Synthesis of active metabolites of carvedilol, an antihypertensive drug

Article abstract of DOI:10.1080/00397910903534072

A simple synthetic route for active metabolites of carvedilol is reported. The metabolites 4'-hydroxycarvedilol and 5'-hydroxycarvedilol have exhibited high activity for -blockade. We have disclosed syntheses of 4'-hydroxycarvedilol and 5'-hydroxycarvedil

Full text of DOI:10.1080/00397910903534072

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Synthesis of Active Metabolites of
Carvedilol, an Antihypertensive Drug
N. Senthilkumar a , Y. S. Somannavar a , Shankar B. Reddy a , Brajesh
Kumar Sinha a , G. K. A. S. S. Narayan a , Ramesh Dandala a & Kaga
Mukkanti b
a APL Research Center, Aurobindo Pharma Ltd., Bachupally,
Hyderabad, India
b Centre for Pharmaceutical Science, J. N. T. University, Kukatpally,
Hyderabad, India
Version of record first published: 15 Dec 2010.
To cite this article: N. Senthilkumar , Y. S. Somannavar , Shankar B. Reddy , Brajesh Kumar Sinha ,
G. K. A. S. S. Narayan , Ramesh Dandala & Kaga Mukkanti (2010): Synthesis of Active Metabolites of
Carvedilol, an Antihypertensive Drug, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:2, 268-276
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Synthetic Communications1, 41: 268–276, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903534072
SYNTHESIS OF ACTIVE METABOLITES OF
CARVEDILOL, AN ANTIHYPERTENSIVE DRUG
N. Senthilkumar,1 Y. S. Somannavar,1 Shankar B. Reddy,1
Brajesh Kumar Sinha,1 G. K. A. S. S. Narayan,1
Ramesh Dandala,1 and Kaga Mukkanti2
1APL Research Center, Aurobindo Pharma Ltd., Bachupally,
Hyderabad, India
2Centre for Pharmaceutical Science, J. N. T. University,
Kukatpally, Hyderabad, India
A simple synthetic route for active metabolites of carvedilol is reported. The metabolites
40-hydroxycarvedilol and 50-hydroxycarvedilol have exhibited high activity for b-blockade.
We have disclosed syntheses of 40-hydroxycarvedilol and 50-hydroxycarvedilol from
commercially available vanillin and isovanillin, respectively.
Keywords: Angina; antihypertension; carvedilol; congestive heart failure; metabolite; 4-oxiranylmethoxy-
9H-carbazole
INTRODUCTION
Carvedilol 1 is a multiple-action drug useful in the treatment of hypertension
and angina,[1,2] which is known to be both a competitive nonselective b-adrenocep-
tor antagonist and a vasodilator. The vasodilatory action of carvedilol 1 results
primarily from a1-adrenoceptor blockade, whereas the b-adrenoceptor blocking
activity of the drug prevents reflex tachycardia when used in the treatment of
hypertension. Common structural features of b-adrenoreceptor blockers include
either an arylethanolamine or an aryloxyisopropanolamine moiety.[3] The com-
pounds differ in the nature of the aryl group as well as the group linked to the
amine moiety.
Carvedilol 1 contains an oxyisopropanolamine moiety with aromatic substitu-
ents linked to both the oxy and amine ends of the molecule, which provide its com-
bined activity, and carvedilol 1 also has much greater antioxidant activity than other
commonly used b-blockers.[4,5]
Additionally, carvedilol 1 is useful in the treatment of congestive heart failure[6]
and is marketed as racemic mixture as Coreg. Carvedilol 1 is used clinically
Received October 1, 2009.
Address correspondence to Shankar B. Reddy, APL Research Center, Aurobindo Pharma Ltd.,
Bachupally, Hyderabad 500090, India. E-mail: crd@aurobindo.com
268

ACTIVE METABOLITES OF CARVEDILOL
269
as a racemic mixture of R(þ)- and S(ꢀ)-enantiomers. Carvedilol 1 is extensively
metabolized primarily by aromatic oxidation and glucuronidation. Hydroxylation
at the phenol ring produces two active metabolites with b-receptor blocking activity.
