Synthesis and cytotoxicity of novel 2-amino-5-thiazolecarboxamide derivatives

Article abstract of DOI:10.3184/174751911X13099483874341

A series of novel 2-amino-5-thiazolecarboxamide derivatives have been designed and synthesised. All the compounds were evaluated for their antiproliferative activity against human leukaemia cancer HL 60 and K562 cell lines by standard MTT assay in vitro. Some of these compounds showed moderate cytotoxic potencies. Structure-activity relationships suggested that the piperazine moiety in the side chain of 2-amino-5-thiazolecarboxamide was associated with an increase in the cytotoxicity.

Full text of DOI:10.3184/174751911X13099483874341

416 RESEARCH PAPER
JULY, 416–419
JOURNAL OF CHEMICAL RESEARCH 2011
Synthesis and cytotoxicity of novel 2-amino-5-thiazolecarboxamide
derivatives
Hu Lia, Yun Yueb, Xiao-Jun Huc and Sheng-Yin Zhaoa*
aDepartment of Chemistry, Donghua University, Shanghai 201620, P. R. China
bDepartment of Pharmacology, Foshan University, Foshan 528000, P. R. China
cDepartment of Drug Research and Development, Nantong Haiers Pharmaceutical Company, Nantong 226400, P. R. China
A series of novel 2-amino-5-thiazolecarboxamide derivatives have been designed and synthesised. All the com-
pounds were evaluated for their antiproliferative activity against human leukaemia cancer HL 60 and K562 cell lines
by standard MTT assay in vitro. Some of these compounds showed moderate cytotoxic potencies. Structure–activity
relationships suggested that the piperazine moiety in the side chain of 2-amino-5-thiazolecarboxamide was associ-
ated with an increase in the cytotoxicity.
Key words: 2-amino-5-thiazolecarboxamide, piperazine, cytotoxicity
Cancer is the second leading cause of death in the world.
Angiogenesis is the process of generating new capillary blood
vessels, which plays an important role in the proliferation,
invasion and metastasis of malignant tumours. Blocking
tumour-induced angiogenesis continues to be an attractive
strategy for cancer therapy.1–3
to the active form of the enzyme. The ability to inhibit SRC-
family kinases such as Hck and Lyn, in addition to binding
to the active conformation of BCR-ABL, may both contribute
to the effectiveness of dasatinib against imatinib-resistant
tumours.10
2-Aminothiazole was discovered as a novel Src family
kinase inhibitor template through screening of our internal
compound collection. Structures of template inhibitors inter-
acting with the ATP-binding site of Src kinase were suggested
and are shown in Fig. 1. We conclude that the 2-amino-5-
thiazolecarboxamide framework should be of significant
importance for antitumor activity, and the piperazine side chain
may play an auxiliary role in receptor bonding.11–13
We reasoned that by introducing an aminoacetyl moiety into
2-amino-5-thiazolecarboxamide rings, the modification of the
amine substituents might be able to enhance the binding of the
compounds to Src kinase. On the other hand, SAR studies
indicated that a hydrogen bond interaction is important for
antitumor activity. An aminoacetyl side chain on the appropri-
ate position of the target compounds could enhance their
inhibitory potency toward Src kinase. This prompted us to
design a series of novel 2-amino-5-thiazolecarboxamide deriv-
atives in an attempt to improve potency and to find more potent
anticancer compounds. Our research group is interested in the
synthesis and development of multiple target kinase inhibitors
as anticancer agents.14,15 We now describe the synthesis and
The c-Src proto-oncogene also play a central role in the
development and progression of several human cancers,
including colon, breast, pancreatic, lung, and brain cancers.
Src kinase modulates signal transduction through multiple
oncogenic pathways downstream of receptor tyrosine kinase
such as EGFR, VEGFR, Her2 and PDGFR. A pan-Src kinase
inhibitor may be considered useful in modulating aberrant
pathways leading to oncologic transformation of cells.4–6
A
number of planar heteroaromatic small-molecule inhibitor
templates have been exploited to identify novel Src kinase
inhibitors. To date, purine, pyrrolopyrimidine, pyridopyrimi-
dine, naphthyridone, quinazoline, and quinoline-based inhibi-
tors have been reported.7 Among these, Dasatinib is a novel
multi-targeted kinase inhibitor recently approved in several
countries for the treatment of chronic myelogenous leukaemia
(CML) as well as Philadelphia chromosome-positive acute
lymphocytic leukaemia.8,9 Dasatinib exhibits greater potency
than imatinib mesylate and inhibits the majority of kinase
mutations in imatinib-resistant CML. Unlike imatinib, which
binds to the inactive conformation of Bcr-Abl, dasatinib binds
Fig. 1 Structures of template inhibitors interacting with the ATP-binding site of Src kinase.
