Design, synthesis, and structure-activity relationships of novel non- imidazole histamine H3 receptor antagonists

Article abstract of DOI:10.1021/jm990952j

Novel, potent, and selective non-imidazole histamine H₃ receptor antagonists have been prepared based on the low-affinity ligand dimaprit (pK(I) 7.32 ± 0.12, pK(B) 5.93 ± 0.17). Detailed structure-activity studies have revealed that N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine (pK(I) 8.38 ± 0.21, pK(B) 8.39 ± 0.13), 30, and N-(4-chlorobenzyl)-N-(7- pyrrolidin-1-ylheptyl)guanidine (pK(I) 8.78 ± 0.12, pK(B) 8.38 ± 0.10), 31, exhibit high affinity for the histamine H₃ receptor. Antagonists 30 and 31 demonstrate significant selectivity over the other histamine, H₁ and H₂, receptor subtypes and a 100-fold selectivity in the σ₁ binding assay. Compounds 30 and 31 are the most potent, selective non-imidazole histamine H₃ receptor antagonists reported in the literature to date.

Full text of DOI:10.1021/jm990952j

2362
J . Med. Chem. 2000, 43, 2362-2370
Design , Syn th esis, a n d Str u ctu r e-Activity Rela tion sh ip s of Novel
Non -Im id a zole Hista m in e H3 Recep tor An ta gon ists
Ian D. Linney,* Ildiko M. Buck, Elaine A. Harper, S. Barret Kalindjian, Michael J . Pether, Nigel P. Shankley,
Gillian F. Watt, and Paul T. Wright
The J ames Black Foundation, 68 Half Moon Lane, Dulwich, London SE24 9J E, U.K.
Received November 10, 1999
Novel, potent, and selective non-imidazole histamine H3 receptor antagonists have been
prepared based on the low-affinity ligand dimaprit (pKI 7.32 ( 0.12, pKB 5.93 ( 0.17). Detailed
structure-activity studies have revealed that N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)-
guanidine (pKI 8.38 ( 0.21, pKB 8.39 ( 0.13), 30, and N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-
ylheptyl)guanidine (pKI 8.78 ( 0.12, pKB 8.38 ( 0.10), 31, exhibit high affinity for the histamine
H3 receptor. Antagonists 30 and 31 demonstrate significant selectivity over the other histamine,
H1 and H2, receptor subtypes and a 100-fold selectivity in the σ1 binding assay. Compounds 30
and 31 are the most potent, selective non-imidazole histamine H3 receptor antagonists reported
in the literature to date.
Ch a r t 1. Non-Imidazole Histamine H3 Receptor
Antagonists
In tr od u ction
The blockade of the monoamine autacoid and neu-
rotransmitter, histamine, acting through its receptor
has been of great therapeutic utility throughout the
latter half of the twentieth century. The commercially
available ‘anti-histamine’ drug molecules act through
the histamine H1 and H2 receptor subtypes. The dis-
covery of a third receptor subtype, designated H3,1 has
renewed interest in the field of histamine research, with
the cloning of a human histamine H3 receptor recently
reported.2 Considerable advances have been achieved
in the medicinal chemical3 understanding of histamine
H3 receptor pharmacology.4 The therapeutic utility,
however, of selective histamine H3 receptor antagonists
has yet to be defined.5
The majority of the previously described potent
histamine H3 receptor ligands consist of a 4(5)-substi-
tuted imidazole separated from a lipophilic moiety by a
suitable chain, which may or may not be interrupted
by a polar linkage.2 This lack of structural diversity has
led to a congested field in the search for novel ligands,
and the need for non-imidazole histamine H3 ligands
has been recognized by many groups.6-10 In addition,
the lack of an imidazole group may confer potentially
advantageous pharmacokinetic and metabolic in vivo
properties to such an antagonist.11
described ligand with only a limited reduction in activ-
ity, has been reported.10 A systematic structure-activity
survey resulted in the discovery of UCL 1972, a potent,
non-imidazole, histamine H3 receptor antagonist (Chart
1).10
In light of this preceding work we wish to report our
findings in this area of non-imidazole H3 receptor
antagonists.15 The starting point for our investigation
was the recognition that dimaprit,16 a histamine H2
partial agonist, acts as a ligand at the histamine H3
receptor (Chart 1).4 The replacement of the potentially
toxic isothiourea moiety with a similarly polar linkage,
alterations to the dimethylamino unit, and spatial
variations of dimaprit were undertaken. This synthetic
approach and the subsequent in vitro histamine H3
receptor activity of these dimaprit-derived ligands are
now presented.
Early attempts to replace the imidazole moiety in
existing H3 receptor ligands with other nitrogen-
containing hetereocycles have met with limited
success.6-8 The reexamination of previously derived
drug entities led to the discovery of a variety of weakly
active non-imidazole H3 receptor ligands such as cloza-
pine,12 phencyclidine,13 and sabeluzole.9,14 The utiliza-
tion of one such low-affinity ligand, sabeluzole, as a
potential lead led to the discovery of the active ben-
zothiazole 1 (Chart 1).9 An alternative approach, in
which the imidazole was removed from a previously
Ch em istr y
The sulfonamide-based ligands 2-4 were readily
prepared by combining one of the two commercially
available diamines (R ) Me and R ) -(CH2)4-) with
2-naphthalenesulfonyl chloride or 4-chlorobenzylsulfo-
nyl chloride, respectively (Scheme 1).
* To whom correspondence should be addressed. Phone: 44 (0)20
77378282. Fax: 44 (0)20 72749687. E-mail: ian.linney@kcl.ac.uk.
10.1021/jm990952j CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/20/2000

Non-Imidazole Histamine H3 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12 2363
Sch em e 1. Synthetic Pathways for Initial Ligandsa
a
(i) 2-Naphthalenesulfonyl chloride, Et3N, DCM, 20 °C, 18 h; (ii) 4-chlorobenzylsulfonyl chloride, Et3N, DCM, -78 to 20 °C, 18 h; (iii)
4-chlorophenylacetic acid, DCC, DCM, 0-20 °C, 1 h; (iv) 4-chlorobenzyl isothiocyanate, DCM, 20 °C, 18 h; (v) 4-chlorobenzylamine, sulfamide,
reflux, 2 h.
Sch em e 2. Synthetic Route for Preparation of the Initial Guanidinesa
a
(i) Sodium hydride, DMF, followed by substituted benzyl bromide, 0-20 °C, 16 h, or diethyl azodicarboxylate, substituted benzyl
alcohol, Ph3P, THF, 0-20 °C, 18 h; (ii) 10% aq THF, reflux, 1 h; (iii) HCl-1,4-dioxan, 20 °C, 18 h.
