Novel coumarin derivatives of heterocyclic compounds as lipid-lowering agents

Article abstract of DOI:10.1016/S0960-894X(03)00490-6

Coumarin derivatives of different heterocycles (5,7a-i, 10 and 11) were designed based on cyclisation of 2-ethoxy-3-phenylpropanoic acid and 2-benzylmalonic acid as novel lipid-lowering agents and their preliminary in vivo screening indicates 7c has moderate triglyceride-lowering activity.

Full text of DOI:10.1016/S0960-894X(03)00490-6

Bioorganic & Medicinal Chemistry Letters 13 (2003) 2547–2551
Novel Coumarin Derivatives of Heterocyclic Compounds as
Lipid-Lowering Agents§
Gurram R. Madhavan,a,* Vadla Balraju,a Bejugam Mallesham,a Ranjan Chakrabartib
and Vidya B. Lohraya
aDiscovery Chemistry, Dr. Reddy’s Discovery Research, Bollarum Road, Miyapur, Hyderabad 500050, India
bDiscovery Biology, Dr. Reddy’s Discovery Research, Bollarum Road, Miyapur, Hyderabad 500050, India
Received 28February 2003; accepted 1 May 2003
Abstract—Coumarin derivatives of different heterocycles (5,7a–i, 10 and 11) were designed based on cyclisation of 2-ethoxy-3-
phenylpropanoic acid and 2-benzylmalonic acid as novel lipid-lowering agents and their preliminary in vivo screening indicates 7c
has moderate triglyceride-lowering activity.
# 2003 Elsevier Ltd. All rights reserved.
Atherosclerotic cardiovascular disease is the leading
cause of death in developed countries. Epidemiological
studies have identified a variety of independent risk
factors that contribute to coronary artery disease
(CAD); most notable are high LDL-cholesterol, trigly-
ceride (TG) and low HDL-cholesterol. Current thera-
pies mostly focus on lowering LDL-cholesterol and
statins used for this purpose are pretty effective and also
safe.1 Yet they are not effective in lowering TG and
HDL. Most patients still experience adverse coronary
events despite statin therapy. In addition, recent reports
of undesirable side effects of some ‘super statins’2 indi-
cate that the scope of improving the potency of this
class of drugs may be limited. Fibrate class of drugs,
which are mostly used to treat hyper triglyceridemia and
low HDL-cholesterol, needs very high doses to show
significant efficacy.3 In addition a combination of fibrate
and statins has recently been reported to increase events
of myotoxicity in patients of CAD.2 Therefore, there is
a constant need for a different class of potent
compounds to treat dyslipidemia.
Oxidative stress has recently been implicated in the
pathogenesis of various diseases such as diabetes and
CAD. Consequently, the potential therapeutic or pre-
ventive effects of antioxidative agents have been men-
tioned.4 Coumarins are known to have antioxidant
potential like a-tocopherol (Vitamin-E). Previously, we
had reported5 that an 2-ethoxy-3-propanoic acid deri-
vative showed blood glucose lowering activity in
experimental animal models. We thought of changing
the pharmacophore by cyclising the 2-ethoxy propanoic
acid to form a coumarin moiety (Fig. 1). Similarly, we
can also cyclise 2-benzylmalonic acid derivatives to
coumarin carboxylic acid derivatives. In this paper, we
report the synthesis of coumarin derivatives having
Figure 1. Conversion of 2-ethoxypropanoic acid to coumarin derivative.
§DRL-publication no. 299
*Corresponding author. Tel.: +91-40-3045439; fax: +91-40-3045438; e-mail: madhavangr@drreddys.com
0960-894X/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00490-6

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G. R. Madhavan et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2547–2551
Table 1. Physical and biological data of coumarin derivativesa
Compd
Structure
M.P. ꢀC
251–252
TGb
5a
2Æ0.5
5b
7a
7b
7c
7d
7e
7f
214–216
153–154
142–144
159–160
168–170
196–198NE
122–124
116–11827
NEc
31Æ1
NE
45Æ2
NE
26Æ1
Æ2
7g
7h
130–132
NE
7i
8
142–144
25Æ2
146–14816
Æ1
(continued on next page)

