Synthesis of 4-(1-oxo-isoindoline) and 4-(5,6-dimethoxy-1-oxo-isoindoline)- substituted phenoxypropanolamines and their β1-, β2-adrenergic receptor binding studies

Article abstract of DOI:10.1016/j.bioorg.2005.05.001

Phenoxypropanolamines with 1-oxo-isoindoline (12-16) and 5,6-dimethoxy-1-oxo-isoindoline groups (17-20) at the para position were synthesized. β₁, β₂-Adrenergic receptor binding affinities for the synthesized compounds were tested and compared with propranolol and atenolol. It was found that the incorporation of para-amidic functionality within the 1-oxo-isoindoline ring and 5,6-dimethoxy-1-oxo- isoindoline ring system led to a high degree of cardioselectivity in the phenoxypropanolamines. Two of the compounds 12 and 20 possessed β₁-adrenergic receptor affinity comparable with that of atenolol and both showed a better cardioselectivity than atenolol. Both 12 and 20 are undergoing further pharmacological evaluation.

Full text of DOI:10.1016/j.bioorg.2005.05.001

Bioorganic Chemistry 33 (2005) 310–324
www.elsevier.com/locate/bioorg
Synthesis of 4-(1-oxo-isoindoline) and
4-(5,6-dimethoxy-1-oxo-isoindoline)-substituted
phenoxypropanolamines and their
ꢀ1-, ꢀ2-adrenergic receptor binding studies
Dharam P. Jindal a, Babita Singh a, Mohane S. Coumar a,¤,
Giancarlo Bruni b, Paola Massarelli b
a University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India
b Dipartimento di Farmacologia “Giorgio Segre”—6, via delle Scotte-53100 Siena, Italy
Received 29 January 2005
Available online 21 June 2005
Abstract
Phenoxypropanolamines with 1-oxo-isoindoline (12–16) and 5,6-dimethoxy-1-oxo-isoindo-
line groups (17–20) at the para position were synthesized. ꢀ1, ꢀ2-Adrenergic receptor binding
aYnities for the synthesized compounds were tested and compared with propranolol and ateno-
lol. It was found that the incorporation of para-amidic functionality within the 1-oxo-isoindoline
ring and 5,6-dimethoxy-1-oxo-isoindoline ring system led to a high degree of cardioselectivity in
the phenoxypropanolamines. Two of the compounds 12 and 20 possessed ꢀ1-adrenergic recep-
tor aYnity comparable with that of atenolol and both showed a better cardioselectivity than
atenolol. Both 12 and 20 are undergoing further pharmacological evaluation.
 2005 Elsevier Inc. All rights reserved.
Keywords: ꢀ-Adrenergic blocking agents; ꢀ-Adrenergic receptor binding; Phenoxypropanolamines;
1-Oxo-isoindoline; Atenolol; Propranolol
*
Corresponding author. Present address: R2-7033, 7F, Division of Biotechnology and Pharmaceutical
Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350,
Taiwan, ROC. Fax: +886 37 586 456.
E-mail address: mohanec1@yahoo.co.in (M.S. Coumar).
0045-2068/$ - see front matter  2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2005.05.001

D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
311
1. Introduction
Cardiovascular diseases are the major cause of deaths worldwide, even surpassing
deaths due to cancer. Among these, hypertension is central to the pathogenesis of
coronary artery disease (angina, myocardial infarction), heart failure, cerebral
(stroke), and peripheral vascular diseases [1]. Pharmacological treatment of hyperten-
sion includes mainly the use of six drug classes: diuretics, ꢀ-adrenergic blocking
agents, calcium antagonist, angiotensin converting enzyme inhibitors, angiotensin II
receptor antagonists, and ꢁ-adrenergic blockers [2].
As a part of our eVorts [3–6] to develop ꢀ-adrenergic blocking agents with better
activity and cardioselectivity than the existing ꢀ-blockers, we have synthesized a new
series of phenoxypropanolamines based on the structure of practolol (1), a cardiose-
lective agent. Use of cardioselective ꢀ-adrenergic blockers has been shown better
suited for patients suVering from asthma and other bronchial disease than a non-
selective ꢀ-adrenergic blocker [7,8]. Following the discovery of practolol with
cardioselective action, numerous attempts were made by various researchers to
develop ꢀ-adrenergic blocking agents with cardioselectivity. All these eVorts led to
the conclusion that signiWcant cardioselectivity could be achieved either by an appro-
priate substitution in the para-position of the phenyl ring or by appropriate substitu-
tion of the side chain amino group [9]. Presence of para-amidic functionality in
phenoxypropanolamines has been found to confer cardioselectivity [3,9]. It was also
found that cardioselectivity could be conferred to phenoxypropanolamine type com-
pounds by replacing isopropyl/tert-butyl groups with 3,4-dimethoxyphenylethyl moi-
ety as the amino substituent [10,11].
In our previous study, we have reported the synthesis and ꢀ-adrenergic receptor
binding of a series of phenoxypropanolamines (Fig. 1, 2a and 2b) with a para-amidic
functionality [3]. Herein, we report the synthesis of phenoxypropanolamines with the
para-amidic functionality incorporated in 1-oxo-isoindoline and 4-(5,6-dimethoxy-1-
oxo-isoindoline) ring system (Fig. 1). Incorporation of para-amidic functionality with
in the ring system leads to rigidiWcation of the functionality, whose eVect on receptor
aYnity and selectivity could be evaluated in this study. Also, the amino side chain
substituent was varied from isopropyl/tert-butyl moiety to 3,4-dimethoxyphenylethyl
moiety, with the aim of obtaining phenoxypropanolamines with good activity and
cardioselectivity.
2. Materials and methods
2.1. Chemical synthesis
2.1.1. Materials
Melting points reported are uncorrected. 1H NMR spectra were recorded on Bru-
ker AC-300F, 300MHz NMR instrument using tetramethylsilane (TMS) as the
internal standard (chemical shifts in ꢂ, ppm). IR spectra were recorded on Perkin-
Elmer 882 spectrophotometer model. IR spectra were obtained with potassium