Based on preclinical studies, the 40-hydroxycarvedilol 2, the active metabolite, is
approximately 13 times more potent than carvedilol for b-blockade. CYP2D6 is
thought to be the major enzyme in the 40- and 50-hydroxylation of carvedilol, with
a potential contribution from CYP3A4.[7]
50-Hydroxycarvedilol 3[3] and 40-hydroxycarvedilol 2 are most valuable meta-
bolites, which are required to determine absorbility and bioavailability of carvedilol.
Synthesis of these metabolites has not been reported in literature. We disclose con-
vergent syntheses of metabolites 2 and 3, starting with commercially available
vanillin 4 and isovanillin 11 respectively.
RESULTS AND DISCUSSION
The synthesis of metabolite 2 (Scheme 1) involves O-alkylation of the phenolic
group of vanillin 4 with 1,2-dibromoethane in the presence of a base at 95 ꢁC gave 5[8]
in 93% yield. Dakin oxidation of the formyl group of 5 using m-chloroperbenzoic
acid (m-CPBA) at room temperature gave 6 in 81% yield.
Further, hydrolysis[9] of 6 with sodium hydroxide in methanol at 0 ꢁC afforded
7 in 75% yield. Compound 7 was condensed with potassium phthalimide in the pres-
ence of NaI (catalyst) in dimethylformamide (DMF) at 60 ꢁC, and compound 8 was
isolated. Dephthalimidation of 8 with methanolic monomethylamine at 30 ꢁC
resulted in corresponding amine 9,[10] which was isolated as hydrochloride salt

270
N. SENTHILKUMAR ET AL.
Scheme 1. Reagents and conditions: (a) 1,2-dibromoethane, NaOH (1.6 N), 95 ꢁC; (b) m-CPBA, CH2Cl2,
30 ꢁC; (c) NaOH (6 N), MeOH, 0 ꢁC; (d) potassium phthalimide, NaI, DMF, 60 ꢁC; (e) MeOH-CH3NH2,
i-PrOH-HCl, MeCN, 30 ꢁC.
9a from acetonitrile. Finally, amine hydrochloride 9a was coupled with oxirane
10[11–13] (Scheme 2) to produce 40-hydroxycarvedilol metabolite 2.
The synthesis of metabolite 3 (Scheme 3) involves O-alkylation of the phenolic
group of isovanillin 11 with 1,2-dibromoethane in the presence of a base at 95 ꢁC and
gave 12[8] in 93% yield. Dakin oxidation of the formyl group of 12 using m-CPBA
at room temperature gave 13 in 81% yield.
Further, hydrolysis[9] of 13 with sodium hydroxide in methanol at 0 ꢁC
afforded 14 in 75% yield. Compound 14 was condensed with potassium phthalimide
in the presence of NaI (catalyst) in DMF at 60 ꢁC, and compound 15 was isolated.
Dephthalimidation of 15 with methanolic monomethylamine at 30 ꢁC resulted in the
corresponding amine 16,[10] which was isolated as hydrochloride salt 16a from
acetonitrile. Finally, amine hydrochloride 16a was coupled with oxirane 10[11–13]
(Scheme 4) to produce 50-hydroxycarvedilol metabolite 3.
Scheme 2. Reagents and conditions: (a) i-PrOH, TEA, 45 ꢁC.

ACTIVE METABOLITES OF CARVEDILOL
271
Scheme 3. Reagents and conditions: (a) 1,2-dibromoethane, NaOH (1.6 N), 95 ꢁC; (b) m-CPBA, CH2Cl2,
30 ꢁC; (c) NaOH (6 N), MeOH, 0 ꢁC; (d) potassium phthalimide, NaI, DMF, 60 ꢁC; (e) MeOH-CH3NH2,
i-PrOH-HCl, MeCN, 30 ꢁC.
Scheme 4. Reagents and conditions: (a) i-PrOH, TEA, 45 ꢁC.
