Discovery of sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (GSK269984A) an EP1 receptor antagonist for the treatment of inflammatory pain

Article abstract of DOI:10.1016/j.bmcl.2009.02.112

We describe the medicinal chemistry programme that led to the identification of the EP₁ receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP₁ antagonists such as GW8

Full text of DOI:10.1016/j.bmcl.2009.02.112

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2599–2603
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)-
methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (GSK269984A)
an EP1 receptor antagonist for the treatment of inflammatory pain
*
Adrian Hall , Andy Billinton, Susan H. Brown, Anita Chowdhury, Nicholas M. Clayton, Gerard M. P. Giblin,
Mairi Gibson, Paul A. Goldsmith, David N. Hurst, Alan Naylor, Caroline F. Peet, Tiziana Scoccitti,
Alexander W. Wilson, Wendy Winchester
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the medicinal chemistry programme that led to the identification of the EP1 receptor antag-
onist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with
previous EP1 antagonists such as GW848687X and was found to display excellent activity in preclinical
models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A
was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human micro-
dose study.
Received 18 February 2009
Revised 25 February 2009
Accepted 26 February 2009
Available online 3 March 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
EP1 antagonist
Inflammatory pain
Pain
CNS penetration
Microdose
Prostaglandin E2 (PGE2) is a proinflammatory mediator, pro-
duced from arachidonic acid by the action of the cyclooxygenase
(COX) enzymes and prostaglandin E2 synthase (PGES).1 The role
of inhibitors of the COX enzymes in the treatment of pain is well
established.2 Recent preclinical data has also highlighted the role
of PGE2 in hyperalgesia via studies with PGES knockout (KO) mice3
and PGES inhibitors.4 PGE2 mediates its physiological actions via
the activation of four G-protein coupled receptors (GPCRs) known
as EP1–4.5 There is substantial literature evidence to link activation
of the EP1 receptor subtype to hyperalgesia,6 thus antagonism of
the EP1 receptor offers a novel approach for the treatment of
inflammatory pain.7 In addition, recent reports have highlighted
the potential of EP1 antagonists in the treatment of visceral pain,8
overactive bladder (OAB)9 and cerebral ischemia.10 Thus novel EP1
antagonists would have the potential to treat several diseases.
We have previously reported on our efforts to identify novel EP1
receptor antagonists for the treatment of inflammatory pain. Thus
we reported the discovery of the clinical candidate GW848687X
(1)11 and analogues such as GSK345931A (2)12 and GW845706X
(3)11 (Fig. 1). We also reported on a novel methylene-linked pyra-
zole series as exemplified by GSK180100B (4).13
Several key issues were encountered with GW848687X (1)
upon further investigation. In the first instance, when the com-
pound was dosed in a 5 day rat joint pain study11,14 analysis of
the blood exposures from animals in the drug treated groups re-
vealed a marked decrease in exposure on days 4–5 relative to ear-
lier time points (e.g., day 1). This was observed when AUC values
Na+
O
O
Cl
N
Cl
N
OH
O
O
F
O
F
1 (GW848687X)
EP1 binding pIC50 8.6
2 (GSK345931A)
EP1 binding pIC50 7.8
Na+
O
O
N
N
Br
F3C
O
OH
O
O
N
Cl
Cl
3 (GW845706X)
EP1 binding pIC50 8.0
4 (GSK180100B)
EP1 binding pIC50 9.88
* Corresponding author. Tel.: +44 1279 643464.
E-mail address: Adrian.2.hall@gsk.com (A. Hall).