Sch em e 3. Synthesis of 16a
a
(i) Iodomethane, acetone, reflux, 1 h; (ii) ethanol, reflux, 16 h.
The amide 5 and thiourea 6 ligands were prepared
in analogous fashion with the appropriate activated acid
and isothiocyanate replacing the sulfonyl chloride. The
reaction of 1-(3-aminopropyl)pyrrolidine and 4-chlo-
robenzylamine with sulfamide in the absence of solvent
resulted in the formation of the corresponding N,N′-
sulfamide 7 (Scheme 1).17
which was formed by the reaction between 4-chlorophen-
ylthiourea and iodomethane (Scheme 3).
The extended guanidines 17-27 required a modifica-
tion to the previous synthetic route. The thiopseudourea
was treated with a ω-hydroxyalkene under Mitsunobu
conditions to generate a suitably functionalized guan-
ylating reagent III which upon treatment with an excess
of the required primary amine gave rise to the protected
N,N′-disubstituted guanidine IV. The ozonolysis of the
alkene followed by reductive amination, utilizing the
appropriate cyclic amine, furnished the fully protected
guanidine V. Acid deprotection afforded the final ligands
for pharmacological evaluation 17-27 (Scheme 4).
Utilizing a related synthetic methodology the isomeric
N,N-disubstituted guanidines were prepared. The key
step in this synthesis was the mercury(II) chloride-
promoted reaction between a suitable diamine VI and
the thiopseudourea.19 The requisite diamines were
readily prepared by the alkylation of the respective tert-
butoxycarbonylamines VII with an excess of a R,ω-
dibromide, followed by displacement of the second
bromine with the necessary cyclic amine. Acidic depro-
The preparation of the N,N′-disubstituted guanidines
8-15 required the formation of a suitably substituted
guanylating reagent I. The formation of this reagent
was achieved by one of two methods: deprotonation of
the commercially available 1,3-bis(tert-butoxycarbonyl)-
2-methyl-2-thiopseudourea with sodium hydride, fol-
lowed by alkylation with an appropriate benzyl bromide,
or Mitsunobu reaction of a suitably substituted benzyl
alcohol with the thiopseudourea, resulting in the gen-
eration of the required reagent I. The treatment of I
with an excess of 1-(3-aminopropyl)pyrrolidine in re-
fluxing aqueous THF,18 followed by acid deprotection,
furnished the initial guanidines 8-15 (Scheme 2).
Compound 16 was prepared by the reaction of 1-(3-
aminopropyl)pyrrolidine with isothiouronium salt, II,

2364 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12
Sch em e 4. Synthesis of the Extended Guanidines
Linney et al.
a
(i) HCdCH(CH2)mCH2OH, diethyl azodicarboxylate, Ph3P, THF, 0-20 °C, 16 h; (ii) R(CH2)nNH2, 10% aq THF, reflux, 24 h; (iii) ozone,
methanol, -78 °C followed by Me2S, -78 to 20 °C, 2 h; (iv) NaB(OAc)3H, pyrrolidine or piperidine, 1,2-DCE, 0-20 °C, 2 h; (v) HCl-1,4-
dioxan, 20 °C, 16 h.
Sch em e 5. Preparation of the N,N-Disubstituted Guanidinesa
a
(i) Boc2O, dioxan, 20 °C, 45 min; (ii) NaH, BrCH2(CH2)nCH2Br, DMF, 0-20 °C, 18 h; (iii) pyrrolidine, acetonitrile, 20 °C, 18 h; (iv)
HCl-1,4-dioxan, 20 °C, 1 h; (v) Hg(II)Cl2, Et3N, guanylating agent, DCM, 0-20 °C, 18 h; (vi) HCl-1,4-dioxan, 20 °C, 16 h.
tection gave the required diamine for the subsequent
mercury(II) chloride-promoted guanylation reaction.
Acid deprotection of the product from the guanylation
gave the N,N-disubstituted ligands 28-32 for in vitro
testing (Scheme 5).
between the two different guinea-pig tissues. It would
not be possible to distinguish which of these various
proposals could give rise to any interassay discrepancy
in this series using the routine assays described above.
Given the numerous possible reasons underlying any
potential interassay discrepancy, any of which may have
serious consequences in the potential drug usage of
these compounds, the major aim of the current work
was to derive a non-imidazole, selective histamine H3
receptor antagonist, which exhibited no significant
difference (∆) between the functional and radioligand
binding histamine H3 receptor assays.
P h a r m a cologica l Resu lts a n d Discu ssion
The affinities of the ligands at the histamine H3
receptor were evaluated in two different assays. The
pharmacological behavior (pKB or p[A]50) and the affinity
(pKB) of the compounds at the histamine H3 receptor
were determined in the isolated guinea-pig ileum func-
tional bioassay, in which histamine H3 receptors medi-
ate the inhibition of cholinergic neurogenic contrac-
tions.20 The apparent affinity (pKI) of the compounds
at the histamine H3 receptor was evaluated in a radio-
ligand binding assay in guinea-pig cerebral cortex
homogenates utilizing the selective histamine H3 ago-
nist [3H]-(R)-R-methylhistamine as the radioligand.21
Radioligand binding assays can provide misleading
affinity estimates if the assumptions on which they are
based are not satisfied.22 Therefore, there may be
numerous explanations for any difference between
functional pKB and radioligand binding pKI affinity
estimates. However, if the radioligand binding assay has
been established so that it satisfies the criteria upon
which the assumptions are based,22 then the number
of possible explanations for these discrepancies is
reduced. One possible remaining reason is that the
tested ligands retain varying degrees of intrinsic efficacy
which, while undetected as agonism in the functional
bioassay, can be detected as a high pKI, in the radioli-
gand binding assay. There is ample literature precedent
for this complex behavior.23 Further possibilities could
be related to the ligand pharmacologically distinguish-
ing between putative multiple histamine H3 receptor
subtypes, either in the guinea-pig cerebral cortex24,25 or
The initial replacement of the isothiourea and the
dimethylamino moieties from dimaprit for naphthlene-
sulfonamide26 and pyrrolidine,10 respectively, resulted
in 3 (Table 1). Ligand 3 exhibited comparable affinity
to dimaprit (∆ ≈ 1.4 log units) in the guinea-pig ileum
functional bioassay but a lower apparent affinity in the
radioligand binding assay (∆ for 3 ≈ 0.5 log unit). The
importance of the 4-chlorobenzyl substituent for high-
affinity histamine H3 receptor antagonists has been
established in previous studies.27 The incorporation of
this unit resulted in an improved compound, 4, which
exhibited comparable affinity in both assays. In an
attempt to increase the affinity of the series, a number
of structurally diverse linkers were examined. The polar
guanidine28 linkage 8 (∆ ≈ 0.8 log unit) exhibited the
highest affinity in both assays (Table 1).
