Synthesis and evaluation of some novel isochroman carboxylic acid derivatives as potential anti-diabetic agents

Article abstract of DOI:10.1016/j.ejmech.2009.03.009

A series of novel isochroman mono-carboxylic acid derivatives were synthesized, characterized and evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B) in vitro in order to use them as potential anti-diabetic agents. Analysis of structure-activity relationships led to the identification of potent compound 4n which inhibited PTP1B with IC₅₀ value of 51.63 ± 0.91 nM. In general, high potency was associated with a dithiolane ring with a spacer of five carbons to the isochroman ring. Compound 4n has been selected for in vivo evaluation as drug candidate for anti-diabetic activity.

Full text of DOI:10.1016/j.ejmech.2009.03.009

European Journal of Medicinal Chemistry 44 (2009) 3147–3157
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and evaluation of some novel isochroman carboxylic acid derivatives as
potential anti-diabetic agents
,
a
a
b
N. Lakshminarayana a, Y. Rajendra Prasad b , Laxmikant Gharat , Abraham Thomas , P. Ravikumar ,
*
Shridhar Narayanan a, C.V. Srinivasan a, Balasubramanian Gopalan a
a Medicinal Chemistry Division, Glenmark Research Center, Mahape, Navi Mumbai 400709, India
b Pharmaceutical Chemistry Division, AU College of Pharmaceutical Sciences, Andhra University, Waltair, Visakhapatnam 530 003, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel isochroman mono-carboxylic acid derivatives were synthesized, characterized and
evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B) in vitro in order to use them
as potential anti-diabetic agents. Analysis of structure–activity relationships led to the identification of
potent compound 4n which inhibited PTP1B with IC50 value of 51.63 ꢀ 0.91 nM. In general, high potency
was associated with a dithiolane ring with a spacer of five carbons to the isochroman ring. Compound 4n
has been selected for in vivo evaluation as drug candidate for anti-diabetic activity.
Received 5 August 2008
Received in revised form
20 February 2009
Accepted 12 March 2009
Available online 24 March 2009
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
Isochroman-3-(S)-carboxylic acid
PTP1B inhibition
Anti-diabetic activity
1. Introduction
oxalylaminobenzoic acids, etc. [3]. Given that most of the catalytic
site-directed PTP1B inhibitors are highly charged molecules, non-
Insulin resistance is associated with a deficit in protein tyrosine
phosphorylation in insulin signal transduction cascade. Genetically
modified mice that lack protein tyrosine phosphatase 1B (PTP1B)
expression and animals treated with a specific PTP1B antisense
oligonucleotide have provided crucial ‘‘proof-of-concept’’ data to
show that eradicating or reducing PTP1B enhances insulin signaling
and glucose tolerance [1]. Zhang and co-workers first identified
a second phosphotyrosine (pTyr) binding site (site 2) in the vicinity
of PTP1B catalytic site. They also pioneered the notion of achieving
selectivity among PTP1B, T-cell protein tyrosine phosphatase
(TCPTP) and other phosphatases by targeting the less homologous
site 2 [2].
Discovery of small-molecule inhibitors has been pursued
extensively in both academia and industry and a number of very
potent and selective inhibitors have been identified. These inhibi-
tors typically incorporate a charged pTyr mimetic to achieve strong
binding to the highly conserved and polarized active site of PTPases.
The commonly used pTyr mimetics include phosphonates,
carboxylic acids, sulfamic acids, difluoromethylphosphonates,
carboxylic acid-containing ligands targeting site 2 are highly
desirable for improving the overall druglike properties. Liu et al.
reported the discovery of first non-acid-containing, salicylate-
based ligands for site 2 of PTP1B, and a structure-based linking
approach for identifying a potent PTP1B inhibitor 1 with selectivity
over TCPTP (Fig. 1) [4]. Another report by Wan et al. described
a series of monocyclic thiophenes with moderate inhibitory
potency against PTP1B [5]. In another attempt, Liu et al. identified
a selective and cell active PTP1B inhibitor 2 an isoxazole carboxylic
acid analog (Fig. 1), from X-ray crystallographic study and NMR-
based screening [6]. Larsen et al. prepared compounds based on
L-
tyrosine with arylalkanoyl groups showing cellular activity [7]. Liu
et al. also disclosed an invention based on 3-phenyl propanoic acid
derivatives as PTP1B inhibitors [8]. Shim et al. reported the
discovery of a formylchromone derivative 3 (Fig. 1) with excellent
potency and twelvefold selectivity over TCPTP [9].
From the literature it is evident that a monoacid based frag-
ment binds with the catalytic site of PTP1B and a hydrophobic end
of a side chain binds with the secondary site imparting more
potency and selectivity towards PTP1B. The objective of our PTP1B
inhibitor program was to identify a novel series of selective and
reversible inhibitors of PTP, employing a phosphate mimic and
a non-peptidyl small molecule. The throughput screening of
* Corresponding author.
E-mail address: dryrp@rediffmail.com (Y. Rajendra Prasad).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.03.009

3148
N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 44 (2009) 3147–3157
2. Chemistry
L
-Phenylalanine was chosen as our chemistry starting point and
HOOC
O
then functionalized the aromatic ring in order to attach the linker
and the hydrophobic group and also modified the amino acid
nature before studying the SAR of the analogs. The designed
compounds were synthesized as outlined in Schemes 1 and 2,
N
O
NH
OH
H
N
O
HO
O
CO2Me
O
wherein
L-phenylalanine was converted to
L-(ꢁ)-3-phenyl lactic
1 Ki: 18 nM (PTP1B)
acid through diazotization [12], which was then cyclized using
paraformaldehyde, to isochroman-3-(S)-carboxylic acid [13] and
was esterified in the presence of catalytic amount of conc. sulphuric
acid. Nitration of isochroman-3-(S)-carboxylic acid methyl ester,
when carried out at 0 ꢂC, not only resulted in the introduction of
nitro group exclusively at the C7 position but also caused oxidation
of the benzylic (C1) carbon to give isochroman-1-one nucleus as
seen in compound 7, whereas nitration at ꢁ40 ꢂC, resulted in the
formation of both the isomers (6-nitro and 7-nitro isochroman-3-
(S)-carboxylic acid esters), without oxidation of the C1 carbon.
Reduction of the isomeric mixture of nitro compounds and chro-
matographic separation of the isomers gave appropriately func-
tionalized isochroman-3-(S)-carboxylic acid methyl ester.
Ki: 65 nM (TCPTP)
O
OH
N
O
MeO
HO
O
O
2 Ki: 5.7 uM (PTP1B)
Ki: 202 uM (TCPTP)
The corresponding carboxylic acid moieties for preparing
various amides were purchased from commercial sources or were
prepared as per procedures described in Schemes 4–6. 4-(2-
Thienyl)-butanoic acid and 5-(2-thienyl)-pentanoic acid were
prepared by Friedel–Craft’s reaction of thiophene with succinic
anhydride and glutaric anhydride respectively, followed by Clem-
mensen reduction of the keto-acid, as shown in Scheme 4 [14]. 2,2-
Dimethyl or 2,2-diphenyl 1,3-dithiolan-4-yl-3/5-alkanoic acid was
prepared in a four step sequence which involved reacting 4-pen-
tenoic acid or 6-heptenoic acid with bromine [15] and esterifica-
tion, catalysed by few drops of conc. sulphuric acid followed by the
reaction of the dibromide with thioacetic acid to give dithioacetyl
compound [16]. Deacetylation of the above in refluxing methanolic
HCl gave the desired dimercapto ester. Cyclization of the dimer-
capto ester by reaction with ketone (2,2-dimethoxypropane or
benzophenone) in the presence of BF3$Et2O [17], followed by ester
hydrolysis gave the desired 2,2,-disubstituted 1,3-dithiolan acids
(Scheme 5). 1,3-Dithian-4-yl-5-pentanoic acid or 2,2-diphenyl 1,3-
dithian-4-yl-5-pentanoic acid was prepared in a four step sequence
which involved esterification of R-Lipoic acid in the presence of
EDCI, HOBT, methanol and DMF followed by reduction of the
disulfide using NaBH4 in methanol. The obtained dithiol was then
reacted with paraformaldehyde or benzophenone in the presence
of BF3$Et2O followed by saponification of the ester with NaOH,
(Scheme 6) [17]. Compounds without cyclization to the isochroman
ring were also prepared. The compounds 13a–d were synthesized
O
CHO
O
3 Ki; 4.3 uM (PTP1B)
Ki: 51 uM (TCPTP)
Fig. 1. Known PTP1B inhibitors with selectivity over TCPTP.
a chemically diverse compound library resulted in the identifica-
tion of a hit 4a showing 50% inhibition of PTP1B at 10 M and had
m
all the requisite functionalities like a carboxylic acid-containing
small molecule with a hydrophobic side chain. This prompted us
to explore the scaffold of our hit, to optimize the activity by
making analogs with sidechains of varying linker lengths and with
various substitutions.
At this point we also thought it is worthwhile to study the
influence of a-Lipoic acid (LA), a disulfide compound which func-
tions naturally as a co-enzyme and occurs in the R (þ) form. LA was
demonstrated to stimulate the autophosphorylation of insulin
receptor and glucose uptake into 3T3-L1 adipocytes by reducing the
thiol reactivity of intracellular proteins. LA also inhibited protein
tyrosine phosphatase activity and decreased thiol reactivity of
PTP1B. These findings indicate that oxidants produced by LA are
involved in activation of insulin receptor and inactivation of protein
tyrosine phosphatases, which eventually result in elevated glucose
uptake into 3T3-L1 adipocytes [10]. The antioxidant activity of LA is
also attributed to its capacity to regenerate intracellular GSH,
vitamin C, and vitamin E. Numerous other studies have reported
that LA is beneficial in a number of oxidative stress models of cell
death pertinent to ischemia–reperfusion injury, neuro-
degeneration, diabetes, inflammation, and radiation injury. Thus,
LA possesses the potential to intervene in various therapeutically
interesting pathways. However, it should be noted that LA report-
edly exerts most of its effects at high micromolar concentration
whereas amides of LA exhibit higher biological activity than the
parent compound and that molecular combinations obtained by
coupling LA with an amino-substituted bioactive moiety possess
multifunctional activity [11].
as outlined in Scheme 3 wherein
L-phenylalanine was nitrated
COOH
CO2Me
a
OH
O
1
2
b
CO2Me
CO2H
c
H2N
O
ROCHN
O
3
4(a-t)
Scheme 1. (a) (1) (HCHO)n, TFA, reflux, 72 h. (2) Methanol, Cat. H2SO4, reflux, 4 h; (b)
(1) fuming HNO3, ꢁ40 ꢂC, 40 min. (2) Pd/C, H2, EtOAc, 3 h; column purification. (c) (1)
RCO2H, EDCI$HCl, Et3N, CH2Cl2, 3 h. (2) K2CO3, aqueous methanol (1:1), 5 h.