Figure 1. Key literature EP1 receptor antagonists from GSK.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.112

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A. Hall et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2599–2603
Cl
Cl
N
CO2Et
Cl
were compared in addition to single time point concentrations. It is
possible this effect on exposure is linked to a secondary observa-
tion that the mRNA of CYP2B1 and 2B2 was significantly upregu-
lated in a 7 day rat toxicology study, where a similar decrease in
exposure was observed. This effect on exposure posed an issue as
it precluded the establishment of a suitable therapeutic index
(TI). The situation became compounded when a potential back-
up molecule, GSK345931A (2) also showed decreased exposure in
the rat joint pain model of inflammatory pain on days 4 and 5. Both
compounds were found to be unstable to light in solution, as has
been described previously for related compounds,15 which posed
a further issue.
a, b
c, d, e
OH
OH
Br
O
OH
7
5
6
f, g
N
Na+
O
Br
N
CO2Et
Cl
O
O
F
9
8h
Cl
Scheme 1. Reagents and conditions: (a) PhCH2Br, K2CO3, Me2CO, reflux, 2 h; (b)
PBr3, CH2Cl2, À10 °C to rt (82%, two steps); (c) activated zinc, THF, then 9, Pd(PPh3)4,
THF, rt; (d) NaSMe, DMF, 100 °C; (e) concn H2SO4, EtOH, reflux (36%, three steps); (f)
4-chloro-2-fluorobenzyl bromide, K2CO3, Me2CO, 50 °C (79%); (g) EtOH, 2 M NaOH,
90 °C (93%).
We had found that analogues of GW848687X (1), such as
GW845706X (3) which did not penetrate the central nervous sys-
tem (CNS) failed to show efficacy in the rat joint pain model.11
Thus, as part of a plan to identify further development candidates
which addressed the issues identified with GW848687X (1) and
GSK345931A (2) we sought to profile compounds of diverse chem-
ical structures which demonstrated CNS penetration, efficacy in
the rat joint pain model, but which did not show decreases in
exposure. As a first step, we profiled compound 4 (GSK180100B,
Fig. 1) in the joint pain model of inflammatory pain (this com-
pound had previously shown efficacy in the CFA model of inflam-
matory pain (70% reversal of hypersensitivity, 1 h post-dose of
10 mg/kg po). In this study, compound 4 failed to show efficacy,
which was attributed to its lack of CNS penetration (rat
Br:Bl < 0.05). However, bioanalysis of blood samples from the joint
pain study showed that the exposure had not decreased over the
5 day dosing schedule.
We had previously observed that picolinic acid derivatives, such
as 1 and 2, were able to penetrate the CNS in preclinical species
and that this had also resulted in efficacy in the joint pain assay.
Thus we sought to combine the positive attributes of compounds
such as 1 and 4 by replacing the pyrazole acid of compounds such
as 4 by a picolinic acid to give compounds of general structure 8,
Figure 2.
Scheme 1 depicts the synthesis of the methylene-linked picoli-
nic acid derivatives. Selective benzylation of the phenolic group of
5-chloro-2-hydroxybenzyl alcohol (5) with 1 equiv of benzyl bro-
mide, followed by reaction with phosphorous tribromide gave ben-
zyl bromide 6. Treatment of 6 with activated zinc16 followed by
Negishi reaction17 with 9 formed the key carbon–carbon methy-
lene linker. This unpurified intermediate was treated with sodium
methane thiolate (debenzylation of the phenol and ester hydroly-
sis) and re-esterified to deliver phenol 7. Alkylation of 7 followed
by ester hydrolysis, as exemplified for derivative 8h, delivered
the target compounds (Scheme 1).
The SAR for derivatives 8a–n is summarized in Table 1. Initial
data for the unsubstituted benzyl derivative (8a) was disappoint-
ing18, and the mono-fluoro derivatives (8b and 8c) offered little
improvement. The 2,4-difluoro analogue (8d) provided an increase
in affinity, but addition of a third fluorine atom (8e) was detrimen-
tal. Mono-chloro benzyl derivatives (8f and 8g) proved marginally
Table 1
Structure–activity relationships of derivatives 8a–n
Na+
O
N
Cl
O
O
R
8a-n
Compds
R
EP1 bindinga pIC50
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
Bn
2-F–Bn
4-F–Bn
2,4-diF–Bn
2,4,6-triF–Bn
2-Cl–Bn
6.8 0.2
7.1 0.2
7.0 0.1
7.6 0.1
7.1 0.2
7.4 0.1
7.4 0.1
7.9 0.2
7.9 0.1
8.0 0.1
7.4 0.1
7.0 0.1
7.5 0.1
6.7 0.0
4-Cl Bn
2-F,4-Cl–Bn
2-Cl,4-F–Bn
2,4-diClBn
i-Bu
CH2cyhex
CH2cypent
CH2cyprop
a
Data from [3H]-PGE2 binding assay in CHO cells overexpressing the human EP1
receptor, values are the mean of at least three experiments with standard
deviations.