In contrast to previously reported histamine H3
ligands, no significant sensitivity to the nature of the
aromatic substitution was observed in the ileum bioas-
say (8-14, Table 1).27 The variation in the observed pKI
was difficult to rationalize. The 4-chlorobenzyl substitu-
ent exhibited the smallest interassay difference (∆ ≈
0.8 log unit). We, therefore, investigated the effect of
increasing the length of the various chains upon affinity.
An increase in affinity was observed upon chain exten-

Non-Imidazole Histamine H3 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12 2365
Ta ble 1. In Vitro Structure-Activity Profile for the First-Generation Non-Imidazole Antagonists
compd
R
R1
X
GP cortex, pKI ( SEM (n)a
GP ileum, pKB ( SEMb
dimaprit
7.32 ( 0.12 (5)
6.00 ( 0.05 (5)
6.49 ( 0.09 (4)
6.27 ( 0.19 (5)
5.77 ( 0.07 (4)
6.39 ( 0.22 (4)
6.64 ( 0.12 (4)
7.25 ( 0.28 (4)
7.70 ( 0.16 (5)
8.33 ( 0.09 (4)
7.59 ( 0.10 (5)
7.37 ( 0.10 (4)
7.27 ( 0.09 (4)
7.00 ( 0.09 (4)
7.08 ( 0.07 (4)
5.93 ( 0.17
5.52 ( 0.14
5.96 ( 0.06
6.24 ( 0.14
NTc
5.66 ( 0.21
6.21 ( 0.14
6.42 ( 0.17
6.20 ( 0.13
6.45 ( 0.20
6.46 ( 0.24
6.27 ( 0.11
6.43 ( 0.20
6.10 ( 0.09
6.08 ( 0.10
2
Me
2-naphthyl
SO2
SO2
SO2
CdO
3
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
2-naphthyl
4
4-chlorobenzyl
4-chlorobenzyl
4-chlorobenzyl
4-chlorobenzyl
4-chlorobenzyl
benzyl
4-bromobenzyl
3-bromobenzyl
2-bromobenzyl
4-iodobenzyl
5
6
(CdS)NH
7
SO2NH
8d
9d
10d
11d
12d
13d
14d
15d
(CdNH)NH
(CdNH)NH
(CdNH)NH
(CdNH)NH
(CdNH)NH
(CdNH)NH
(CdNH)NH
(CdNH)NH
4-trifluoromethylbenzyl
4-methoxybenzyl
a
pKI ( SEM values were estimated from n separate competition experiments in which [3H]-(R)-R-methylhistamine was used to label
b
histamine H3 binding sites in guinea-pig (GP) cerebral cortex homogenates. pKB ( SEM values were estimated from single shifts of
(R)-R-methylhistamine concentration-effect curves in the isolated, electrically stimulated, guinea-pig (GP) ileum assay, in at least four
separate tisssues, in which the compounds behaved as surmountable antagonists. c NT ) not tested. Tested as the dihydrochloride salt.
d
Ta ble 2. Modifications to 8a
histamine H3
σ1
compdb
R
l
m
n
GP cortex, pKI ( SEM (n)
GP ileum, pKB ( SEM
GP cortex,c pKI ( SEM (n)
8
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
4-chlorophenyl
cyclohexyl
1
1
1
1
1
1
1
1
1
1
2
3
4
1
1
2
3
1
2
3
3
3
3
3
3
3
1
0
1
1
2
2
2
1
1
1
1
1
1
7.25 ( 0.28 (4)
7.27 ( 0.12 (5)
8.29 ( 0.13 (5)
8.27 ( 0.07 (4)
9.03 ( 0.17 (4)
8.17 ( 0.07 (4)
8.12 ( 0.08 (4)
8.85 ( 0.05 (4)
8.45 ( 0.05 (5)
8.45 ( 0.14 (4)
7.97 ( 0.18 (5)
8.10 ( 0.14 (5)
7.52 ( 0.11 (4)
6.42 ( 0.17
6.03 ( 0.11
7.32 ( 0.19
7.30 ( 0.11
6.68 ( 0.14
6.24 ( 0.12
7.06 ( 0.06
7.52 ( 0.28
7.67 ( 0.18
7.90 ( 0.09
8.14 ( 0.14
7.84 ( 0.16
7.37 ( 0.23
6.1
16
17
18
19
20
21
22
23
24
25
26
27
NT
6.63 ( 0.07 (3)
7.05 ( 0.03 (3)
7.15 ( 0.04 (3)
6.47 ( 0.09 (3)
7.21 ( 0.05 (3)
8.30 ( 0.11 (3)
8.24 ( 0.11 (3)
8.19 ( 0.17 (4)
8.11 ( 0.03 (3)
8.17 ( 0.02 (3)
8.02 ( 0.06 (3)
cycloheptyl
1-adamantyl
1-adamantyl
1-adamantyl
1-adamantyl
a
b
For explanation of terms in the table, see footnotes to Table 1. All compounds were tested as their dihydrochloride salts. c pKI (
SEM values were estimated from n separate competition experiments in which [3H]-(+)-pentazocine was used to label σ1 binding sites in
guinea pig (GP) cerebral cortex homogenates.
Ta ble 3. In Vitro Receptor Results for the N,N-Disubstituted
chain length between the aromatic ring and the guani-
dine (8, 16, 19-21), although 19 exhibited particularly
Guanidinesa
high affinity in the radioligand binding assay (∆ ≈ 2.3
log units). As previously described, 19 could potentially
either be imbued with high residual efficacy, still
undetected in the ileum functional bioassay, or be
particularly able to distinguish between possible recep-
tor subtypes either within or between tissues.
histamine H3
σ1
GP cortex
GP ileum
GP cortexc
pKI ( SEM (n)
compdb
m
pKI ( SEM (n)
pKB ( SEM
28
29
30
31
32
1
2
3
4
5
8.10 ( 0.15 (5)
8.97 ( 0.10 (4)
8.38 ( 0.21 (4)
8.70 ( 0.12 (3)
8.33 ( 0.08 (4)
7.34 ( 0.12
7.91 ( 0.05
8.39 ( 0.13
8.38 ( 0.10
8.09 ( 0.08
6.12 ( 0.07 (3)
6.54 ( 0.04 (3)
6.29 ( 0.24 (4)
6.59 ( 0.03 (3)
6.34 ( 0.24 (3)
In an attempt to reduce the interassay difference,
aliphatic lipophilic units were introduced resulting in
compounds 22-24. Of these compounds the change to
the more sterically demanding adamantyl moiety,29 24,
resulted in a modest increase in affinity in the ileum
bioassay, with respect to 18, and a concomitant reduc-
tion in the interassay variance (∆ ≈ 0.6 log unit).
a
For explanation of terms in the table, see footnotes to Table
1. b All compounds were tested as their dihydrochloride salts. c See
footnote to Table 2.