312
D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
Fig. 1. para-Amidic group incorporation in 1-oxo-isoindoline ring system.
bromide pellets (ꢃ max in cm¡1). The purity of the compounds were established by
thin layer chromatography (TLC) and by elemental analysis (C, H, and N). Elemen-
tal analyses were carried out on a Perkin-Elmer-2400. Anhydrous sodium sulfate was
used as drying agent. Plates for TLC were prepared with silica gel G using ethyl ace-
tate. Iodine vapors were used to develop the plates.
2.1.2. Synthesis
The classical phenol–epoxide–aminoalcohol sequence of reactions was carried out
to synthesize the new phenoxypropanolamines. The compounds prepared under
this study have been divided into two structural groups for convenience of discus-
sion, 1-oxo-isoindoline derivatives (12–16) and 5,6-dimethoxy-1-oxo-isoindoline
derivatives (17–20). The synthetic scheme for both the series are shown in Fig. 2.
N-(Hydroxyphenyl)-1-oxo-isoindoline (8) was synthesized by condensing p-ami-
nophenol (5) with phthalic anhydride (3), followed by zinc-acetic acid reduction. The
intermediate oxirane (10) was prepared by condensing epichlorohydrin with 8. Reac-
tion of 10 with isopropylamine, tert-butylamine, N-methylpiperazine, homoveratryl-
amine, and N-methylhomoveratrylamine gave 12, 13, 14, 15, and 16, respectively.
While N-(hydroxyphenyl)-5,6-dimethoxy-1-oxo-isoindoline (9) was prepared from
dimethoxyphthalic anhydride (4) and p-aminophenol, which was further elaborated
to 17, 18, 19, and 20 in similar fashion. All the compounds were converted to their

D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
313
Fig. 2. Synthetic procedure to compounds 12–20. Reagents and conditions: (i) toluene, reXux (6) or pyri-
dine, reXux (7); (ii) zinc/glacial acetic acid; (iii) epichlorohydrin/K2CO3, reXux; (iv) isopropylamine (12, 17)
or tert-butylamine (13, 18) or N-methylpiperazine (14) or homoveratrylamine/methanol, reXux (15) or N-
methylhomoveratrylamine/methanol, reXux (16) or homoveratrylamine, 80 °C (19) or N-methylhomov-
eratrylamine, 80 °C (20).
hydrochloride salt by treatment with hydrogenchloride gas. The structures of all
1
the compounds were established on the basis of H NMR, IR, and elemental
analyses.

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D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
2.1.3. General procedure for the preparation of HCl salt of amines (Method A)
Freshly prepared dry HCl gas was passed through a solution of amine in dry ace-
tone (20 ml). The precipitated material was Wltered and crystallized from appropriate
solvent to aVord HCl salt of the amine.
2.1.4. N-(4-Hydroxyphenyl)phthalimide (6)
4-Aminophenol 5 (4.0 g, 36.7 mmol) and triethylamine (2ml) were added to a solu-
tion of phthalic anhydride 3 (6.0 g, 40.5mmol) in ethanol (150 ml) and the reaction
mixture was stirred at room temperature for 4 h. The solvent was removed under
reduced pressure and the solid residue was dried in a vacuum desiccator for 24h. The
residue so obtained was reXuxed in dry toluene (250ml) for 4 h using Dean and Stark
apparatus to eVect cyclization. The solvent was removed under reduced pressure and
the solid was washed with ether. The residue was reXuxed in distilled water for 0.5h
to remove unreacted materials. The solid obtained was crystallized from methanol to
aVord 6 (4.75g, 58.78%), mp. 291–293°C. IR (KBr): 3415, 1711, 1690, 1593, 1515,
1
1462, 1439, 1275, 1200, and 721 cm¡1. H NMR (CDCl3-DMSO-d6): ꢂ 6.92 (d, 2H,
J D9 Hz, Aro to hydroxy), 7.26 (d, 2H, J D 9 Hz, Aro to imide), 7.92 (s, 4H, Ar) and
9.70 ppm (br, 1H, disappeared on D2O exchange, –OH).
2.1.5. N-(4-Hydroxyphenyl)-5,6-dimethoxypthalimide (7)
4-Aminophenol 5 (0.52g, 4.8 mmol) was added to a solution of 4,5-dimethoxyph-
thalic anhydride 4 (1.0 g, 4.8 mmol) in dry pyridine (15ml) and the reaction mixture
was reXuxed for 2 h. The excess of pyridine was removed under reduced pressure, the
solid obtained was taken in water, Wltered, and washed with distilled water till its free
from pyridine. The residue given washings with methanol and crystallized from etha-
nol to yield 7 (0.82 g, 57.04%), mp 278–280 °C. IR (KBr): 3534, 3115, 2961, 1709, 1690,
1
1598, 1466, 1391, 1266, 1082, and 840cm¡1. H NMR (CDCl3-DMSO-d6): ꢂ 3.98 (s,
6H, 2 £ –OCH3), 6.73 (d, 2H, J D9 Hz, Aro to hydroxy), 7.08 (d, 2H, J D 9 Hz, Aro to
imide), 7.41 (s, 2H, Ar) and 9.43ppm (br, 1H, disappeared on D2O exchange, –OH).
Calcd. for C16H13NO5: C, 64.21; H, 4.38; N, 4.68. Found: C, 63.90; H, 4.31; N, 4.74.
2.1.6. N-(4-Hydroxyphenyl)-1-oxo-isoindoline (8)
To a solution of N-(4-hydroxyphenyl)phthalimide 6 (3.0 g, 12.5mmol) in glacial
acetic acid (700ml), zinc dust (2.0 g) was added and the reaction mixture was shaken
manually for 2h, then reXuxed for 2 h, cooled and Wltered. The glacial acetic acid was
removed under reduced pressure. The solid residue obtained was washed with dis-
tilled water and crystallized from methanol to give 8 (1.98g, 70.10%), mp 222–225 °C.
1
IR (KBr): 3173, 1656, 1615, 1591, 1515, 1443, 1399, 1236, and 834cm¡1. H NMR
(DMSO-d6): ꢂ 4.85 (s, 2H, methylene protons of isoindoline), 6.86–7.88 (m, 8H, Ar)
and 9.29 ppm (s, 1H, disappeared on D2O exchange, –OH). Calcd. for C14H11NO2: C,
74.65; H, 4.92; N, 6.22. Found: C, 74.32; H, 4.81; N, 6.15.
2.1.7. N-(4-Hydroxyphenyl)-5,6-dimethoxy-1-oxo-isoindoline (9)
N-(4-Hydroxyphenyl)-5,6-dimethoxypthalimide 7 (2.0 g, 6.7mmol) was reduced
with zinc dust (5.0g) in glacial acetic acid (700ml) as for 8 and the resulting product