N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 44 (2009) 3147–3157
3149
diet. Fasting (18 h) biochemical parameter estimation was done on
days 10 and 14. Fed-state WBG was done on day 7. Body weight and
feed intake were recorded twice a week.
CO2Me
CO2Me
d
c
O
O
O2N
O
2
5
6
4. Results and discussion
e
Compound 4a showed an IC50 of 429 nM, which is our initial hit
and its regio isomer 4b showed 383.7 nM, whereas compounds 4g
and 4h with saturated alicyclic rings in place of aromatic ring in the
side chain, showed improved activity. Reducing the length of the
carbon chain, as in compounds 4c and 4d resulted in slight loss of
activity. Increasing the size of the saturated ring from five
membered to six membered as in compounds 4q and 4r did not
alter the activity much but increasing the bulkiness in the saturated
ring by introducing phenyl groups as in compounds 4i, 4j, 4s and 4t
caused loss of activity. Shifting from 1,3-dithiolane to 1,2-dithiolane
ring resulted in hugely potent compounds 4k–4n. The stereo-
chemistry of the LA also seems to be playing a role as is evident
with compounds 4m and 4n showing greater potency than their
racemic compounds. Replacing the LA group with Biotin as in
compounds 4o and 4p also resulted in loss of activity. Best activity
was found to be associated with compounds which have a linker of
five carbons. The regioisomers 4m and 4n both showed excellent
activity, which revealed that there is no specificity associated with
the position of the substituent on the isochroman ring, with respect
to activity against PTP1B. The activity associated with compounds
4k–4n may also be attributed to the intrinsic activity of LA against
PTP1B. Having studied and optimized the side chain part, it is
decided to optimize the isochroman ring, by making the oxidized
analog of 4n and also the uncyclized analogs of it. While compound
7 showed much less potency, the uncyclized ethyl ether 13b
showed reasonable activity. Compounds with lengthier ethers 13c
and 13d also showed much less potency. Among all the compounds
prepared, compound 4n showed high potency and very good
specificity over other PTPases, and hence it was selected for in vivo
study, using rosiglitazone maleate as the standard. The hypergly-
cemic condition in ob/ob mice was normalized when treated with
compound 4n. The treatments showed significant reduction
(p < 0.001) in fed-state WBG on day 7 of the study. Similar trend
was observed in fasting WBG on day 10 of the study with 4n and
rosiglitazone showing a reduction compared with vehicle (93 ꢀ15,
90 ꢀ 5 and 139 ꢀ 8 mg/dl) respectively (Figs. 2 and 3). Compound
4n did not show any significant difference in glucose excursion.
Rosiglitazone showed significant reduction on fasting plasma
glucose and triglyceride levels whereas 4n showed significant
reduction in fasting plasma glucose levels only (Fig. 4).
CO2H
CO2Me
O
O
ROCHN
H2N
O
O
7
Scheme 2. (d) Fuming HNO3, 0 ꢂC, 40 min; (e) Pd/C, H2, EtOAc, 3 h; (c) 1). LA,
EDCI$HCl, Et3N, CH2Cl2, 3 h. (2) K2CO3, aqueous methanol (1:1), 5 h.
using nitric acid in the presence of conc. sulphuric acid and the
L-phenylalanine was subjected to diazotization in
1 N sulphuric acid followed by esterification to yield 4-nitro-
phenyl lactic acid ethyl ester. Etherification was done with different
alkyliodides in the presence of silver oxide and then the nitro group
was converted to amine by catalytic reduction followed by ami-
dation with the carboxylic acid moiety. The physical constants of
compounds 4a–4t, and 7 and 13a–13d are as shown in (Tables 1 and
2), respectively. The data from the SAR studies is mentioned in
Table 3.
obtained 4-nitro-
L-
3. Pharmacology
The inhibitory activities of the compounds were determined
with minor modifications of the procedure described in the liter-
ature using p-nitrophenyl phosphate (pNPP) as a substrate at 37 ꢂC
[9]. IC50 values were derived from three independent experiments
using the inhibitors at concentrations of 30 nM, 100 nM, 300 nM,
1.0 mM, 3.0 mM and 10.0 mM. For inhibition assay, inhibitor (10 mM in
DMSO) was added to a mixture containing enzyme (5 mL), reaction
buffer (Hepes 25 mM, 3 mM DTT, 0.15 M NaOH, 1 mM EDTA and
Nonidet-P40 (NP-40) 0.01%) and was incubated at 37 ꢂC for 10 min.
The reaction was initiated by addition of para-nitro phenyl phos-
phate (pNPP, 2.5 mM) and, after 30 min at 37 ꢂC, the reaction was
quenched by addition of NaOH solution (2.5 mM). The progress of
the reaction was determined for the formation of p-nitrophenolate
by measuring the absorbance at 405 nm. PTP1B was diluted before
use to an appropriate concentration (typically 40 mg/mL) by
enzyme dilution buffer: 2 ꢃ reaction buffer (NP-40 0.01%, 3 mM
DTT, pH 7.5). Healthy male ob/ob mice (eight animals in each group)
were used for the in vivo study and were provided with 11% high fat
CO2H
NH2
CO2H
CO2Me
OH
CO2Me
OR'
g
h
f
NH2
O2N
O2N
O2N
9
10
8
11
e
1. R-(+)-Lipoic acid, EDCI.HCl,
TEA, CH2Cl2, rt, 3h
CO2H
OR'
CO2Me
OR'
O
2. K2CO3, water, Methanol, rt, 5h
H2N
N
H
a: R' = Me
S
S
b: R' = Et
c: R' = Propyl
d: R' = Butyl
13(a-d)
12
Scheme 3. (f) Conc. HNO3, conc. H2SO4, 0 ꢂC, 1 h; (g) (1) 1 N H2SO4, aqueous NaNO2, 0–rt, 6 h, (2) methanol, cat. H2SO4, reflux, 4 h; (d) R0I, Ag2O, toluene, reflux, 5 h; (e) Pd/C, H2,
EtOAc, 3 h.

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N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 44 (2009) 3147–3157
O
a
O
O
OH
OH
n
O
S
S
a
OMe
OMe
S
O
14
22
SH SH
23
S
15
b
O
b
OH
S
S
c
S
S
24
25
''R
R''
''R
R''
OH
a: R'' = H
b: R'' = Ph
n
S
a: n = 2
b: n = 3
O
16
Scheme 6. (a) (1) CH3OH, EDCI$HCl, DMF, HOBT, rt, 5 h; (2) NaBH4, MeOH, rt, 1.5 h; (b)
BF3$Et2O, paraformaldehyde or benzophenone, CH2Cl2, rt, 6 h; (c) NaOH, MeOH, rt, 4 h.
Scheme 4. (a) AlCl3, succinic anhydride or glutaric anhydride, nitrobenzene, 0–5 ꢂC,
4 h; (b) Zn amalgam, 5 N HCl, reflux, 6 h.
6. Experimental
5. Conclusion
Melting points were measured using POLMON MP-96T-X
melting point apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded on Varian Mercury VX 300 spectrometer,
using tetramethylsilane as an internal standard and DMSO-d6 as
solvent, unless otherwise specified. IR spectra were acquired on
Perkin–Elmer spectrum-one FT-IR spectrometer. Mass spectra were
run on Finnigan Navigator spectrometer at 20 eV or 50 eV.
Elemental analyses were carried out with a Perkin–Elmer model
2400 series II apparatus. The results of elemental analyses (C, H, N)
were within ꢀ0.4% of the calculated values. Specific optical rotation
was recorded on JASCO P-1030 polarimeter.
In summary we have discovered a series of potent, novel, non-
phosphonic acid-containing PTP1B inhibitors with good specificity
for PTP1B over TCPTP, the most homologous phosphatase to PTP1B.
A strategy of occupying both the catalytic site and the nearby, less
homologous, non-catalytic phosphotyrosyl binding site is
employed in the present study. An examination of the PTP1B
inhibitors synthesized revealed the residues important for
achieving PTP1B specificity and thus provided an opportunity for
designing more potent and selective PTP1B inhibitors. SAR studies
revealed the critical role of the dithiolane moiety in the amide
chain of the ring which showed promising activity in vivo. Although
there is much work reported on aryl difluorophosphonate-con-
taining PTP1B inhibitors, the present study was of considerable
interest to define a small molecule, nonphosphonate-containing,
non-peptide, carboxy-based phenylphosphonate mimetic for use as
PTP1B inhibitors. The hitherto unreported mono-carboxy motif and
its synergistic activity with LA reported herein provides a new
approach, which may be of use in the design of carboxy-based
PTP1B inhibitors and could serve as advanced lead for further
optimization.
6.1. Synthesis of intermediates
6.1.1. Synthesis of
L
-(ꢁ)-3-phenyl lactic acid (1)
-phenylalanine (50 mmol) in 1 N H2SO4
To a solution of
L
(100 mL), while stirring at 0 ꢂC, was added an aqueous solution of
sodium nitrite (100 mmol in 20 mL water), dropwise and the
reaction mixture was stirred for 6 h while allowing the reaction
mixture to warm to room temperature. The reaction mixture was
then extracted with ethyl acetate and the organic layer was washed
with water and brine and concentrated to give
L
-(ꢁ)-3-phenyl lactic
acid. Yield: 82%; 1H NMR:
d
7.30–7.10 (br s, 5H), 4.20–4.10 (m, 1H),
3.00–2.90 (dd, J ¼ 3.9 Hz and 13.5 Hz, 1H), 2.80–2.70 (dd, J ¼ 8.1 Hz
and 13.5 Hz, 1H); MS (m/z): 167.18 (M þ H)þ; [
a]
24: ꢁ22ꢂ (C 2.0,
H2O). Mp: 123–125 ꢂC; [Lit. value: [
122–124 ꢂC].
a
]
24: ꢁ20.8ꢂ (C 2.0, H2O). Mp:
O
O
a
Br
O
OMe
OH
n
n
17
Br
18
6.1.2. Synthesis of isochroman-3-(S)-carboxylic acid methyl
ester (2)
b
To a solution of
L-(ꢁ)3-phenyl lactic acid (40 mmol) in tri-
O
n
O
fluoroacetic acid (25 mL), was added paraformaldehyde
(13.33 mmol) and the reaction mixture was refluxed for 72 h.