In a bid to increase the affinity at the histamine H3
receptor, an increase in the size of the cyclic amine
moiety from a five- to a six-membered ring resulted in
25. Although this alteration gave no significant increase
in affinity, a reduction in the interassay variance to a
nonsignificant level (∆ ≈ 0.2 log unit) was observed.
Further expansion in the ring size resulted in some loss
sion between the pyrrolidine and guanidine moieties
from propyl 8 to butyl 17 (Tables 1 and 2). No additional
increase in affinity was observed upon further chain
extension, nor was there a reduction in the interassay
difference (∆ ≈ 1.0 log unit). Furthermore, there was
no substantial increase in the pKB value obtained on
the functional ileum bioassay with variations in the

2366 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12
Linney et al.
of affinity for the H3 receptor, but interestingly the low
interassay variance was maintained.
Antagonists 30 and 31, when assayed against the σ1
binding site (pKI 6.29 ( 0.24 and 6.59 ( 0.03, respec-
tively), histamine H1 receptor33 (pKB 5.41 ( 0.17 and
5.46 ( 0.16, respectively), and histamine H2 receptor34
(inactive at 1 × 10-6 M and pKB 5.26 ( 0.10, respec-
tively) showed excellent selectivity for the histamine H3
receptor.
Early receptor selectivity screening had shown that
8 expressed an affinity for the σ1 binding site (pKI 6.1),
as labeled by [3H]-(+)-pentazocine in guinea-pig cerebral
cortex homogenates.30 Prompted by this finding all the
compounds of this series were routinely assessed in a
σ1 radioligand binding assay. The aliphatic lipophilic
substituted guanidines universally exhibited affinities
in the nanomolar range at this particular site (Table
2). In contrast the corresponding 4-chlorobenzyl-substi-
tuted guanidines displayed significantly lower affinity
for this σ1 binding site.
Con clu sion s
The systematic modification of the low-affinity H3
receptor ligand dimaprit (pKI 7.32 ( 0.12, pKB 5.93 (
0.17) has resulted in the identification of N-(4-chlo-
robenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine, 30, and
N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-ylheptyl)guani-
dine (log PpH7.4 octanol/Krebs buffer -0.21), 31, as
potent, competitive, non-imidazole H3 receptor antago-
nists. These antagonists exhibit excellent selectivity
over the other histamine receptor subtypes and over the
σ1 binding site.
The aim of a negligible interassay difference, with
respect to the histamine H3 receptor assays, had been
achieved. However, the lack of selectivity of 25 over the
σ1 binding site caused attention to refocus upon the
4-chlorobenzyl-substituted guanidines. These com-
pounds exhibited interassay variance, which could, as
previously described, be attributed to either receptor
heterogeneity or functionally undetected residual ef-
ficacy. It was, therefore, necessary that this property
be eliminated. With regard to one of these possibilities,
that the interassay variance was caused by residual
efficacy, we speculated that the guanidine functional
group bound to the site on the histamine H3 receptor
normally occupied by the imidazole moiety in the parent
hormone. A possible mechanism for receptor activation
at the histamine H3 receptor lies in the ability of the
imidazole group in agonists to tautomerize, hence
facilitating a proton transfer from one residue in the
receptor to another, thus triggering a response. It was
postulated that the ability of the guanidine to tautomer-
ize could fulfill this role, allowing some of these non-
imidazole ligands to possess a degree of undetected
residual efficacy. Previous work had suggested that any
perturbation in the ability of the imidazole to tautomer-
ize had a beneficial reduction in efficacy while main-
taining receptor affinity.31 Therefore, in this new series
it was proposed that any disruption to the ability of the
guanidine to tautomerize might result in a reduction
in potential receptor activation. Thus, if the interassay
difference was due to residual efficacy, a reduction in
the interassay difference might be observed.
In an attempt to influence the nature of tautomer-
ization of the guanidine, attention was turned toward
the isomeric N,N-disubstituted guanidines. These iso-
meric guanidine ligands would be expected to experience
potentially different inter- and intramolecular hydrogen-
bonding interactions, raising the possibility of a change
in the tautomeric nature of the guanidine moiety with
respect to the initial N,N′-disubstituted compounds, as
exemplified by 25.
The initial compound prepared, 28, exhibited a simi-
lar in vitro profile to the corresponding N,N′-disubsti-
tuted guanidine 17. Further homologation, resulting in
compounds 30-32, gave rise to ligands with increased
affinity at the histamine H3 receptor, combined with an
insignificant interassay variance.
Exp er im en ta l Section
All reagents were obtained from commercial suppliers and
were used without further purification. Solvents used were of
either AR or HPLC grade. Thin-layer chromatography was
carried out on Merck Kieselgel 60 F254 glass-backed plates.
Preparative flash column chromatography was performed on
Merck Kieselgel 60 (particle size 0.063-0.040) under pressure.
1H NMR spectra were recorded on a Bruker DRX-300 MHz
spectrometer. Chemical shifts are reported in ppm (δ) relative
to the solvent peak (CHCl3 in CDCl3 at 7.26 ppm and DMSO
in DMSO-d6 at 2.54). Signals are designated as follows: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
All J values are given in hertz (Hz). Elemental analyses were
performed at the London School of Pharmacy. All reactions
were carried out under a positive pressure of argon unless
otherwise stated.
Gen er a l P r oced u r e for th e P r ep a r a tion of Na p h th a -
len esu lfon a m id es 2 a n d 3. To an ice-cooled solution of
3-(dimethylamino)propylamine or 1-(3-aminopropyl)pyrroli-
dine (4.41 mmol) and NEt3 (0.61 mL, 4.41 mmol) in DCM (10
mL) was added portionwise 2-naphthalenesulfonyl chloride
(1.00 g, 4.41 mmol). The coolant was removed and the mixture
was stirred at 20 °C for 18 h. The reaction mixture was washed
with water and brine. The organic phase was dried (MgSO4)
and filtered and the filtrate evaporated to yield the required
compound.
N-(3-Dim et h yla m in op r op yl)-2-n a p h t h a len esu lfon a -
m id e (2): 1H NMR (300 MHz, CDCl3) 8.43 (m, 1H), 7.99-
7.82 (m, 4H), 7.67-7.61 (m, 2H), 7.61-7.27 (br s, 1H), 3.09 (t,
J ) 5.7 Hz, 2H), 2.29 (t, J ) 5.7 Hz, 2H), 2.19 (s, 6H), 1.63-
1.56 (m, 2H). Anal. (C15H20N2O2S) C, H, N.