CONCLUSION
To summarize, we have developed simple syntheses of 40-hydroxycarvedilol 2
and 50-hydroxycarvedilol 3 from easily available starting materials.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on a Bruker 300 spectrometer at
300 MHz, and the chemical shifts were reported as d values in parts per million relative
to tetramethylsilane (TMS) as an internal standard. Infrared (IR) spectra were
recorded in the solid state as KBr dispersions using a Perkin-Elmer spectrophotometer.
Mass spectra were recorded on an API 2000 Perkin-Elmer PE-SCIEX mass spec-
trometer. The melting points were recorded on open capillaries and are uncorrected.
4-(2-Bromoethoxy)-3-methoxybenzaldehyde (5)
Vanillin (4, 50 g, 0.329 mol) was added to mixture of 1,2-dibromoethane (246 g,
1.31 mol) and aq. 1.6 N NaOH (416 mL) at 30 ꢁC. The reaction mixture was heated

272
N. SENTHILKUMAR ET AL.
to 95 ꢁC and maintained until completion of reaction. The reaction mixture was
cooled to 30 ꢁC and extracted with CH2Cl2 (700 mL), followed by washing with
H2O (400 mL). The organic layer was concentrated at 50 ꢁC under reduced pressure
to yield 5 (58 g, 96.6%). Mp 68–69 ꢁC; IR (KBr): n ¼ 3343, 3080, 3040, 3002, 1698,
1683, 1673, 1594, 1585, 1509, 1463, 1444, 1427, 1397, 1380, 1348, 1280, 1268, 1215,
1196, 1177, 1156, 1079, 1016, 1003, 960, 865, 812 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d ¼ 3.68–3.75 (t, 2H), 3.94 (s, 3H), 4.40–4.44 (t, J ¼ 6 Hz, 2H), 6.98–7.01 (d, J ¼ 9 Hz,
1H), 7.44–7.46 (m, 2H), 9.9 (s, 1H); 13C NMR (75 MHz, CDCl3): d ¼ 28, 56, 69, 110,
112, 126, 131, 150, 153, 191; MS: m=z ¼ 261.0 [Mþ].
3-(2-Bromoethoxy)-4-methoxybenzaldehyde (12)
Mp 80–81 ꢁC; IR (KBr): n ¼ 3426, 3075, 3040, 2977, 2925, 1679, 1596, 1583,
1
1510, 1436, 1392, 1263, 1241, 1132, 798, 737 cmꢀ1; H NMR (300 MHz, CDCl3):
d ¼ 3.67–3.71 (t, 2H), 3.96 (s, 3H), 4.37–4.41 (t, J ¼ 6.3 Hz, 2H), 6.9–7.0 (d, 1H),
7.4 (s, 1H), 7.49–7.52 (d, J ¼ 8.4 Hz, 1H), 9.85 (s, 1H); 13C NMR (75 MHz, CDCl3):
d ¼ 29, 56, 69, 111, 112, 127, 130, 148, 155, 191; MS: m=z ¼ 261.0 [Mþ].
Formic Acid 4-(2-Bromoethoxy)-3-methoxyphenylester (6)
Compound 5 (50 g, 0.193 mol) was added to the solution of m-CPBA (66.7 g,
0.387 mol) in CH2Cl2 (500 mL) at 30 ꢁC. The reaction mixture was maintained at
30 ꢁC until completion of the reaction. The reaction mixture was quenched into
10% w=w aq. Na2CO3 (2 L). The organic layer was separated and concentrated
completely to yield 6 (43 g, 81.1%) as a solid. Mp 67–68 ꢁC; IR (KBr): n ¼ 3435,
3124, 3087, 3067, 1723, 1606, 1514, 1474, 1448, 1275, 1268, 1225, 1159, 1109, 1031,
1
871 cmꢀ1; H NMR (300 MHz, CDCl3): d ¼ 3.62–3.64 (t, 2H), 3.8 (s, 3H), 4.29–
4.34 (t, J ¼ 13.2 Hz, 2H), 6.65–6.69 (m, 2H), 6.91–6.93 (d, J ¼ 8.1 Hz, 1H), 8.28
(s, 1H); 13C NMR (75 MHz, CDCl3): d ¼ 29, 56, 70, 106, 113, 115, 145, 146, 151,
160; MS: m=z ¼ 294.1 [M þ NH4]þ.