Solvent was then distilled off from the reaction mixture, diluted
with water and was extracted with ethyl acetate. The organic layer
was then washed with brine and concentrated to give isochroman-
3-(S)-carboxylic acid. The obtained acid was then dissolved in
methanol (80 mL) and was added catalytic amount of conc. Sul-
phuric acid and the reaction mixture was refluxed for 4 h. Solvent
was then evaporated from the reaction mixture on rotavapor,
diluted the residue with ethyl acetate and was washed with sat.
sodium bicarbonate solution followed by water and brine and
concentrated to give isochroman-3-(S)-carboxylic acid methyl
ester. Yield: 74%; Mp: 68 ꢂC; IR (KBr): 3485, 2948, 2843, 1751, 1457,
1441, 1370, 1246,1220, 1203, 1187, 1116, 1052 and 982 cmꢁ1. 1H NMR
HS
OMe
S
OMe
n
c
SH
O
S
20
19
d
O
OH
a: n = 1, R'' = Me
b: n = 1, R'' = Ph
c: n = 3, R'' = Me
n
S
S
21
''R R''
Scheme 5. (a) (1) Br2, CH2Cl2, ꢁ40 ꢂC, 1.5 h; (2) MeOH, cat. conc. H2SO4, reflux, 4 h. (b)
CH3COSH, alc. KOH, rt, 3 h; (c) methanolic HCl, reflux, 3 h; (d) (1) BF3$Et2O, 2,2-
dimethoxypropane or benzophenone, CH2Cl2, rt, 6 h; (2) aqueous NaOH, MeOH, rt, 4 h.

N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 44 (2009) 3147–3157
3151
Table 1
Physical constants of compounds 4a–4t.
Compound no.
R
Isomer
Yield (%)
M.p. (ꢂC)
M. F/M. wt/; C, H, N (% Calc.)
C, H, N (% Found)
4a
4b
6
7
85
82
242–245
211–213
C, 63.41; H, 5.82; N, 3.93
C, 63.39; H, 5.92; N, 3.85
S
359.43/C19H21NO4S; C, 63.49; H, 5.89; N, 3.90
4c
4d
6
7
91
93
203–205
187–190
C, 62.49; H, 5.43; N, 4.10
C, 62.65; H, 5.59; N, 4.12
S
345.41/C18H19NO4S; C, 62.59; H, 5.54; N, 4.06
381.50/C18H23NO4S2; C, 56.67; H, 6.08; N, 3.67
4e
4f
6
7
85
89
96–97
113–118
C, 56.75; H, 6.01; N, 3.72
C, 56.60; H, 6.17; N, 3.61
S
S
Me Me
4g
4h
6
7
90
87
97–99
93–94
C, 58.73; H, 6.72; N, 3.50
C, 58.60; H, 6.78; N, 3.37
S
S
409.55/C20H27NO4S2; C, 58.65; H, 6.64; N, 3.42
Me Me
4i
4j
6
7
88
92
83–86
96–97
C, 66.45; H, 5.45; N, 2.70
C, 66.41; H, 5.45; N, 2.68
S
S
505.66/C28H27NO4S2; C, 66.51; H, 5.38; N, 2.77
Ph
Ph
4k
4l
6
7
91
87
128–129
139–142
C, 56.75; H, 6.15; N, 3.59
C, 56.61; H, 6.02; N, 3.75
S
381.52/C18H23NO4S2; C, 56.67; H, 6.08; N, 3.67
381.52/C18H23NO4S2; C, 56.67; H, 6.08; N, 3.67
S
S
4m
4n
6
7
90
88
133–135
145–147
C, 56.59; H, 5.95; N, 3.75
C, 56.76; H, 6.15; N, 3.59
S
4o
4p
6
7
86
91
230–232
211–215
C, 57.39; H, 6.17; N, 9.91
C, 57.33; H, 6.10; N, 10.15
O
HN
NH
419.50/C20H25N3O5S; C, 57.26; H, 6.01, N, 10.02
S
4q
4r
6
7
84
89
88–92
78–80
C, 57.81; H, 6.32; N, 3.48.
C, 57.65; H, 6.29; N, 3.59
S
S
395.54/C19H25NO4S2; C, 57.70; H, 6.37; N, 3.54
547.74/C31H33NO4S2; C, 67.98; H, 6.07; N, 2.56
4s
4t
6
7
89
87
73–76
73–76
C, 68.16; H, 6.14; N, 2.65
C, 67.89; H, 6.02; N, 2.48
S
S
Ph
Ph
(CDCl3):
d
7.20–7.11 (m, 3H), 7.02–6.98 (m, 1H), 5.03–4.84 (AB q,
anhydrous Na2SO4 and concentrated to give a mixture of 6-nitro
and 7-nitro isochroman-3-(S)-carboxylic acid methyl ester in 77%
yield.
J ¼ 15.0 Hz, 2H), 4.41–4.36 (m, 1H), 3.82 (s, 3H), 3.10–3.06 (m, 2H);
MS (m/z): 193.24 (M þ H)þ; [
a]
20: ꢁ109ꢂ (C 1.0, MeOH).
6.1.3. Synthesis of 6 and 7-nitro isochroman-3-(S)-carboxylic acid
methyl ester
6.1.4. Synthesis of 6 and 7-amino isochroman-3-(S)-carboxylic acid
methyl ester (3)
To fuming nitric acid (15 mL) previously cooled to ꢁ40 ꢂC, was
added isochroman-3-(S)-carboxylic acid methyl ester (25 mmol)
in portions over a period of 15 min. The reaction mixture was then
maintained at ꢁ40 ꢂC while monitoring by TLC. The reaction was
complete in 40 min. The reaction mixture was then poured in to
ice water and was extracted with chloroform. The organic layer
was then washed with sat. sodium bicarbonate solution, followed
by water and brine. The organic layer was then dried over
To a solution of 6/7-nitro isochroman-3-(S)-carboxylic acid
methyl ester (18 mmol) in ethyl acetate (50 mL) in a hydrogenation
flask, 10%pd/C (0.3 g) was added and the reaction mixture was
subjected to hydrogenation at 60 psi hydrogen pressure in a Parr
apparatus, for 3 h. The reaction mixture was then filtered through
celite, the celite bed was washed with ethyl acetate, the filtrate and
washings were combined and concentrated to give a mixture of 6
and 7-amino isochroman-3-(S)-carboxylic acid methyl ester. The

3152
N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 44 (2009) 3147–3157
Table 2
Physical constants of compounds 7 and 13(a–d).
Compound no.
Structure
Yield (%)
76
M.p. (ꢂC)
189–192
M. wt./; M. F./; C, H, N (% Calc.)
C, H, N (% Found)
CO2H
CO2H
CO2H
CO2H
O
O
O
O
N
H
7
395.50; C18H21NO5S2; C, 54.67; H, 5.35; N, 3.54
C, 54.57; H, 5.41; N, 3.48
S
S
O
O
O
N
H
13a
13b
89
93
135–137
122–124
383.53; C18H25NO4S2; C, 56.37; H, 6.57; N, 3.65
C, 56.43; H, 6.60; N, 3.61
S
S
N
H
397.56; C19H27NO4S2; C, 57.40; H, 6.85; N, 3.52
C, 57.35; H, 6.81; N, 3.58
S
S
O
O
N
H
13c
13d
86
88
145–148
132–134
411.59; C20H29NO4S2; C, 58.37; H, 7.10; N, 3.40
C, 58.29; H, 7.05; N, 3.49
C, 59.19; H, 7.40; N, 3.21
S
S
CO2H
O
O
425.61; C21H31NO4S2; C, 59.26; H, 7.34; N, 3.29
N
H
S
S
isomeric mixture was then purified by column chromatography on
a silica gel column using a mixture of ethyl acetate and chloroform
as the eluent.
6.1.4.1. 6-Amino
ester. Yield: 40%; Mp: 121 ꢂC; IR (KBr): 3461, 3373, 2960, 1745,
1625, 1509, 1437, 1375, 1312, 1271, 1210, 1112, 1052, and 1031 cmꢁ1
1H NMR (CDCl3):
and 8.4 Hz, 1H), 6.45 (s, 1H), 4.92–4.75 (AB q, J ¼ 13.8 Hz, 2H), 4.36–
4.31 (m, 1H), 3.81 (s, 3H), 3.60 (br s, 2H), 3.00–2.95 (m, 2H); MS (m/
z): 208.21 (M þ H)þ.
isochroman-3-(S)-carboxylic
acid
methyl
.
d
6.78 (d, J ¼ 7.8 Hz, 1H), 6.55–6.51 (dd, J ¼ 1.8 Hz
Table 3
IC50 ꢀ SEM (nM)a of compounds against various phosphatases.
Compound
PTP1B
TCPTP
LAR
6.1.4.2. 7-Amino
isochroman-3-(S)-carboxylic
acid
methyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
429(7.21)
6471(11.86)
5564(7.53)
677.7(4.91)
550.3(4.05)
436.7(2.40)
403.3(3.41)
322.7(11.46)
321.3(6.74)
4673(9.24)
4856(10.74)
2309(6.77)
2160(10.11)
2546(7.22)
1821(10.12)
6878(11.59)
6251(7.36)
3855(14.73)
4112(11.20)
7040(10.91)
6791(6.49)
6207(12.73)
3559(10.97)
2674(11.61)
5470(10.15)
5362(8.57)
7034(13.89)
5912(9.84)
765.3(5.70)
624.7(10.27)
493(12.29)
458.3(6.36)
380(9.24)
ester. Yield: 37%; Mp: 115 ꢂC; IR (KBr): 3472, 3365, 2952, 1758,
383.7(2.03)
553.3(6.12)
510.3(6.12)
385.7(6.57)
353.7(7.22)
164.7(4.37)
135.7(4.63)
668.7(3.76)
637.7(3.53)
104.3(2.85)
95.67(2.40)
80(0.58)
51.63(0.91)
2897(3.51)
2753(6.38)
167.3(5.04)
114.3(5.17)
566.7(4.10)
518.7(1.45)
304(2.89)
1496, 1369, 1287, 1252, 1199, 1116, and 1037 cmꢁ1. 1H NMR (CDCl3):
d
6.91 (d, J ¼ 8.4 Hz, 1H), 6.55–6.51 (dd, J ¼ 2.1 Hz and 8.1 Hz, 1H),
6.32 (s, 1H), 4.92–4.74 (AB q, J ¼ 15.0 Hz, 2H), 4.35–4.31 (m, 1H),
3.80 (s, 3H), 3.59 (br s, 2H), 3.00–2.82 (m, 2H); MS (m/z): 208.21
(M þ H)þ.