N -(3-P yr r olid in -1-ylp r op yl)-2-n a p h t h a le n e su lfon a -
m id e (3): 1H NMR (300 MHz, CDCl3) 8.43 (s, 1H), 7.99-7.59
(m, 7H), 3.11 (t, J ) 5.7 Hz, 2H), 2.54-2.49 (m, 6H), 1.81 (m,
4H), 1.68-1.63 (m, 2H). Anal. (C17H22N2O2S) C, H, N.
N-(3-P yr r olid in -1-ylp r op yl)(4-ch lor op h en yl)m eth a n e-
su lfon a m id e (4). To a cooled (-78 °C) solution of 1-(3-
aminopropyl)pyrrolidine (0.20 g, 1.56 mmol) and NEt3 (0.28
mL, 1.57 mmol) in DCM (3 mL) was added dropwise a solution
of (4-chlorophenyl)methanesulfonyl chloride35 (0.34 g, 1.50
mmol) in DCM (5 mL). The resultant solution was allowed to
warm to 20 °C while stirring was continued for 18 h. The
solution was washed (H2O), dried (MgSO4), and filtered and
the filtrate was evaporated. The material was purified by flash
column chromatography (DCM:EtOAc, 90:10) to afford the
product (0.19 g, 39%): 1H NMR (300 MHz, CDCl3) 7.36 (s, 4H),
4.19 (s, 2H), 3.10 (m, 2H), 2.60 (m, 2H), 2.47 (br s, 4H), 1.68
(m, 6H). Anal. (C14H21ClN2O2S) C, H, N.
Ligands 30 and 31 were shown to be simple, competi-
tive histamine H3 receptor antagonists when analyzed
over a range of concentrations in the ileum functional
bioassay and under Schild analysis exhibited a slope not
significantly different from unity.32
2-(4-Ch lor op h e n yl)-N -(4-p yr r olid in -1-ylb u t yl)a ce t -
a m id e (5). To an ice-cooled solution of DCC (3.28 g, 15.90
mmol) in DCM (10 mL) was added a solution of 4-chlorophe-

Non-Imidazole Histamine H3 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12 2367
nylacetic acid (2.02 g, 11.84 mmol) in DCM (10 mL). The
coolant was removed and the resultant suspension stirred at
20 °C for 10 min. 1-(3-Aminopropyl)pyrrolidine (1.00 mL, 7.91
mmol) was added dropwise and the reaction stirred at 20 °C
for 1 h. The suspension was filtered and the filtrate was
extracted with 10% aqueous citric acid. The organic phase was
discarded and the aqueous phase washed (DCM). The aqueous
phase was basified with NH4OH and extracted with DCM. The
solvent was removed in-vacuo to yield the title compound (1.98
g, 89%): 1H NMR (300 MHz, CDCl3) 7.34-7.02 (m, 4H), 7.02
(br s, 1H), 3.49 (s, 2H), 3.36 (m, 2H), 2.52 (t, J ) 6.6 Hz, 2H),
2.46 (m, 4H), 1.77-1.62 (m, 6H). Anal. (C15H21ClN2O) C, H,
N.
N-(4-Ch lor ob en zyl)-N′-(3-p yr r olid in -1-ylp r op yl)su lf-
a m id e (6). A solution of 4-chlorobenzylamine (0.610 mL, 5.00
mmol), 1-(3-aminopropyl)pyrrolidine (0.63 mL, 5.00 mmol) and
sulfamide (480 mg, 4.99 mmol) was heated at reflux for 2 h.
The reaction was allowed to cool and partitioned between
EtOAc and H2O. The aqueous phase was discarded and the
organic phase washed with H2O and brine. The organic phase
was dried (MgSO4) and filtered and the filtrate was evaporated
at reduced pressure. The residue was purified by flash column
chromatography (100/10/1 DCM/MeOH/NH4OH) to obtain the
title compound (365 mg, 22%): 1H NMR (300 MHz, CDCl3)
7.35-7.28 (m, 4H), 4.18 (s, 2H), 3.15 (J ) 6 Hz, 2H), 2.61 (t,
J ) 6 Hz, 2H), 2.51 (br m, 4H), 1.82-1.67 (m, 6H). Anal.
(C14H22ClN3O2S‚0.26H2O) C, H, N.
1-(4-Ch lor ob e n zyl)-3-(3-p yr r olid in -1-ylp r op yl)t h io-
u r ea (7). To an ice-cooled solution of 4-chlorobenzyl isothio-
cyanate (3.67 g, 20.0 mmol) in DCM (20 mL) was added a
solution of 1-(3-aminopropyl)pyrrolidine (2.65 mL, 21.0 mmol)
in DCM (20 mL). The coolant was removed and the reaction
stirred at 20 °C for 18 h. The reaction mixture was washed
with H2O and brine, dried (MgSO4), and filtered and the
filtrate evaporated. The residue was purified by flash column
chromatography (90/10/1 DCM/MeOH/NH4OH) to yield the
title compound (4.65 g, 75%): 1H NMR (300 MHz, CDCl3) 9.50
(br s, 1H), 7.32-7.26 (m, 4H), 6.20 (br s, 1H), 3.46 (br s, 2H),
2.55 (br s, 2H), 2.40 (br s, 4H), 1.73 (br s, 2H), 1.57 (br s, 4H).
The compound was further analyzed as the hydrochloride salt.
Anal. (C15H22ClN3S‚HCl) C, H, N.
N-(4-Ch lor oben zyl)-N′-(3-p yr r olid in -1-ylp r op yl)gu a n i-
d in e Bis-h yd r och lor id e Sa lt (8). Step a . To an ice-cooled
solution of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseu-
dourea (1.00 g, 3.45 mmol) in DMF (10 mL) was added sodium
hydride (60% dispersion in mineral oil, 167 mg, 4.18 mmol) in
a single portion. The resultant suspension was stirred at this
temperature for 1 h and then treated in a single portion with
4-chlorobenzyl bromide (780 mg, 3.80 mmol). The cooling bath
was removed and the reaction mixture stirred at 20 °C for 16
h. H2O was added and the aqueous phase was extracted with
EtOAc. The aqueous phase was discarded and the organic
phase was washed with brine (×2) and dried (MgSO4). The
filtrate was evaporated at reduced pressure and the residue
was purified by flash column chromatography (9/2 hexane/
EtOAc) to give 1,3′-bis(tert-butoxycarbonyl)-1-(4-chlorobenzyl)-
2-methyl-2-thiopseudourea as a colorless oil (987 mg, 69%):
1H NMR (300 MHz, CDCl3) 7.30 (s, 4H), 4.74 (s, 2H), 2.31 (s,
3H), 1.53 (s, 9H), 1.42 (s, 9H).
dioxan (4 M, 15 mL, 60 mmol) and the reaction mixture stirred
at 20 °C for 16 h. The solvent was evaporated at reduced
pressure and the residue evaporated from DCM to give the
title compound as a foam (700 mg, 95%): 1H NMR (300 MHz,
DMSO-d6) 10.97 (br s, 1H), 8.29 (br s, 1H), 8.07 (t, J ) 6 Hz,
1H), 7.69 (br s, 2H), 7.40 (d, J ) 8.4 Hz, 2H), 7.30 (d, J ) 8.4
Hz, 2H), 4.37 (s, 2H), 3.48-3.45 (m, 2H), 3.24-3.20 (m, 2H),
3.08-3.03 (m, 2H), 2.94-2.91 (m, 2H), 2.00-1.84 (m, 6H).
