5-Lipoxygenase inhibitors: Convenient synthesis of 4-[3-(4- heterocyclylphenylthio)phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide analogues

Article abstract of DOI:10.1016/j.bmcl.2005.03.041

A convenient synthetic route to 4-[3-(4-heterocyclylphenylthio)phenyl]-3,4, 5,6-tetrahydro-2H-pyran-4-carboxamide analogues as 5-LO inhibitors is described. This methodology enabled rapid development of structure-activity relationships (SARs) leading to i

Full text of DOI:10.1016/j.bmcl.2005.03.041

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2611–2615
5-Lipoxygenase inhibitors: convenient synthesis of
4-[3-(4-heterocyclylphenylthio)phenyl]-3,4,5,6-tetrahydro-
2H-pyran-4-carboxamide analogues
Takashi Mano,* Rodney W. Stevens, Yoshiyuki Okumura, Makoto Kawai,
Takako Okumura and Minoru Sakakibara
Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan
Received 29 January 2005; revised 26 February 2005; accepted 10 March 2005
Available online 11 April 2005
Abstract—A convenient synthetic route to 4-[3-(4-heterocyclylphenylthio)phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide ana-
logues as 5-LO inhibitors is described. This methodology enabled rapid development of structure–activity relationships (SARs) lead-
ing to improvement of pharmacological properties. Thus, new compounds with higher 5-LO inhibitory potency were discovered.
The stereo-chemistry requirements of the tetrahydropyran ring are also discussed.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In our previous publications, 1 was disclosed to be a po-
tent and orally active inhibitor of 5-lipoxygenase (5-
LO).1–3 With the aim of improving pharmacological
properties of this novel series of 5-LO inhibitors, (i)
modification of the tetrahydorpyran (THP) ring, (ii)
replacement of 2-methylimidazole moiety with other
heterocycles, and (iii) replacement of the carboxamide
moiety with other functional groups were systematically
investigated (Fig. 1). In the course of this study, a novel
nickel(0) catalyzed aryl halide cross-coupling reaction
was developed and is reported on herein.
Figure 1. Strategy of structural modification of 1.
Scheme 1. New synthesis of 1. Reagents and conditions: (i) NaH,
DMSO, rt, 30 min, then (ClCH2CH2)2O, rt, 1 h (75%); (ii)
Ni(PEt3)2Cl2; NaBH3CN, thiourea, 60 °C, 4 h; CaO, DMF, rt for
1.5 h; Ni(PEt3)2Cl2; NaBH3CN, 12, 60 °C, 4 h; (iii) powdered KOH, t-
BuOH, 80 °C, 4 h (63% from 11).
Keywords: Leukotriene; Lipoxygenase; Inhibitor; Structure–activity
relationship; Unsymmetric thioether.
*
Corresponding author. Tel.: +81 569 74 4430; fax: +81 569 74
4748; e-mail: Takashi.Mano@pfizer.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.041

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2. Chemistry
triazole 14 was constructed in 39% yield from p-iodoani-
line and N,N-dimethylformamide azine dihydrochloride,
according to the literature procedure.7 Pyrazole 15 was
conveniently prepared by aromatic nucleophilic substi-
tution of 4-fluoro-1-iodobenzene with 3,5-dimethylpy-
razole. Bicyclic iodides 16 and 17 were synthesized as
shown in Scheme 4. Diiodide 25 was prepared from
the known ditosylate,8 and the [3.2.1] bicyclic ring was
formed by reacting 25 and 3-iodophenylacetonitrile
(10) with sodium hydride as a base in DMSO. The
resulting mixture of stereo-isomers was separated by col-
umn chromatography to afford 16 and 17. The stereo-
chemistry of 16 and 17 was elucidated by NOE as shown
in Figure 2.
2.1. Nickel(0) catalyzed cross-coupling
It has been reported that nickel(0) catalyzed coupling
can produce an unsymmetric thioether from the corre-
sponding aryl halide in the presence of thiourea.4,5
Under similar reaction conditions the unsymmetric
thioether 13 was synthesized from the known iodides
11 and 12 as shown as step ii in Scheme 1. Subsequent
hydrolysis by standard methodology as developed in
our laboratory afforded 1 in 63% total yield from 11.3,6
2.2. Synthesis of analogues of 1
The novel nickel(0) catalyzed cross-coupling methodol-
ogy described above was applied to the syntheses of 2–
5 and 8, and results are shown in Scheme 2. Key inter-
mediates were prepared as shown in Schemes 3–5. Thus,
Scheme 5 shows the preparation of the O-methylated
oxime 18. The nitrile 11 was reduced to the corresponding
carbaldehyde 26, which was reacted with O-methyl
hydroxylamine hydrochloride to give the desired iodide.
Scheme 2. Convenient synthesis of unsymmetric thioether 5-LO inhibitors. Reagents and conditions: (i) 4-X-phenyliodide, Ni(PEt3)2Cl2; NaBH3CN,
thiourea, 60 °C, 4 h; CaO, DMF, rt for 1.5 h Ni(PEt3)2Cl2; NaBH3CN, 3-R2–phenyliodide, 60 °C, 4 h; (ii) powdered KOH, t-BuOH, 80 °C, 4 h.

