Synthesis and bioactivities of novel 4,5,6,7-tetrahydrothieno[2,3-c]pyridines as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production.

Article abstract of DOI:10.1016/S0960-894X(02)00228-7

Novel 4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivatives were synthesized and evaluated for their abilities to inhibit lipopolysaccharide (LPS)-stimulated production of TNF-alpha in rat whole blood. Several of these compounds exhibited potent inhibitory activity.

Full text of DOI:10.1016/S0960-894X(02)00228-7

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1607–1611
Synthesis and Bioactivities of Novel 4,5,6,7-Tetrahydrothieno
[2,3-c]pyridines as Inhibitors of Tumor Necrosis Factor-ꢀ
(TNF-ꢀ) Production
Masakazu Fujita,* Taketsugu Seki, Haruaki Inada and Naoko Ikeda
Omiya Research Laboratory, Nikken Chemicals Co., Ltd., 1-346, Kitabukuro-cho, Saitama-shi, Saitama 330-0835, Japan
Received 13 February 2002; accepted 5 April 2002
Abstract—Novel 4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivatives were synthesized and evaluated for their abilities to inhibit
lipopolysaccharide (LPS)-stimulated production of TNF-a in rat whole blood. Several of these compounds exhibited potent inhi-
bitory activity. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
4,5,6,7-tetrahydothieno[2,3-c]pyridine (2a) and its deri-
In the case of normal conditions, the production of
cytokines helps clear viral or bacterial infections and
damaged cells from injured tissues. However, the over-
production of pro-inflammatory cytokines such as
tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b)
and interleukin-6 (IL-6) is known to cause immune and
inflammatory diseases.1 Especially, the overproduction
of TNF-a has been strongly implicated in the patho-
genesis of such diseases as septic shock,2 rheumatoid
arthritis (RA),3 inflammatory bowel disease (IBD),4
multiple sclerosis,5 type II diabetes6 and AIDS.7 In
addition, TNF-a is a potent inducer of IL-1, IL-6, IL-8,
GM-CSF and so on.8 Therefore, agents which can inhi-
bit the production of TNF-a have attracted much
attention as potential therapies for the direct or indirect
treatment of these diseases. In clinical trials, the mono-
clonal TNF-a antibodies, Remicade (infliximab),9 and
the soluble TNF p75 receptor fusion protein (TNFRp75:
Fc), Enbrel (etanercept)3,10 have been shown to be
effective in the treatment of RA and Crohn’s disease.
However, these drugs as proteins are expensive and
inconvenient to patients. Given these backgrounds,
currently, small molecule anti-TNF-a agents are being
exploited through multiple approaches.11
vatives (3c and 3e–g) that were the intermediates of
agents combining platelet activating factor (PAF)
receptor antagonist with thromboxane synthase inhi-
bitor (TxSI)12 were found to have such activity. Based
on this information, chemical modifications of com-
pound 2a were started. In this paper, we describe synth-
esis and the structure–activity relationships (SARs) on
4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivatives.
Chemistry and Biology
A series of the compounds listed in Tables 1–5 were
synthesized by the methods illustrated in Schemes 1 and
4.
6-Substituted 2-amino-3-acyl-4,5,6,7-tetrahydrothieno[2,
3-c]pyridines (2) were prepared by the Gewald synth-
esis.13 Namely, reaction of N-substituted 4-piperidone
with sulfur and acylacetonitrile in the presence of Et3N/
DMF or Et2NH/EtOH at 60 ꢀC-reflux yielded com-
pounds 2.
N-Substituted 4-piperidones were commercially avail-
able except for 1-(c-propanecarbonyl)-4-piperidone.
1-(c-Propanecarbonyl)-4-piperidone was easily prepared
by acylation of 4-hydroxypiperidine followed by Swern
oxidation.14 On the other hand, N-substituted 4-piper-
idones were also prepared from the corresponding amines
by Dieckmann reaction followed by decarboxylation, if
the N-substituents were stable against acid (Scheme 2).