Anal. (C15H23ClN4‚2HCl) C, H, N.
The following compounds (9-14) were prepared in a similar
fashion with the requisite benzyl bromide.
N-Ben zyl-N′-(3-p yr r olid in -1-ylp r op yl)gu a n id in e b is-
h yd r och lor id e sa lt (9): 1H NMR (300 MHz, DMSO-d6) 11.10
(br s, 1H), 8.36 (br s, 1H), 8.16 (s, 1H), 7.76 (br s, 2H), 7.39-
7.26 (m, 5H), 4.37 (d, J ) 6 Hz, 2H), 3.47-3.27 (m, 4H), 3.10-
2.92 (m, 4H), 1.96-1.86 (m, 6H). Anal. (C15H24N4‚2HCl) C, H,
N.
N-(4-Br om oben zyl)-N′-(3-p yr r olid in -1-ylp r op yl)gu a n i-
d in e bis-h yd r och lor id e sa lt (10): 1H NMR (300 MHz,
DMSO-d6) 10.92 (br s, 1H), 8.26 (br s, 1H), 8.03 (br s, 1H),
7.68 (br s, 2H), 7.56 (d, J ) 9 Hz, 2H), 7.28 (d, J ) 9 Hz, 2H),
4.40-4.42 (m, 2H), 3.52-3.46 (m, 2H), 3.37-3.10 (m, 2H),
3.11-2.94 (m, 4H), 1.93-1.86 (m, 6H). Anal. (C15H23BrN4‚
2HCl) C, H, N.
N-(3-Br om oben zyl)-N′-(3-p yr r olid in -1-ylp r op yl)gu a n i-
d in e bis-h yd r och lor id e sa lt (11): 1H NMR (300 MHz,
DMSO-d6) 11.0 (br s, 1H), 8.32 (br s, 1H), 8.08 (br s, 1H), 7.72
(br s, 2H), 7.55-7.47 (m, 2H), 7.35-7.29 (m, 2H), 4.45-4.44
(m, 2H), 3.47-3.30 (m, 4H), 3.13-3.08 (br s, 2H), 2.96 (br s,
2H), 1.94-1.87 (m, 6H). Anal. (C15H23BrN4‚2HCl‚3H2O) C, H,
N.
N-(2-Br om oben zyl)-N′-(3-p yr r olid in -1-ylp r op yl)gu a n i-
d in e bis-h yd r och lor id e sa lt (12): 1H NMR (300 MHz,
DMSO-d6) 11.11 (br s, 1H), 8.17 (br s, 2H), 7.79 (br s, 2H),
7.67-7.64 (m, 1H), 7.43-7.25 (m, 3H), 4.53-4.44 (m, 2H),
3.50-3.45 (m, 2H), 3.31 (m, 2H), 3.17-3.11 (m, 2H), 2.99-
2.95 (m, 2H), 1.97-1.88 (m, 6H). Anal. (C15H23BrN4‚2HCl‚
3H2O) C, H, N.
N-(4-Iod ob en zyl)-N′-(3-p yr r olid in -1-ylp r op yl)gu a n i-
d in e bis-h yd r och lor id e sa lt (13): 1H NMR (300 MHz,
DMSO-d6) 11.04 (br s, 1H), 8.32 (br s, 1H), 8.13 (t, J ) 6 Hz,
1H), 7.75-7.72 (m, 4H), 7.17 (d, J ) 9 Hz, 2H), 4.41 (d, J ) 6
Hz, 2H), 3.49-3.44(m, 2H), 3.31-3.29 (m, 2H), 3.09-3.06 (m,
2H), 2.93-2.92 (br m, 2H), 1.97-1.86 (m, 6H). Anal. (C15H23N4I‚
2HCl‚4H2O) C, H, N.
N-(4-(Tr iflu or om et h yl)b en zyl)-N′-(3-p yr r olid in -1-yl-
p r op yl)gu a n id in e bis-h yd r och lor id e sa lt (14): 1H NMR
(300 MHz, DMSO-d6) 11.06 (br s, 1H), 8.47 (br s, 1H), 8.21-
8.18 (br m, 1H), 7.77-7.73 (m, 4H), 7.57 (d, J ) 9 Hz, 2H),
4.58 (d, J ) 6 Hz, 2H), 3.49-3.44 (m, 4H), 3.35-3.29 (m, 2H),
3.13-3.07 (m, 2H), 2.94 (br s, 2H), 1.96-1.88 (m, 6H). Anal.
(C16H23N4F3‚2HCl) C, H, N.
N-(4-Meth oxyben zyl)-N′-(3-pyr r olidin -1-ylpr opyl)gu an i-
d in e Bis-h yd r och lor id e (15). Step a . To an ice-cooled
solution of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseu-
dourea (1.45 g, 5.00 mmol), 4-methoxybenzyl alcohol (759 mg,
5.50 mmol) and PPh3 (1.97 g, 5.50 mmol) in THF (20 mL) was
added diethyl azodicarboxylate (1.29 mL, 5.50 mmol). The
coolant was removed and the reaction was stirred at 20 °C for
16 h. The solvent was removed at reduced pressure, and the
residue purified by flash column chromatography (90/10 hex-
ane/EtOAc) to give 1,3′-bis(tert-butoxycarbonyl)-1-(4-methoxy-
benzyl)-2-methyl-2-thiopseudourea as a colorless oil (1.11 g,
54%): 1H NMR (300 MHz, CDCl3) 7.30-7.27 (m, 2H), 6.87-
6.84 (m, 2H), 4.71 (s, 2H), 3.80 (s, 3H), 2.27 (s, 3H), 1.53 (s,
9H), 1.44 (s, 9H).
