Microwave assisted synthesis of isothiazolo-, thiazolo-, imidazo-, and pyrimido-pyrimidinones as novel MCH1R antagonists

Article abstract of DOI:10.1016/j.tetlet.2006.11.120

An efficient microwave assisted condensation of α-heteroarylamines with 3-dimethylamino-2-aryl-propenoates has been developed to synthesize various fused bi-heterocyclic compounds, including isothiazolo-, thiazolo-, imidazo-, and pyrimido-pyrimidinones as

Full text of DOI:10.1016/j.tetlet.2006.11.120

Tetrahedron Letters 48 (2007) 613–615
Microwave assisted synthesis of isothiazolo-, thiazolo-, imidazo-,
and pyrimido-pyrimidinones as novel MCH1R antagonists
Tao Guo,a,* Rachael C. Hunter,a Rui Zhanga and William J. Greenleeb
aPharmacopeia Drug Discovery, Inc., PO Box 5350, Princeton, NJ 08543, USA
bSchering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 23 October 2006; revised 13 November 2006; accepted 17 November 2006
Available online 8 December 2006
Abstract—An efficient microwave assisted condensation of a-heteroarylamines with 3-dimethylamino-2-aryl-propenoates has been
developed to synthesize various fused bi-heterocyclic compounds, including isothiazolo-, thiazolo-, imidazo-, and pyrimido-pyrimid-
inones as novel MCH1R antagonists.
Ó 2006 Elsevier Ltd. All rights reserved.
Melanin concentrating hormone (MCH), a cyclic 19-
amino acid neuropeptide, plays an important role in
the central regulation of food intake and energy homeo-
stasis in mammals.1 Central administration of MCH in
mice stimulates food intake while fasting results in an
increase in MCH expression. Transgenic mice over-
expressing MCH are susceptible to obesity and insulin
resistance, whereas MCH deficient mice are hypophagic
and leaner than wild-type mice but otherwise healthy.
MCH-1 receptor (MCH1R) is a G-protein-coupled
receptor (GPCR) found in all mammals. MCH1R
knockout mice are lean and resistant to a diet induced
obesity. As such, MCH1R antagonists are believed to
have potential as possible treatments for obesity. A wide
variety of small molecule MCH1R antagonists have
been reported recently,1 among which, GW-803430, an
orally efficacious MCH1R antagonist discovered by
GSK scientists,2 has advanced into human clinical inves-
tigation for the treatment of obesity.
In our search for novel MCH1R antagonists, we
designed a series of bi-heterocyclic compounds (1) that
include isothiazolo-, thiazolo-, imidazo-, and pyrimido-
pyrimidinone cores to replace the thienopyrimidinone
core in GW-803430.
O
O
N
N
X
Y
N
OMe
R
1
The synthesis of fused bi-heterocyclic compounds has
been reported via condensation of heteroarylamines
with 3-dimethylamino-2-aryl-propenoates using conven-
tional heating methods which requires long reaction
time and gives only poor to moderate yields,3,4a for
example, heating of 2-aminothiazole with 3-dimethyl-
amino-2-(indol-3-yl)-propenoate in AcOH at reflux for
5 h produced a fused bicyclic thiazolo-pyrimidinone
product in 30% yield.4a In contrast, microwave assisted
synthesis has been described for the preparation of sev-
eral fused bi-heterocyclic compounds, which requires
much reduced reaction time but gives significantly
increased yields,4b,c for example, microwave heating of
2-aminopyridine with 3-dimethylamino-2-(benzamido)-
propenoate in AcOH at 180 °C for 10 min generated a
fused bicyclic pyrido-pyrimidinone product in 77%
yield.4b We wish to report here an efficient microwave
assisted synthesis of bi-heterocyclic compounds (1) as
novel MCH1R antagonists.
O
N
O
S
OMe
N
Cl
N
GW-803430
MCH1R Ki = 0.5 nM
Keywords: Microwave assisted synthesis; MCH1R antagonist; Iso-
thiazolo-, thiazolo-, imidazo-, pyrimido-pyrimidinones.
*
Corresponding author. Tel.: +1 609 452 3746; fax: +1 609 452
3699; e-mail: tguo@pcop.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.120