D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
315
was crystallized from methanol to aVord 9 (1.68g, 88.12%), mp 140–142 °C. IR (KBr):
1
3159, 1658, 1615, 1558, 1462, 1259, 1057, 1031, and 833cm¡1. H NMR (CDCl3-
DMSO-d6): ꢂ 3.89 (s, 6H, 2£–OCH3), 4.70 (s, 2H, methylene protons of isoindoline),
6.86 (d, 2H, JD9Hz, Aro to hydroxy), 7.10 (s, 1H, Ar), 7.32 (s, 1H, Ar), 7.62 (d, 2H,
JD9Hz, Aro to imide) and 9.20 ppm (br, 1H, disappeared on D2O exchange, –OH).
Calcd. for C16H15NO4: C, 67.36; H, 5.30; N, 4.91. Found: C, 67.22; H, 5.20; N, 4.90.
2.1.8. N-[4-(2,3-Epoxypropoxy)phenyl]-1-oxo-isoindoline (10)
A mixture of N-(4-hydroxyphenyl)-1-oxo-isoindoline 8 (1.0g, 4.4 mmol), epichlo-
rohydrin (25ml) and potassium carbonate (1.0g) was reXuxed for 6 h. The reaction
mixture was Wltered and the excess of epichlorohydrin was removed under reduced
pressure. The white solid residue was crystallized from methanol to give 10 (0.88g,
70.46%), mp 162–164°C. IR (KBr): 3114, 2924, 1674, 1514, 1389, 1299, 1237, 1029,
1
and 817cm¡1. H NMR (CDCl3): ꢂ 2.76 and 2.91 (dd, 1H; t, 1H, –CH2 of oxirane
ring), 3.36 (m, 1H, –CH of oxirane ring), 3.95 and 4.24 (2£ dd, 2H, –OCH2–), 4.79 (s,
2H, methylene protons of isoindoline) and 6.79–7.89ppm (m, 8H, Ar). Calcd. for
C17H15NO3: C, 72.58; H, 5.38; N, 4.98. Found: C, 72.25; H, 5.31; N, 5.03.
2.1.9. N-[4-(2,3-Epoxypropoxy)phenyl]-5,6-dimethoxy-1-oxo-isoindoline (11)
N-(4-Hydroxyphenyl)-5,6-dimethoxy-1-oxo-isoindoline 9 (0.5 g, 1.8mmol) was
condensed with epichlorohydrin (10ml) in the presence of potassium carbonate
(1.0g) as for 10, and the resulting product crystallized from ethanol to give 11 (0.42 g,
70.21%), mp 158–160°C. IR (KBr): 3054, 2937, 2832, 1681, 1518, 1450, 1388, 1244,
1056, and 820cm¡1. 1H NMR (CDCl3): ꢂ 2.76 and 2.85 (dd, 1H; t, 1H, –CH2 of oxi-
rane ring), 3.35 (m, 1H, –CH of oxirane ring), 4.00 (s, 6H, 2£ –OCH3), 4.18 and 4.24
(2£ d, 2H, –OCH2–), 4.86 (s, 2H, methylene protons of isoindoline) and 6.92–
7.79 ppm (m, 6H, Ar). Calcd. for C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found: C,
66.58; H, 5.57; N, 4.12.
2.1.10. N-[4-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-1-oxo-isoindoline (12)
Isopropylamine (2ml, 23.3mmol) was added to a solution of N-[4-(2,3-epoxyprop-
oxy)phenyl]-1-oxo-isoindoline 10 (0.25g, 0.9mmol) in aldehyde free ethanol (10 ml)
and the reaction mixture was reXuxed for 5 h. The solvent and excess of isopropyl-
amine were removed under reduced pressure and the solid obtained was crystallized
from methanol to yield 12 (0.25 g, 82.64%), mp 138–141°C. IR (KBr): 3095, 2961,
1683, 1582, 1450, 1392, 1336, 1241, 1064, and 826cm¡1. 1H NMR (CDCl3): ꢂ 1.09 (d,
6H, –CH(CH3)2), 2.21 (br, 2H, disappeared on D2O exchange, –OH and –NH–),
2.69–2.92 (m, 3H, –CH2NHCH<), 4.01 (m, 3H, –OCH2CH<), 4.81 (s, 2H, methylene
protons of isoindoline) and 6.98–7.91ppm (m, 8H, Ar). Calcd. for C20H24N2O3: C,
70.56; H, 7.11; N, 8.23. Found: C, 70.30; H, 7.13; N, 8.21.
2.1.11. N-[4-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-1-oxo-isoindoline (12)
HCl
Method A. Crystallization solvent: methanol–acetone mixture; yield: 75.87%;
mp 212–214 °C. IR (KBr): 3319, 2971, 1688, 1512, 1445, 1387, 1298, 1241, 1030, 843,