Step b. A solution of the product of step a (1.10 g, 2.24
mmol) and 1-(3-aminopropyl)pyrrolidine (0.850 mL, 6.79 mmol)
in THF (20 mL) and water (2 mL) was heated at reflux for 2
h. The reaction mixture was diluted with EtOAc, washed with
water (×2) and dried (MgSO4). The filtrate was evaporated at
reduced pressure and the residue purified by flash column
chromatography (90/10/1 DCM/MeOH/NH4OH) to give N,N′-
bis(tert-butoxycarbonyl)-N′-(4-methoxybenzyl)-N′′-(3-pyrrolidin-
Step b. A solution of the product from step a (920 mg, 2.00
mmol) and 1-(3-aminopropyl)pyrrolidine (669 mg, 5.22 mmol)
in THF (20 mL) and water (2 mL) was heated at reflux for 1
h. The solvent was evaporated at reduced pressure and the
residue was dissolved in EtOAc. The organic phase was
washed sequentially with H2O and brine and dried (MgSO4).
The filtrate was evaporated at reduced pressure and the
residue was purified by flash column chromatography (90/10/1
DCM/MeOH/NH4OH) to give N,N′-bis(tert-butoxycarbonyl)-N′-
(4-chlorobenzyl)-N′′-(3-pyrrolidin-1-ylpropyl)guanidine as
a
colorless oil (1.14 g, q): 1H NMR (300 MHz, CDCl3) 7.27 (br s,
4H), 4.78 (s, 2H), 3.16 (m, 2H) 2.43-2.37 (br s, 6H), 1.76 (m,
4H), 1.57-1.50 (m, 2H), 1.50 (s, 9H), 1.43 (s, 9H).
Step c. A solution of the product from step b (1.14 g, 2.00
mmol) in dioxan (5 mL) was treated with hydrogen chloride-

2368 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12
Linney et al.
1-ylpropyl)guanidine as a colorless oil (1.04 g, 79%): 1H NMR
(300 MHz, CDCl3) 10.00-9.50 (br s, 1H), 7.27-7.22 (m, 2H),
6.82-6.80 (m, 2H), 4.73 (s, 2H), 3.77 (s, 3H), 3.09 (br s, 2H),
2.40 (br s, 4H), 2.31 (br m, 2H), 1.73 (s, 4H), 1.49 (s, 9H), 1.42
(s, 9H).
was dried (MgSO4) and the filtrate was evaporated at reduced
pressure. The residue was purified by flash column chroma-
tography (4/1 hexane/EtOAc) to give the N,N′-bis(tert-butoxy-
carbonyl)-N′-(4-chlorobenzyl)-N′′-(1-pent-4-enyl)guanidine as
a colorless oil (1.46 g, 74%): 1H NMR (300 MHz, CDCl3) 7.36-
7.23 (m, 4H), 5.82-5.73 (m, 1H), 5.03-4.96 (m, 2H), 4.40 (br
s, 2H), 3.68 (br t, J ) 7.2 Hz, 2H), 2.08-2.01 (m, 2H), 1.68-
1.54 (m, 2H), 1.49 (s, 9H), 1.48 (s, 9H).
Step c. Ozone gas was bubbled through a solution of the
product of step b (500 mg, 1.11 mmol) in MeOH (10 mL) at
-78 °C for 5 min. The blue solution was purged of color with
nitrogen and then treated at this temperature with Me2S (0.81
mL, 11.0 mmol). The reaction mixture was allowed to warm
to 20 °C and stirred at this temperature for 2 h. The solvent
was evaporated at reduced pressure and the residue purified
by flash column chromatography (1/1 hexane/EtOAc) to give
N,N′-bis(tert-butoxycarbonyl)-N′-(4-chlorobenzyl)-N′′-(1-butan-
4-al)guanidine as an oil (403 mg, 80%): 1H NMR (300 MHz,
CDCl3) 9.75 (s, 1H), 9.50 (br s, 1H), 7.34 (d, J ) 8.4 Hz, 2H),
7.24 (d, J ) 8.4 Hz, 2H), 4.40 (s, 2H), 3.70 (t, J ) 7.2 Hz, 2H),
2.48 (t, J ) 7.2 Hz, 2H), 1.93-1.83 (m, 2H), 1.54 (s, 9H), 1.49
(s, 9H).
Step d . To an ice-cooled suspension of the product of step c
(400 mg, 0.88 mmol) and pyrrolidine (0.080 mL, 0.96 mmol)
in 1,2-dichloroethane (3 mL) was added sodium triacetoxy-
borohydride (280 mg, 1.32 mmol) in a single portion. The
coolant was removed and the resultant suspension stirred at
20 °C for 2 h. The reaction was quenched with saturated
aqueous NaHCO3 and extracted with EtOAc (×2). The com-
bined organics were dried (MgSO4) and the filtrate was
evaporated at reduced pressure. The residue was purified by
flash column chromatography (90/10/1 DCM/MeOH/NH4OH)
to give N,N′-bis(tert-butoxycarbonyl)-N′-(4-chlorobenzyl)-N′′-
(4-pyrrolidin-1-ylbutyl)guanidine as an oil (389 mg, 87%): 1H
NMR (300 MHz, CDCl3) 9.50 (br s, 1H), 7.33 (d, J ) 7.8 Hz,
2H), 7.24 (d, J ) 7.8 Hz, 2H), 4.42-4.41 (m, 2H), 3.68 (m, 2H),
2.51 (br s, 6H), 1.78 (m, 4H), 1.69-1.55 (m, 4H), 1.49 (s, 9H),
1.48 (s, 9H).
Step e. A solution of the product of step d (389 mg, 0.77
mmol) in chloroform (5 mL) was treated with hydrogen
chloride-dioxan (4 M, 5 mL, 20 mmol) and the reaction stirred
at 20 °C for 16 h. The solvent was removed at reduced pressure
and the residue was evaporated from CHCl3 (×2) to give the
title compound as a foam (312 mg, 100%): 1H NMR (300 MHz,
DMSO-d6) 11.00 (br s, 1H), 8.26 (br s, 1H), 8.03 (br s, 1H),
7.64 (m, 2H), 7.24 (d, J ) 8.4 Hz, 2H), 7.33 (d, J ) 8.4 Hz,
2H), 4.42 (d, J ) 6 Hz, 2H), 3.49-3.44 (m, 2H), 3.20-3.16 (m,
2H), 3.11-3.06 (m, 2H), 2.95-2.91 (m, 2H), 1.97-1.86 (m, 4H),
1.73-1.63 (m, 2H), 1.56-1.49 (m, 2H). Anal. (C16H25ClN4‚
2HCl‚1.61H2O) C, H, N.
The following compounds (18, 20-27) were prepared in a
similar manner utilizing the appropriate ω-hydroxyalkene,
amine, and cyclic secondary amine in steps a, b, and d,
respectively.
