1,3-Dihydro-2,1,3-benzothiadiazol-2,2-diones and 3,4-dihydro-1H-2,1,3- benzothidiazin-2,2-diones as ligands for the NOP receptor

Article abstract of DOI:10.1016/j.bmcl.2004.08.001

A series of 1,3-dihydro-2,1,3-benzothiadiazol-2,2-diones (I) and 3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones (II) were prepared. While the five-member ring series (I) did not show good affinity for opioid receptors, the six-member ring series (II) exhi

Full text of DOI:10.1016/j.bmcl.2004.08.001

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5045–5050
1,3-Dihydro-2,1,3-benzothiadiazol-2,2-diones and
3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones as ligands for the
NOP receptor
R. Richard Goehring,* John F. W. Whitehead, K. Brown, Khondaker Islam, Xin Wen,
Xiaoming Zhou, Zhengming Chen, Kenneth J. Valenzano, Wendy S. Miller,
Shen Shan and Donald J. Kyle
Discovery Research, Purdue Pharma LP, 6 Cedar Brook Drive, Cranbury, NJ 08512, USA
Received 15 July 2004; accepted 2 August 2004
Available online 1 September 2004
Abstract—A series of 1,3-dihydro-2,1,3-benzothiadiazol-2,2-diones (I) and 3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones (II) were
prepared. While the five-member ring series (I) did not show good affinity for opioid receptors, the six-member ring series (II) exhib-
ited extremely high affinity and selectivity for the NOP receptor and showed full agonist activity, as determined by stimulation of
GTPc[35S] binding.
Ó 2004 Elsevier Ltd. All rights reserved.
1.Introduction
formed in rats, icv administration of N/OFQ partially
inhibits serotonin and dopamine release in the nucleus
accumbens, suggesting an involvement in reward/abuse
behavior.6
In 1994, several research groups identified a new opioid
receptor to join the three already well-known MOP,
KOP and DOP (formerly mu, kappa and delta) recep-
tors.1,2 The following year the endogenous, peptide lig-
and N/OFQ (nociceptin/orphanin FQ) was paired with
it.3 Although this new NOP receptor (previously named
ORL-1) is a member of the G-protein coupled receptor
superfamily with ca. 47% identity to the classical opioid
receptors, typical opioid ligands (small molecule or pep-
tide) do not bind to the NOP receptor with appreciable
affinity. In addition, N/OFQ itself has little affinity for
the other opioid receptors.
Given the potential usefulness of the NOP receptor and
the inherent problems in working with peptide ligands
(e.g. lack of permeability, metabolic instability), it is not
surprising that reports of small molecule NOP receptor
ligands have appeared in the literature (Fig. 1). Structural
types showing either agonist (1,7 2,8 and 59) or antagonist
(3,10 4,11 6,12 and 713) activity at the NOP receptor, or
both (814 and 915), have been reported. Recently, several
structural requirements associated with agonist and/or
antagonist function have been proposed.15
NOP receptors have been identified both centrally and
peripherally in several mammalian species, including
humans.4 They have been implicated in a number of bio-
logical processes including pain and analgesia, learning
and memory, motor performance, feeding, cough, cardio-
vascular function and anxiety.5 In rodents N/OFQ has
been shown to block conditioned place preference to
morphine, while not producing any place preference
on its own. Moreover, in microdialysis experiments per-
As part of a program targeting small molecules as
potential new therapeutic agents for the treatment of
pain, we have identified several structures showing activ-
ity at the NOP receptor. In this paper we wish to report
the synthesis and biological activity for two of these
structural types.
2.Design of NOP receptor ligands
*
In planning potential ligands for the NOP receptor,
examination of known ligands led us to a working
Corresponding author. Tel.: +1 609 409 5128; fax: +1 609 409
6930; e-mail: richard.goehring@pharma.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.08.001