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D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
1
and 731 cm¡1. H NMR (DMSO-d6): ꢂ 1.35 (d, 6H, –CH(CH3)2), 3.03 and 3.16
(2 £ m, 2H, –CH2NH–), 3.36 (m, 1H, –CH(CH3)2), 4.04 (m, 2H, –OCH2–), 4.32 (m,
1H, –CH(OH)–), 4.93 (s, 2H, methylene protons of isoindoline), 5.89 (d, 1H, disap-
peared on D2O exchange, –CH(OH)–), 7.00–7.80 (m, 8H, Ar) and 8.69 ppm (br, 1H,
disappeared on D2O exchange, –NH–). Calcd. for C20H25N2O3Cl: C, 63.73; H, 6.69;
N, 7.44. Found: C, 63.55; H, 6.61; N, 7.48.
2.1.12. N-[4-(3-tert-Butylamino-2-hydroxypropoxy)phenyl]-1-oxo-isoindoline (13)
N-[4-(2,3-Epoxypropoxy)phenyl]-1-oxo-isoindoline 10 (0.25g, 0.9 mmol) was
reacted with tert-butylamine (2ml, 19.0 mmol) as for 12 and the resultant product
crystallized from methanol to aVord 13 (0.25g, 79.36%), mp 150–153 C. IR (KBr):
3062, 2971, 1670, 1580, 1466, 1388, 1334, 1245, 1066, and 827cm¡1 1H NMR
.
(CDCl3): ꢂ 1.13 (s, 9H, –C(CH3)3), 2.17 (br, 2H, ‘ on D2O exchange, –OH and –NH–),
2.69 and 2.86 (2£dd, 2H, –CH2NH–), 3.98 (m, 3H, –CH2CH(OH)–), 4.81 (s, 2H,
methylene protons of isoindoline) and 6.99–7.92ppm (m, 8H, Ar). Calcd. for
C21H26N2O3: C, 71.16; H, 7.40; N, 7.91. Found: C, 70.90; H, 7.39; N, 7.96.
2.1.13. N-[4-(3-tert-Butylamino-2-hydroxypropoxy)phenyl]-1-oxo-isoindoline (13)
HCl
Method A. Crystallization solvent: acetone; yield: 77.07%; mp 212–215°C. IR
1
(KBr): 2976, 1686, 1615, 1581, 1442, 1393, 1246, 1066, and 832cm¡1. H NMR
(DMSO-d6): ꢂ 1.24 (s, 9H, –C(CH3)3), 3.10 and 3.34 (2£ m, 2H, –CH2NH–), 3.36 (m,
1H, –CH(CH3)2), 4.00 and 4.10 (2 £ m, 2H, –OCH2–), 4.64 (m, 1H, –CH(OH)–), 4.71
(s, 2H, methylene protons of isoindoline), 5.71 (d, 1H, disappeared on D2O exchange,
–CH(OH)–), 6.95–7.86 (m, 8H, Ar) and 8.23 (br, 1H, disappeared on D2O exchange,
–NH–). Calcd. for C21H27N2O3Cl: C, 64.52; H, 6.96; N, 7.17. Found: C, 64.26; H, 6.98;
N, 7.17.
2.1.14. N-{4-[2-Hydroxy-3-(4-methylpiperazino)propoxy]phenyl}-1-oxo-isoindoline
(14)
N-[4-(2,3-Epoxypropoxy)phenyl]-1-oxo-isoindoline 10 (0.25 g, 0.9 mmol) was
reacted with N-methylpiperazine (1 ml, 9.0 mmol) as for 12 and the resultant
product crystallized from acetone to aVord 14 (0.23 g, 67.84%), mp 92–95 °C. IR
1
(KBr): 3412, 2941, 1685, 1460, 1296, 1248, 1043, and 831 cm¡1. H NMR (CDCl3):
ꢂ 2.24 (s, 3H, –NCH3), 2.30–3.03 (m, 10H, –CH2N(CH2CH2)2N–), 4.00 (m, 3H,
–CH2CH(OH)–), 4.78 (s, 2H, methylene protons of isoindoline) and 7.02–7.84 ppm
(m, 8H, Ar). Calcd. for C22H27N3O3: C, 69.27; H, 7.14; N, 11.02. Found: C, 69.00; H,
7.18; N, 10.98.
2.1.15. N-{4-[2-Hydroxy-3-(4-methylpiperazino)propoxy]phenyl}-1-oxo-isoindoline
(14) HCl
Method A. Crystallization solvent: methanol; yield: 67.12%; mp 250–253°C. IR
1
(KBr): 3399, 2925, 1691, 1515, 1442, 1390, 1244, 1159, 1066, and 828cm¡1. H NMR
(DMSO-d6): ꢂ 2.89 (s, 3H, –NCH3), 3.37 (m, 2H, –CH2N<), 3.56 (br, 9H, 1H
disappeared on D2O exchange, –N(CH2CH2)2N–, –OH), 3.99 (m, 2H, –OCH2–), 4.35

