Novel 3-(4-piperidinylthio)-1H-indoles as potent nonopioid orally active central analgesics

Article abstract of DOI:10.1016/S0960-894X(00)00102-5

A series of 3-(4-piperidinylthio)-1H-indoles was synthesized and evaluated in mice in the phenylbenzoquinone(PBQ)-induced writhing and hot plate tests. Most of these compounds are good analgesics with activities comparable to that of morphine. Among them compound 1i (UP 237-61), which has a strong serotonin binding profile, has an interesting antinociceptive activity which is not reserved by naloxone. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00102-5

Bioorganic & Medicinal Chemistry Letters 10 (2000) 805±809
Novel 3-(4-Piperidinylthio)-1H-Indoles as Potent Nonopioid
Orally Active Central Analgesics
Dominique Potin,* Veronique Parnet, Jean-Marie Teulon, Francoise Camborde,
Francois Caussade, Joelle Meignen, Daniel Provost and Alix Cloarec
Laboratoires UPSA, 128 rue Danton, BP 325, 92506 Rueil Malmaison Cedex, France
Received 3 December 1999; accepted 10 February 2000
AbstractÐA series of 3-(4-piperidinylthio)-1H-indoles was synthesized and evaluated in mice in the phenylbenzoquinone(PBQ)-
induced writhing and hot plate tests. Most of these compounds are good analgesics with activities comparable to that of morphine.
Among them compound 1i (UP 237-61), which has a strong serotonin binding pro®le, has an interesting antinociceptive activity
which is not reversed by naloxone. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
already been found active on 5-HT receptors, for
6
example: RU-24969 a 5-HT1A agonist, RP-683037 a
Among centrally acting analgesics, opioids are the most
commonly used.1 However these compounds often
induce side e€ects including sedation, constipation,
respiratory depression, tolerance and physical depen-
dence.2 In the search for new central analgesic drugs
devoid of side e€ects, di€erent targets have been identi-
®ed such as noradrenergic, dopaminergic, cholinergic
(muscarinic or nicotinic), adenosinergic and sero-
toninergic pathways.3
5-HT reuptake inhibitor, naratriptan8 (GR-85548) a
5-HT1D agonist launched as an antimigraine drug or
sertindole9 (LU-23-174) a dopamine D2/5-HT antago-
nist launched as an antipsychotic drug.
We have decided to synthesize 3-(4-piperidinylthio)-1H-
indole corresponding to the general formula 1 and to
evaluate their pharmaceutical potential as anti-
nociceptive agents.
We have focused our e€orts on this last mechanism of
action. Actually, considerable evidence exists for the
implication of serotonin (5-HT) in the modulation of
nociceptive transmission.4 Thus, activation of the des-
cending serotoninergic bulbospinal system produces
inhibition of the dorsal horn neuronal responses to
noxious stimuli. This activation could be obtained either
directly by 5-HT receptor agonists or indirectly through
an increase in 5-HT concentrations by 5-HT reuptake
inhibition.
Chemistry
The synthetic approach selected for the preparation of
the desired compounds involved the Fischer indole
synthesis by condensation of an arylhydrazine with an
eventually protected carbonyle compound, bearing a 4-
piperidinylthio substituent. The requisite 1-substituted-
4-piperidinethiols 4 were prepared by the synthetic
sequence outlined in Scheme 1 from commercially
available 4-piperidinones or from 1-methoxy-4-piperi-
dinone.10 Thus treatment of ketones 2 with H2S in
iPrOH a€orded the corresponding gem-dithiols 3, which
were reduced with NaBH4 to give the thiols 4a±f.11
1-Methyl-4-piperidinethiol was converted to the N-
unsubstituted thiol 4g using a described procedure.12
The minimal structural requirements for mimicking
5-HT are often considered to be one basic nitrogen atom
and an aromatic ring.5 We chose to keep the indole
nucleus of 5-HT and use a piperidine ring as a con-
formationally restricted analogue of its aminoethyl side
chain. Compounds bearing these two features have
Thiols 4 were converted to their sodium salt with either
sodium methylate or ethylate and reacted in THF with a
chloroketone (Method A) or 1-bromo-2,2-diethoxy-
ethane (Method B) to a€ord the ketones 5 and the
*Corresponding author at present address: Cerep, Chemistry Depart-
ment, 128 rue Danton, BP 50601, 92506 Rueil Malmaison Cedex,
France. Fax: +33-1-5594-8410; e-mail: d.potin@cerep.fr
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00102-5