During screening of our compounds on inhibition of
TNF-a production, 6-acetyl-2-amino-3-(2-chlorobenzoyl)-
*Corresponding author. Tel.: +81-48-641-2334; fax: +81-48-641-
5749; e-mail: mfujita-nikken@nifty.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00228-7

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M. Fujita et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1607–1611
Table 1. In vitro inhibition of TNF-a production for compounds 1,
2a–b, 3c and 3e–g and the positive control
Table 3. In vitro inhibition of TNF-a production for the N-dialkyl
substitution
Compd
R1
R2
IC50 (mM)a
Compd
R1
R3
IC50 (mM)a
1
2a
2b
3c
3e
3f
3g
Ac
Ac
H
Ac
Ac
Ac
Ac
H
NH2
NH2
38
72
>100
>100
6.0
8a
8b
9a
9b
Ac
Ac
Me2CHCH2
c-HexylCH2
Me2CHCH2
c-HexylCH2
30
100
>100
>100
ClCH2CONH
Br(Me)CHCONH
Cl(Me)CHCONH
NH2(Me)CHCONH
c-PropaneCO
c-PropaneCO
12
8.0
aIC50 of LPS-stimulated TNF-a production in rat whole blood.
FR133605
Dexamethasone
Pentoxifylline
6.0ꢁ4.2
0.02
40ꢁ2
Table 4. In vitro inhibition of TNF-a production for the amides and
the ureas without 3-(2-chlorobenzoyl) group
aIC50 of LPS-stimulated TNF-a production in rat whole blood.
Table 2. In vitro inhibition of TNF-a production for the amides and
the ureas
Compd
R1
R2
R3
Ar
IC50 (mM)a
3u
3v
3w
3x
3y
3z
3aa
3bb
3cc
3dd
3ee
3ff
3gg
3hh
3ii
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Et
Ac
Ac
Ac
Ac
Ac
Ac
Me2CH
c-Propane
3-Pyridyl
Me2CH
Me2CH
c-Propane
Me2CH
c-Propane
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3-ClPh
3-ClPh
3-ClPh
4-ClPh
2-MePh
2-MePh
Ph
Ph
Ph
Ph
7.6
20
36
>100
3.9
2.9
3.0
3.0
48
Compd
R1
R2
R3
IC50 (mM)a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Me
Et
ClCH2
H
H
H
H
H
H
H
H
Me
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
Et
9.5
15
>100
>100
6.0
12
8.1
2.6
33
3.4
3.0
74
2.9
39
46
100
12
3-Pyridyl
Me
Me
14
26
46
88
78
35
28
22
Me(CH2)5
Br(Me)CH
Cl(Me)CH
NH2(Me)CH
Me2CH
Me2CH
Me3C
c-Propane
c-Propane
c-Butane
c-Hexane
Ph
4-MeOPh
3,4-(MeO)2Ph
2,6-(MeO)2Ph
3,4-(OCH2O) Ph
Me
Me
Me2CH
Me2CH
c-Propane
Me2CH
c-Propane
3-Pyridyl
Et2N
3jj
3kk
3ll
3mm
4d
Me
OEt
OEt
OEt
10
22
3.8
2,6-(MeO)2Ph
aIC50 of LPS-stimulated TNF-a production in rat whole blood.
4-FPh
Ac
Ac
Ac
Ac
Ac
Ac
3-Pyridyl
4-Pyridyl
Ph(CH2)2
PhCH=CH
EtNH
Et2N
Et2N
Me2CH
c-Propane
Ph
3-Pyridyl
Me2CH
c-Propane
Ph
3-Pyridyl
Me2CH
c-Propane
Me2CH
Me2CH
Me2CH
21
Table 5. In vitro inhibition of TNF-a production for modification of
the oxygen atom
3s
3t
>100
>100
10
4a
4b
4c
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
10a
10b
10c
0.51
10
2.6
Ac
c-PropaneCO
c-PropaneCO
c-PropaneCO
c-PropaneCO
0.9
>100
3.9
5.0
Compd
R1
R2
Ar
Y
IC50 (mM)a
Bn
Bn
Bn
Bn
Me
Me
H
6.5
3j
Ac
Ac
Ac
Ac
Ac
Ac
Et
Me3C
Me3C
Me3C
Me2CH
Me2CH
Me2CH
Me2CH
Me2CH
2-ClPh
2-ClPh
2-ClPh
Me
Me
Me
¼O
OH
H
¼O
OH
H
3.4
19
29
35
38
23
0.92
100
>100
7.1
2.0
11a
12a
3ii
11b
12b
10b
11c
1.3
4.0
0.92
10
Et
Et
2-ClPh
2-ClPh
¼O
Et
OH
aIC50 of LPS-stimulated TNF-a production in rat whole blood.
aIC50 of LPS-stimulated TNF-a production in rat whole blood.