Formic Acid 3-(2-Bromoethoxy)-4-methoxyphenylester (13)
Mp 73–74 ꢁC; IR (KBr): n ¼ 3442, 2969, 1729, 1605, 1512, 1454, 1426, 1281,
1267, 1226, 1162, 1126, 1097, 873, 783 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d ¼ 3.64–3.69 (t, 2H), 3.8 (s, 3H), 4.29–4.34 (t, J ¼ 6 Hz, 2H), 6.72–6.77 (m, 2H),
6.88–6.91 (d, J ¼ 9 Hz, 1H), 8.2 (s, 1H); 13C NMR (75 MHz, CDCl3): d ¼ 29, 56,
69, 109, 113, 114, 144, 148, 160; MS: m=z ¼ 293.9 [M þ NH4]þ.
4-(2-Bromoethoxy)-3-methoxyphenol (7)
Compound 6 (38 g, 0.138 mol) was added to methanol (266 mL) and treated
with aq. 6 N NaOH (38 mL) at 0 ꢁC. The reaction mixture was maintained for 2 h
at 0 ꢁC. Methanol was distilled out completely from the reaction mixture at 45 ꢁC
under reduced pressure. The solid obtained was added to mixture of CH2Cl2
(200 mL) and H2O (100 mL), filtered, and separated. The organic layer was washed
with H2O (2 ꢂ 100 mL), dried with Na2SO4, filtered, and concentrated completely at

ACTIVE METABOLITES OF CARVEDILOL
273
35 ꢁC under reduced pressure to yield 7 (27 g, 79.6%) as a solid. Mp 95–96 ꢁC; IR
(KBr): n ¼ 3371, 3126, 3010, 2972, 1604, 1522, 1471, 1463, 1455, 1282, 1220, 1197,
1125, 1036, 1014, 829 cmꢀ1; 1H NMR (300 MHz, CDCl3): d ¼ 3.61–3.65 (t, J ¼ 6.3 Hz,
Hz, 2H), 3.8 (s, 3H), 4.24–4.29 (t, 2H), 6.39–6.41 (m, 1H), 6.47–6.48 (s, 1H), 6.75–6.78
(d, J ¼ 8.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): d ¼ 29, 56, 71, 101, 106, 118, 141,
151, 152; MS: m=z ¼ 247 [Mþ].
3-(2-Bromoethoxy)-4-methoxyphenol (14)
Mp 84–85 ꢁC; IR (KBr): n ¼ 3365, 3126, 3010, 2972, 1602, 1525, 1513, 1441,
1271, 1227, 1172, 1124, 1020, 828, 733 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d ¼ 3.58–3.62 (t, 2H), 3.8 (s, 3H), 4.22–4.27 (t, 2H), 6.32–6.34 (m, 1H), 6.43–6.47
(s, 1H), 6.80–6.83 (d, J ¼ 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d ¼ 29, 57, 69,
103, 108, 114, 143, 149, 151; MS: m=z ¼ 247 [Mþ].