higher in affinity than their fluoro counterparts (8b and 8c, respec-
tively). Highest affinity was achieved with the chloro-fluoro benzyl
derivatives (8h and 8i) and the dichloro derivative (8j). These three
compounds also showed good in vitro metabolic stability (intrinsic
clearance values of <0.5 mL/min/g liver in both rat and human liver
microsomes for 8h and 8j, which equates to <15% turnover after
30 min incubation and slightly higher values for 8i (<1.5 mL/min/
g liver).19
The alkyl analogues (8k–n) displayed sub-optimal affinity, and
furthermore, 8m displayed higher in vitro metabolic instability
(CLi 10.0 mL/min/g liver in human liver microsomes).
Na+
O
O
N
On the basis of the data in Table 1 compounds 8h–j were se-
lected for further profiling. All three compounds were found to
be functional antagonists (Table 2) as measured by their ability
to block PGE2-mediated intracellular Ca2+ mobilization in CHO cells
recombinantly overexpressing the human EP1 receptor. Further-
more, in a functional assay, compound 8h was found to cause a
concentration-dependent rightward shift of the PGE2 dose–re-
sponse curve and Schild analysis20 showed it to be a competitive
antagonist with pA2 8.1 0.3, slope 1.0. As expected, the dichloro
analogue 8j was found to be the most lipophilic of the three com-
Br
O
N
Cl
N
O
OH
N
X
OH
O
O
F
O
R
Cl
Cl
F
1 (GW848687X)
4 (GSK180100B)
8
CNS penetration
low CNS penetration
CNS pentration?
efficacious in joint pain
reduced exposure
not efficacious in joint pain
no reduction in exposure
efficacy in joint pain?
no reduction in exposure?
Figure 2. Medicinal chemistry strategy to combine the desirable attributes from
compound 1 with compound 4 into a single molecule (8).

A. Hall et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2599–2603
2601
Table 2
Table 5
Functional antagonism data, measured logD data and CYP450 inhibition data for
compounds 8h–j
CNS penetration for compound 8h in the mouse, rat, and landrace pig
Species
Blood concn (nM)
Brain concn (nM)
Br:Bl
a
c
Compds EP1
logDb CYP450 IC50
(lM)
Mousea
Ratb
199 12
955 72
56 10
225 25
374 32
627
0.28 0.05
0.24 0.04
0.21 0.02
0.27
FLIPR pKi
8h
8i
8.1 0.5
2.1
2.0
2.6
20 (1A2), >100 (2C19), 8 (2C9), >100 (2D6), no data
@ 3A4
61 (1A2), 28 (2C19), 15 (2C9), >100 (2D6), 35 (3A4
DEF), >100 (3A4 PPR)
32 (1A2), >50 (2C19), 4.8 (2C9), >50 (2D6), no data
@ 3A4
Ratc
1798
2304
7
Landrace pigd
7.0 0.6
7.6 0.8
a
Steady-state infusion (12 h) of 5 mL/kg/h to achieve target dose of 0.5 mg/kg/h,
data are the mean from three animals.
8j
b
Steady-state (12 h) infusion of 5 mL/kg/h to achieve target dose of 0.5 mg/kg/h,
data are the mean from three animals.
a
c
Data from PGE2-mediated Ca2+ mobilization assay in CHO cells overexpressing
1 h infusion.
1 h infusion, single animal.
d
the human EP1 receptor, values are the mean of at least three experiments with
standard deviations.
b
Measured data at pH 7.4.