806
D. Potin et al. / Bioorg. Med. Chem. Lett. 10 (2000) 805±809
protected aldehydes 6 respectively (Scheme 2). These
compounds were then reacted in iPrOH with arylhy-
drazines in the presence of gaseous hydrochloric acid to
yield the desired indoles 1 (Method C).
in the latter test were then subjected to the hot plate
test,15 which in turn is more speci®c for compounds
with a central mechanism of action. Results for both of
these tests are shown in Table 1.
Alkylation of the indole nitrogen atom with alkyl
iodides was performed using sodium amide as a base in
a mixture of liquid ammonia and THF (Method D).
Compound 1y was synthesized by metallation with
nBuLi followed by quenching with gaseous carbon
dioxide (Method E). The 5-hydroxy substituted indole
1k having a substitution pattern similar to that of sero-
tonin was obtained through demethylation of 1l with
boron tribromide in chloroform (Method F). Acylation
of the piperidine nitrogen atom was done under stan-
dard conditions (Methods G,H). Finally, oxidation of
the sulfur atom was carried out using 1 or 2 equivalents
of oxone1 to yield either the sulfoxide 1ae or the sul-
fones 1af±ag13 (Methods I, J).
Discussion
It is apparent from the data presented in Table 1 that
the studied 3-piperidinylthio-1H-indoles are generally
interesting analgesics as compared to the activity of
morphine. Hydrogen or methyl substituents at indole 1-
position give equally potent compounds. When the size
of this substituent is increased the activity drops rapidly,
as shown by the comparison of 1r (R1=nBu) with 1q
(R1=Me), and of 1g (R1=4-Cl-Bn) with 1b (R1=H).
The same trend is observed with the 2-position sub-
stitution where activity decreases with the size, hydro-
gen being more potent than methyle (1a and 1b) and
aryle being inactive (1f). Halogen atoms at the 5-posi-
tion were by far the best compounds, with 5-chloro and
5-bromo being more active than 5-¯uoro or 5-iodo. 5-
CF3, 5-methyl, 5-methoxy or the unsubstituted indole
give less active compounds whereas other substitutions
(OH, CO2H, iPr) give mostly inactive compounds. It
should be noticed that the 5-hydroxy compound, having
the same indole substitution as 5-HT has no anti-
nociceptive activity.
Results
To assess the in vivo analgesic activity of our com-
pounds, they were ®rst evaluated in mice in the phe-
nylbenzoquinone (PBQ)-induced writhing test,14 which
points out analgesic compounds acting either through a
peripheral or a central mechanism of action. In this
model, compounds were administered orally 1 h prior to
the intraperitoneal administration of PBQ. Their
potency was then measured as the inhibition of painful
reactions (writhings and stretches). Active compounds
Various substitutions of the piperidine nitrogen have
been studied. The most favorable groups are hydrogen,
methoxy or acetyl. Less active compounds are obtained
Scheme 1. (a) H2S, iPrOH, 10 ꢀC; (b) NaBH4, iPrOH, re¯ux; (c) (i) ClCO2Et, acetone, 15±20 ꢀC, (ii) ClCO2Et, toluene, 80±110 ꢀC, (iii) concd HCl,
AcOH, re¯ux.