* Correspondent. E-mail:syzhao8@dhu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2011 417
Reagents and conditions: (a) 0–5 °C, 12 h, and then 120 °C, 2h; (b) 2-Chloro-6-methylbenzenamine, N(C2H5)3, CH2Cl2, 0–5 °C, 6h;
(c) NBS, dioxane, thiourea; CH2Cl2, r.t.; (d) ClCH2COCl, NEt3, CH2Cl2, rt. 4h; (e) amines, acetone, reflux 6h.
Scheme 1 Synthetic route for the compounds 7a–g.
preliminary biological evaluation of novel 2-amino-5-thiazole-
carboxamide derivatives against various human cancer cell
lines in vitro.
Next, we subjected β-ethoxy acrylamide 4 to NBS mediated
thiazole formation in a mixture of dioxane and water, followed
by addition of thiourea and heating to effect the ring closure.17,22
To our satisfaction, the desired 2-aminothiazole-5-carbox-
amide 5 was obtained in 88% yield. With an efficient method
available for the large-scale synthesis of N-(2-chloro-6-meth-
ylphenyl)-2-amino-5-thiazolecarboxamide 5, it was subjected
to acylation with chloroacetyl chloride to afford compound
6 in 86% yield. The title compound 7 was prepared by the
treatment of compound 6 with different amines in acetone and
obtained as a white crystal powder. In addition, the compounds
8 and 9 were prepared by the treatment of compound 6 with
succinic anhydride or maleic anhydride, respectively. Their
structures were confirmed by IR, 1HNMR, MS and elementary
analysis (Scheme 2).
The in vitro cytotoxicity of the novel 2-amino-5-thiazolecar-
boxamide derivatives 7, 8 and 9 against human promyelocytic
leukaemia cell HL-60 and human immortalised myelogenous
leukaemia cell K562 were evaluated by the standard MTT
assay. Dasatinib was used as a positive control. The antitumour
potency of the compounds was expressed as IC50 values which
were calculated by linear regression analysis of the concentra-
tion-response curves obtained for each compound. The results
are summarised in Table 1.
The target compounds were synthesised according to the
route shown in Scheme 1. Several methodologies have been
developed for the synthesis of (E)-3-ethoxyacryloyl chloride 3,
including the reaction of vinyl ether with oxalyl chloride16,17
1
or phosgene18, Refomasky reaction of triethyl ester orthofor-
mic acid with 2-bromoacetc acid ethyl ester19, as well as via
chlorination of 3-ethoxy-2-propenoic acid by oxalyl chloride20.
Nucleophilic addition of vinyl ether 2 to oxalyl chloride 1
according to the procedure of Tietze at room temperature and
decarbonylation upon distillation gave (E)-3-ethoxyacryloyl
chloride 3.16,21 Then, the coupling of the readily available
β-ethoxyacryloyl chloride 3 with 2-chloro-6-methylaniline
in THF using triethylamine as base afforded N-(2-chloro-6-
methylphenyl)-β-ethoxyacrylamide 4 in 70% yield. The TLC
analysissuggested animpurityexisting in this crude compound.
After purification with flash column chromatography, white
crystals were isolated to permit spectroscopic measurements.
1
The H NMR spectrum shows the signal of an ethyl group at
δ 1.42 ppm and 3.90 ppm, and a proton signal of the double
bond has disappeared. The EI mass spectrum of this compound
showed a molecular ion at 241 (M+). On the basis of the spectral
data, the structures was assigned to 2-oxo-2-(2-chloro-6-
methylphenylamino)acetic acid ethyl ester 10.
As shown in Table 1, most of the prepared compounds
showed moderate inhibitory activity, with compounds 7c, 7d,

418 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 2 Synthetic routes for compounds 8 and 9.