382.3(8.45)
4982(12.24)
5061(16.75)
2846(12.22)
2375(8.29)
2386(9.53)
1941(6.08)
7045(8.22)
6469(9.17)
4072(9.82)
4368(10.79)
7303(5.86)
7026(12.81)
5858(10.60)
4658(11.78)
3285(8.08)
5982(8.48)
5859(6.89)
6.1.5. Synthesis of 7-nitro-1-oxo isochroman-3-(S)-carboxylic acid
methyl ester (5)
To fuming nitric acid (15 mL) previously cooled to 0 ꢂC, was
added isochroman-3-(S)-carboxylic acid methyl ester (25 mmol)
in portions over a period of 15 min. The reaction mixture was then
maintained at 0 ꢂC while monitoring by TLC. The reaction was
complete in 30 min. The reaction mixture was then poured in to
ice water and extracted with chloroform. The organic layer was
then washed with sat. sodium bicarbonate solution, followed by
water and brine. The organic layer was then dried over anhydrous
Na2SO4 and concentrated to give 7-nitro-1-oxo-isochroman-3-(S)-
carboxylic acid methyl ester. Yield: 82%; Mp: 163 ꢂC; IR (KBr):
2969, 1757, 1738, 1614, 1532, 1435, 1351, 1236, 1131, 1039 and
4s
4t
7
13a
13b
13c
13d
148.7(2.60)
113(2.16)
373.7(12.55)
358.3(4.05)
998 cmꢁ1. 1H NMR (CDCl3):
J ¼ 2.4 Hz and 8.4 Hz, 1H), 7.48 (d, J ¼ 8.4 Hz, 1H), 5.26 (t,
d
8.93 (d, J ¼ 2.1 Hz, 1H), 8.40–8.37 (dd,
a
Values are the mean of three independent experiments with SEM in
parentheses.

N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 44 (2009) 3147–3157
3153
One-way ANOVA, Dunnett's multiple comparison test:
One-way ANOVA, Dunnett's multiple
comparison test: ***p<0.0001 vs Vehicle
p<0.0001vs Vehicle
***
300
200
100
0
Vehicle
400
300
200
100
0
Vehicle
Cpd No.4n,10mg, ip
Rosi,10mg, po
Cpd No.4n,10mg,ip
Rosi,10mg,po
***
***
***
Treatment
Fig. 4. Effect on plasma glucose in ob/ob mice on day 14.
Treatments
mixture was stirred at the same temperature for 1 h. The reaction
mixture was then poured in to crushed ice and the precipitated
solid was then filtered, washed with water and crystallised in hot
Fig. 2. Effect on fed WBG in ob/ob mice on day 7.
water to give 4-nitro-
L-phenylalanine. Yield: 70%; IR (KBr): 3294,
J ¼ 5.4 Hz, 1H), 3.96 (s, 3H), 3.63–3.56 (dd, J ¼ 5.7 Hz and 17.1 Hz,
1H), 3.45–3.38 (dd, J ¼ 4.8 Hz and 17.1 Hz, 1H); MS (m/z): 254.20
(M þ H)þ.
2895,1613, 1571, 1419, 1349,1312, 1106,1012 and 863 cmꢁ1. 1H NMR
(D2O þ DCl):
d
8.24–8.20 (d, J ¼ 7.2 Hz, 2H), 7.58–7.54 (d, J ¼ 6.9 Hz,
2H), 4.53–4.50 (t, J ¼ 8.1 Hz, 1H), 3.54–3.45 (dd, J ¼ 5.1 Hz and
12.3 Hz, 1H), 3.46–3.35 (dd, J ¼ 4.8 Hz and 12 Hz, 1H); MS (m/z):
6.1.6. Synthesis of 7-amino-1-oxo isochroman-3-(S)-carboxylic
acid methyl ester (6)
213.23 (M þ H)þ; [
a
]
25: þ6.26ꢂ (C 1.3, 3 M HCl). Mp: 243–247 ꢂC
dec.; [Lit. value: [
(dec.)].
a]
25: þ6.8ꢂ (C 1.3, 3 M HCl). Mp: 245–251 ꢂC
To a solution of 7-nitro-1-oxo-isochroman-3-(S)-carboxylic acid
methyl ester (20 mmol) in ethyl acetate (60 mL) in a hydrogenation
flask, 10%Pd/C (0.5 g) was added and the reaction mixture was
subjected to hydrogenation at 60 psi hydrogen pressure in a Parr
apparatus, for 3 h. The reaction mixture was then filtered through
celite, the celite bed was washed with ethyl acetate, combined the
filtrate and washings and concentrated to give 7-amino-1-oxo
isochroman-3-(S)-carboxylic acid methyl ester. Yield: 84%; Mp:
133 ꢂC; IR (KBr): 3442, 2972, 1759, 1736, 1616, 1528, 1435, 1355,
6.1.8. Synthesis of
L
-(ꢁ)-3-(4-nitro phenyl) lactic acid
-phenylalanine (20 mmol) in 1 N H2SO4
To a solution of 4-nitro-
L
(120 mL) while stirring at 0 ꢂC, was added an aqueous solution of
sodium nitrite (40 mmol), dropwise and the reaction mixture was
stirred for 6 h while allowing the reaction mixture to warm to
room temperature. The reaction mixture was then extracted with
ethyl acetate and the organic layer was washed with water and
1238, 1134, 1042 and 994 cmꢁ1 1H NMR (CDCl3):
. d 8.95 (d,
brine and concentrated to give
Yield: 77%; Mp: 126 ꢂC; IR (KBr): 3485, 3419, 2930, 1715, 1601,
1539, 1515, 1342, 1279, 1223, 1104, and 932 cmꢁ1 1H NMR
L
-(ꢁ)-3-(4-nitro phenyl)-lactic acid.
J ¼ 2.4 Hz, 1H), 8.39–8.35 (dd, J ¼ 2.7 Hz and 8.1 Hz, 1H), 7.49 (d,
J ¼ 8.7 Hz, 1H), 5.19 (t, J ¼ 5.7 Hz, 1H), 3.89 (s, 3H), 3.71 (br s, 3H),
3.59–3.51 (dd, J ¼ 5.4 Hz and 17.1 Hz, 1H), 3.45–3.38 (dd, J ¼ 5.1 Hz
and 17.4 Hz, 1H); MS (m/z): 222.19 (M þ H)þ.
.
(CDCl3 þ DMSO-d6): 8.14 (d, J ¼ 7.8 Hz, 1H), 7.48 (d, J ¼ 7.8 Hz, 2H),
d
4.45 (br s, 1H), 3.32–3.22 (m, 1H), 3.14–3.00 (m, 1H); MS (m/z):
214.18 (M þ H)þ.
6.1.7. Synthesis of 4-nitro-
To a mixture of conc. nitric acid (13 mL) and conc. sulphuric acid
(18 mL) while stirring at 0 ꢂC, was added
-phenylalanine
L-phenylalanine (9)
6.1.9. Synthesis of
ester (10)
L
-(ꢁ)-3-(4-nitro phenyl) lactic acid methyl
-(ꢁ)-3-(4-nitro phenyl)-lactic acid (15 mmol) in
L
(60 mmol) in portions over a period of 30 min and the reaction
To a solution of
L
methanol (50 mL) was added catalytic amount of conc. sulphuric
acid and the reaction mixture was refluxed for 4 h. Solvent was
then evaporated from the reaction mixture on rotavapor, diluted
the residue with ethyl acetate and was washed with sat. sodium
bicarbonate solution followed by water and brine and the organic
One-way ANOVA, Dunnett's multiple
comparison test: ,*** p<0.0001vs Vehicle
150
Vehicle
Cpd No.4n, 10mg, ip
Rosi,10mg, po
layer was concentrated to give
L
-(ꢁ)-3-(4-nitro phenyl)-lactic acid
methyl ester. Yield: 88%; Mp: 113 ꢂC; 1H NMR (CDCl3):
d
8.15 (d,
Lean animal
***
100
J ¼ 9.0 Hz, 2H), 7.39 (d, J ¼ 8.7 Hz, 2H), 4.50–4.47 (m, 1H), 3.80 (s,
3H), 3.27–3.21 (dd, J ¼ 4.2 Hz and 14. 1 Hz, 1H), 3.09–3.02 (dd,
J ¼ 4.2 Hz and 14.1 Hz, 1H), 2.86 (br s, 1H); MS (m/z): 228.21
(M þ H)þ.
***
***
50
6.1.10. General procedure for etherification of
phenyl) lactic acid methyl ester (11)
L
-(ꢁ)-3-(4-nitro
To a solution of
L
-(ꢁ)-3-(4-nitro phenyl)-lactic acid methyl ester
0
(2 mmol) in toluene (10 mL) was added the alkyl iodide (6 mmol)
followed by silver(I)oxide (2 mmol) and refluxed the reaction
mixture for 5 h. The reaction mixture was then filtered through
Treatment
Fig. 3. Effect on fasting WBG in ob/ob mice on day 10.

3154
N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 44 (2009) 3147–3157
celite, the celite bed was washed with ethyl acetate, the filtrate and
the washings were combined and concentrated to give the corre-
sponding ether. The crude ether was purified by column chroma-
tography on a silica gel column using a mixture of ethyl acetate and
chloroform as the eluent.
6.2. Spectral data of intermediate acids
6.2.1. 4-Oxo-4-(2-thienyl)butanoic acid (15a)
IR (KBr): 3101,1697, 1659,1514,1415, 1395, 1361, 1229,1176,1067
and 946 cmꢁ1
.
1H NMR (CDCl3):
d
7.74 (d, J ¼ 3.3 Hz, 1H), 7.63 (d,
J ¼ 5.1 Hz, 1H), 7.12 (t, J ¼ 4.5 Hz, 1H), 3.25 (t, J ¼ 6.6 Hz, 2H), 2.80 (t,
6.1.10.1. 2(S)-Methoxy-3-(4-nitro phenyl) propanoic acid methyl
J ¼ 6.6 Hz, 2H); MS (m/z): 185.20 (M þ H)þ.
ester (11a). Yield: 66%; Mp: 147 ꢂC; 1H NMR (CDCl3):
d 8.14 (d,
J ¼ 8.7 Hz, 2H), 7.38 (d, J ¼ 8.4 Hz, 2H), 4.02–3.96 (m, 1H), 3.75 (s,
6.2.2. 4-(2-Thienyl)butanoic acid (16a)
3H), 3.36 (s, 3H), 3.19–3.05 (m, 2H); MS (m/z): 242.24 (M þ H)þ.
IR (Neat): 3107, 2937, 1707, 1411, 1252, 1230, 1172, 1078, 1022 and
848 cmꢁ1
.