D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
317
(m, 1H, –CH(OH)–), 4.84 (s, 2H, methylene protons of isoindoline) and 7.01–8.14 ppm
(m, 8H, Ar). Calcd. for C22H28N3O3Cl: H, 6.75; N, 10.06. Found: H, 6.69; N, 9.94.
2.1.16. N-{4-[2-Hydroxy-3-(3,4-dimethoxyphenylethylamino)propoxy]phenyl}-
1-oxo-isoindoline (15)
N-[4-(2,3-Epoxypropoxy)phenyl]-1-oxo-isoindoline 10 (0.25 g, 0.9 mmol) was
reacted with homoveratrylamine (1 ml, 6.0 mmol) as for 12 and the resultant prod-
uct was given washings with hot hexane and then crystallized from acetone to
aVord 15 (0.19 g, 46.22%), mp 118–120 °C. IR (KBr): 3061, 2940, 1696, 1588, 1447,
1
1385, 1296, 1242, 1024, and 818 cm¡1. H NMR (CDCl3): ꢂ 2.18 (br, 2H, disap-
peared on D2O exchange, –OH and –NH–), 2.74 (m, 6H, –CH2NHCH2CH2–), 3.75
(m, 9H, –OCH2CH< and 2 £ –OCH3), 4.66 (s, 2H, methylene protons of isoindo-
line) and 6.50–7.75 ppm (m, 11H, Ar). Calcd. for C27H30N2O5: C, 70.11; H, 6.54; N,
6.06. Found: C, 69.98; H, 6.50; N, 6.08.
2.1.17. N-{4-[2-Hydroxy-3-(3,4-dimethoxyphenylethylamino)propoxy]phenyl}-
1-oxo-isoindoline (15) HCl
Method A. Crystallization solvent: acetone; yield: 88.99%; mp 178–180°C. IR
(KBr): 3345, 2946, 1678, 1591, 1466, 1391, 1243, 1155, 1066, and 825cm¡1. 1H NMR
(CDCl3): ꢂ 3.23–3.31 (br, 6H, –CH2NHCH2CH2–), 3.78 and 3.82 (2£ s, 6H,
2 £OCH3), 3.93–4.07 (m, 2H, –OCH2–), 4.61 (m, 3H, methylene protons of isoindo-
line, –CH(OH)–), 5.51 (br, 1H, disappeared on D2O exchange, –OH), 6.71–7.81 (m,
11H, Ar) and 8.94ppm (br, 1H, disappeared on D2O exchange, –NH–). Calcd. for
C27H31N2O5Cl: C, 64.99; H, 6.26; N, 5.62. Found: C, 64.74; H, 6.19; N, 5.57.
2.1.18. N-{4-[2-Hydroxy-3-(3,4-dimethoxy-N-methylphenylethylamino)
propoxy]phenyl}-1-oxo-isoindoline HCl (16)
N-[4-(2,3-Epoxypropoxy)phenyl]-1-oxo-isoindoline 10 (0.25 g, 0.9 mmol) was
reacted with N-methylhomoveratrylamine (1 ml, 5.4 mmol) as for 12 and the resul-
tant product was given washings with hot hexane. The residue was not crystallizable
and converted to HCl salt by the general procedure (Method A) and then crystal-
lized from methanol to aVord HCl salt of 16 (0.23 g, 50.45%), mp 186–188 °C. IR
(KBr): 3282, 3077, 2938, 1681, 1613, 1449, 1334, 1243, 1040, and 819cm¡1. 1H NMR
(CDCl3): ꢂ 3.0 (s, 3H, –NCH3), 3.14–3.49 (m, 7H, 1H disappeared on D2O exchange,
–OCH2(OH)CH2N(CH3)CH2CH2–), 3.85 (d, 6H, 2 £ –OCH3), 3.95 and 4.15 (2 £ m,
2H, –OCH2–), 4.75 (m, 3H, methylene protons of isoindoline and –CH(OH)–) and
6.80–7.88 ppm (m, 11H, Ar). Calcd. for C28H33N2O5Cl: C, 65.55; H, 6.48; N, 5.46.
Found: C, 65.52; H, 6.43; N, 5.41.
2.1.19. N-[4-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-5,6-dimethoxy-
1-oxo-isoindoline (17)
N-[4-(2,3-Epoxypropoxy)phenyl]-5,6-dimethoxy-1-oxo-isoindoline 10 (0.5 g,
1.5 mmol) was reacted with isopropylamine (2 ml, 23.3 mmol) as for 12 and the
resultant product crystallized from acetone to aVord 17 (0.43 g, 73.31%), mp
138–141 °C. IR (KBr): 3084, 2966, 1678, 1450, 1388, 1244, 1058, and 827 cm¡1
.

318
D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
1H NMR (CDCl3): ꢂ 1.12 (d, 6H, –CH(CH3)2), 2.56 (br, 2H disappeared on D2O
exchange, –OH and –NH–), 2.75 (m, 1H, –CH(CH3)2), 2.88 (m, 2H, –CH2NH–),
3.96 (m, 8H, –OCH2– and 2 £ –OCH3), 4.06 (m, 1H, –CH(OH)–), 4.69 (s, 2H,
methylene protons of isoindoline) and 6.95–7.68 ppm (m, 6H, Ar). Calcd. for
C22H28N2O5: C, 65.98; H, 7.05; N, 7.00. Found: C, 65.76; H, 6.99; N, 6.91.
2.1.20. N-[4-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-5,6-dimethoxy-
1-oxo-isoindoline (17) HCl
Method A. Crystallization solvent: methanol–acetone mixture; yield: 84.32%; mp
245–248°C. IR (KBr): 3268, 2945, 1665, 1606, 1449, 1390, 1258, 1061, and 820cm¡1
.
Calcd. for C22H29N2O5Cl: C, 60.47; H, 6.69; N, 6.41. Found: C, 60.39; H, 6.65; N, 6.39
2.1.21. N-[4-(3-tert-Butylamino-2-hydroxypropoxy)phenyl]-5,6-dimethoxy-
1-oxo-isoindoline (18)
N-[4-(2,3-Epoxypropoxy)phenyl]-5,6-dimethoxy-1-oxo-isoindoline 11 (0.5g, 1.5mmol)
was reacted with tert-butylamine (2ml, 19.0mmol) as for 12 and the resultant product
crystallized from acetone to aVord 18 (0.42g, 69.18%), mp 142–145°C. IR (KBr): 3344,
2964, 2865, 1670, 1609, 1462, 1387, 1226, 1059, and 825cm¡1. 1H NMR (CDCl3): ꢂ 1.20
(s, 9H, –C(CH3)3), 2.86 (m, 4H, 2H disappeared on D2O exchange, –CH(OH)-
CH2NH–), 4.06 (m, 9H, 2 –OCH3, –OCH2CH<), 4.72 (s, 2H, methylene protons of
isoindoline) and 7.01–7.75ppm (m, 6H, Ar). Calcd. for C23H30N2O5: C, 66.64; H, 7.30;
N, 6.76. Found: C, 66.43; H, 7.34; N, 6.72.
2.1.22. N-[4-(3-tert-Butylamino-2-hydroxypropoxy)phenyl]-5,6-dimethoxy-1-oxo-
isoindoline (18) HCl
Method A. Crystallization solvent: methanol–acetone mixture; yield: 73.53%; mp
224–226°C. IR (KBr): 3365, 3055, 2978, 1670, 1605, 1518, 1449, 1386, 1317, 1250,
1
1129, and 822cm¡1. H NMR (CDCl3-DMSO-d6): ꢂ 1.40 (s, 9H, –C(CH3)3), 2.99
and 3.16 (t, 1H; d, 1H, –CH2NH–), 3.92 and 3.95 (2£ s, 6H, 2£ –OCH3), 4.05 (m, 2H,
–OCH2–), 4.33 (m, 1H, –CH(OH)–), 4.81 (s, 2H, methylene protons of isoindoline),
5.95 (br, 1H, disappeared on D2O exchange, –OH), 7.01–7.75 (m, 6H, Ar) and
8.85ppm (br, 1H, disappeared on D2O exchange, –NH–). Calcd. for C23H31N2O5Cl:
C, 61.26; H, 6.93; N, 6.21. Found: C, 60.99; H, 6.90; N, 6.26.
2.1.23. N-{4-[2-Hydroxy-3-(3,4-dimethoxyphenylethylamino)propoxy]phenyl}-
5,6-dimethoxy-1-oxo-isoindoline (19)
N-[4-(2,3-Epoxypropoxy)phenyl]-5,6-dimethoxy-1-oxo-isoindoline 11 (0.25g,
0.7mmol) and homoveratrylamine (1 ml, 6.0mmol) were heated at 80 °C for 8h,
added distilled water and left overnight. The solid obtained was Wltered and crystal-
lized from acetone to aVord 19 (0.35g, 91.45%), mp 60–62 °C. IR (KBr): 2936, 1675,
1
1609, 1455, 1385, 1263, 1057, and 822cm¡1. H NMR (CDCl3): ꢂ 2.15 (br, 2H,
disappeared on D2O exchange, –OH and –NH–), 2.80 (m, 6H, –CH2NHCH2CH2–),
3.68–4.10 (m, 15H, –OCH2CH< and 4 –OCH3), 4.67 (s, 2H, methylene protons of iso-
indoline) and 6.70–7.65ppm (m, 9H, Ar). Calcd. for C29H34N2O7: C, 66.65; H, 6.56; N,
5.36. Found: C, 66.50; H, 6.46; N, 5.32.