D. Potin et al. / Bioorg. Med. Chem. Lett. 10 (2000) 805±809
807
Scheme 2. (a) NaOMe or NaOEt, THF, 20 ꢀC; (b) ClCH2COCH2R2, 20 ꢀC; (c) BrCH2CH(OEt)2, 20 ꢀC; (d) R5-PhNR1NH2, HCl gas, iPrOH, 0 to
20 ꢀC; (e) (1) NaNH2, NH3 liq, THF, 40 ꢀC, (2) R1I, 40 to 20 ꢀC; (f) (1) nBuLi, THF, 78 ꢀC, (2) CO2 gas, 78 to 0 ꢀC; (g) BBr3, CHCl3, 0 ꢀC; (h)
HCO2H, DCC, DMAP cat, CH2Cl2, 20 ꢀC; (i) ClCO2Et or ClCOR0, Et3N, CH2Cl2, 0 to 20 ꢀC; (j) KHSO5 (1 eq), H2O, MeOH, 0 to 20 ꢀC; (k)
KHSO5 (2 eq), H2O, MeOH, 0 to 20 ꢀC.
with either methyl, benzyl, phenethyl or butyryl sub-
stituents. Finally, poorly active molecules are found
among those N-substituted by ethyl, isopropyl or for-
myl groups. The oxidation state of the sulfur atom also
plays an important role. The sulfoxide 1ae is con-
siderably less active than the corresponding thioether 1i,
whereas sulfone 1af is equivalent in potency to 1i and
sulfone 1ag is slightly less active than 1a.
kaolin-induced arthritis model17 (ED50=4.9 mg/kg,
rats, po; morphine: 4.4 mg/kg) and in the tail pinch
test18 (ED50=25.3 mg/kg, mice, ip; morphine: 15 mg/
kg), but poorly active in the Freund's adjuvant-induced
polyarthritis model19 (62% inhibition at 60 mg/kg, rats,
po; morphine: 5.2 mg/kg). Its activity was not blocked
in the hot plate test after the administration of the
opioid antagonist naloxone (3 mg/kg, sc), demonstra-
ting its nonopioid mechanism of action. In fact its strong
serotonin binding pro®le20 (Fig. 1), especially with a Ki
value of 3.01 nM on 5-HT uptake sites, might suggest a
serotoninergic antinociceptive mechanism of action.
Extremely active compounds such as 1a±c, 1i, 1p±q, 1w±
x, 1aa±ab and 1af were discovered. Due to its good
activity:tolerance ratio,16 1i (UP 237-61) was further
evaluated. In addition to its good activity in our two
screening assays (ED50 values (po) of 4 mg/kg (PBQ)
and 16.9 mg/kg (hot plate)), it is highly potent in the
Further mechanistic and pharmacokitenic studies of 1i
are under way and will be reported in due time.

808
D. Potin et al. / Bioorg. Med. Chem. Lett. 10 (2000) 805±809
Table 1.
Compd.
R
R1
R2
R5
n
Mp (ꢀC)
Synthetic methods
PBQ writhinga
Hot platea
Morphine
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
1x
1y
1z
1.5
0.3
0.8
0.7
28.9
1.2
9.9
3.1
12.7
41%
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
iPr
H
H
H
H
H
H
Me
Me
Me
Me
4-Cl-Ph
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Br
F
CF3
Cl
Cl
H
Cl
I
OH
OMe
Me
iPr
F
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
2
2
251±252b
198±199
207±208
201
298±301b
230±231
121±122
143±144
136±137
136±137
183±184
153
134
110
158±159
78±79
83±84
65±66
75±77c
123
158±160c
137±140
132
134±135
170±172
204±207
160±161
155±156
129±130
147±149
221±222
220±225
225±227
B, C
A, C
A, C
A, C
A, C
A, C
A, C
B, C
B, C
5.9
19.4
26%
27%
26%
4
54.2
9%
24.9
25%
48%
35.6
3.9
H
4-Cl-Bn
H
H
H
H
H
H
H
H
Me
Me
nBu
H
H
H
H
H
H
Me
H
16.9
B, C
B, C, F
B, C
B, C
B, C
A, C
B, C, D
B, C, D
B, C, D
B, C
B, C
B, C
Cl
9.3
8.6
Br
Br
Cl
Cl
Cl
Cl
Cl
Br
COOH
Br
Cl
Br
Cl
Br
Cl
Cl
Cl
5.4
21%
42%
38%
9.7
8.9
1.4
33.3
Bn
32%
14%
2.3
CH2CH2Ph
OMe
OMe
OMe
CHO
Ac
B, C
B, C
B, C
1.6
3.2
B, C, D, E
B, C, G
B, C, H
B, C, H
B, C, H
B, C, H
B, C, I
B, C, J
B, C, J
25%
31%
2.9
2.9
8.9
6.3
44%
5.4
1aa
1ab
1ac
1ad
1ae
1af
1ag
H
H
H
H
H
H
H
3.8
2.8
22.7
27.3
Ac
COC3H7
CO2Et
Me
Me
H
16
8.4
12.5
aED50 (mg/kg) or inh% at 30 mg/kg.
bHCl salt.
cHCl salt, 0.5 H2O.
Figure 1. Serotonin binding pro®le of 1i.
References and Notes
2. (a) Vanegas, G.; Ripamonti, C.; Sbanotto, A.; De Conno,
F. Cancer Nurs. 1998, 21, 289. (b) Eco€ey, C. Cah. Anesthe-
siol. 1991, 39, 115. Walsh, T. D. J. Pain Symptom. Manage.
1990, 5, 362.
1. Hayes, S. R.; Vogelsang, J. J. Post. Anesth. Nurs. 1991, 6,
125.