614
T. Guo et al. / Tetrahedron Letters 48 (2007) 613–615
O
OH
O
N
a
O
b
EtO
OMe
EtO
OMe
3
2
X
N
R
O
O
O
N
Y
NH2
N
O
N
5
EtO
OMe
X
Y
OMe
N
R
NMe2
c
1
4
Scheme 1. Reagents and conditions: (a) NaH, 1-(2-chloroethyl)pyrrolidine, DMF, 80 °C, 16 h, 53%; (b) tert-butoxy-bis(dimethylamino)methane
(Bredereck’s reagent), 65 °C, 16 h, 80%; (c) AcOH, microwave, 200–220 °C, 200–600 s, 44–89%.
Scheme 1 illustrates the synthetic procedure for target
compounds 1. First, heating ethyl homovanilate (2) with
NaH and 1-(2-chloroethyl)pyrrolidine in DMF provided
arylacetate 3. Then, treatment of 3 with Bredereck’s
heating of 4 with various a-heteroarylamines 5 using
microwave gave bi-heterocyclic compounds 1.
Table 1 lists the detailed microwave conditions and
yields for the preparation of isothiazolo-, thiazolo-, imid-
azo-, and pyrimido-pyrimidinone compounds 1a–e. It
reagent
(tert-butoxy-bis-(dimethylamino)-methane)
generated 3-dimethylamino-2-aryl-propenoate 4. Finally,
Table 1. Microwave conditions, yields, and MCH1R binding affinities for 1a–e
Entry
Substratea
Microwave condition
Product (yield)
MCH1R Kib (lM)
O
N
O
S
N
S
OMe
Cl
N
Cl
1
200 °C, 600 s, AcOH
1.4
NH2
N
5a5
1a (44%)
O
N
O
N
OMe
N
S
2
3
200 °C, 300 s, AcOH
3.0
3.0
NH2
S
5b6
N
1b (89%)
O
N
N
O
N
Cl
Cl
OMe
N
S
200 °C, 300 s, AcOH
Cl
NH2
S
N
5c6
1c (65%)
O
O
N
N
OMe
N
N
H
NH2
4
220 °C, 200 s, AcOH
0.077
Cl
N
H
5d7
1d (63%)
O
N
O
N
OMe
N
N
NH2
5
200 °C, 300 s, AcOH
1.8
N
N
Cl
5e8
Cl
1e (49%)
a Substrates 5a–e were prepared according to literature procedures (Refs. 5–8).
b MCH1R Ki was determined in a receptor binding assay (Ref. 10).