Table1 Thecytotoxicitydataof2-amino-5-thiazolecarboxamide
derivatives 7a–g, 8 and 9 in vitro
cytotoxicity against HL-60 and K562 cell lines. Structure–
activity relationships are discussed based on the experimental
data obtained. This study may provide valuable information
for designing more potent anticancer drugs.
IC50 (µM):
Compound
HL-60
K562
Experimental
7a
78.6
50.2
40.1
25.3
28.6
8.5
50.6
70.5
>100
2.5
96.3
72.5
45.5
32.1
24.3
12.8
72.5
90.6
7b
Melting points were determined with an RY-1 apparatus, and were
uncorrected. IR spectra were determined as KBr pellets on a Shi-
madzu model 470 spectrophotometer. 1H NMR spectra were recorded
using a Bruker AV 400 MHz spectrometer in DMSO-d6 with tetra-
methylsilane as internal standard. EI mass spectra were recorded on a
Shimadzu QP-2010 GC-MS system and a Waters Micromass GCT
system. Electrospray impact mass spectra were obtained on Shimadzu
LCMS-2010 instrument. Elemental analyses were performed on a
Vario EL III elemental analyser. All reagents were obtained from com-
mercial sources and used without further purification unless stated.
The compounds (E)-3-ethoxy-2-acryloyl chloride, N-(2-chloro-
6-methylphenyl)-3-ethoxyacrylamide and N-(2-chloro-6-methylphe-
nyl)-2-amino-5-thiazolecarboxamide were synthesised according
to the literature procedures with minor changes.16–17,22 The target
compounds were prepared according to the synthetic route shown in
Schemes 1 and 2.
2-Oxo-2-(2-chloro-6-methylphenylamino)acetic acid ethyl ester
(10): The compound was isolated by flash column chromatography
(dichloromethane / methanol=20:1, v/v) as the by-product from the
preparation of (2-chloro-6-methyl phenyl)-3-ethoxyacrylamide. M.p.
70–72 °C. IR(KBr, cm−1) νmax: 3297, 2945, 1700, 1639, 1533, 1518,
1461, 1405, 1283, 1270, 1238; 1H-NMR (CDCl3): δ 1.45(t, J = 7.2 Hz,
3H, CH3), 2.29 (s, 3H, CH3), 3.90 (q, J = 7.2 Hz, 2H, CH2), 7.17–7.23
(m, 2H, ArH), 7.29 (d, 1H, J = 8.2 Hz, ArH), 8.60 (s, 1H, NH); MS
(EI, m/z): [M+]241, 205, 170, 142, 104, 77; HRMS (EI): Calcd for
C11H12ClNO3 241.0505 (M+). Found 241.0508.
Synthesis of N-(2-Chloro-6-methylphenyl)-2-(2-chloroacetamido)-
5-thiazolecarboxamide (6): To a solution of N-(2-chloro-6-meth-
ylphenyl)-2-amino-5-thiazolecarboxamide (11.2 g, 42 mmol) and
triethylamine (8.3 mL, 60 mmol) in dichloromethane (80 mL), chloro-
acetyl chloride (6.9 g, 63 mmol) was added dropwise during 30 min at
0 °C. The reaction mixture was stirred for 4 h at room temperature.
The solution was washed with saturated NaHCO3 solution (40 mL×2),
water (40 mL×2), and dried over MgSO4. The solvent was removed
under vacuum, followed by recrystallisation of the residue from etha-
nol to give compound 6 as a white solid. Yield 10.4 g (73.6%). m.p.
223–225 °C. IR(KBr, cm−1) νmax:; 3184, 3121, 2973, 1710, 1523, 1588,
1527, 1293, 1184; 1HNMR (CDCl3): δ 2.25 (s, 3H, CH3), 4.42 (s, 2H,
CH2), 7.24–7.29 (m, 2H, ArH), 7.39–7.42 (m, 1H, ArH), 8.32 (s, 1H,
ArH), 10.01 (s, 1H, NH), 12.79 (s, 1H, NH); MS (EI, m/z): [M+] 343,
308, 232, 203, 141, 127, 99, 77; HRMS, Calcd for C13H11Cl2N3O2S:
342.9949. Found: 342.9953.
7c
7d
7e
7f
7g
8
9
>100
4.6
Dasatinib
7e and 7f, having IC50 values against HL-60 cell lines ranging
from 8.5 to 40.1 µM, respectively. It also could be concluded
that the cytotoxity of the tested compounds against HL-60 was
higher than that for K-562 cell lines, reflecting the excellent
selectivity for a particular human leukaemia cell line type.