M. Fujita et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1607–1611
1609
Scheme 1. Reagents and conditions: (a) NCCH2COAr, S, Et3N/DMF or Et2NH/EtOH, 60 ꢀC–reflux, 70–93%; (b) (i) NaNO2, 75% H2SO4, 0 ꢀC;
(ii) 50% H3PO2, 0 ꢀC, 51%; (c) NaOH, MeOH–H2O, reflux, quant; (d) for all compounds except for 4a–b and 4d: R2COX, pyridine, 51%–quant.
For 4a–b and 4d: EtNH2 or Et2NH, triphosgene, Et3N, CH2Cl2, 0 ꢀC–rt, 21%–quant; (e) R3X, NaH, DMF, 11–87%; (f) (i) NaI, THF, reflux;
(ii) NH3, THF, ꢂ20 ꢀC, 81%; (g) NaOH, MeOH–H2O, 0 ꢀC–rt, 77%.
Scheme 4. Reagents and conditions: (a) NaBH4, MeOH, 89%–quant;
(b) Et3SiH, CF3COOH, 85–94%.
THF solution to give compound 3g. Compounds 4a–b
and 4d were obtained by treatment with triphosgene
and amine in the presence of Et3N. Alkylation of
Scheme 2. Reagents and conditions: (a) c-propaneCOCl, Et3N,
CH2Cl2, ꢂ60 ꢀC, 95%; (b) Swern oxidation, 72%; (c)
Br(CH2)2COOEt, Et3N, MeCN, 80 ꢀC, 84%; (d) NaH, PhMe–EtOH,
reflux, quant; (e) concd HCl, reflux, 93%.
amines gave dialkylamines without monoalkylamines
using alkyl halide and NaH in 11–30% yield (8a–b and
9a–b). Amides and urea were alkylated by similar
methodology at rt–60 ꢀC in 52–87 and 80% yields,
respectively (3i, 3l, 10c and 4c). Saponification of com-
pound 2a and selective saponification of compound 3h
afforded compound 2b in quantitative yield and com-
pound 10a in 77% yield, respectively.
Scheme 3. Reagents and conditions: (a) MeCN, LDA, ꢂ78 to ꢂ70 ꢀC,
20–92%; (b) concd HCl, rt–reflux, 90%–quant.
Acylacetonitrile were commercially available or easily
prepared by the condensation of acetonitrile anion with
the corresponding nitriles shown in Scheme 3.15
Selective reduction of the ketones 3j, 3ii and 10b with
NaBH4 gave compounds 11 in high yield. With LAH,
reduction of the amido group at the 6-position or
decomposition were easily accomplished. Further,
selective reduction of the alcohols 11 by treatment with
Et3SiH in CF3COOH easily afforded compounds 12 in
excellent yield (Scheme 4).
6-Acetyl-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydrothieno
[2,3-c] pyridine 1 was synthesized by treatment of com-
pound 2a with sodium nitrite followed by denitrogena-
tion with phosphinic acid. N-Acylation at the 2-position
of compound 2a with the requisite acid halide were
easily accomplished in pyridine (3a–f, 3h, 3j–k, 3m–mm,
5a–d, 6a–d, 7a–b and 10b). Iodoacetamide was prepared
by the reaction of compound 3e with NaI in refluxing
THF and was ammonolyzed by passing NH3 gas in
These compounds were evaluated for their abilities to
inhibit LPS-stimulated production of TNF-a in rat
whole blood. IC50 of TNF-a production was determined
by comparison of yield with a control to which no test
compound was added.16 FR13360517 of TNF inhibitor,

1610
M. Fujita et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1607–1611
Dexamethasone and Pentoxifylline were used as the
positive control.
Therefore, first, we investigated in vitro SAR concern-
ing substituents of the phenyl group (Table 4). The
position of the chlorine atom showed the decrease in
activity in the order of 4-<3-<2- (3h, 3k, 3q and 3u–x).
In particular, the 4-position was essentially inactive at
100 mM. The 2-Me phenyl derivatives 3y–z and the non-
substituted phenyl derivatives 3aa–dd were approxi-
mately equipotent with 3h, 3k, 3o and 3q, respectively.