D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
319
2.1.24. N-{4-[2-Hydroxy-3-(3,4-dimethoxyphenylethylamino)propoxy]phenyl}-
5,6-dimethoxy-1-oxo-isoindoline (19) HCl
Method A. As no precipitation occurs the solvent was removed under reduced pres-
sure to give an oily residue, which on treatment with ethyl acetate aVorded the HCl salt
of 19 (40.73%; mp 188–190°C). IR (KBr): 3394, 2836, 1679, 1606, 1507, 1456, 1385, 1024,
and 816cm¡1. 1H NMR (DMSO-d6): ꢂ 3.27 (br, 6H, –CH2NHCH2CH2–), 3.78 and 3.82
(2£s, 6H, 2£–OCH3), 3.91 (s, 6H, 2£–OCH3), 3.95–4.06 (m, 3H, –OCH2CH<),
4.47 (s, 2H, methylene protons of isoindoline), 5.58 (br, 1H, disappeared on D2O
exchange, –OH), 6.70–7.53 (m, 9H, Ar) and 8.95ppm (br, 1H, disappeared on D2O
exchange, –NH–). Calcd. for C29H35N2O7Cl: C, 62.30; H, 6.31; N, 5.01. Found: C, 62.13;
H, 6.21; N, 4.93.
2.1.25. N-{4-[2-Hydroxy-3-(3,4-dimethoxy-N-methylphenylethylamino)propoxy]
phenyl}-5,6-dimethoxy-1-oxo-isoindoline (20)
N-[4-(2,3-Epoxypropoxy)phenyl]-5,6-dimethoxy-1-oxo-isoindoline 11 (0.50g,
1.5mmol) and N-methylhomoveratrylamine (1 ml, 5.4mmol) were heated at 80°C for
7 h, added distilled water and left overnight. The solid obtained was Wltered and crys-
tallized from acetone to aVord 20 (0.75 g, 95.42%), mp 74–76 °C. IR (KBr): 3437,
1
2842, 1671, 1604, 1559, 1466, 1388, 1262, 1057, and 827cm¡1. H NMR (CDCl3): ꢂ
2.40 (s, 3H, –NCH3), 2.53–2.82 (m, 7H, –CH(OH)CH2N(CH3)CH2CH2–, 1H D2O
exchanged), 3.85 and 3.88 (2£ s, 6H, 2 £–OCH3), 4.05 (m, 2H, –OCH2–), 4.71 (m, 3H,
–CH(OH)–, methylene protons of isoindoline), and 6.72–7.69ppm (m, 9H, Ar).
Calcd. for C30H36N2O7: C, 67.14; H, 6.76; N, 5.22. Found: C, 66.92; H, 6.73; N, 5.21.
2.1.26. N-{4-[2-Hydroxy-3-(3,4-dimethoxy-N-methylphenylethylamino)
propoxy]phenyl}-5,6-dimethoxy-1-oxo-isoindoline (20) HCl
Method A. As no precipitation occurs the solvent was removed under reduced
pressure to give an oily residue, which on treatment with ether and then with ethyl
acetate aVorded a solid residue which was crystallized from acetone to aVord HCl
salt of 20 (44.95%; mp 202–205°C). IR (KBr): 3295, 2942, 2541, 1673, 1615, 1512,
1
1466, 1389, 1238, and 828cm¡1. H NMR (DMSO-d6): ꢂ 2.30 (s, 3H, –NCH3), 3.41
(br, 6H, –CH2N(CH3)CH2CH2–), 3.85 and 3.88 (2 £ s, 6H, 2 £–OCH3), 3.96 (s, 6H,
2 £–OCH3), 4.16 (m, 2H, –OCH2–), 4.68 (m, 3H, –CH(OH)–, methylene protons of
isoindoline), 5.60 (br, 1H, disappeared on D2O exchange, –OH), and 6.81–7.68ppm
(m, 9H, Ar). Calcd. for C30H37N2O7Cl: C, 62.87; H, 6.51; N, 4.89. Found: C, 62.69; H,
6.56; N, 4.87.
2.2. Pharmacological methods
2.2.1. Materials
All the used solvents and powders were for analysis (J.T. Baker, Deventer, Hol-
land). Propranolol HCl and ICI 118551 were purchased from Sigma Chemical, St.
Louis, MO, USA. [3H]dihydroalprenolol ([3H]DHA) (New England Nuclear, Boston,
MA), having a speciWc activity of 99.9Ci/Mol and radiochemical purity >98.5%, was
used as ligand.