Some compounds showed moderate cytotoxicity against
K-562 cancer cell lines, although they were less potent than
Dasatinib. The potencies of some compounds were compara-
tive to the lead compound Dasatinib. For example, cytotoxici-
ties of the compound 7f against leukaemia HL 60 and K562
cell lines are 8.5 and 12.8 µM, respectively.
The cytotoxicities of the resulting derivatives appeared to
be related to the nature of the substituent on the acetamido
side chain in the 2-amino-5-thiazolecarbamide, which was in
agreement with the cytotoxic mechanism reported.11 It has
been observed from Table 1 that most of the derivatives with
piperazine moieties showed higher cytotoxicity profiles than
those compounds with just an amino group. The activity of
compound 7f bearing a piperazine moiety increased 1 to 5
times compared to the compounds with an amino group.
In addition, compounds 8 and 9 were designed and
synthesised to increase their water solubility. Unfortunately,
they showed only weak cytotoxicity. Although a limited set of
compounds is reported here, this study may provide valuable
information in designing more potent anticancer agents.
Structural optimisation of 2-amino-5-thiazolecarbamide
derivatives is currently underway in our laboratories.
Conclusion
Preparation of 7a–g; general procedure
In summary, we have synthesised a new series of 2-amino-5-
thiazolecarboxamide derivatives as antitumour agents from
ethenyl ethyl ether. Cytotoxicity was evaluated for the synthe-
sised compounds against a leukaemia cell by standard MTT
assays in vitro. Some of the compounds exhibited more potent
Compound 6 (5 mmol) and triethylamine (10 mmol) were mixed
thoroughly in acetone (10 mL). To this solution, a substituted amine
(6 mmol) was added. The reaction mixture was stirred at reflux for
6 h. The reaction mixture was condensed, and water (10 mL) was
added, extracted with ethyl acetate, washed with saturated NaHCO3

JOURNAL OF CHEMICAL RESEARCH 2011 419
and water. The solvent was removed and purified by flash column
chromatography (dichloromethane/methanol=20:1, v/v) to give the
compounds 7a–g as white solids.
4-[5-((2-Chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino]-4-
oxobutanoic acid (8): White solid; Yield: 71%; m.p. 135–137 °C; IR
(KBr, cm−1) νmax: 3314, 3094, 2923, 1739, 1694, 1620, 1530, 1439,
1208, 1159, 769; 1H NMR (DMSO-d6): δ 2.22 (s, 3H, Ph-CH3), 2.57
(t, 2H, J = 8.4 Hz, CH2), 2.71 (t, 2H, J = 8.4 Hz, CH2), 7.23–7.29 (m,
2H, ArH), 7.38–7.44 (m, 1H, ArH), 8.28 (s, 1H, ArH), 10.02 (s, 1H,
NH), 12.21–12.46 (brs, 2H, OH, NH); MS (ESI, m/z): [M+H+] 368.5,
[M+Na+] 390.5. Anal. Calcd for C15H14ClN3O4S: C, 48.98; H, 3.84;
N, 11.42. Found: C, 49.24; H, 3.63; N, 11.73%.
N-(2-Chloro-6-methylphenyl)-2-[2-(diethylamino)acetamido]-5-
thiazolecarboxamide (7a): White solid;Yield: 72%; m.p. 135–137 °C;
IR (KBr, cm−1) νmax: 3273, 2967, 2925, 2853, 1700, 1645, 1511, 1488,
1291, 1188; 1H NMR (CDCl3): δ 0.99 (t, 6H, J = 8.4 Hz, 2CH3), 2.23
(s, 3H, CH3), 2.63 (q, 4H, J = 8.4 Hz, 2CH2), 3.41 (s, 2H, CH2), 7.25–
7.29 (m, 2H, ArH), 7.38–7.42 (m, 2H, ArH), 8.29 (s, 1H, NH), 10.03
(s, 1H, NH); MS (EI, m/z): [M+] 380, 294, 231, 127, 113, 86. Anal.