G. R. Madhavan et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2547–2551
2549
Table 1 (continued)
Compd
Structure
M.P. ꢀC
TGb
10a
140–142
169–170
261–262
—
2Æ0.5
32Æ2
NE
11a
11c
Fenofibrate
36
(at 30 mg/kg)
DRF-2725
—
47
aChecked in Swiss albino mice.
bTriglyceride lowering activity (%). Test compounds were administered at 3 mg/kg for 6 days.
cNE=Not effective.
different heterocycles, which are attached mostly with a
linker of one or two carbon chain and interesting
triglyceride lowering activity.
Well known TG lowering drugs like fibrates having 2-
methyl-propanoic acid moiety as a pharmacophore. In
compound 8, we attached this moiety to comarin to
explore the biological activity of such compounds.
We have synthesized several coumarin derivatives
(Table 1) and checked for their triglyceride lowering
activity.
In order to prepare the 3-carboxylic derivatives 11
(Scheme 2), 3-ethoxycarbonyl-7-hydroxy coumarin
(compound 9) used as a starting material and obtained
from 2,4-dihydroxybenzaldehyde, was alkylated at the
7-hydroxy group of 9 with 4 to give 10 in good yield.
The ester 10 was hydrolysed with 10% NaOH solution
in methanol to give carboxylic acid 11.
Chemistry
Initially, we synthesized 3-ethoxy coumarin starting
from 2,4-dihydroxybenzaldehyde by cyclising with N-
acetylglycine as represented in Scheme 1. Later the 3-
acetylamino coumarin was linked to a heterocycle with
a linker having one of the following leaving groups
(compound 4): 4-(2-methane sulphonyloxy ethyl)-5-
methyl-2-phenyl oxazol;7a N-Benzoxazol-2-yl-N-(2-
chloroethyl)methyl amine;7b 1-(2-bromoethyl)-1H-indo-
le;7c 2-Phenoxazine-10-ylethyl-(methane sulfonate) ;6 2-
(2-bromoethyl)-2H-phthalazinone;7d 3-(2-bromoethyl)-
Biological Activity
Plasma triglyceride lowering activity of 5a, 5b, 7a–i, 8,
9
10a, 11a and 11c was determined in SAM at 3 mg/kg
oral dose as shown in Table 1. 7c showed maximum
(45%) activity and 11a also showed good (32%) trigly-
ceride lowering activity. 7a (25%), 7g (27%) and 7f
(26%) showed moderate plasma triglyceride lowering
activity. In the same model, the reference standard
fenofibrate, showed a 36% reduction in plasma trigly-
ceride levels at 30 mg/kg/day, but the other compounds
failed to show any significant reduction in TG at 3 mg/
kg/day dose.
7e
3H-quinazolin-4-one and 3-(2-chloroethyl)-2-ethyl-6-
methyl-4(3H)-pyrimidinone. The acetylamino group of 5
was converted to 3-hydroxy coumarin 6 by the treatment
with 3N HCl.8 The 3-hydroxy coumarin derivative 6
was alkylated with ethyl iodide in the presence of KOH
(powdered) in dry DMSO to give ethoxy derivative 7.

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Scheme 1. (a) N-acetylglycine, Ac2O, NaOAc, reflux, 2 h; (b) 25% aq NH3, MeOH, rt, 0.5 h; (c) HET-(CH2) n–X [X=Cl, Br, OSO2CH3, etc.] (4),
K2CO3, DMF, 80 ꢀC, 24 h; (d) 3N HCl, EtOH, reflux, 1.5 h; (e) EtI, KOH, DMSO, RT, 12 h; (f) ethyl-2-bromoiso butyrate, K2CO3, 8 0ꢀC, 18h; (g)
3N HCl, EtOH, 80 ꢀC, 2 h; (h) (1) EtI, KOH, DMSO, rt, 12 h, (2) H2O, rt, 4 h.
Scheme 2. (i) Diethyl malonate, piperidine, AcOH, EtOH, reflux, 4 h. (j) 4, NaH, DMF, 0 ꢀC–rt, 12 h. (k) 10% NaOH, MeOH, rt, 24 h.
Conclusion
mouse model and was several times better than that of
the reference standard fenofibrate. Further studies on 7c
are in progress, and will be published in the future.
We have designed and synthesized 3-ethoxy and 3-car-
boxyl derivatives of coumarins with different hetero-
cycles which are attached with a linker of a one or two
carbon chain, leading to a general structure 7a–i and
11a–c based on the cylisation of the pharmacophore of 2-
ethoxypropanoic acid derivatives. Of all the compounds,
ethoxy coumarin derivative with phthalazinone was the
most potent (compound 7c) showing 45% of triglycer-
ide lowering activity at 3 mg/kg/day in the Swiss albino
Acknowledgements
The authors are thankful to the management of
Dr Reddy’s group for their encouragement. We thank
Dr. R. Rajagopalan, President, for his constant
encouragement.