T. Mano et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2611–2615
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Scheme 3. Syntheses of 14 and 15. Reagents and conditions: (i) p-
iodoaniline, toluene, reflux, 3.5 h (39%); (ii) NaH, DMF, 4-fluoro-1-
iodobenzene, 100 °C, 3 h (61%).
Scheme 5. Synthesis of 18. Reagents and conditions: (i) DIBAL,
À78 °C, 3 h, then 1 N HCl, rt, 30 min (79%); (ii) MeONH2ÆHCl, rt,
overnight (83%).
Scheme 4. Synthesis of bicyclic iodides, 16 and 17. Reagents and
conditions: (i) 10, NaH, DMSO, rt, 15 min, then 25, rt, overnight (16,
43%; 17, 17%).
Pyrrol-1-ylmethyl analogue 6 was prepared from aryl
iodide 279,10 in a stepwise manner similar to that for
the original preparation of 13 with the exception that
amidation was performed with ammonium bicarbonate
and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, as
shown in Scheme 6.2 Amidation of the carboxylic acid
via acid chloride failed most likely due to pyrrole ring
decomposition. The imidazol-1-ylmethyl analogue 7
was prepared from iodide 30 in a similar manner
(Scheme 7).
Scheme 6. Synthesis of 6. Reagents and conditions: (i) Pd(PPh3)4,
t-BuONa, EtOH, reflux, overnight (54%); (ii) LiOH, H2O, MeOH,
THF, reflux, 5 h (quant.); (iii) 2-ethoxy-1-ethoxycarbonyl-1,2-dihy-
droquinoline, (NH4)HCO3, rt, overnight (54%).
3. Biological testing
Scheme 8 depicts the synthesis of 9. Although the direct
reduction of nitrile 13 to carbaldehyde was tried, the de-
sired compound was not obtained. However, two-step
conversion of methyl ester 32,3 prepared from the carb-
oxamide 1, afforded the desired carbaldehyde, which
was then converted to oxime 9 in the usual manner.
SAR studies were routinely conducted based on inhibi-
tion of LTB4 (leukotriene B4) synthesis in A-23187 simu-
lated human whole blood (HWB) for 5-LO, and
oral activity was assessed by platelet activating factor
(PAF) induced thrombosis in male mice.1
Figure 2. NOE experiment of 16 and 17 possessing [3.2.1] ring system.