1H NMR (CDCl3):
d
7.13–7.11 (dd, J ¼ 0.9 Hz and 5.4 Hz,
6.1.10.2. 2(S)-Ethoxy-3-(4-nitro phenyl) propanoic acid methyl ester
1H), 6.93–6.90 (dd, J ¼ 3.6 Hz and 5.1 Hz, 1H), 6.80 (d, J ¼ 3.0 Hz,
1H), 2.91 (t, J ¼ 7.2 Hz, 2H), 2.42 (t, J ¼ 7.2 Hz, 2H), 2.07–1.97 (p,
J ¼ 7.5 Hz, 2H); MS (m/z): 171.19 (M þ H)þ.
(11b). Yield: 71%; Mp: 172 ꢂC; 1H NMR (CDCl3):
d
8.15 (d, J ¼ 8.4 Hz,
2H), 7.39 (d, J ¼ 8.1 Hz, 2H), 4.00–3.94 (m, 1H), 3.78 (s, 3H), 3.65–
3.59 (m, 1H), 3.26–3.19 (m, 1H), 3.19–3.05 (m, 2H), 1.24 (t, J ¼ 7.8 Hz,
3H); MS (m/z): 256.18 (M þ H)þ.
6.2.3. 5-Oxo-5-(2-thienyl)pentanoic acid (15b)
IR (KBr): 2964, 1694, 1655, 1511, 1411, 1289, 1234, 1194, 1060 and
6.1.10.3. 3-(4-Nitro phenyl)-2(S)-propoxy propanoic acid methyl
922 cmꢁ1
.
1H NMR (CDCl3):
d
7.71 (d, J ¼ 3.3 Hz, 1H), 7.62 (d,
ester (11c). Yield: 60%; Mp: 168 ꢂC; 1H NMR (CDCl3):
d
8.17
J ¼ 5.1 Hz, 1H), 7.12 (t, J ¼ 4.5 Hz, 1H), 3.02 (t, J ¼ 6.9 Hz, 2H), 2.50 (t,
(d, J ¼ 8.1 Hz, 2H), 7.41 (d, J ¼ 8.4 Hz, 2H), 4.06–3.98 (m, 1H), 3.80
(s, 3H), 3.63–3.60 (m, 1H), 3.25–3.21 (m,1H), 3.17–3.04 (m, 2H),1.26
(m, 2H), 0.87 (t, J ¼ 7.5 Hz, 3H). MS (m/z): 270.22 (M þ H)þ.
J ¼ 6.9 Hz, 2H), 2.09 (p, J ¼ 7.2 Hz, 2H); MS (m/z): 199.16 (M þ H)þ.
6.2.4. 5-(2-Thienyl)pentanoic acid (16b)
IR (Neat): 2931, 1709, 1464, 1409, 1310, 1262, 1203, 1072, 929 and
6.1.10.4. 2(S)-Butoxy-3-(4-nitro phenyl) propanoic acid methyl ester
848 cmꢁ1
.
1H NMR (CDCl3):
d
7.10–7.07 (dd, J ¼ 1.2 Hz and 5.7 Hz,
(11d). Yield: 63%; Mp: 191 ꢂC; 1H NMR (CDCl3):
d
8.14 (d, J ¼ 8.7 Hz,
1H), 6.96–6.93 (dd, J ¼ 3.9 Hz and 5.4 Hz, 1H), 6.83 (d, J ¼ 3.6 Hz,
1H), 2.94 (t, J ¼ 7.5 Hz, 2H), 2.42 (t, J ¼ 7.2 Hz, 2H), 2.07–1.97 (p,
J ¼ 7.5 Hz, 2H), 1.87–1.83 (m, 2H); MS (m/z): 185.24 (M þ H)þ.
2H), 7.40 (d, J ¼ 8.7 Hz, 2H), 4.05–4.00 (m, 1H), 3.74 (s, 3H), 3.62–
3.55 (m, 1H), 3.26–3.18 (m, 1H), 3.12–3.08 (m, 2H), 1.55–1.42 (m,
2H), 1.30–1.21 (m, 2H), 0.84 (t, J ¼ 7.5 Hz, 3H); MS (m/z): 284.23
(M þ H)þ.
6.2.5. 4,5-Dibromo valeric acid methyl ester (18a)
1H NMR (CDCl3):
d
4.27–4.18 (m, 1H), 3.88–3.83 (dd, J ¼ 4.5 Hz
6.1.11. General procedure for catalytic hydrogenation of 2(S)-
alkoxy-3-(4-nitro phenyl) propanoic acid methyl ester (12)
and 10.2 Hz, 1H), 3.69 (s, 3H), 3.66–3.58 (dd, J ¼ 6.0 Hz and 10.5 Hz,
1H), 2.68–2.47 (m, 2H), 2.10–2.00 (m,1H),1.92–1.74 (m,1H); MS (m/
z): 275.01 (M þ H)þ.
To a solution of 2(S)-alkoxy-3-(4-nitro phenyl) propanoic acid
methyl ester (1.2 mmol) in ethyl acetate (10 mL) in a hydrogenation
flask, 10%pd/C (20 mg) was added and the reaction mixture was
subjected to hydrogenation at 60 psi hydrogen pressure in a Parr
apparatus, for 3 h. The reaction mixture was then filtered through
celite, the celite bed was washed with ethyl acetate, the filtrate and
washings were combined and concentrated to give 2(S)-alkoxy-3-
(4-amino phenyl) propanoic acid methyl ester in sufficiently pure
form to be used in the next step without further purification.
6.2.6. 4,5-Bis (acetyl sulfanyl)valeric acid methyl ester (19a)
1H NMR (CDCl3):
d 3.70–3.60 (m, 1H), 3.66 (s, 3H), 3.26–3.10 (m,
2H), 2.44–2.37 (m, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 2.14–2.02 (m, 1H),
1.89–1.76 (m, 1H); MS (m/z): 265.40 (M þ H)þ.
6.2.7. 4,5-Dimercapto valeric acid methyl ester (20a)
1H NMR (CDCl3):
d 3.67 (s, 3H), 2.94–2.84 (m, 1H), 2.79–2.75 (m,
1H), 2.69–2.43 (m, 2H), 2.25–2.05 (m, 1H), 1.80–1.63 (m, 2H); MS
6.1.11.1. 3-(4-Amino phenyl)-2-methoxy-2(S)-propanoic acid methyl
(m/z): 167.28 (M þ H)þ.
ester (12a). Yield: 89%; Mp: 129 ꢂC; 1H NMR (CDCl3):
d 6.96 (d,
J ¼ 6.9 Hz, 2H), 6.54 (d, J ¼ 7.2 Hz, 2H), 4.00–3.96 (m, 1H), 3.72 (s,
6.2.8. 3-(2,2-Dimethyl-1,3-dithiolan-4-yl)propanoic acid (21a)
3H), 3.30 (s, 3H), 3.14–3.02 (m, 2H); MS (m/z): 210.18 (M þ H)þ.
1H NMR (CDCl3):
d
3.96–3.86 (m, 1H), 3.46–3.40 (dd, J ¼ 5.1 Hz
and 12.0 Hz, 1H), 3.15–3.08 (dd, J ¼ 6.6 Hz and 12.0 Hz, 1H), 2.58–
2.44 (m, 2H), 2.18–2.05 (m, 2H), 1.82 (s, 3H), 1.78 (s, 3H); MS (m/z):
207.35 (M þ H)þ.
6.1.11.2. 3-(4-Amino phenyl)-2-ethoxy-2(S)-propanoic acid methyl
ester (12b). Yield: 92%; Mp: 158 ꢂC; 1H NMR (CDCl3):
d 7.02 (d,
J ¼ 6.9 Hz, 2H), 6.73 (d, J ¼ 7.8 Hz, 2H), 3.97–3.92 (m, 1H), 3.82 (s,
3H), 3.62–3.58 (m, 1H), 3.24–3.19 (m, 1H), 3.19–3.05 (m, 2H), 1.26 (t,
J ¼ 7.5 Hz, 3H); MS (m/z): 224.22 (M þ H)þ.
6.2.9. 3-(2,2-Diphenyl-1,3-dithiolan-4-yl)propanoic acid (21b)
1H NMR (CDCl3):
d 7.62–7.53 (m, 4H), 7.30–7.20 (m, 6H), 4.00–
3.92 (p, J ¼ 6.3 Hz, 1H), 3.38–3.32 (dd, J ¼ 5.7 Hz and 11.7 Hz, 1H),
3.12–3.06 (dd, J ¼ 6.3 Hz and 11.7 Hz, 1H), 2.55–2.49 (m, 2H), 2.17–
2.10 (m, 2H); MS (m/z): 331.51 (M þ H)þ.
6.1.11.3. 3-(4-Amino phenyl)-2-propoxy-2(S)-propanoic acid methyl
ester (12c). Yield: 79%; Mp: 147 ꢂC; 1H NMR (CDCl3):
d 7.05 (d,
J ¼ 6.9 Hz, 2H), 6.71 (d, J ¼ 7.2 Hz, 2H), 3.98–3.92 (m, 1H), 3.79 (s,
3H), 3.60–3.58 (m, 1H), 3.23–3.20 (m, 1H), 3.15–3.04 (m, 2H), 1.28
(m, 2H), 0.83 (t, J ¼ 7.8 Hz, 3H); MS (m/z): 238.17 (M þ H)þ.
6.2.10. 6,7-Dibromoheptanoic acid methyl ester (18c)
1H NMR (CDCl3):
d 4.21–4.11 (m, 1H), 3.68 (s, 3H), 3.62 (t,
J ¼ 9.9 Hz, 1H), 2.36 (t, J ¼ 7.5 Hz, 2H), 2.24–2.12 (m, 1H), 1.88–1.58
6.1.11.4. 3-(4-Amino phenyl)-2-butoxy-2(S)-propanoic acid methyl
(m, 5H), 1.55–1.45 (m, 1H); MS (m/z): 303.05 (M þ H)þ.
ester (12d). Yield: 84%; Mp: 162 ꢂC; 1H NMR (CDCl3):
d 7.00 (d,
J ¼ 6.6 Hz, 2H), 6.60 (d, J ¼ 7.5 Hz, 2H), 3.93 (t, J ¼ 6.9 Hz, 1H), 3.69
(s, 3H), 3.56–3.48 (m, 1H), 3.28–3.21 (m, 1H), 2.91–2.86 (m, 2H),
1.56–1.46 (m, 2H), 1.36–1.23 (m, 2H), 0.85 (t, J ¼ 7.2 Hz, 3H); MS (m/
z): 252.24 (M þ H)þ.
6.2.11. 6,7-Bis (acetylsulfanyl)heptanoic acid methyl ester (19c)
1H NMR (CDCl3):
d
3.72 (s, 3H), 3.3–3.13 (dd, J ¼ 6.0 Hz, 2H), 2.39
(s, 3H), 2.38 (s, 3H), 1.77–1.64 (m, 7H), 1.53–1.43 (m, 2H); MS (m/z):
293.45 (M þ H)þ.