Inhibition of metabolism of fluorometric substrates using Gentest protocol,
c
no reduction in exposure was observed throughout the course of
the study (from a satellite study group dosed at 10 mg/kg b.i.d.
single experiment.21
for 5 days blood concentrations were 2.393 0.552
lM 1 h post-
dose on day 1 and 2.607 0.286 M 1 h post-dose on day 5). This
was later confirmed in rat 7 and 28 day toxicological studies (data
not shown).
l
pounds, and this subtle increase in lipophilicity could be the cause
of the increase in CYP inhibition.
Further profiling of compound 8h using an alternative enzyme
source confirmed the low potential for CYP450 inhibition, Table 3.
Based on these results, compounds 8h and 8i were progressed
to the rat CFA model of inflammatory pain. Compounds were dosed
orally at doses of 1, 3 and 10 mg/kg, 23 h after intraplantar admin-
istration of the adjuvant. Analgesia was assessed 1 h post-dose of
compound by the weight-bearing protocol. Compound 8h demon-
strated an ED50 of 2.6 mg/kg (po), with the 10 mg/kg dose showing
equivalent reversal of hypersensitivity to the standard
(GW855454X,22 30 mg/kg po). On the other hand, compound 8i
gave an ED50 of 5.6 mg/kg (po) but did not show reversal of hyper-
sensitivity equivalent to the standard (GW855454X,22 30 mg/kg
po). Bioanalysis from these studies showed both compounds pen-
etrated the CNS to a similar degree and that the Br:Bl ratio for each
compound was constant over the dose range investigated, Table 4.
On the basis of this data, compound 8h was selected for pro-
gression to the rat joint pain model of inflammatory pain (dosed
at 3 and 10 mg/kg orally b.i.d. for 5 days) where it demonstrated
full reversal of hypersensitivity at 10 mg/kg (equivalent to rofecox-
ib) and an ED50 of ꢀ3 mg/kg. Bioanalysis again confirmed similar
CNS penetration to the CFA study (Br:Bl 0.41 0.08 at 10 mg/kg
and Br:Bl 0.34 0.03 at 3 mg/kg, 1 h post-final dose). Pleasingly,
The CNS penetration of compound 8h was assessed in several
species, Table 5, and found to be consistent across the species
investigated.
The pharmacokinetics of compound 8h were assessed in the rat,
dog and cynomolgus monkey, data are summarized in Table 6.
Compound 8h displayed moderate blood clearance in the rat
and dog and high clearance in the monkey which is reflected in
the half-life for each species. The bioavailability appeared to be
limited by first pass hepatic extraction for each species. This data
is supported by the permeability data, (MDCKII-MDR123 Pgp assay;
Pexact24 A–B = 700 nm/s, efflux ratio = 0.9) and solubility data (all
data at 0.5 h time point; H2O: 890
358 g/mL).
lg/mL, FaSSIF: 60 lg/mL, FeSSIF:
l
In vitro metabolic stability profiling of compound 8h showed
that it was stable across species, Table 7, which thus highlighted
a clear discrepancy between in vitro and in vivo metabolic stability,
particularly in the dog and cynomolgus monkey. As this data posed
difficulties in the prediction of human pharmacokinetics, further
work was undertaken with rat, monkey and human hepatocytes
and S9 fraction to include phase 2 pathways in the clearance deter-
Table 6
Summary of in vivo pharmacokinetic data for compound 8h, values are the mean
from three animals standard deviation
Table 3
CYP450 (Cypex) inhibition data for compound 8ha
a
Species
CLba (mL/min/kg)
Vssa (L/kg)
t½ (h)
Fpob (%)
94 26
CYP isoform
1A2
51
2C19
2C9
20
2D6
3A4
Ratc
19
18
41
2
2
2
2.1 0.3
0.6 0.1
0.6 0.2
2.3 0.5
1.1 0.2
0.6 0.5
Dogd
Cynoe
39
7
9
4
IC50
(lM)
9
85 19
2
P100
P100
a
Inhibition of metabolism of fluorometric substrates using Cypex protocol, val-
a
Intravenous administration, 1 h infusion of 1 mg/kg dose.
