH2)3Br
KtB
OH
(n -B u)
K2CO3
2N
(26)
Br(CH2)3Br
60%
70 %85 %
NH (n-Bu)2
(1)
(2)
(3)
K2CO3/MEK
(5)
(4)
8
US.Pat.5223510
THF=tetrahydrofuran scheme2
(1)
(6)
Cl O
(7) (8)
O(CH2)3N(n-Bu)2.HCl
90%
9
WO.2002048132
scheme3
(9)
(10)
(11)
Base
(12)
Base
Multichannel blocking agent
Singh D. Dronedarone for Atrial Fibrillation :Have We Expanded the Antiarrhythmic Armamentarium? 2010
Potential Role for Dronedarone in AF
left ventricular hypertrophy +
left ventricular hypertrophy -
dofetilide sotalol
advanced or recently decompensated heart failure
less advanced and without recently decompensated heart failure
Samples
1.healthy humans (plasma）、 2.goats (plasma and myocardium)
mobile phase
acetonitrile,isopropanol, water and ammonia (80/10/10/0.025, v/v/v/v)
flow-rate Sample preparation
dronedarone
7
Singh D. Dronedarone for Atrial Fibrillation :Have We Expanded the Antiarrhythmic Armamentarium? 2010
Synthesis
scheme1
DCE=Dichloroethane MEK= Methyl Ethyl Ketone
(13)
(14)
aq,HCl,-H2O
one pot
(8) (15)
aq,HCl,-H2O
(16)
(7)
91.0%
(17)
10
US.Pat.20050049302
Key Intermediates
Cl
O n-Bu NO2
(1)
.
HCl N
O O
(8)
2-(n-butyl)-5-nitrobenzofunan
It needs further studies!!!
16
17
DMF=N,N-Dimethylformamide
US5223510 WO2008139056A1 WO2008152217A2
(20) (18) (19)
(1) (22)
NaH,DMF
(23)
(25) (21) (24)
Байду номын сангаас12
盐酸决奈达隆合成路线图解、WO2008152217
Synthesis of (8)
amiodarone dofetilide dronedarone
amiodarone dronedarone
Flecainide propafenone sotalol
amiodarone dofetilide
amiodarone dofetilide
amiodarone dofetilide dronedarone
14
Robert W. Boldermana ，Journal of Chromatography B.2009
Conclusion
Plasma
Calibration curves ：0.01–5 µg/ml Lower limit of quantification (LLOQ) ：0.04 µg/ml
1.deproteinization with acetonitrile 2.extraction with a mixture of heptane and dichloromethane 1 ml/min
column
a Pathfinder PS polymeric C18 column (50 mm × 4.6 mm, 2.5 µm)
决奈达隆
DRONEDARONE
——一种治疗房颤的抗心律失常药物 ——一种治疗房颤的抗心律失常药物
1
CONTENTS
Intruduction
Synthesis
Determination
2
Antiarrhythmic Drug
Cardiac Arrhythmia——a condition in which the heart beats with an irregular or abnormal rhythm
Myocardium
linear curves ：0.02–500 µg/g LLOQ：0.08 µg/g.
All
Within- and between-day precision：<18%, Accuracy ：97.5 - 109.7%, Recovery ：67.6 - 79.9%.
The present method is sensitive and specific!
DRONEDARONE
Sanofi-Aventis,
N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5benzofuranyl]methylsulfonamide
N-(2-丁基-3-(4-(3-二丁基氨基丙氧基)苯甲酰基) -5苯并呋喃基)甲磺酰胺
tachycardia
classification
bradycardia Class I Na+channel blocker ：flecainide氟卡胺
Class II β-blocker：propranolol普萘洛尔
drugs
Class III K+channel blocker ：amiodarone胺碘达隆 Class IV Ca2+channel blocker ：diltiazem地尔硫卓 3 3
AF Efficacy
Class III antiarrhythmic drug Delay in recurrences of AF or maintenance of sinus rhythm Rate control：the ability to control both rhythm and rate Safty：as second-line agents for lowintermediate risk stable patients
11
4-(3-dibutylaminopropoxy)benzoyl chloride hydrochloride
4-(3-二正丁基氨基丙氧基 苯甲酰氯 二正丁基氨基丙氧基)苯甲酰氯 二正丁基氨基丙氧基 盐酸盐
11
2-正丁基 硝基苯并呋喃 正丁基-5-硝基苯并呋喃 正丁基
Synthesis of (1)
Atrial Fibrillation（房颤） （房颤）
Atrial fibrillation (AF) is the most common of the serious cardiac rhythm disturbances
AF AF
P wave
Conduction
ECG
Common drugs amiodarone 胺碘达隆、dofetilide多非利特、sotalol索他洛尔 flecainide氟卡胺、propafenone丙胺苯丙酮 4
15
Dronedarone may be best viewed only as half a step forward in our efforts to expand the antiarrhythmic armamentarium.
Uncertainties remain in the clinical effectiveness and cost-effectiveness of dronedarone
dronedarone
Dronedarone is a noniodinated benzofuran derivative that is pharmacologically related to amiodarone
amiodarone
5
JEAN-YVES LE HEUZEY. M.D. Study to Evaluate the Efficacy and Safety of Dronedarone versus Amiodarone.2010
H
aq,HCl aq HCl
HOOC
(30)
O(CH2)3N(n-Bu)2.HCl SOCl2
75.5-90%
O Cl Cl O
(28)
(8)
O(CH2)3N(n-Bu)2.HCl
13
CN101153012 B
Determination
The determination of dronedarone and its metabolite in both plasma and myocardial tissue by HPLCcoupled with uv-detection.
Drug therapy for maintenance of sinus rhythm
No(or minimal) heart disease
Hypertension
Coronary artery disease
Heart failure
Flecainide propafenone sotalol
Cl N
K2CO3/DMF COOCH3 COOCH3
H3COOC
(29)
O(CH2)3N(n-Bu)2
COOCH3
tol ue ne
(27)
Cl K2CO3/MEK Br
O(CH2)3Br
KtB
OH
(n -B u)
K2CO3
2N
(26)
Br(CH2)3Br
60%
70 %85 %
NH (n-Bu)2
(1)
(2)
(3)
K2CO3/MEK
(5)
(4)
8
US.Pat.5223510
THF=tetrahydrofuran scheme2
(1)
(6)
Cl O
(7) (8)
O(CH2)3N(n-Bu)2.HCl
90%
9
WO.2002048132
scheme3
(9)
(10)
(11)
Base
(12)
Base