5046
R. R. Goehring et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5045–5050
R
N
2,1,3-benzothiadiazol-2,2-diones (I) and 3,4-dihydro-
1H-2,1,3-benzothiadiazin-2,2-diones (II) were prepared.
R
N
b
R
b
H
b
H
H
N
a
R
b
N
O
O
N
O
N
N
N
H
R
c
N
R
3.Synthesis and screening of NOP receptor ligands
N
N
R
N
R
R
a
1
a
a
Ourapproachtothesynthesisof1,3-dihydro-2,1,3-benzo-
thiadiazol-2,2-diones and 3,4-dihydro-1H-2,1,3-benzo-
thiadiazin-2,2-diones as ligands for the NOP receptor
involved synthesis of the two head groups 13 and 18
(Schemes 1 and 2, respectively),20 followed by attach-
ment of a series of lipophilic tail groups (Scheme 3).
2
3
4
H
R
b
NH
N
2
H
N
R
b
N
NH
2
O
O
R
a
R
R
a
a
6
5
Reductive amination of ketone 10 with 1,2-phenylene-
diamine gave 11 in 53% yield. As in our previous
work,11 we attribute the relatively low yield of the
desired product to further reaction of 11 with a second
equivalent of ketone 10 to give a dialkylated product.
Cyclization of 11 to the 1,3-dihydro-2,1,3-benzothia-
diazol-2,2-dione ring system, 12, was effected in good
yield by refluxing with sulfamide in pyridine. Cleavage
of the Boc protecting group under acidic conditions
furnished the head group 13. The synthesis of the 3,4-
dihydro-1H-2,1,3-benzothiadiazin-2,2-dione head group
18 followed a similar approach. Reductive amination of
ketone 14 with anthranilamide gave the diamine 15.
Reduction of the amide functionality in 15 to the pri-
mary amine with lithium aluminum hydride, followed
by cyclization with sulfamide as in the five-member ring
series gave the 3,4-dihydro-1H-2,1,3-benzothiadiazin-
2,2-dione 17. Removal of the benzyl protecting group
via standard hydrogenolysis conditions gave the head
group 18.
O
R
R
b
N
N
b
R
N
R
c
c
R
a
N
R
a
R
a
7
8
9
Figure 1. Structures of representative NOP receptor ligands.
R
N
2
R
2
N
SO
SO
2
2
N
N
hydrogen bond
acceptor
lipophilic
groups
N
N
N
R
1
R
1
I
II
Figure 2. Working model leading to 1,3-dihydro-2,1,3-benzothiadia-
zol-2,2-diones (I) and 3,4-dihydro-1H-2,1,3-benzothiadiazin-2,2-
diones (II).
With the two head groups in hand, attachment of tail
groups was accomplished by either alkylation with an
alkyl halide (R1 = a–d) or reductive amination with an
appropriate ketone (R1 = e–k).21 The choice of tail
groups was based on previous work by ourselves and
others.7–15 In the case of tail groups g–j, the products
obtained were diastereomeric mixtures and were
screened as such. In only one case (20h) were the diaste-
reomers separated and screened independently (vide
infra).
model consisting of a basic nitrogen at one end of the
molecule, to which is attached a lipophilic tail group
(Fig. 2). At the other end of the molecule there appears
to be the requirement for a second lipophilic portion
(not necessarily aromatic, e.g. 4). In addition, at this
end of the molecule there also appears to be the prefer-
ence for a hydrogen bond acceptor.16–18 We chose to
investigate the use of an SO2 group as a hydrogen bond
acceptor. The incorporation of an SO2 group has the
potential to influence metabolic stability, bioavailability
and permeability, as well as binding and functional
activity.19 Based upon this, a series of 1,3-dihydro-
Compounds were screened for binding affinity at the hu-
man NOP receptor using [3H]-nociceptin concentration–
inhibition binding assays. In addition, compounds were
screened for binding affinity at the human MOP, KOP
H
N
H
N
NH
O
2
SO
SO
2
2
N
N
a
b
c
NH
N
Boc
N
Boc
N
H
N
Boc
10
13
12
11
Scheme 1. Synthesis of head group 13. Reagents and conditions: (a) 1,2-phenylenediamine, NaBH(OAc)3, HOAc, DCE (53%); (b) NH2SO2NH2,
pyridine, reflux (79%); (c) HCl, EtOAc (91%).