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T. Mano et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2611–2615
Table 1. 5-LO Inhibitory activities of 1 and analogues
Compd HWB IC50 (lM) PAF thrombosis ED50 (mg/kg)
1 HCla 0.23 0.05 (15)b 3.7 0.3 (3)b
2
3
4
5
6
7
8
9
0.83 0.16 (3)b
>1 (À7% Inh)c
>1 (1% Inh)c
>1 (À1% Inh)c
0.27 0.09 (3)b
0.14
7
N.D.d
N.D.d
N.D.d
3
>20
2
N.D.d
0.15 0.03 (6)b
2.0 0.1 (3)b
a Ref. 3.
b Shown with SD (number of determinations).
c % Inhibition at 1 lM.
Scheme 7. Synthesis of 7. Reagents and conditions: (i) K2CO3, MeCN,
reflux, 15 h, (44%); (ii) 28, Pd(PPh3)4, t-BuONa, EtOH, reflux,
overnight; (iii) LiOH, H2O, MeOH, THF, reflux, 5 h; (iv) 2-ethoxy-
1-ethoxycarbonyl-1,2-dihydroquinoline, (NH4)HCO3, rt, overnight
(28% from 31).
d Not determined.
Figure 3. Stereochemistry of 2 and 3.
5-LO inhibitor ZM230487.12 Therefore, our finding on
the stereo-requirements on the THP ring may be unique
to the imidazole 5-LO inhibitor analogues, such as 1, 2,
and 3.
Scheme 8. Synthesis of 9. Reagents and conditions: (i) HCl–MeOH,
reflux, overnight (35%); (ii) LiAlH4, THF, 0 °C then rt, 30 min, 69%;
(iii) (COCl)2, DMSO, CH2Cl2, À78 °C, 30 min, then À20 °C, 2 h
(77%); (iv) MeONH2ÆHCl, MeOH, pyridine, rt, 5 h (70%).
4.2. Replacement of 2-methylimidazole moiety
Replacement of the imidazole ring with other heterocy-
cles such as triazole (4) or pyrazole (5) resulted in loss of
intrinsic in vitro potency. On the other hand, pyrrol-1-
ylmethyl analogue 6 retained the in vitro and in vivo po-
tency of 1. While 2-methylimidazol-1-ylmethyl analogue
7 exhibited comparable in vitro potency to 1, in vivo
activity (oral dosing) was not observed. Thus, the effect
of methylene insertion between the heterocyclic moiety
and the neighboring phenyl ring seems to be dependent
upon the remaining part of the molecules and the details
are not unclear at the moment.
4. Results and discussion
4.1. Modification of tetrahydropyran ring
In order to elucidate stereo-chemistry requirements on
the THP ring of 1, bicyclic compounds 2 and 3 were de-
signed and synthesized. As shown in Table 1, compound
2 was found to be active in vitro and in vivo (IC50
=
0.83 0.16 lM (n = 3) in HWB and ED50 = 7 mg/kg in
PAF thrombosis, respectively), whereas 3 was essentially
inactive. From the NOE experiments carried out on
intermediates 16 and 17 (Fig. 2), the biologically active
form has the phenyl ring at the 4-position on THP ring
of 2 oriented equatorially, as depicted in Figure 3. Zen-
eca has reported that 5-LO inhibitory activities of a sim-
ilar THP series were dependent upon the proportion of
the equatorial phenyl ring orientation at the 4-position,
and that the potent intrinsic inhibitory activity resides in
equatorial-oriented phenyl ring analogues.11 Our finding
appears to be consistent with their report. However, it
was also reported that the binding mode of 1 to 5-LO
is different from that for the representative Zenecaꢀs
4.3. Replacement of carboxamide moiety
Replacement of the carboxamide with hydroxyimine
was also investigated. O-Methyl hydroxyimine (8) was
more potent in vitro and in vivo than 1. On the other
hand, hydroxyimine (9) was approximately 10-fold less
active in vitro.
5. Conclusion
A convenient synthesis of analogues of 1 was developed
using a nickel(0) catalyzed aryl halide cross-coupling

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2615
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chemistry requirements on THP ring were elucidated,
and finally, the O-methyl hydroxyimine (8) was found
to be the more potent inhibitor of 5-LO than 1. In order
to determine the therapeutic potential of 8 and its ana-
logues and investigate their mechanistic feature of 5-
LO inhibition, further work is required.
6. Mano, T.; Stevens, R. W.; Nakao, K.; Okumura, Y.;
Kawamura, K.; Ando, A.; Matsuoka, Y. Synthesis 2004,
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Supplementary data
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8. Cope, A. C.; Baxter, W. N. J. Am. Chem. Soc. 1955, 77,
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2005.03.041.
9. Dowell, R. I.; Edwards, P. N.; Oldham, K. Eur. Patent
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