N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 44 (2009) 3147–3157
3155
6.2.12. 6,7-Dimercapto heptanoic acid methyl ester (20c)
1H NMR (CDCl3):
3.72 (s, 3H), 2.91–2.80 (m, 1H), 2.77–2.74 (m,
6.3.1. (3S)-6-[4-(2-Thienyl) butylcarboxamido]-
isochroman-3-carboxylic acid (4a)
IR (KBr): 3425, 3298, 2936, 1749, 1723, 1651, 1529, 1415, 1195 and
1104 cmꢁ1. 1H NMR:
9.82 (s, 1H), 7.37–7.32 (m, 2H), 7.29–7.26 (dd,
J ¼ 1.2 Hz and 5.1 Hz, 1H), 6.95–6.90 (m, 2H), 6.84–6.82 (m, 1H),
4.80–4.60 (AB q, J ¼ 15 Hz, 2H), 4.20–4.15 (dd, J ¼ 4.8 Hz and 9.0 Hz,
1H), 2.88–2.80 (m, 4H), 2.31 (br s, 2H), 1.68–1.58 (m, 4H); MS (m/z):
360.43 (M þ H)þ.
d
1H), 2.70–2.49 (m, 2H), 2.23–2.02 (m, 1H), 1.82–1.63 (m, 4H), 1.42–
1.29 (m, 2H); MS (m/z): 195.35 (M þ H)þ.
d
6.2.13. 5-(2,2-Dimethyl-1,3-dithiolan-4-yl)pentanoic acid (21c)
1H NMR (CDCl3):
d
3.94–3.85 (m, 1H), 3.48–3.41 (dd, J ¼ 5.4 Hz
and 11.7 Hz, 1H), 3.17–3.10 (dd, J ¼ 6.9 Hz and 12.0 Hz, 1H), 2.60–
2.48 (m, 2H), 2.21–2.10 (m, 2H), 1.82 (s, 3H), 1.78 (s, 3H), 1.45–1.30
(m, 4H); MS (m/z): 233.41 (M ꢁ H)þ.
6.3.2. (3S)-7-[4-(2-Thienyl)butylcarboxamido]-
isochroman-3-carboxylic acid (4b)
6.2.14. 5-[(3R)-1,2-Dithiolan-3-yl]pentanoic acid methyl ester (R-
IR (KBr): 3420, 3302, 2936, 1727, 1658, 1524, 1424, 1242, 1198,
lipoic acid methyl ester)
1104 and 1031 cmꢁ1. 1H NMR:
d 9.83 (s, 1H), 7.31 (s, 1H), 7.28–7.25
1H NMR (CDCl3):
d
3.67 (s, 3H), 3.62–3.52 (m, 1H), 3.21–3.09 (m,
(m, 2H), 7.03 (d, J ¼ 8.4 Hz, 1H), 6.92–6.90 (m, 1H), 6.83–6.81 (m,
1H), 4.81–4.59 (AB q, J ¼ 15 Hz, 2H), 4.11–4.06 (dd, J ¼ 5.4 Hz and
9.3 Hz, 1H), 2.85–2.78 (m, 4H), 2.34–2.28 (m, 2H), 1.68–1.60 (m,
4H); MS (m/z): 360.43 (M þ H)þ.
2H), 2.50–2.40 (m, 1H), 2.38–2.30 (m, 2H), 1.95–1.85 (m, 1H), 1.75–
1.60 (m, 4H), 1.55–1.45 (m, 2H); MS (m/z): 221.38 (M þ H)þ.
6.2.15. (6R)-6,8-Dimercapto octanoic acid methyl ester (23)
IR (Neat): 2934, 2861, 1708, 1412, 1282, 1088 and 934 cmꢁ1. 1H
6.3.3. (3S)-6-[3-(2-Thienyl)propylcarboxamido]-
isochroman-3-carboxylic acid (4c)
NMR (CDCl3):
d 3.69 (s, 3H), 2.97–2.86 (m, 1H), 2.82–2.62 (m, 2H),
2.39 (t, J ¼ 7.5 Hz, 2H), 1.98–1.87 (m, 1H), 1.82–1.74 (m, 1H), 1.72–
IR (KBr): 3433, 3289, 2918, 1748, 1724, 1654, 1592, 1529, 1423,
1.61 (m, 4H), 1.60–1.45 (m, 2H); MS (m/z): 223.41 (M þ H)þ.
1301, 1228, 1196, 1105 and 1027 cmꢁ1. 1H NMR:
d 9.83 (s, 1H), 7.40
(s, 1H), 7.34 (d, J ¼ 8.4 Hz, 1H), 7.30 (d, J ¼ 4.8 Hz, 1H), 6.96–6.91
(m, 2H), 6.85 (s, 1H), 4.81–4.62 (AB q, J ¼ 15 Hz, 2H), 4.28–4.23
(dd, J ¼ 5.1 Hz and 8.7 Hz, 1H), 2.88–2.80 (m, 4H), 2.34 (t,
J ¼ 7.5 Hz, 2H), 1.96–1.85 (p, J ¼ 7.2 Hz, 2H); MS (m/z): 346.41
(M þ H)þ.
6.2.16. 5-[(4R)-1,3-Dithian-4yl]-pentanoic acid methyl ester (24a)
1H NMR (CDCl3):
d
4.04 (d, J ¼ 14.1 Hz, 1H), 3.55 (d, J ¼ 14.1 Hz,
1H), 3.87 (s, 3H), 3.16–3.00 (m, 2H), 2.85–2.80 (m, 1H), 2.36 (t,
J ¼ 7.5 Hz, 2H), 2.19–2.14 (br d, 1H), 1.78–1.68 (m, 3H), 1.60–1.47 (m,
4H); MS (m/z): 233.34 (M þ H)þ.
6.3.4. (3S)-7-[3-(2-Thienyl)propylcarboxamido]-
isochroman-3-carboxylic acid (4d)
6.2.17. 5-[(4R)-1,3-Dithian-4yl]-pentanoic acid (25a)
1H NMR (CDCl3):
d
4.05 (d, J ¼ 14.1 Hz, 1H), 3.57 (d, J ¼ 14.1 Hz,
IR (KBr): 3292, 2920, 2851, 1729, 1654, 1597, 1533, 1419, 1361,
1H), 3.15–3.05 (m, 2H), 2.87–2.81 (m, 1H), 2.38 (t, J ¼ 7.5 Hz, 2H),
2.19–2.14 (br d, 1H), 1.78–1.68 (m, 3H), 1.60–1.47 (m, 4H); MS (m/z):
221.39 (M þ H)þ.
1239, 1190, 1104 and 1030 cmꢁ1. 1H NMR:
d 9.83 (s, 1H), 7.36 (s, 1H),
7.30–7.26 (m, 2H), 7.07 (d, J ¼ 8.4 Hz, 1H), 6.94–6.91 (m, 1H), 6.85–
6.84 (m, 1H), 4.83–4.67 (AB q, J ¼ 15 Hz, 2H), 4.33–4.28 (dd,
J ¼ 4.8 Hz and 9.3 Hz, 1H), 2.95–2.80 (m, 4H), 2.34 (t, J ¼ 7.2 Hz, 2H),
1.95–1.80 (p, J ¼ 7.2 Hz, 2H); MS (m/z): 346.41 (M þ H)þ.
6.2.18. 5-[(4R)-2,2-Diphenyl-1,3-dithian-4yl]-pentanoic acid
methyl ester (24b)
1H NMR (CDCl3):
d
7.48–7.42 (m, 2H), 7.36–7.16 (m, 8H), 3.91 (s,
6.3.5. (3S)-6-[2-(2,2-Dimethyl-1,3-dithiolan-
3H), 2.85–2.80 (m, 1H), 2.70–2.62 (m, 2H), 2.64 (t, J ¼ 7.2 Hz, 2H),
2.06–2.01 (br d,1H), 1.60–1.48 (m, 4H), 1.47–1.40 (m, 3H); MS (m/z):
387.52 (M þ H)þ.
4-yl)ethylcarboxamido]-isochroman-3-carboxylic acid (4e)
IR (KBr): 3289, 2915, 1726, 1652, 1530, 1426, 1363, 1242, 1193,
1105 and 1037 cmꢁ1. 1H NMR:
d
7.37 (s, 1H), 7.31 (d, J ¼ 8.4 Hz, 1H),
7.16 (s, 1H), 6.97 (d, J ¼ 8.1 Hz, 1H), 5.01–4.85 (AB q, J ¼ 15 Hz, 2H),
4.38–4.33 (dd, J ¼ 4.5 Hz and 10.5 Hz, 1H), 3.98–3.90 (m, 1H), 3.47–
3.40 (dd, J ¼ 5.1 Hz and 12 Hz, 1H), 3.17–3.04 (m, 3H), 2.52–2.41 (m,
2H), 2.32–2.22 (m, 1H), 2.16–2.08 (m, 1H), 1.82 (s, 3H), 1.79 (s, 3H);
MS (m/z): 382.50 (M þ H)þ.
6.2.19. 5-[(4R)-2,2-Diphenyl-1,3-dithian-4yl]-pentanoic acid (25b)
1H NMR (CDCl3):
d 7.50–7.43 (m, 2H), 7.38–7.12 (m, 8H), 2.91–2.83
(m,1H), 2.75–2.63 (m, 2H), 2.67 (t, J ¼ 7.2 Hz, 2H), 2.10–2.03 (br d,1H),
1.65–1.48 (m, 4H), 1.47–1.40 (m, 3H); MS (m/z): 373.58 (M þ H)þ.
6.3. General procedure for amidation and hydrolysis
6.3.6. (3S)-7-[2-(2,2-Dimethyl-1,3-dithiolan-4-
yl)ethylcarboxamido]-isochroman-3-carboxylic acid (4f)
IR (KBr): 3291, 2917, 1729, 1655, 1533, 1429, 1367, 1246, 1197,
To a solution of the amine (1 mmol) in CH2Cl2 (10 mL) under N2
atmosphere, was added the carboxylic acid (1 mmol) followed by
N-ethyl-N0-dimethylaminopropyl carbodiimide hydrochloride
(EDCI$HCl) (1.2 mmol) and triethylamine (3 mmol) and the reac-
tion mixture was stirred at room temperature for 3–5 h. The
reaction mixture was then diluted with chloroform and washed
with 1 N HCl. The organic layer was then washed with water, fol-
lowed by brine, dried over Na2SO4 and concentrated. To a solution
of the above crude ester in aqueous methanol (1:1, 5 mL), was
added potassium carbonate (2 mmol) and the reaction mixture
was stirred at room temperature for 5–7 h. Methanol was then
evaporated from the reaction mixture on rotavapor, diluted the
residue with water, washed with diethyl ether and the aqueous
layer was then acidified with 1 N HCl. The precipitated product was
then filtered, washed with water and dried under vacuum to give
the title compounds as off white to pale yellow solids.