3-Methoxy-4-(2-phthalimidoethoxy)phenol (8)
Compound 7 (10 g, 0.0407 mol) was added to the mixture of potassium phthali-
mide (11.3 g, 0.0609 mol) and DMF (40 mL) at 30 ꢁC. NaI (1 g, 10 wt%) was added
and heated to 60 ꢁC until the completion of reaction. The reaction mixture was
cooled to 30 ꢁC. The mixture of CH2Cl2 (50 mL) and H2O (160 mL) was added to
rection mixture and stirred for 10 min. The organic layer was separated, washed with
H2O (2 ꢂ 25 mL) and dried with Na2SO4. The resulting organic layer was concen-
trated completely at 35 ꢁC under reduced pressure. The solid obtained was slurried
with CH2Cl2 (20 mL), filtered, and dried to yield 8 (10.96 g, 84.96%). Mp
164–165 ꢁC; IR (KBr): n ¼ 3323, 2941, 1764, 1693, 1615, 1596, 1509, 1479, 1466,
1431, 1400, 1309, 1203, 1170, 1014, 831, 723 cmꢀ1; 1H NMR (300 MHz, DMSO-d6):
d ¼ 3.48(s, 3H), 3.86–3.90 (m, 2H), 4.02–4.06 (m, 2H), 6.17–6.21 (m, 1H), 6.33–6.34
(s, 1H), 6.74–6.77 (d, J ¼ 8.7 Hz, 1H), 7.82–7.91 (m, 4H), 9.0 (s, 1H); 13C NMR
(75 MHz, DMSO-d6): d ¼ 38, 56, 68, 101, 106, 118, 124, 132, 135, 141, 151, 154,
168; MS: m=z ¼ 314.1 [Mþ].
4-Methoxy-3-(2-phthalimidoethoxy)phenol (15)
Mp 136–137 ꢁC; IR (KBr): n ¼ 3454, 2940, 1768, 1653, 1621, 1515, 1465, 1448,
1435, 1422, 1400, 1397, 1211, 1191, 1173, 1020, 983, 828 cmꢀ1; 1H NMR (300 MHz,
DMSO-d6): d ¼ 3.4 (s, 3H), 3.92–3.96 (m, 2H), 4.11–4.15 (m, J ¼ 5.7 Hz, 2H),
6.25–6.28 (m, 1H), 6.40–6.41 (s, 1H), 6.68–6.71 (d, J ¼ 8.7 Hz, 1H), 7.81–7.87 (m,
4H), 9.0 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d ¼ 38, 57, 66, 104, 108, 115,
123, 132, 135, 143, 149, 152, 168; MS: m=z ¼ 314.1 [Mþ].
4-(2-Aminoethoxy)-3-methoxyphenol Hydrochloride (9a)
Compound 8 (3 g, 0.0096 mol) was reacted with 20% w=w monomethyl amine
(12 mL in CH3OH) at 30 ꢁC. The reaction mixture was stirred at 30 ꢁC for 1 h,
and the by-product was filtered. The filtrate was concentrated completely at 45 ꢁC
under reduced pressure. The resulting residue was dissolved in methanol and treated

274
N. SENTHILKUMAR ET AL.
with isopropyl alcohol (IPA)-HCl. The methanol was distilled out completely at
45 ꢁC under reduced pressure. The solid obtained was purified with acetonitrile to
yield 9a (1.52 g, 72.3%). Mp 137–138 ꢁC; IR (KBr): n ¼ 3435, 3304, 3117, 2979,
2905, 1611, 1520, 1479, 1465, 1454, 1289, 1214, 1189, 1138, 1123, 1010, 952,
1
832 cmꢀ1; H NMR (300 MHz, DMSO-d6): d ¼ 3.06–3.10 (m, 2H), 3.72 (s, 3H),
4.01–4.05 (m, 2H), 6.29 (m, 1H), 6.46–6.47 (s, 1H), 6.85–6.87 (d, J ¼ 8.4 Hz, 1H),
8.16 (br, 3H), 9.25 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d ¼ 39, 56, 68, 101,
106, 118, 140, 151, 154; MS: m=z ¼ 184.2 [Mþ].
3-(2-Aminoethoxy)-4-methoxyphenol Hydrochloride (16a)
Mp 125–126 ꢁC; IR (KBr): n ¼ 3429, 3252, 2985, 2902, 1674, 1616, 1518, 1484,
1
1464, 1291, 1226, 1163, 1125, 1016, 827 cmꢀ1; H NMR (300 MHz, DMSO-d6):
d ¼ 3.22–3.29 (m, 2H), 3.72 (s, 3H), 4.08–4.13 (m, 2H), 6.33–6.37 (m, 1H),
6.47–6.48 (s, 1H), 6.78–6.81 (d, J ¼ 8.7 Hz, 1H), 8.13 (br, 3H), 9.1 (s, 1H); 13C
NMR (75 MHz, DMSO-d6): d ¼ 39, 57, 66, 104, 108, 114, 143, 148, 152; MS:
m=z ¼ 184.2 [Mþ].