R. R. Goehring et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5045–5050
5047
O
O
NH
NH
SO
NH
SO
2
NH
2
2
2
a
b
c
d
NH
N
N
NH
N
Bn
N
Bn
N
Bn
N
H
18
N
Bn
14
16
17
15
Scheme 2. Synthesis of head group 18. Reagents and conditions: (a) anthranilamide, NaBH(OAc)3, HOAc, DCE (58%); (b) LiAlH4, dioxane, reflux
(71%); (c) NH2SO2NH2, pyridine, reflux (67%); (d) H2, 10% Pd/C, MeOH, H2O (89%).
H
H
N
N
SO
2
SO
2
N
N
R1 =
O
c
b
a
N
N
H
13
R
1
a or b
19
e
NH
SO
g
f
d
h
NH
SO
2
N
2
N
j
N
R
i
k
N
H
1
18
20
Scheme 3. Attachment of R1 tail groups to head groups 13 and 18. Reagents and conditions: (a) alkyl halide, Et3N, DMF, 80°C; (b) ketone,
NaBH3CN, HOAc, MeOH.
and DOP receptors in similar radioligand binding assays
that utilized [3H]-diprenorphine, [3H]-U69,593 and [3H]-
naltrindole, respectively. Functional activities at both
the NOP and MOP receptors were determined using
GTPc[35S] binding assays. The activities of N/OFQ
and DAMGO were used for normalization of functional
GTPc[35S] binding data generated for the NOP and
MOP receptors, respectively (maximal effect (Emax) elic-
ited by 60nM N/OFQ or 10lM DAMGO = 100%;
background binding in the absence of agonist = 0%).
Because of our interest in identifying NOP receptor lig-
ands, only those compounds that showed binding affin-
ities (Ki values) at the NOP receptor of 61lM were
evaluated at the other three receptors. All compounds
that were screened at the KOP and DOP receptors
showed poor binding affinity (Ki > 2lM). Additional
details of the in vitro assays employed have been de-
scribed in previous papers from our labs.11,22
Compound 19g shows 24-fold selectivity for the NOP
receptor over the MOP receptor, whereas 19h showed
only 2-fold selectivity. This class of compounds as a
whole, however, did not show enough activity to war-
rant further investigation.
The
3,4-dihydro-1H-2,1,3-benzothiadiazin-2,2-dione
series (20) showed greater promise. While some com-
pounds containing aromatic tail groups showed poor
affinity for the NOP receptor (20b,c and 20f), others
were much better, with 20d and 20e showing excellent
potency and agonist activity. As we have noted in other
series, the 3,3-diphenylpropyl tail group as in 20d im-
parts greater selectivity for the MOP receptor (6-fold).
It is interesting that 20e with its 2-indanyl tail group is
57-fold more potent than the related 2-tetralin analog
20f. Introduction of aliphatic tail groups provided us
with compounds that demonstrated some interesting
SAR. Compound 20g with its fully reduced decalin tail
group is 91-fold more potent at the NOP receptor than
20f. The highly flexible tail group in 20j shows excellent
potency, although the selectivity over the MOP receptor
is somewhat reduced compared to other tail groups in
this series. Finally, relocating a single methyl group in
going from 20i to 20h improves potency 38-fold. In addi-
tion, 20h is 34-fold selective for the NOP receptor,
whereas 20i is essentially equipotent at NOP and MOP
In the case of the 1,3-dihydro-2,1,3-benzothiadiazol-2,2-
dione series (19), despite the variety of lipophilic tail
groups only two compounds showed sub-micromolar
activity at the NOP receptor (Table 1). Compound 19g
contains a decalin ring system as a tail group, whereas
19h contains a 4-isopropylcyclohexyl tail group. Both
of these tail groups have been shown in previous studies
to impart good NOP receptor potency and selectivity.