1103 and 1039 cmꢁ1 1H NMR:
. d 7.46 (s, 1H), 7.23 (s, 1H), 7.10 (s,
2H), 5.02–4.87 (AB q, J ¼ 15 Hz, 2H), 4.37–4.32 (dd, J ¼ 3.9 Hz and
10.5 Hz, 1H), 3.96–3.91 (m, 1H), 3.46–3.41 (dd, J ¼ 5.4 Hz and
12 Hz, 1H), 3.17–2.96 (m, 3H), 2.51–2.36 (m, 2H), 2.31–2.23 (m,
1H), 2.14–2.05 (m, 1H), 1.81 (s, 3H), 1.79 (s, 3H); MS (m/z): 382.50
(M þ H)þ.
6.3.7. (3S)-6-[4-(2,2-Dimethyl-1,3-dithiolan-4-
yl)butylcarboxamido]-isochroman-3-carboxylic acid (4g)
IR (KBr): 3292, 2916, 1729, 1656, 1537, 1429, 1365, 1246, 1197,
1107 and 1035 cmꢁ1. 1H NMR:
d
7.38 (s, 1H), 7.32 (d, J ¼ 8.1 Hz, 1H),
7.15 (s, 1H), 7.02 (d, J ¼ 8.1 Hz, 1H), 4.96–4.79 (AB q, J ¼ 15 Hz, 2H),
4.30–4.40 (m, 1H), 3.90–3.79 (m, 1H), 3.39–3.33 (dd, J ¼ 4.5 Hz, 1H),
3.12–3.04 (m, 3H), 2.38–2.34 (t, J ¼ 6.9 Hz, 2H), 1.82–1.69 (m, 10H),
1.51–1.43 (m, 2H); MS (m/z): 410.55 (M þ H)þ.

3156
N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 44 (2009) 3147–3157
6.3.8. (3S)-7-[4-(2,2-Dimethyl-1,3-dithiolan-4-
J ¼ 15 Hz, 2H), 4.24–4.19 (dd, J ¼ 6.0 Hz and 9.0 Hz, 1H), 3.54–3.45
(m, 1H), 3.14–3.00 (m, 2H), 2.96–2.90 (m, 2H), 2.43–2.32 (m, 1H),
2.27 (t, J ¼ 7.5 Hz, 2H), 1.89–1.80 (m, 1H), 1.68–1.58 (m, 4H), 1.47–
yl)butylcarboxamido]-isochroman-3-carboxylic acid (4h)
IR (KBr): 3292, 2917, 1725, 1651, 1535, 1422, 1369, 1254, 1201,
1111 and 1042 cmꢁ1. 1H NMR:
d
7.4 (s, 1H), 7.35 (br s, 1H), 7.13 (d,
1.39 (m, 2H); 13C (75 MHz, DMSO-d6,
d): 172.20, 171.02, 137.48,
J ¼ 7.5 Hz, 1H), 7.05 (d, J ¼ 8.1 Hz, 1H), 4.98–4.79 (AB q, J ¼ 15 Hz,
2H), 4.31–4.41 (m, 1H), 3.91–3.80 (m, 1H), 3.40–3.34 (dd, J ¼ 4.5 Hz,
1H), 3.11–3.05 (m, 3H), 2.39–2.35 (t, J ¼ 7.2 Hz, 2H), 1.82–1.69 (m,
10H), 1.51–1.43 (m, 2H); MS (m/z): 410.55 (M þ H)þ.
134.27, 128.98, 126.42, 117.67, 114.57, 72.55, 66.77, 56.33, 38.86,
38.35, 36.43, 34.43, 29.93, 28.61, 25.20. MS (m/z): 382.53
(M þ H)þ.
6.3.15. (3S)-6-{4-[(4S)-2-Oxoperhydrothieno-[3,4-d]imidazol-4-
yl]butylcarboxamido}-isochroman-3-carboxylic acid (4o)
IR (KBr): 3284, 2933, 1701, 1674, 1651, 1532, 1426, 1313, 1195 and
6.3.9. (3S)-6-[2-(2,2-Diphenyl-1,3-dithiolan-4-
yl)ethylcarboxamido]-isochroman-3-carboxylic acid (4i)
IR (KBr): 3290, 2919, 1729, 1647, 1538, 1427, 1372, 1257, 1204,
1031 cmꢁ1. 1H NMR:
d
9.80 (s, 1H), 7.40 (s, 1H), 7.34 (d, J ¼ 9.0 Hz,
1108 and 1047 cmꢁ1 1H NMR:
. d 7.60–7.53 (m, 3H), 7.32–7.21 (m,
1H), 6.95 (d, J ¼ 8.1 Hz, 1H), 6.42 (s, 1H), 6.35 (s, 1H), 4.81–4.64 (AB
q, J ¼ 15 Hz, 2H), 4.33–4.26 (m, 2H), 4.14–4.10 (m, 1H), 3.15–3.07 (m,
1H), 2.90–2.77 (m, 2H), 2.56 (d, J ¼ 12.6 Hz, 1H), 2.27 (t, J ¼ 7.2 Hz,
2H), 1.65–1.55 (m, 3H), 1.40–1.30 (m, 2H); MS (m/z): 418.51
(M ꢁ H)ꢁ.
10H), 6.96 (d, J ¼ 8.1 Hz, 1H), 5.00–4.84 (AB q, J ¼ 15 Hz, 2H), 4.37–
4.32 (dd, J ¼ 4.2 Hz and 10.8 Hz, 1H), 4.02–3.97 (m, 1H), 3.39–3.33
(m, 1H), 3.15–3.02 (m, 3H), 2.54–2.42 (m, 2H), 2.33–2.26 (m, 1H),
2.22–2.14 (m, 1H); MS (m/z): 506.66 (M þ H)þ.
6.3.16. (3S)-7-{4-[(4S)-2-Oxoperhydrothieno-[3,4-d]imidazol-4-
yl]butylcarboxamido}-isochroman-3-carboxylic acid (4p)
IR (KBr): 3286, 2937, 1697, 1678, 1654, 1536, 1429, 1317, 1201 and
6.3.10. (3S)-7-[2-(2,2-Diphenyl-1,3-dithiolan-4-
yl)ethylcarboxamido]-isochroman-3-carboxylic acid (4j)
IR (KBr): 3287, 2921,1731,1649,1528,1423,1370,1252,1207,1102
1028 cmꢁ1. 1H NMR:
d
9.79 (s, 1H), 7.42 (s, 1H), 7.36 (d, J ¼ 8.7 Hz,
and 1049 cmꢁ1. 1H NMR:
d 7.60–7.53 (m, 3H), 7.43 (br s, 1H), 7.30–
1H), 6.97 (d, J ¼ 8.4 Hz, 1H), 6.41 (s, 1H), 6.36 (s, 1H), 4.81–4.66 (AB
q, J ¼ 15 Hz, 2H), 4.34–4.27 (m, 2H), 4.12–4.10 (m, 1H), 3.15–3.09 (m,
1H), 2.90–2.78 (m, 2H), 2.56 (d, J ¼ 12.3 Hz, 1H), 2.28 (t, J ¼ 7.2 Hz,
2H), 1.65–1.57 (m, 3H), 1.40–1.32 (m, 2H); MS (m/z): 418.51
(M ꢁ H)ꢁ.
7.21 (m, 8H), 7.09 (br s, 2H), 5.02–4.88 (AB q, J ¼ 15 Hz, 2H), 4.38–
4.33 (dd, J ¼ 3.9 Hz and 10.5 Hz, 1H), 4.05–3.95 (m, 1H), 3.39–3.34
(dd, J ¼ 6.0 Hz and 12 Hz, 1H), 3.17–3.00 (m, 3H), 2.54–2.41 (m, 2H),
2.33–2.26 (m, 1H), 2.22–2.14 (m, 1H); MS (m/z): 506.66 (M þ H)þ.
6.3.11. (3S)-6-[4-(1,2-Dithiolan-3-yl)butylcarboxamido]-
isochroman-3-carboxylic acid (4k)
6.3.17. (3S)-6-{4-[(4R)-1,3-Dithian-4-yl]butylcarboxamido}-
isochroman-3-carboxylic acid (4q)
IR (KBr): 3515, 3294, 2929, 1653, 1592, 1528, 1425, 1331, 1257,
IR (KBr): 3285, 2939, 1701, 1673, 1657, 1539, 1432, 1315, 1198 and
1093 and 1052 cmꢁ1. 1H NMR:
d 9.80 (s, 1H), 7.40–7.30 (m, 2H), 6.90
1031 cmꢁ1
.
1H NMR:
d
7.39 (s, 1H), 7.31 (d, J ¼ 7.8 Hz, 1H), 7.18 (s,
(d, J ¼ 8.2 Hz, 1H), 4.80–4.49 (AB q, J ¼ 14.6 Hz, 2H), 3.76–3.42 (m,
2H), 3.22–3.06 (m, 3H), 2.90–2.70 (m, 2H), 2.45–2.30 (m, 1H), 2.27
(t, J ¼ 7.0 Hz, 2H), 1.92–1.81 (m, 1H), 1.76–1.30 (m, 5H); 13C (75 MHz,
1H), 6.97 (d, J ¼ 8.1 Hz, 1H), 5.01–4.85 (AB q, J ¼ 15 Hz, 2H), 4.40–
4.35 (dd, J ¼ 4.5 Hz and 10.2 Hz, 1H), 4.04 (d, J ¼ 13.8 Hz, 1H), 3.55
(d, J ¼ 14.1 Hz, 1H), 3.16–3.00 (m, 2H), 2.86–2.79 (m, 3H), 2.37 (t,
J ¼ 6.9 Hz, 2H), 2.19–2.14 (br d, 1H), 1.78–1.68 (m, 3H), 1.60–1.47 (m,
4H); MS (m/z): 396.54 (M þ H)þ.
DMSO-d6, d): 173.92, 171.01, 137.53, 134.24, 129.47, 119.12, 117.04,
75.63, 66.87, 56.33, 38.86, 38.35, 36.42, 34.44, 31.94, 28.65, 25.21.
MS (m/z): 382.53 (M þ H)þ.