The mono- and di-alkoxyphenyl derivatives 3ee–hh
indicated weak activity. Urea 4d compared with analo-
gue 4b was 7-fold weaker activity. Thus, there was little
difference in activity in terms of the electron with-
drawing or donating nature of the phenyl moiety.
However, the position of the substituents appeared to
be important for the activity. On the other hand, as
shown in Table 6, in the in vivo activity, the 2-Me
phenyl derivative 3z showed more potent activity than
the other phenyl analogues. Replacement of the phenyl
moiety with methyl and ethoxy groups displayed
decreased potency. Namely, the substitutions led to
increase in activity in the order of 2-ClPh>EtO>Me
(3h, 3k and 3q vs 3ii–jj vs 3kk–mm). However, as shown
in Table 6, in the in vivo activity, the ethoxy derivatives
3kk–ll exhibited most potent activity.
Results and Discussion
We initially investigated in vitro SAR concerning the
amino group at the 2-position and the acetyl group at
the 6-position (Table 1). Compounds 3e–g showed
excellent activity. These initial results appeared to indi-
cate that nonbasic amino group at the 2-position and
the 6-substituents were important for potent activity.
Therefore, based on this information, chemical modifi-
cations of their substituents were started.
Table 2 summarizes the in vitro activity for the amides
and the ureas. Keeping an acetyl group at the 6-sub-
stituent, acetyl and propionyl derivatives were tolerated,
whereas heptanoyl derivative was inactive (3a–b and
3d). From this result, it was clear that long-chain alka-
noyl group was not desirable. Introduction of the
branching alkanoyl group such as isobutyryl, pivaloyl,
2-chloropropionyl and so on exhibited potency com-
parable to the straight-chain alkanoyl derivatives (e.g.,
3h, 3j vs 3b and 3f vs 3c). Moreover, substituents at the
2-position of propionyl group led to increase in activity
in the order of Me>Br>NH2>Cl (3e–h). Substitution
of a cycloalkanoyl group makes little difference to
excellent activity between c-propanecarbonyl analogue
(3k) and c-butanecarbonyl analogue (3m). However,
c-hexanecarbonyl analogue (3n) displayed much weaker
activity. Nicotinoyl derivatives (3q–r) were tolerated
despite benzoyl derivatives (3o–p) and phenylalkanoyl
derivatives (3s–t) had diminished potency. The activity
of the ureas compared with the amides showed increased
potency (3b vs 4a and 3h vs 4b). These appeared to
demonstrate the importance of the pyridine nitrogen
and the urea nitrogen for activity. N-Methylation of the
amides and the urea indicated 13–25 times weaker
activity (3h, 3k, 4b vs 3i, 3l, 4c, respectively). Replace-
ment of acetyl group with c-propanecarbonyl or benzyl
group at the 6-position showed similar results in activity
as with 6-acetyl. Namely, isobutyryl analogues (5a and
6a) and c-propanecarbonyl analogues (5b and 6b)
revealed more excellent activity. Likewise, in the case
of 6-methyl, they exhibited excellent activity (7a–b).
Furthermore, based on these results, we investigated the
in vitro activity for isobutyryl analogues. In particular,
non-6-substituted isobutyryl analogue (10a) was approx-
imately equipotent with 6-acetyl, 6-(c-propanecarbonyl)
and 6-benzyl isobutyryl analogues (3h, 5a and 6a) The
activity of compounds 10b and 10c demonstrated that
3-(2-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyr-
idine derivatives bearing alkyl group such as methyl or
ethyl at the 6-position and acylamino group such as
isobutyramido at the 2-position were desirable.
Lastly, we modified a part of the oxygen atom at the
3-position (Table 5). Changing acetyl to hydroxyethyl
and ethyl made little difference to activity (3ii vs 11b vs
12b). Nevertheless, in the case of benzoyl, the modi-
fication led to increase in activity in the order of
benzoyl>phenylhydroxymethyl>benzyl (3j vs 11a vs
12a). Especially, compound 11c compared with com-
pound 10b was 100-fold weaker activity. It seems that
the oxygen atom of carbonyl group is the important
factor for the activity.
Moreover, from the result of Table 6, logP values
appear to almost never affect the in vivo activity.