5048
R. R. Goehring et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5045–5050
Table 1. Binding and functional data for 19 and 20 at NOP and MOP receptors
H
N
NH
SO
SO
2
2
N
N
N
R
N
R
1
1
19
20
Compds
NOP
MOP
Ki (nM)a
GTPc[35S] EC50 (nM)
GTPc[35S] Emax (%)
Ki (nM)a
GTPc[35S] EC50 (nM)
GTPc[35S] Emax(%)
N/OFQ
DAMGO
19a
0.18 0.04
Nd
>10,000
0.09 0.06
Nd
Nd
98 0.6
Nd
Nd
Ndb
Nd
Nd
95 0.4
Nd
Nd
Nd
Nd
Nd
Nd
Pa
36.7 18.6
Nd
Nd
202 52
Nd
Nd
19b
19c
>10,000
Nd
Nd
Nd
Nd
7114 913
4461 1722
5670 1294
3454 441
225 117
357 58
Nd
Nd
Nd
Nd
19d
19e
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Pac
19f
19g
Nd
Nd
66 11
3363 551
3067 838
Nd
5545 1414
748 122
Nd
19h
19i
78
9
Pa
Nd
Pa
5102 1065
3592 686
2297 567
609 81
Nd
Nd
Nd
Nd
Nd
Nd
19j
19k
Nd
Nd
Nd
Nd
Nd
Nd
20a
20b
5589 2116
Nd
Nd
83 12
Nd
Nd
294 39
Nd
Nd
> 10,000
Nd
Nd
66
6
5
9535 2699
1878 638
Nd
Nd
81
20c
20d
83 6
46 13
1651 459
496 71
Nd
99
98
1
2
13
3
801 116
ANTd
Nd
20e
20f
660 110
Nd
ANT
Nd
2614 586
28.7 8.3
6.1 1.7
231 33
Nd
20g
20h
160 44.6
38 11
1609 1102
1581 228
2009 310
94 7.8
92
96 5.3
91.7 17.2
207 36
188 20
73 20
1475 178
Pa
14 3.4
Pa
7
20i
20j
3138 406
3162 292
ANT
620 115
799 122
26
59
2
1
40
8
84
79
99
93
2
5
1
7
20k
20h cis
20h trans
187 14
2.6 0.2
3.7 0.6
1376 543
89 28
112 37
ANT
12
14
2
1
16
16
4
3
a Values are the mean of at least three experiments.
b Nd = not determined.
c Pa = partial agonist.23
d ANT = antagonist.24
receptors. Chromatographic separation of 20h into its
cis- and trans-isomers did not show any significant dif-
ference in potency or selectivity between the two iso-
mers. This is in contrast to the results seen for this tail
group in other NOP small molecule series (e.g. 1, 2
and 9).
selectivity (23- and 21-fold, respectively). In the case of
25, the compound is essentially equipotent at both
NOP and MOP receptors.
Finally, as a measure of metabolic stability, compounds
were incubated with rat liver microsomes for 30min fol-
lowed by HPLC analysis to determine the percentage of
compound remaining. Compounds in the five-member
ring series showed good metabolic stability (50–90%)
while compounds in the six-member ring series surpris-
ingly showed very poor metabolic stability (0–23%),
with 20h having 0% remaining after 30min.
With compound 20h showing good affinity and agonist
potency for the NOP receptor, as well as good selectivity
over the MOP receptor, we wished to determine what
would be the effect of introduction of an additional
substituent (R2) on the six-member ring head group.
Such compounds were prepared in a straightforward
manner by simple alkylation of 20h (Scheme 4). Screen-
ing of these compounds showed good affinity for the
NOP receptor (Table 2). However, most of the R2
substituents lowered the selectivity of the compounds
for the NOP receptor versus the MOP receptor. Com-
pounds 24 and 27, however, still showed respectable
4.Conclusion
In summary, based on a working model we have pre-
pared a series of 1,3-dihydro-2,1,3-benzothiadiazol-2,2-

R. R. Goehring et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5045–5050
Table 2. Binding and functional data for 21–27 at NOP and MOP receptors
5049
R
2
N
CN
21
22
R
R
=
=
25
26
R
R
=
=
2
2
2
2
2
SO
2
N
N
O
O
O
OH
SO Me
OMe
27
R
=
23
24
R
R
=
=
2
2
2
N
O-t-Bu
H
NH
2
Compds
NOP
MOP
Ki (nM)a
GTPc[35S] EC50 (nM)
GTPc[35S]Emax (%)
Ki (nM)a
GTPc[35S] EC50 (nM)
GTPc[35S]Emax (%)
N/OFQ
DAMGO
0.18 0.04
Nd
0.09 0.06
Nd
98 0.6
Nd
Ndb
36.7 18.6
Nd
Nd
95 0.4
202 52
>10,000
Pac
21
22
23
24
25
26
27
18
41 21
63
7
78 12
166 30
484 125
94
92
61
97
98
95
98
1
3
4
4
1
3
1
38
9
14
Pa
Pa
14
4
182 24
289 95
92 15
1
Pa
3.9 1.7
33 11
7.4 2.1
22
227 19
33
34 19
5
555 141
344 95
Pa
4
25
86 23
4
19 0.1
Pa
Pa
6
5
2
106 26
Pa
a Values are the mean of at least three experiments.
b Nd = not determined.
c Pa = partial agonist.23
Acknowledgements
R
2
NH
N
SO
SO
2
2
N
N
We thank Ms. Elizabeth Dharmgrongartama for LC/
MS assistance.
N
N
a
References and notes
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21 - 27
Scheme 4. Attachment of R2 groups to 20h. Reagents and conditions:
(a) NaH, alkyl halide, DMF.
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