6.3.18. (3S)-7-{4-[(4R)-1,3-Dithian-4-yl]butylcarboxamido}-
isochroman-3-carboxylic acid (4r)
6.3.12. (3S)-7-[4-(1,2-Dithiolan-3-yl)butylcarboxamido]-
isochroman-3-carboxylic acid (4l)
IR (KBr): 3288, 2941, 1693, 1678,1655, 1541, 1434, 1319, 1204 and
1034 cmꢁ1. 1H NMR:
d 7.47 (br s, 1H), 7.11 (br s, 3H), 5.02–4.86 (AB q,
IR (KBr): 3512, 3297, 2931, 1650, 1589, 1526, 1423, 1328, 1259,
1096 and 1049 cmꢁ1. 1H NMR:
d 9.81 (s, 1H), 7.42–7.31 (m, 2H), 6.92
J ¼ 15 Hz, 2H), 4.39–4.34 (dd, J ¼ 4.2 Hz and 10.2 Hz, 1H), 4.04 (d,
J ¼ 14.1 Hz, 1H), 3.55 (d, J ¼ 14.1 Hz, 1H), 3.17–2.95 (m, 2H), 2.88–
2.80 (m, 3H), 2.36 (t, J ¼ 7.5 Hz, 2H), 2.19–2.14 (br d, 1H), 1.82–1.67
(m, 3H), 1.60–1.50 (m, 4H); MS (m/z): 396.54 (M þ H)þ.
(d, J ¼ 8.1 Hz, 1H), 4.82–4.51 (AB q, J ¼ 14.6 Hz, 2H), 3.78–3.43 (m,
2H), 3.21–3.07 (m, 3H), 2.92–2.73 (m, 2H), 2.47–2.32 (m, 1H), 2.27
(t, J ¼ 7.0 Hz, 2H), 1.92–1.83 (m, 1H), 1.76–1.32 (m, 5H); MS (m/z):
382.53 (M þ H)þ.
6.3.19. (3S)-6-{4-[(4R)-2,2-Diphenyl-1,3-dithian-4-
yl]butylcarboxamido}-isochroman-3-carboxylic acid (4s)
IR (KBr): 3283, 2942, 1697, 1671, 1659, 1541, 1434, 1317, 1201 and
6.3.13. (3S)-6-{4-[(3R)-1,2-Dithiolan-3-yl]butylcarboxamido}-
isochroman-3-carboxylic acid (4m)
1029 cmꢁ1. 1H NMR:
d
9.83 (s, 1H), 7.91 (d, J ¼ 8.4 Hz, 2H), 7.46 (t,
IR (KBr): 3535, 3303, 2930, 1718, 1652, 1591, 1526, 1414, 1248,
1195, 1118 and 1060 cmꢁ1. 1H NMR:
d 9.80 (s, 1H), 7.41 (s, 1H), 7.35
J ¼ 7.8 Hz, 2H), 7.40 (s, 1H), 7.36–7.32 (m, 2H), 7.30–7.16 (m, 5H),
6.95 (d, J ¼ 8.4 Hz, 1H), 4.82–4.63 (AB q, J ¼ 15 Hz, 2H), 4.31–4.26
(dd, J ¼ 5.1 Hz and 8.7 Hz, 1H), 2.95–2.82 (m, 3H), 2.70–2.60 (m,
2H), 2.27 (t, J ¼ 7.5 Hz, 2H), 2.03 (d, J ¼ 12.9 Hz, 1H), 1.60–1.40 (m,
7H); MS (m/z): 548.74 (M þ H)þ.
(d, J ¼ 8.4 Hz, 1H), 6.95 (d, J ¼ 8.4 Hz, 1H), 4.82–4.65 (AB q, J ¼ 15 Hz,
2H), 4.34–4.29 (dd, J ¼ 4.8 Hz and 8.7 Hz, 1H), 3.68–3.58 (m, 2H),
3.23–3.07 (m, 3H), 2.95–2.87 (m, 2H), 2.48–2.36 (m, 1H), 2.28 (t,
J ¼ 6.9 Hz, 2H), 1.93–1.82 (m, 1H), 1.71–1.56 (m, 2H), 1.44–1.37 (m,
2H); 13C (75 MHz, DMSO-d6,
d): 172.15, 170.98, 137.67, 132.18,
128.71, 124.52, 119.02, 117.45, 72.39, 66.41, 56.29, 38.88, 38.32,
6.3.20. (3S)-7-{4-[(4R)-2,2-Diphenyl-1,3-dithian-4-
yl]butylcarboxamido}-isochroman-3-carboxylic acid (4t)
IR (KBr): 3289, 2950,1692,1676,1653,1545,1437,1319,1205 and
36.41, 34.39, 30.55, 28.57, 25.15. MS (m/z): 382.53 (M þ H)þ.
6.3.14. (3S)-7-{4-[(3R)-1,2-Dithiolan-3-yl]butylcarboxamido}-
isochroman-3-carboxylic acid (4n)
1032 cmꢁ1. 1H NMR:
d
9.85 (s, 1H), 7.91 (d, J ¼ 7.5 Hz, 2H), 7.45 (t,
J ¼ 7.8 Hz, 2H), 7.34–7.16 (m, 8H), 7.04 (d, J ¼ 8.1 Hz, 1H), 4.81–4.62
(AB q, J ¼ 15 Hz, 2H), 4.21–4.16 (dd, J ¼ 4.2 Hz and 9.3 Hz, 1H), 2.92–
2.80 (m, 3H), 2.70–2.60 (m, 2H), 2.27 (t, J ¼ 7.5 Hz, 2H), 2.03 (d,
J ¼ 12.9 Hz, 1H), 1.60–1.40 (m, 7H); MS (m/z): 548.74 (M þ H)þ.
IR (KBr): 3483, 3290, 2935, 1729, 1655, 1599, 1534, 1505, 1423,
1238, 1195 and 1105 cmꢁ1. 1H NMR:
d
9.81 (br s, 1H), 7.35 (s, 1H),
7.16 (d, J ¼ 8.4 Hz, 1H), 6.96 (d, J ¼ 8.4 Hz, 1H), 4.90–4.71 (AB q,

N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 44 (2009) 3147–3157
3157
6.3.21. (3S)-7-{4-[(3R)-1,2-Dithiolan-3-yl]butylcarboxamido}-1-
oxo-isochroman-3-carboxylic acid (7)
2H), 7.11 (d, J ¼ 8.7 Hz, 2H), 3.94–3.88 (m, 1H), 3.66–3.58 (m, 1H),
3.50–3.42 (m, 2H), 3.25–3.06 (m, 4H), 2.92–2.74 (m, 2H), 2.46–2.36
(m, 1H), 2.32–2.25 (m, 2H), 1.92–1.82 (m, 1H), 1.72–1.50 (m, 2H),
1.45–1.35 (m, 2H), 1.28–1.16 (m, 4H), 0.82–0.77 (t, J ¼ 7.2 Hz, 3H);
MS (m/z): 426.60 (M þ H)þ.
IR (KBr): 3486, 3287, 2937, 1731, 1674, 1658, 1601, 1532, 1507,
1428, 1235, 1199 and 1107 cmꢁ1 1H NMR:
. d 10.08 (s, 1H), 8.17 (d,
J ¼ 2.4 Hz, 1H), 7.76–7.72 (dd, J ¼ 2.1 Hz and 8.4 Hz, 1H), 7.31 (d,
J ¼ 8.4 Hz, 1H), 5.28–5.24 (m, 1H), 3.67–3.55 (m, 2H), 3.22–3.06 (m,
4H), 2.48–2.35 (m, 1H), 2.31 (t, J ¼ 7.2 Hz, 2H), 1.92–1.81 (m, 1H),
1.76–1.35 (m, 5H); MS (m/z): 396.51 (M þ H)þ.
Acknowledgements
One of the authors (N.L.N.) thanks Glenmark pharmaceuticals
limited for granting permission to carry out this research work.
6.3.22. (2S)-3-(4-{4-[(3R)-1,2-Dithiolan-3-
yl]butylcarboxamido}phenyl)-2-methoxypropanoic acid (13a)
IR (KBr): 3486, 3287, 2938, 1732, 1658, 1601, 1530, 1508, 1428,
1242, 1193 and 1097 cmꢁ1. 1H NMR (CDCl3):
d 7.59 (s, 1H), 7.41 (d,
J ¼ 8.4 Hz, 2H), 7.14 (d, J ¼ 8.1 Hz, 2H), 4.04–3.96 (m, 1H), 3.62–3.52
(m, 1H), 3.39 (s, 3H), 3.21–2.96 (m, 4H), 2.50–2.40 (m, 1H), 2.40–
2.30 (m, 2H), 1.96–1.84 (m, 1H), 1.80–1.65 (m, 4H), 1.55–1.44 (m,
2H); MS (m/z): 384.54 (M þ H)þ.
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IR(KBr):3493,3284, 2933,1736,1654,1604,1527,1505,1431,1246,
1198 and 1094 cmꢁ1. 1H NMR:
d
9.80 (s, 1H), 7.45 (d, J ¼ 8.7 Hz, 2H),
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2.31–2.26(t, J ¼ 7.8 Hz, 2H),1.92–1.80(m,1H),1.70–1.50(m, 3H),1.45–
1.30 (m, 2H),1.05–1.01 (t, J ¼ 6.9 Hz, 3H); MS (m/z): 398.56 (M þ H)þ.
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6.3.24. (2S)-3-(4-{4-[(3R)-1,2-Dithiolan-3-
yl]butylcarboxamido}phenyl)-2-propoxypropanoic acid (13c)
IR (KBr): 3489, 3288, 2937, 1738, 1658, 1607, 1531, 1508, 1436,
1248,1203 and 1097 cmꢁ1. 1H NMR:
d
9.81 (s,1H), 7.47 (d, J ¼ 8.4 Hz,
2H), 7.10 (d, J ¼ 8.4 Hz, 2H), 3.92–3.86 (m, 1H), 3.67–3.55 (m, 1H),
3.52–3.44 (m, 2H), 3.27–3.09 (m, 4H), 2.89–2.73 (m, 2H), 2.43–2.34
(m,1H), 2.30–2.27(m, 2H),1.94–1.85(m,1H),1.70–1.49 (m, 2H),1.26–
1.17 (m, 4H), 0.85–0.79 (t, J ¼ 7.2 Hz, 3H); MS (m/z): 412.60 (M þ H)þ.
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6.3.25. (2S)-2-Butoxy-3-(4-{4-[(3R)-1,2-dithiolan-3-
yl]butylcarboxamido}phenyl)propanoic acid (13d)
IR (KBr): 3484, 3289, 2934, 1735, 1656, 1606, 1533, 1511, 1431,
1245, 1197 and 1095 cmꢁ1. 1H NMR:
d
9.78 (s, 1H), 7.45 (d, J ¼ 8.7 Hz,