Oral administration of 3 mg/kg dose, vehicle = 1% (w/v) methylcellulose.
Male Sprague–Dawley rats.
Beagle dog.
ues are the mean of three experiments standard deviation.
b
c
d
e
Cynomolgus monkey.
Table 4
Summary of rat CFA data for compounds 8h and 8i
Compds Dose (mg/
kg) p.o.
ED50 (mg/
kg) p.o.
Blood concna Brain concnb Br:Blc
(nM)
(nM)
Table 7
8h
1
3
10
1
3
10
2.6
144 44
60 12
0.37 0.04
0.37 0.03
0.39 0.05
0.31 0.03
0.30 0.02
0.31 0.03
Summary of in vitro metabolic stability (intrinsic clearance, mL/min/g liver) data for
compound 8h in different hepatic fractions
415 106
1512 355
346 114
836 161
3013 841
175 30
501 65
93 29
256 29
1117 59
8i
5.6
Fraction
Mouse
Rat
Dog
Monkey
Human
Microsomes
Hepatocytes
S9
<0.5
Not tested
Not tested
60.7
2.1a
61.0
<0.5
Not tested
61.0
<0.5
<0.5
4.8,a 2.7b
61.0
3.7,a 0.7b
61.0
a
b
c
Values are the mean from seven animals.
Values are the mean from three animals.
Values are the mean from three animals where the blood and brain samples are
a
Cell density 0.15–0.2 Â 106 cells/mL.
Cell density 0.54–0.7 Â 106 cells/mL.
b
from the same animal.

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A. Hall et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2599–2603
B(OH)2
O
Cl
Lindsay Mulligan, Shiyam Mohamed for DMPK data, Alan K. Bri-
stow for solubility data and Thomas G. Hayhow for assistance with
large scale chemical synthesis.
I
Cl
a
Cl
I
b, c
O
OH
F
Cl
10
11
12
References and notes
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Na+
O
O
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Cl
.HCl
N
HO2C
N
CO2H
CO2Et
f, g, h
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O
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Cl
13
14
8h
Scheme 2. Reagents and conditions: (a) BBr3, CH2Cl2, À78 °C to rt (99%); (b) 4-
chloro-2-fluorobenzyl bromide, K2CO3, Me2CO, reflux, 2 h (98%); (c) i-PrMgCl, THF,
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(1:1), 90 °C, 2 h (51%); (e) EtOH, 2 M NaOH, reflux to rt (96%); (f) EtOH, concn H2SO4,
reflux (95%); (g) NaBH4, EtOH, rt (72–83%); (h) SOCl2, CH2Cl2 (100%).
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minations, Table 7. The metabolic stability in hepatocytes and S9
again failed to predict the in vivo metabolic stability in the rat
and monkey and did not therefore help understand this mismatch.
As a result of this, compound 8h was progressed to a human micro-
dose study in order to assess the human pharmacokinetics.25
It was found that the synthetic route in Scheme 1 was not suit-
able to support large scale synthesis of 8. Thus, an alternative route
employing a Suzuki reaction as the key step was developed,
Scheme 2, and was used to supply more than 100 g of compound.
Commercially available 4-chloro-2-iodoanisole (10) was demethy-
lated with boron tribromide to give the corresponding phenol 11 in
high yield. Alkylation of the phenol and subsequent halogen-metal
exchange using Knochel’s conditions,26 followed by reaction with
trimethylborate gave boronic acid 12. Suzuki–Miyaura coupling27
of 12 with the chloromethylpyridine derivative 14 delivered the
ester in moderate yield, which underwent ester hydrolysis to give
8h as the sodium salt.28 Intermediate 14 was prepared from diacid
13 as outlined in Scheme 2 and was used without purification.