Calcd for C17H21ClN4O2S: C, 53.61; H, 5.56; N, 14.71. Found:
C, 53.52; H, 5.76; N, 14.69%.
N-(2-Chloro-6-methylphenyl)-2-[2-(pyrrolidin-1-yl)acetamido]-5-
thiazolecarboxamide (7b): White solid;Yield: 62%; m.p. 180–183 °C;
IR (KBr, cm−1) νmax: 3445, 3233, 2920, 2968, 1707, 1637, 1512, 1292,
1181; 1H NMR (CDCl3-d6): δ 1.85–1.89 (m, 4H, 2CH2), 2.31 (s, 3H,
CH3), 2.72–2.78 (m, 4H, 2CH2), 3.43 (s, 2H, CH2), 7.15–7.18 (m, 2H,
ArH), 7.29–7.34 (m, 1H, ArH), 7.42 (s, 1H, ArH), 8.09 (s, 1H, NH),
10.03 (s, 1H, NH); MS (EI, m/z): [M+] 378, 309, 268, 192, 172, 127,
111, 84. Anal. HRMS (EI): Calcd for C17H19ClN4O2S 378.0917. Found
378.0919.
N-(2-Chloro-6-methylphenyl)-2-[2-(piperidin-1-yl)acetamido]-5-
thiazolecarboxamide (7c): White solid;Yield: 72%; m.p. 174–176 °C;
IR (KBr, cm−1) νmax: 3447, 3238, 2934, 2854, 1684, 1653, 1618, 1519,
1303, 1220; 1H NMR (DMSO-d6): δ 1.38 (t, 2H, CH2), 1.50–1.54 (m,
4H, 2CH2), 2.42–2.46 (m, 4H, 2CH2), 2.42 (s, 3H, CH3), 4.03 (s, 2H,
CH2), 7.24–7.30 (m, 2H, ArH), 7.36–7.40 (m, 1H, ArH), 8.29 (s, 1H,
ArH), 10.04 (s, 1H, NH), 12.10 (s, 1H, NH); MS (EI, m/z): [M+] 392,
309, 268, 125, 98. Anal. Calcd for C18H21ClN4O2S: C, 55.03; H, 5.39;
N, 14.26. Found: C, 55.32; H, 5.63; N, 14.55%.
4-[5-((2-Chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino]-4-
oxobutenoic acid (9): White solid; Yield: 61%; m.p. 120–122 °C;
1
IR(KBr, cm−1) νmax: 2924, 1717, 1645, 1522, 1295, 1177; H NMR
(DMSO-d6): δ 2.21 (s, 3H, PhCH3), 6.24 (d, 1H, J = 8.4 Hz, -CH=),
6.55 (d, 1H, J = 8.4 Hz, -CH=), 7.25–7.31 (m, 2H, ArH), 7.41–7.45
(m, 1H, ArH), 8.32 (s, 1H, ArH), 10.05 (s, 1H, NH), 12.32–12.55 (m,
2H, OH, NH); MS (ESI, m/z): [M+H+] 366.7, [M+Na+] 398.7. Anal.
Calcd for C15H12ClN3O4S: C, 49.25; H, 3.31; N, 11.49. Found: C,
49.02; H, 3.64; N, 11.73%.
Bioassay of cytotoxicity testing
Cytotoxicities of the novel compounds (7a–g, 8 and 9) were evaluated
against HL 60 and K562 human leukaemia cancer cell lines in vitro
by MTT assay using Dasatinib as the positive control. The results
expressed as IC50 are summarised in Table 1. The cells were seeded in
a 96-well plate at the concentration of 40,000 cells per well in 100 mL
RPM I 1640 medium. After culturing for 24 h at 37 °C and 5% CO2,
cells were incubated with various concentrations of samples for 48 h.
MTT was added at a terminal concentration of 0.5 mg mL−1 and incu-
bated with cells for 4 h. The formazan crystals were dissolved in
100 µL DMSO into each well, and the optical density was measured
at 492 nm (for absorbance of MTT formazan) and 630 nm (for the
reference wavelength).
N-(2-Chloro-6-methylphenyl)-2-[2-(morpholin-1-yl)acetamido]-5-
thiazolecarboxamide (7d): White solid;Yield: 68%; m.p. 230–233 °C;
IR (KBr, cm−1) νmax: 3431, 3255, 2956, 2926, 2852, 1696, 1643, 1527,
We thank Donghua University for funding through the
Outstanding Young Faculty Award.