T. Guo et al. / Tetrahedron Letters 48 (2007) 613–615
615
3. For a recent review of heterocycle synthesis from 3-
(dimethylamino)propenoates and related enaminones, see:
Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433–2480.
4. (a) Jakse, R.; Svete, J.; Stanovnik, B.; Golobic, A.
Tetrahedron 2004, 60, 4601–4608; (b) Westman, J.; Lun-
din, R. Synthesis 2003, 1025–1030; (c) Westman, J.;
Lundin, R.; Stalberg, J.; Ostbye, M.; Franzen, A.;
Hurynowicz, A. Comb. Chem. High Throughput Screening
2002, 5, 565–570.
5. Boeshagen, H. U.S. 3692795, 1972.
6. Hargrave, K. D.; Hess, F. K.; Oliver, J. T. J. Med. Chem.
1983, 26, 1158–1163.
7. Matsushita, T.; Fujita, A. JP 2001328980, 2001.
8. Konradi, A. W.; Pleiss, M. A.; Thorsett, E. D.; Ashwell,
S.; Welmaker, G. S.; Kreft, A.; Sarantakis, D.; Dressen,
D. B.; Grant, F. S.; Semko, C.; Xu, Y.-Z. WO
2002008222, 2002.
should be noted that conventional heating proved in-
effective for the preparation of 1a–e, for example, treat-
ment of 4 with 5c in AcOH at reflux (120 °C) for 15 h
did not yield any detectable amount of target compound
1c. In contrast, good to excellent yields (44–89%) of tar-
get compounds 1a–e were obtained via condensation of
4 with a-heteroarylamines 5a–e (prepared according to
literature procedures5–8) under microwave conditions
(AcOH, 200–220 °C, 200–600 s).9 Also shown in Table
1 are the MCH1R binding affinities (Ki’s) for 1a–e.10
Compounds 1a–e displayed low to sub-micromolar
Ki’s, with imidazo-pyrimidinone 1d being the most
potent (Ki = 0.077 lM).
In summary, an efficient microwave assisted condensation
of a-heteroarylamines with 3-dimethylamino-2-aryl-pro-
penoates has been developed to synthesize various fused
bi-heterocyclic compounds including isothiazolo-, thiaz-
olo-, imidazo-, and pyrimido-pyrimidinones as novel
MCH1R antagonists.
9. Representative microwave procedure: A mixture of ethyl 3-
(dimethylamino)-2-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)-
phenyl)acrylate (4) (154 mg, 0.42 mmol) and 5-(4-chloro-
phenyl)-1H-imidazol-2-amine (5d) (82 mg, 0.42 mmol,
prepared according to Ref. 7) in AcOH (0.33 ml) was
heated at 220 °C for 200 s in an Emrys optimizer. The
reaction mixture was then neutralized with 1% KOH in
MeOH to pH ꢀ7. The solvent was evaporated and the
residue was purified using reverse phase prep-HPLC (10–
90% CH3CN/H2O with 0.05% TFA) to give 2-(4-chloro-
phenyl)-6-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-
imidazo[1,2-a]pyrimidin-5(1H)-one (1d) as a TFA salt
Acknowledgements
We are grateful to Laura L. Rokosz and Tara M. Stauf-
fer for their assistance in the MCH1R Ki determination
and Brian A. McKittrick (Schering-Plough) and Doug
W. Hobbs for their valuable comments and suggestions.
1
(154 mg, yield 63%). H NMR (DMSO-d6) d 10.00 (br s,
1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.21 (d, 2H, J = 9.0 Hz),
7.75 (d, 2H, J = 8.4 Hz), 7.61 (d, 1H, J = 2.4 Hz), 7.53 (m,
1H), 7.32 (d, 1H, J = 5.4 Hz), 4.52 (t, 2H, J = 5.0 Hz),
4.07 (s, 3H), 3.82–3.90 (m, 4H), 3.39 (m, 2H), 2.27 (m,
2H), 2.12 (m, 2H). MS(ESI) m/z 465.2 [(M+H)+].
References and notes
10. MCH1R Ki determination: Membranes prepared from
CHO cells that express human MCH1R (0.1 mg/ml final)
were incubated with wheatgerm–agglutinin (WGA) coated
SPA beads (1 mg/ml final, Amersham Biosciences, Piscat-
away, NJ) in an assay buffer (25 mM HEPES, 10 mM
NaCl, 10 mM MgCl2, 5 mM MnCl2, 0.1% BSA pH 7.4)
for 5 min on ice and subsequently washed two times in an
assay buffer. Test compound (5 ll) prepared in DMSO,
DMSO (vehicle) or MCH (2.5 lM final—used to quantify
the non-specific signal) were mixed with 45 ll assay buffer
in 96-well assay plates (Corning #3604). Bead/membrane
mixture (100 ll) was added to the compounds followed by
50 ll of [125I]-MCH (0.5 nM final, Perkin Elmer, Boston,
MA). The assay plates were shaken for 5 min on a plate
shaker and then incubated for 2 h. Binding of [125I]-MCH
to the bead/membrane mixture was detected using a
Microbeta TriluxTM scintillation counter (Perkin Elmer).
The data were fit to a one-site competition binding model
for IC50 determination using the program GraphPad
Prism (GraphPad Software, Inc., San Diego, CA) and Ki
values were calculated using the Cheng–Prusoff equation.
All Ki’s represent the average of two or more determina-
tions. The standard deviations were no greater than 30%
from the mean.
1. For recent reviews of MCH and MCH1R antagonists, see:
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4017–4022; (b) Kowalski, T. J.; McBriar, M. D. Annu.
Rep. Med. Chem. 2005, 40, 119–133; (c) Dyke, H. J.; Ray,
N. C. Expert Opin. Ther. Pat. 2005, 15, 1303–1313.
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C. E.; Ignar, D. M.; Peckham, G. E.; Speake, J. D.; Britt,
C.; Swain, W. R. In 228th ACS National Meeting,
Philadelphia, PA, 2004; Paper MEDI193; (b) Hertzog,
D. L.; Al-Brazanji, K. A.; Bigham, E. C.; Bishop, M. J.;
Britt, C. S.; Carlton, D. L.; Cooper, J. P.; Daniels, A. J.;
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