320
D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
2.2.2. ꢀ1-Adrenergic receptor binding assay
Pellets containing ꢀ1-type adrenergic receptors were obtained from turkey eryth-
rocyte membranes as described in the literature [12].
ꢀ1-Adrenergic receptor binding assay was determined as follows: 300ꢄl of mem-
brane (»1.2 mg/ml protein, dilution 1:8 v/v) were incubated for 15min at 37 °C with
100 ꢄl of 4 nM [3H]DHA and 100ꢄl of various concentrations of the test compounds
(dissolved in water and diluted with saline buVer) and 12 M Tris–HCl, pH 7.5 (total
vol. 1ml). The incubations were stopped adding 4ml of cold buVer (12 M Tris–HCl)
followed by rapid Wltration through glass Wber Wlter Whatman GF/B disks (Brandel
Biomedical Research and Laboratories, Gaithersburg, MD). The samples were sub-
sequently washed 3 times with 4.5ml of the same buVer and placed into scintillation
vials 10ml Filter-Count liquid scintillation cocktail (Packard BioScience s.r.l., Pero,
Milan, Italy) was then added to each vial and counting was carried out by scintilla-
tion spectrometer (Packard TRI-CARB 2000CA—Packard BioScience s.r.l., Pero,
Milan, Italy).
Non-speciWc binding was deWned as non-displaceable binding in the presence of
100 ꢄl of 10 ꢄM propranolol.
Competition experiments were analyzed by the “Easy Fit” program (EasyFit 1.4,
1989–1991, Matteo Vaccari and Mario Negri Institute, Milan, Italy) to obtain the
concentration of unlabeled drug that caused 50% inhibition of ligand binding (IC50),
with six concentrations or displacers, each performed in triplicate.
The IC50 values obtained were used to calculate apparent inhibition constants (Ki)
by the method of Cheng and PrussoV [13], from the following equation: Ki DIC50/
(1+ S/KD) where S represents the concentration of the ligand used and KD its recep-
tor dissociation constant (KD values, obtained by Scatchard analysis [14], for
[3H]DHA is 3.6 £10¡9 M).
2.2.3. ꢀ2-Adrenergic receptor binding assay
Preparation of lung homogenate: male Sprague–Dawley rats (Harlan Italy s.r.l.,
Correzzana, Milan) were sacriWced by decapitation. The right lung was removed free
of the major bronchi. Lungs were homogenized with Polytron Apparatus—Kinemat-
ica GmbH, Littau, Switzerland (setting 5 for 15 s) in 50 volumes buVer, 75 M
Tris–HCl (pH 7.65), 25 M MgCl2 and then centrifuged at 30,000g for 10min twice.
The resulting pellets were resuspended in 100 volumes of buVer 75 M Tris–HCl (pH
7.65), 25 M MgCl2, then were frozen at ¡80°C before being assayed [15,16].
[3H]Dihydroalprenolol was used as ligand.
Three hundred microliters of membrane of lung (»13.05 mg of fresh tissue, dilu-
tion 1:10) were incubated for 30 min at 37 °C with 100 ꢄl of 6nM [3H]DHA, 100 ꢄl
ketanserine 10¡7 M 5HT antagonist and 100ꢄl of various concentrations of the test
compounds (dissolved in water and diluted with buVer) and 75M Tris–HCl (pH
7.65), 25M MgCl2 (total vol. 1ml). The samples were subsequently washed with
4.5ml of the same buVer and placed into scintillation vials. 10ml of Filter-Count liq-
uid scintillation cocktail (Packard BioScience s.r.l., Pero, Milan, Italy) was then
added to each vial and counting was carried out by scintillation spectrometer (Pack-
ard TRI-CARB 2000CA—Packard BioScience s.r.l., Pero, Milan, Italy).

D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
321
Non-speciWc binding was measured in the presence of 100ꢄl of 10ꢄM unlabeled
ICI 118551, and speciWc binding as the diVerence between total and non-speciWc
binding.
The concentration of the test compounds that inhibited [3H]DHA binding by 50%
(IC50) were determined as above reported.
3. Results and discussion
HCl salts of compounds 12–20 were subjected to in vitro ꢀ1- and ꢀ2-adrenergic
receptor binding assay using turkey erythrocyte membrane (ꢀ1) and lung homoge-
nate of rats (ꢀ2). The percentage inhibition of [3H]DHA binding to both ꢀ1- and ꢀ2-
adrenergic receptors and selectivity ratio (ꢀ1/ꢀ2) are shown in Table 1 and their Ki
values shown in Table 2. The results of binding assay were compared with that of the
standard non-selective ꢀ-adrenergic blocking agent propranolol and cardioselective
ꢀ-adrenergic blocking agent atenolol used clinically.
All the newly synthesized compounds exhibited aYnity to ꢀ1/ꢀ2-adrenergic recep-
tor in the concentration range tested. In general the 5,6-dimethoxy-1-oxo-isoindoline
derivatives (17–19) were less active than the 1-oxo-isoindoline derivatives (12–15) at
the ꢀ1-adrenergic receptor site, while the reverse is true at ꢀ2-adrenergic receptor site,
i.e., 5,6-dimethoxy-1-oxo-isoindoline derivatives (17, 18) were more potent than the
unsubstituted derivative (12, 13). Thus, it seems that incorporation of dimethoxy
Table 1
Percentage inhibition of [3H]DHA binding on ꢀ1- and ꢀ2-adrenergic receptor and selectivity ratio of com-
pounds 12–20 (hydrochloride salt) at the highest used concentration [10¡5 M]
Compounda
R1
R2
%I ꢀ1
%I ꢀ2
Selectivity ratiob
12
13
14
H
H
H
NHCH(CH3)2
NHC(CH3)3
77.24 § 13.79
45.75 § 6.79
26.44 § 5.59
None
None
None
—
—
—
15
16
17
18
19
20
H
H
OCH3
OCH3
OCH3
OCH3
H
CH3
NHCH(CH3)2
NHC(CH3)3
H
36.02 § 0.71
52.31 § 6.01
17.18 § 0.96
2.91 § 0.50
23.90 § 1.19
68.81 § 5.30
97.12 § 3.00
73.06 § 1.25
16.22 § 1.58
None
82.51 § 2.05
39.00 § 5.94
11.59 § 0.47
None
2.22
—
0.21
0.08
2.06
—
CH3
Propranolol
Atenolol
99.80 § 0.28
0.97
2.13
34.34 § 0.84
a
HCl salt of the compounds were used for binding studies.
Expressed as (%I ꢀ1/%I ꢀ2).
b