D. Potin et al. / Bioorg. Med. Chem. Lett. 10 (2000) 805±809
809
3. For a recent review of approaches to pain therapy: Wil-
liams, M.; Kowaluk, E. A.; Arneric, S. P. J. Med. Chem. 1999,
42, 1481.
4. Serotonin and Pain: Proceedings of the International Sympo-
sium on Serotonin and Pain, La Roque-Gageac, 17±21 September
1989; Besson, J.-M., Ed.; Excerpta Medica: Amsterdam, New
York, Oxford, 1990; pp 1±339.
12. Engel, J.; Bork, A.; Nubert, I.; Schonenberger, H. Arch.
Pharm. (Weinheim) 1988, 321, 821.
13. It is not necessary to protect the piperidine nitrogen atom
from oxydation since this amine is protonated under the reac-
tion conditions (pH around 4±5).
14. Siegmund, E.; Cadmus, R.; Lu, G. A. Proc. Soc. Exp. Biol.
Med. 1957, 95, 729.
5. Hibert, M. F.; Gittos, M. W.; Middlemiss, D. N.; Mir, A.
K.; Fozard, J. R. J. Med. Chem. 1988, 31, 1087.
6. Guillaume, J.; Dumont, C.; Laurent, J.; Nedelec, L. Eur. J.
Med. Chem. 1987, 22, 33.
7. Mignani, S.; Damour, D.; Doble, A.; Labaudiniere, R.;
Malleron, J. L.; Piot, O.; Gueremy, C. Bioorg. Med. Chem.
Lett. 1993, 3, 1913.
15. Eddy, N. B.; Toucheberry, C. F.; Lieberman, J. E. J.
Pharmacol. Exp. Ther. 1950, 98, 121.
16. In tolerance studies 1i exhibited serotonin-related side
e€ects (¯at body posture, tremors, forepaw treadings) at doses
approximately 25 times the active dose in both mice and rats.
17. Hertz, F.; Ranson, M.; Lwo€, J. M. Arzneim. Forsch.
1980, 30, 1549.
8. Bomhof, M.; Enahoro, H.; Winter, P.; Hassani, H. Cepha-
lalgia 1997, 17, 424.
9. Perregaard, J.; Arnt, J.; Bùgesù, K. P.; Hyttel, J.; Sanchez,
C. J. Med. Chem. 1992, 35, 1092.
18. Ha€ner, F. Dtsch. Med. Wochenschr. 1929, 55, 731.
19. Pearson, C. M.; Wood, F. D. Arthritis Rheum. 1959, 2,
440.
20. Receptor binding pro®le performed at Cerep [5-HT1A
,
10. Major, R. T.; Dursch, F. J. Org. Chem. 1961, 26, 1867.
11. Barrera, H.; Lyle, R. E. J. Org. Chem. 1962, 27, 641.
5-HT1B, 5-HT2A, 5-HT uptake (rat); 5-HT1D (bovine); 5-HT2C
(pig); 5-HT3 (mouse); 5-HT4 (guinea pig)].