(2RS)-1-(9H-Carbazol-4-yloxy)-3-[[2-(2-methoxy-4-
hydroxyphenoxy)ethyl]amino]propan-2-ol (2)
Compound 9a (1 g, 0.00456 mol) was neutralized in isopropyl alcohol (5 mL) at
30 ꢁC by the addition of triethylamine (0.69 g, 0.00684 mol). The reaction mixture
was heated to 45 ꢁC. Compound 10 (0.54 g, 0.00226 mol) was added and stirred at
45 ꢁC for 6 h (high-performance liquid chromatographic analysis showed 40% con-
version). The reaction mixture was concentrated completely at 45 ꢁC under vacuum.
The resulting crude product was purified by column chromatography on silica gel
(100–200 mesh, EtOAc–hexane, 3:2) to yield 2. IR (KBr): n ¼ 3402, 3056, 2933,
1
2874, 1626, 1606, 1509, 1455, 1402, 1347, 1161, 1100, 935, 785 cmꢀ1; H NMR
(300 MHz, DMSO-d6): d ¼ 2.83–2.90 (m, 4H), 3.68 (s, 3H), 3.90–3.93 (m, 2H),
4.12–4.15 (m, 3H), 5.2 (m, 1H), 6.19–6.23 (m, 1H), 6.39–6.40 (m, 1H), 6.67–6.76
(m, 2H), 7.05–7.12 (m, 2H), 7.26–7.33 (m, 2H), 7.43–7.45 (d, 1H), 8.20–8.23 (d,
J ¼ 9 Hz, 1H), 9.0 (s, 1H), 11.25 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d ¼ 49,
53, 56, 68, 70, 71, 101, 104, 105, 111, 117, 119, 122, 123, 125, 127, 139, 141, 142,
151, 153, 155; MS: m=z ¼ 423.3 [Mþ].
(2RS)-1-(9H-Carbazol-4-yloxy)-3-[[2-(2-methoxy-
5-hydroxyphenoxy)ethyl]amino]propan-2-ol (3)
IR (KBr): n ¼ 3399, 3300, 2934, 2836, 1627, 1606, 1509, 1455, 1442, 1347, 1167,
1
1101, 991, 755, 724 cmꢀ1; H NMR (300 MHz, DMSO-d6): d ¼ 2.96–2.97 (m, 4H),
3.68 (s, 3H), 3.99–4.02 (m, 3H), 4.13–4.16 (m, 3H), 5.2 (m, 1H), 6.25–6.28 (m,
1H), 6.42–6.43 (m, 1H), 6.67–6.76 (m, 2H), 7.05–7.12 (m, 2H), 7.26–7.33 (m, 2H),
7.43–7.45 (d, 1H), 8.20–8.23 (d, J ¼ 9 Hz, 1H), 8.96 (s, 1H), 11.24 (s, 1H); 13C
NMR (75 MHz, DMSO-d6): d ¼ 49, 53, 57, 69, 71, 101, 103, 104, 107, 111, 112,
114, 119, 122, 123, 125, 127, 139, 142, 143, 149, 152, 155; MS: m=z ¼ 423.3 [Mþ].

ACTIVE METABOLITES OF CARVEDILOL
275
ACKNOWLEDGMENTS
The authors thank Aurobindo Pharma Ltd. for supporting this work. The
authors are also thankful to colleagues at the analytical research department and
chemical research department of Aurobindo Research Center for the cooperation
and fruitful discussions.
REFERENCES
1. Packer, M.; Fowler, B. M.; Roecker, B. E.; Coats, J. S. A.; Katus, A. H.; Krum, H.;
Mohacsi, P.; Rouleau, L. J.; Tendera, M.; Staiger, C.; Holcslaw, L. T.; Amann-Zalan, I.;
DeMets, L. D. Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS)
study group: Effect of carvedilol on the morbidity of patients with severe chronic heart
failure: Results of the carvedilol prospective randomized cumulative survival (COPERNI-
CUS) study. Circulation 2002, 106(22), 2194–2199.