The selectivity of compound 8h was profiled at a number of
prostaglandin and thromboxane targets (EP2 pIC50 5.8, EP3 FLIPR
pKi 5.9, EP4 pIC50 < 5, FP pIC50 < 5, IP pIC50 < 6, TP pKi 8.0, COX-1
pIC50 < 4.5, COX-2 pIC50 < 4) where it showed good selectivity ex-
cept for the thromboxane A2 (TP) receptor. No data was generated
against the DP1 or DP2 (CRTH2) receptors, however, in general
compounds from this programme were found to be inactive at
the DP1 receptor, for example, GW848687X displayed >400-fold
selectivity over the DP1 receptor.11 When screened against a panel
of 50 receptors, enzymes and ion channels (Cerep, France) at 1 lM,
16. Knochel, P.; Yeh, C. M. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53, 2390.
17. Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
18. Hall, A.; Bit, R. A.; Brown, S. H.; Chowdhury, A.; Giblin, G. M. P.; Hurst, D. N.;
Kilford, I. R.; Lewell, X.; Naylor, A.; Scoccitti, T. Bioorg. Med. Chem. Lett. 2008, 18,
1592.
compound 8h showed no significant activity (inhibition 6 30%).
Compound 8h had a low risk of QT interval prolongation, mediated
by blockade of the hERG channel, dofetilide binding pIC50 < 4.5
(IC50 > 32 lM).
19. Clarke, S. E.; Jeffrey, P. Xenobiotica 2001, 31, 591.
In summary, we have described the identification of compound
8h (GSK269984A) which overcame the major issues that precluded
development of previous EP1 antagonists. Compound 8h was se-
lected as a development candidate for the treatment of inflamma-
tory pain and was progressed to a human microdose study. Full
details of the in vivo biological profile and the human microdose
PK data will be the subject of future publications.
20. For Schild analysis, the effect of various single concentrations of antagonist on
PGE2 concentration response curves were observed in a luciferase reporter
assay. Antagonist concentrations between the pIC50 value and maximum
response were incubated with
a concentration range of PGE2 and cells
containing the human EP1 receptor and an NFAT reporter gene for 4 h at
37 °C, 5% CO2 and 95% humidity. Following incubation, reporter gene activity
was assessed by addition of a luciferin substrate and the subsequent light
response measured in a luminescence counter, as an indication of EP1 function.
For further details see: (a) Schild, H. O. Br. J. Pharmacol. Chemother. 1949, 4, 277;
(b) Arunlakshana, O.; Schild, H. O. Br. J. Pharmacol. Chemother. 1959, 14, 48.
21. Crespi, C. L.; Miller, V. P.; Penman, B. W. Anal. Biochem. 1997, 248, 188.
22. Hall, A.; Brown, S. H.; Chessell, I. P.; Chowdhury, A.; Clayton, N. M.; Coleman, T.;
Giblin, G. M. P.; Hammond, B.; Healy, M. P.; Johnson, M. R.; Metcalf, A.; Michel,
A. D.; Naylor, A.; Novelli, R.; Spalding, D. J.; Sweeting, J.; Winyard, L. Bioorg.
Med. Chem. Lett. 2007, 17, 916.
Acknowledgements
The authors thank Helen Hooper, Lee Abberley, Alison Gilbert,
Karen Davies, Barry Passingham, Teresa Heslop, Sadhia Mahmood,

A. Hall et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2599–2603
2603
23. Keogh, J. P.; Kunta, J. R. Eur. J. Pharm. Sci. 2006, 27, 543.
24. Tran, T. T.; Mital, A.; Gales, T.; Maleeff, B.; Aldinger, T.; Polli, J. W.; Aryton, A.;
Ellens, H.; Bentz, J. J. Pharm. Sci. 2004, 93, 2108.
25. Details of the full pharmacological profile and human pharmacokinetic data
will be published elsewhere.
27. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
28. Full experimental details and characterising data have been published, see:
Giblin, G. M. P.; Hall, A.; Hurst, D. N.; Rawlings, D. A.; Scoccitti, T. PCT patent
application WO2006066968A1, 2006.
26. Knochel, P.; Dohle, W.; Gommermann, N.; Kniesel, F. F.; Kopp, F.; Korn, T.;
Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302.