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References and Notes
Rajagopalan, R.; Mamidi, N. V. S. R.; Jajoo, H. K.; Sub-
ramaniam, S. J. Med. Chem. 1998, 41, 1619. (d) Csampai, A.;
Koermendy, K.; Sohar, P.; Ruff, F. Tetrahedron 1989, 45,
5539. (e) Ranganathan, D.; Farooqui, F.; Mehrotra, S.;
Kesavan, K. Heterocycles 1986, 24, 2493 and in house
prepared.
1. La Rosa, J. C.; Hi, J.; Vupputuri, S. J. Am. Med. Assoc.
1999, 282, 2340.
2. Evans, M.; Rees, A. Curr. Opin. Lipidol. 2002, 13, 415.
3. Staels, B.; Dallongeville, J.; Auwerx, J.; Schoonjans, K.;
Leitersdorf, E.; Fruchart, J. C. Circulation 1998, 98, 2088.
4. Balz, F. Natural Antioxidants in Human Health and Disease;
Acedamic Press: San Diego, CA, 1994.
5. Lohray, B. B.; Lohray, V. B.; Bajji, A. C.; Kalchar, S.;
Poondra, R. R.; Padakanti, S.; Chakrabarthi, R.; Vikrami-
dithyan, R. K.; Misra, P.; Juluri, S.; Mamidi, N. V. S. R.;
Rajagopalan, R. J. Med. Chem. 2001, 44, 2675.
8. Shin, C.; Nakajima, Y.; Sato, Y. Chem. Lett. 1984, 1301.
9. An inbreed colony (at our own animal house) of Swiss
Albino Mice (SAM) of 21–29 g body weight, moderately
hypertriglycerimic, has been used for screening the com-
pounds. Animals (5 per group) were treated orally with 3 mg/
kg/day of 5a–b, 7a–i, 8, 10a, 11a, 11c for 6 days. The control
animals were treated with the vehicle (0.25% carboxymethyl
cellulose, 3 mL/kg) only. Animals were bled through retro
orbital sinus on day-1 and day-6 of the experiment. Plasma
samples were prepared and triglyceride levels were measured
by using a commercial kit (Pointe Scientific, USA). For
calculating of percentage reduction of triglycerides, the standard
method published previously (Reddy, K. A.; Lohray, B. B.;
Reddy, A. S.; Mamidi, N. V. S. R.; Reddy, P. P.; Saibaba, V.;
Jaipal Reddy, N.; Suryaprakash, A.; Misra, P.; Vikramidithyan,
R. K.; Rajapopalan, R. J. Med. Chem. 1999, 42, 3265 and
Saibal, K. D.; Krorrida, V. L. N.; Jagadhesan, H; Iqbal, J.
Bioorg. Med. Chem. Lett., 2002, 12, 3579.) was applied.
6. Shirley, D. A.; Sen, K.; Glimer, J. C. J. Org. Chem. 1961,
26, 3587.
7. (a) Hisashi, S.; Syoji, O.; Mashiro, T.; Tsutomu, S.;
Megumi, I.; Korekiyo, W.; Itsuo, U. J. Med. Chem. 1998, 41,
1927. (b) Buckle, D. R.; Cantello, B. C. C.; Cawthorne, M. A.;
Coyle, P. J.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley,
R. M.; Jefcott, L. J.; Lister, C. A.; Pinto, I. L.; Rami, H. K.;
Smith, D. G.; Smith, S. A. Bioorg. Med. Chem. Lett. 1996, 6,
2127. (c) Lohray, B. B.; Vidya, B.; Rao, P. B.; Madhavan,
G. R.; Murali, N.; Rao, K. N.; Reddy, A. K.; Rajesh, B. M.;
Reddy, P. G.; Chakraborthy, R.; Vikramadithyan, R. K.;