322
D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
Table 2
Inhibition of [3H]DHA binding on ꢀ1- and ꢀ2-adrenergic receptor of compounds 2a, 2b, 12, 13, 16, 17, and
20
Compounda
Kiꢀ1 § SD (M)
Kiꢀ2 § SD (M)
2a (Ref. [3])
2b (Ref. [3])
12
13
16
17
20
4.85 £ 10¡7 § 0.23
1.62 £ 10¡9 § 0.37
1.36 £ 10¡7 § 0.40
1.44 £ 10¡5 § 0.15
2.20 £ 10¡6 § 0.85
—
1.72 £ 10¡5 § 0.98
—
—
—
—
1.47 £ 10¡9 § 0.33
1.66 £ 10¡6 § 0.24
1.60 £ 10¡9 § 0.13
2.70 £ 10¡8 § 0.40
—
Propranolol
Atenolol
2.50 £ 10¡9 § 0.18
—
a
HCl salt of the compounds were used for binding studies.
substituent at 5,6-position of 1-oxo-isoindoline derivatives leads to a decrease in
ꢀ1-adrenergic receptor aYnity and increase in ꢀ2-adrenergic receptor aYnity. This
Wnding is in accordance to our previous report, i.e., introduction of additional meth-
oxy group in para-substituent in a series of 4-acylamino substituted phenoxypropa-
nolamines decreases aYnity to ꢀ1-adrenergic receptor and increases the binding
aYnity to ꢀ2-adrenergic receptor [3].
In both the series the isopropyl derivative (12, 17) is more active than the tert-
butyl derivative (13, 18), while the N-methylhomoveratrylamine derivative (16, 20) is
more active than the homoveratrylamine derivative (15, 19) at ꢀ1-adrenergic receptor.
In 1-oxo-isoindoline series most of the compounds (12–14, 16) do not exhibit aYnity
to ꢀ2-adrenergic receptor. While in 5,6-dimethoxy-1-oxo-isoindoline series isopropyl
derivative is the most active and N-methylhomoveratrylamine derivative is the least
active with respect to ꢀ2-adrenergic receptor.
Regarding the selectivity of compounds, 1-oxo-isoindoline series of compounds
were more selective to ꢀ1-adrenergic receptor than the 5,6-dimethoxy-1-oxo-isoindo-
line series of compounds (12/13/15 vs 17/18/19). In the 5,6-dimethoxy-1-oxo-isoindo-
line series N-methylhomoveratrylamine derivative (20) is the most cardioselective
compound, while the isopropyl derivative (17) being selective towards the ꢀ2-adrener-
gic receptor.
Comparison of the Ki values of the previously reported compounds 2a and 2b [3],
with the compounds 12 and 13 (Table 2), show that the incorporation of para-amidic
functionality within the 1-oxo-isoindoline ring system retain the aYnity to ꢀ-adrener-
gic receptor with cardioselectivity. While incorporation of para-amidic functional-
ity within the 5,6-dimethoxy-1-oxo-isoindoline ring system still retains aYnity for
ꢀ-adrenergic receptor, but the selectivity is reversed to ꢀ2-adrenergic receptor as
exempliWed by compounds 17 and 18. So it can be said rigidiWcation of the para-ami-
dic substituent in phenoxypropanolamines retain aYnity to ꢀ-adrenergic receptor,
but the selectivity could be determined by the nature of amino substituent and the
substituents in the 1-oxo-isoindoline ring system.
Among the two series of compounds, 12 and 20 possessed good aYnity compara-
ble with that of atenolol, a commonly used cardioselective beta blocker. Both 12 and

D.P. Jindal et al. / Bioorganic Chemistry 33 (2005) 310–324
323
20 showed a high degree of cardioselectivity (they did not show aYnity to ꢀ2-adrener-
gic receptor) and were far higher than the selectivity ratio of atenolol, which was 2.13.
Propranolol a non-selective ꢀ-adrenergic blocking agent had showed better aYnity
than 12 and 20, but did not posses cardioselectivity. Both 12 and 20 have been
selected from this series of compounds for further pharmacological investigations
and the results will be published elsewhere.
Use of para-amidic substituents in phenoxypropanolamines has been well
documented to lead to cardioselective beta blocking action [3,9]. In this study,
the incorporation of amidic functionality within the 1-oxo-isoindoline ring and 5,6-
dimethoxy-1-oxo-isoindoline ring system retained the high degree of cardioselectivity
normally seen in open chain analogues. Thus, it could be concluded that the aYnity
and selectivity to ꢀ1- and ꢀ2-adrenergic receptor of phenoxypropanolamines could be
inXuenced by the nature of the substituent present at both the para-position of the
phenyl ring and also by the amino substituent. Skillful manipulation of these two
substituents could lead to phenoxypropanolamines with a good aYnity and selectiv-
ity to ꢀ1-adrenergic receptor.
Acknowledgments
We wish to thank University Grants Commission, New Delhi, India and PAR by
University of Siena, Italy for Wnancial support. Also thanks are due to M/S Rohini
Chemicals, Ghaziabad for generous supply of 4-aminophenol.
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