1
1509, 1294, 1193, 1118. H NMR (DMSO-d6): δ 2.23 (s, 3H, CH3),
3.32 (t, 4H, J = 8.4 Hz, CH2), 3.63 (t, 4H, J = 8.4 Hz, 2CH2), 4.20 (s,
2H, CH2), 7.28 (m, 2H, ArH), 7.39 (m, 1H, ArH), 8.30 (s, 1H, ArH),
10.01 (s, 1H, NH), 12.4 (s, 1H, NH); MS (EI, m/z): [M+] 394, 309,
294, 268, 127, 100, 86. Anal. Calcd for C17H19ClN4O3S: C, 51.71; H,
4.85; N, 14.19. Found: C, 51.52; H, 4.63; N, 14.48%.
Received 18 May 2011; accepted 23 June 2011
Paper 1100705 doi: 10.3184/174751911X13099483874341
Paper published: 5 August 2011
N-(2-Chloro-6-methylphenyl)-2-[2-((4-methyl)-1-piperazinyl)
acetamido]-5-thiazolecarbo xamide (7e): White solid; Yield: 66%;
m.p. 200–202 °C; IR (KBr, cm−1) νmax: 3431, 3255, 2956, 2926, 2852,
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1
1701, 1638, 1575, 1522, 1295, 1179, 1158; H NMR (DMSO-d6):
8
9
δ 2.22 (s, 3H, CH3), 2.31–2.43 (m, 6H, 3CH2), 2.50–2.62 (m, 6H,
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N-(2-Chloro-6-methylphenyl)-2-[2-(4-(4-chlorobenzoyl)-1-piper-
azinyl)acetamido] -5-thiazolecarboxamide (7g): White solid; Yield:
58%; m.p. 250–252 °C; IR(KBr, cm−1) νmax: 3445, 3233, 2920, 2968,
1
1707, 1637, 1512, 1292, 1181; HNMR (DMSO-d6): δ 2.25 (s, 3H,
CH3), 2.48–2.52 (m, 4H, 2CH2), 3.31–3.37 (m, 4H, 2CH2), 3.58 (s,
2H, CH2), 7.29 (m, 2H, ArH), 7.39–7.44 (m, 3H, ArH), 7.51–7.54 (m,
2H, ArH), 8.30 (s, 1H, ArH), 10.05 (s, 1H, NH), 12.65 (s, 1H, NH);
MS (EI, m/z): [M+] 532, 378, 120, 111,85; HRMS (EI): Calcd for
C24H23Cl2N5O3S 531.0898. Found 531.0896.
15 S.Y. Zhao, Z.Y. Shao, W.M. Qin, and D.Q. Zhang, Chin. J. Org. Chem.,
2008, 28, 1676.
Preparation of compound (8); general procedure
16 L.F. Tietze, C. Schneider, and M. Pretor, Synthesis, 1993, 1079.
17 B.C. Chen, R. Hao, B. Wang, R. Droghini, J. Lajeunesse, P. Sirard,
M. Endo, B. Balasubramanian, and J.C. Barrish, Arkivoc, 2010, (vi), 32.
18 C. Janiak, S. Deblon, and L. Uehlin, Synthesis, 1999, 959.
19 L.J.J. Hronowski, and W.A.Szarek, Can. J. Chem., 1985, 63, 2787.
20 R. Csuk, and Y. von Scholz,. Tetrahedron, 1996, 51, 7193.
21 F. Fernandez, X. Garcia-Mer, M. Morales, and J.E. Rodriguez-Borges,
Synthesis, 2001, 239.
Compound 6 (5 mmol) and succinic anhydride (6 mmol) were mixed
thoroughly in acetone (10 mL). The reaction mixture was stirred
at reflux for 6 h. The reaction mixture was concentrated and water
(10 mL) added. The product was extracted into ethyl acetate and then
washed with saturated NaHCO3 and water. The solvent was removed
and the product was purified by flash column chromatography to give
a white solid 8. Compound 9 were prepared in a similar procedure as
described for compound 8.
22 B.C. Chen, R. Droghini, J. Lajeunesse, J.D. Dimarco, M. Galella, and
R. Chidambaram, US2006004067, 2006.

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