All compounds which possess excellent in vitro
activity (IC50<10 mM) were tested in vivo after oral
Table 6. In vivo inhibition of TNF-a production and logP for
representative compounds
Compd
logPa
Inhibition (%) at 50mg/kg, po b
3h
3k
3y
3z
3aa
3bb
3ii
3jj
3.54
3.33
3.603.9
3.25
3.19
2.84
2.54
2.19
3.19
2.84
NTc
NT
2.4
35.0
58.6
35.0
34.1
22.7
31.3
49.1
3kk
3ll
64.2
90.3ꢁ5.9
FR133605
Dexamethasone
Pentoxifylline
NTd
NT
NTe
On the other hand, dialkyl analogues except for com-
pound 8a showed considerably less activity (Table 3).
aDetermined by HPLC analysis.
bInhibition of LPS-stimulated serum TNF-a production in the rat.
cNT, not tested.
Next, we considered that phenyl moiety and oxygen
atom were the very important factor for activity, so that
the modification of the 3-position affected the activity.
dED50=0.12ꢁ0.06 mg/kg, po.
e74.4% at 100 mg/kg, po.

M. Fujita et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1607–1611
1611
administration. TNF-a inhibitory activity was assessed
by in vivo inhibition of serum TNF-a production in the
rat.18 As the results, the ED50 values for these com-
pounds except for 3z and 3ll were >50mg/kg.
Elliott, M. J.; Woody, J. N.; Schaible, T. F.; Feldmann, M.
Arthritis Rheum. 1998, 41, 1552.
11. Newton, R. C.; Decicco, C. P. J. Med. Chem. 1999, 42,
2295.
12. Fujita, M.; Seki, T.; Inada, H.; Shimizu, K.; Takahama,
A.; Sano, T. Bioorg. Med. Chem. Lett. 2002, 12, 771.
13. Sabnis, R. W. Sulfur Reports 1994, 16, 1.
14. Miyazawa, S.; Okano, K.; Kawahara, T.; Machida, Y.;
Yamatsu, I. Chem. Pharm. Bull. 1992, 40, 762.
15. Ridge, D. N.; Hanifin, J. W.; Harten, L. A.; Johnson,
B. D.; Menschik, J.; Nicolau, G.; Sloboda, A. E.; Watts, D. E.
J. Med. Chem. 1979, 22, 1385.
16. TNF-a inhibition assay was performed according to pre-
viously described method with slight modification.17,19 Whole
blood from male SD rats (Charles River Laboratories) was
collected into 2% heparinized vacuum tubes. The blood was
In conclusion, starting from 3-(2-chlorobenzoyl)-4,
5,6,7-tetrahydrothieno[2,3-c]pyridine analogues, we
have found that 3-ethoxycarbonyl-4,5,6,7-tetrahydro-
thieno[2,3-c]pyridine derivatives indicate more excellent
activity by oral dosing. It is likely that esters may play
an important role in the in vivo activity. Therefore, to
our discovery of orally more excellent agents, the SAR
of 3-alkoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyr-
idine derivatives are in progress in our work.
suspended in RPMI-1640supplemented with 100
mg/mL
streptomycin and 100 U/mL penicillin at a concentration of
50%, and seeded into 24- well plate (950 mL). Vehicle (DMSO)
or test compounds in DMSO was added to each well, and the
plate was incubated at 37 ꢀC in 5% CO2 for 30min. Finally,
10 mg/mL LPS (Escherichia coli B055:B5) in RPMI-1640 was
added, and plates were incubated at 37 ꢀC in 5% CO2 for 4 h.
Supernatants were then harvested, and assayed for TNF-a
using ELISA kits. IC50 of TNF-a production was determined
by comparison of yield with a control to which no test com-
pound was added.
17. Yamamoto, N.; Sakai, F.; Yamazaki, H.; Kawai, Y.;
Nakahara, K.; Okuhara, M. J. Rheumatol. 1996, 23, 1778.
18. TNF-a inhibition assay was performed according to pre-
viously described method with slight modification.17,19 Male
SD rats (6 weeks old, Charles River Laboratories) were dosed
intravenously or orally with test compounds suspended in
0.5% CMC. 1 h later, each rat was injected iv with LPS (E.
coli B055:B5, 0.1 mg/kg). The rats were sacrificed and bled 90
min later, which is a time point of maximal elevation of serum
TNF-a activity. Serum TNF-a activity was measured using
ELISA kits. ED50 of TNF-a production was determined by
comparison of yield with a control to which no test compound
was added.
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