2. Ruffolo, R. R.; Boyle, D. A.; Brooks, D. P.; Feuerstein, G. Z.; Venuti, R. P.; Lukas, M.
A.; Poste, G. Carvedilol: A novel cardiovascular drug with multiple actions. Cardiovasc.
Drug Rev. 1992, 10, 127–157.
3. Schaefer, W. H.; Politowski, J.; Hwang, B.; Dixon, F. J.; Goalwin, A.; Gutzait, L.;
Anderson, K.; Debrosse, C.; Bean, M.; Rhodes, G. R. Metabolism of carvedilol in dogs,
rats, and mice. Drug Metab. Dispos. 1998, 26, 958–969.
4. Nakamura, K.; Kusano, K.; Nakamura, Y.; Kakishita, M.; Ohta, K.; Nagase, S.;
Yamamoto, M.; Miyaji, K.; Saito, H.; Morita, H.; Emori, T.; Matsubara, H.; Toyokuni,
S.; Ohe, T. Carvedilol decreases elevated oxidative stress in human failing myocardium.
Circulation 2002, 105, 2867–2871.
5. Kukin, L. M.; Kalman, J.; Charney, H. R.; Levy, K. D.; Buchholz-Varley, C.; Ocampo,
N. O. Prospective, randomized comparison of effect of long-term treatment with meto-
prolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart
failure. Eng. C Circulation 1999, 99, 2645–2651.
6. Poole-Wilson, P. A.; Swedberg, K.; Cleland, J. G.; Di Lenarda, A.; Hanrath, P.;
Komajda, M.; Lubsen, J.; Lutiger, B.; Metra, M.; Remme, W. J.; Torp-Pedersen, C.;
Scherhag, A.; Skene, A. Rationale and design of the carvedilol or metoprolol tartrate
European trial in patients with chronic heart failure: COMET. Eur. J. Heart. Fail.
2002, 4, 321–329.
7. Oldham, H. G.; Clarke, S. E. In vitro identification of the human cytochrome P450
enzymes involved in the metabolism of R(þ)- and S(ꢀ)-carvedilol. Drug Metab. Dispos.
1997, 25, 970–977.
8. Jhy-Chong, L.; Jwu-Lai, Y.; Chia-Sui, W.; Shwu-Fen, L.; Chieh-Ho, T.; Ing-Jun, C. The
new generation dihydropyridine-type calcium blockers, bearing 4-phenyl oxypropanola-
mine, display a,b-adrenoceptor antagonist and long-acting antihypertensive activities.
Bioorg. Med. Chem. Lett. 2002, 10, 719–730.
9. Dakin, H. D. The oxidation of hydroxyl derivatives of benzaldehyde, acetophenone, and
related substances. Am. Chem. J. 1909, 42, 477–481.
10. Alker, D.; Arrowsmith, L. E.; Campbell, S. F.; Cross, P. E. Long-acting dihydropyridine
calcium antagonists, IX: Structure–activity relationships around amlodipine. Eur. J. Med.
Chem. 1991, 26, 907–913.
11. Trepat Guixer, E.; Munoz Alvarex, A.; Pomares Marco, M.; Marquillas Olondriz, F.
Process for the preparation of carvedilol and its enantiomers. WO patent 2006061364,
2006; Chem. Abstr. 2006, 145, 62782.

276
N. SENTHILKUMAR ET AL.
12. KanKan, R. N.; Rao, D. R. Process for the preparation of carvedilol with improved yields
on an industrial scale. WO Patent 2005113502, 2005; Chem. Abstr. 2006, 143, 266815.
13. Vijay, C. C.; Rajeev, B. R.; Rajamannar, T. A process for preparation of 1-[9 h-carbazol-
4-yloxy]-3-[{2-(2-(methoxy)phenoxy)-ethyl}-amino]-propan-2-ol. US Patent 20060270858,
2006; Chem. Abstr. 2004, 142, 93675.