N-(4-Ch lor oben zyl)-N′-(5-p yr r olid in -1-ylp en tyl)gu a n i-
d in e bis-h yd r och lor id e (18): 1H NMR (300 MHz, DMSO-
d6) 11.00 (br s, 1H), 8.28 (br s, 1H), 8.00 (br s, 1H), 7.64 (m,
2H), 7.42 (d, J ) 8.4 Hz, 2H), 7.33 (d, J ) 8.4 Hz, 2H), 4.42 (d,
J ) 6 Hz, 2H), 3.50-3.45 (m, 2H), 3.20-3.13 (m, 2H), 3.06-
2.93 (m, 4H), 1.97-1.86 (m, 4H), 1.71-1.61 (m, 2H), 1.53-
1.43 (m, 2H), 1.35-1.28 (m, 2H). Anal. (C17H27ClN4‚2HCl‚
1.57H2O) C, H, N.
N-(2-(4-Ch lor oph en yl)eth yl)-N′-(4-pyr r olidin -1-ylbu tyl)-
gu a n id in e bis-h yd r och lor id e (20): 1H NMR (300 MHz,
DMSO-d6) 10.90 (br s, 1H), 7.81 (br s, 1H), 7.69 (br s, 1H),
7.51 (m, 2H), 7.37 (d, J ) 8.7 Hz, 2H), 7.29 (d, J ) 8.7 Hz,
2H), 3.48-3.35 (m, 4H), 3.14-3.06 (m, 4H), 2.97-2.93 (m, 2H),
2.78 (t, J ) 7.2 Hz, 2H), 2.00-1.87 (m, 4H), 1.73-1.63 (m, 2H),
1.53-1.43 (m, 2H). Anal. (C17H27ClN4‚2HCl‚3H2O) C, H, N.
N-(2-(4-Ch lor op h en yl)eth yl)-N′-(5-p yr r olid in -1-ylp en -
tyl)gu a n id in e bis-h yd r och lor id e (21): 1H NMR (300 MHz,
DMSO-d6) 10.80 (br s, 1H), 7.78 (br s, 1H), 7.69 (br s, 1H),
7.49 (br s, 2H), 7.38-7.29 (m, 4H), 3.51-3.37 (m, 4H), 3.14-
3.03 (m, 4H), 2.98-2.90 (m, 2H), 2.78 (t, J ) 7.2 Hz, 2H), 1.99-
Step c. A solution of the product of step b (1.04 g, 2.12
mmol) in chloroform (15 mL) was treated with hydrogen
chloride-dioxan (4 M, 15 mL, 60 mmol) and the reaction
mixture was stirred at 20 °C for 18 h. The solvent was
evaporated at reduced pressure and the residue evaporated
from DCM (×2) to give the title compound as a yellow foam
(850 mg, 100%): 1H NMR (300 MHz, DMSO-d6) 11.00 (br s,
1H), 8.25 (br s, 1H), 8.11 (t, J ) 6 Hz, 1H), 7.71 (br s, 2H),
7.29 (d, J ) 8.4 Hz, 2H), 6.93 (d, J ) 8.4 Hz, 2H), 4.36 (s, 2H),
3.73 (s, 3H), 3.55-3.26 (m, 4H), 3.07 (m, 2H), 2.93 (s, 2H),
1.96-1.86 (m, 6H). Anal. (C16H26N4O‚2HCl‚1.5H2O) C, H, N.
Compound 19 was prepared in analogous fashion with
4-chlorophenethyl alcohol replacing 4-methoxybenzyl alcohol
in step a.
N-(2-(4-Ch lor op h en yl)eth yl)-N′-(3-p yr r olid in -1-ylp r o-
p yl)gu a n id in e bis-h yd r och lor id e (19): 1H NMR (300 MHz,
DMSO-d6) 11.00 (br s, 1H), 7.92 (br s, 1H), 7.80 (br s, 1H),
7.59 (br s, 2H), 7.38-7.30 (m, 4H), 3.50-3.23 (m, 6H), 3.11-
3.08 (m, 2H), 2.98-2.92 (m, 2H), 2.79 (t, J ) 7.5 Hz, 2H), 2.00-
1.82 (m, 6H). Anal. (C16H25ClN4‚2HCl) C, H, N.
N-(4-Ch lor op h en yl)-N′-(3-p yr r olid in -1-ylp r op yl)gu a n i-
d in e (16). Step a . To ice-cooled stirred aqueous NH4OH (20
mL) was added dropwise a solution of 4-chlorophenyl isothio-
cyanante (3.39 g, 20.0 mmol) in dioxan (20 mL). The coolant
was removed and the resultant suspension was stirred at 20
°C for 2 h. The solid was removed by filtration and the filter-
cake washed with H2O (50 mL). The filter-cake was dried in
vacuo (50 °C) for 16 h to give (4-chlorophenyl)thiourea as a
white solid (2.90 g, 78%): 1H NMR (300 MHz, DMSO-d6) 9.72
(br s, 1H), 7.61-7.32 (br m, 6H).
Step b. To a solution of the product of step a (2.82 g, 15.1
mmol) in acetone (30 mL) was added iodomethane (1.41 mL,
22.65 mmol) and the resultant solution was heated at reflux
for 1 h. The solvent was removed at reduced pressure and the
residue suspended in EtOAc. The solid was removed by
filtration and the filter-cake washed with further EtOAc and
dried in vacuo to give 1-(4-chlorophenyl)-2-methylisothiourea
hydroiodide (4.53 g, 91%): 1H NMR (300 MHz, DMSO-d6)
11.00-9.00 (br s, 3H), 7.57 (d, J ) 8.7 Hz, 2H), 7.36 (d, J )
8.7 Hz, 2H), 2.68 (s, 3H).
Step c. A solution of the product from step b (986 mg, 3.00
mmol) and 1-(3-aminopropyl)pyrrolidine (0.948 mL, 7.50 mmol)
in ethanol (10 mL) was heated at reflux for 16 h. The solvent
was removed at reduced pressure and the residue suspended
in aqueous NH4OH. The solid was removed by filtration and
the filter-cake washed sequentially with H2O and Et2O to give
the title compound as a white solid (585 mg, 69%): 1H NMR
(300 MHz, DMSO-d6) 7.18-7.12 (m, 2H), 6.76-6.66 (m, 2H),
5.80-4.80 (br s, 3H), 3.12 (t, J ) 6.9 Hz, 2H), 2.43-2.36 (m,
6H), 1.69-1.56 (m, 6H). Anal. (C14H21ClN4) C, H, N.
N-(4-Ch lor ob en zyl)-N′-(4-p yr r olid in -1-ylb u t yl)gu a n i-
d in e Bis-h yd r och lor id e (17). Step a . To an ice-cooled
solution of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseu-
dourea (5.00 g, 17.2 mmol), 4-penten-1-ol (2.67 mL, 25.5 mmol)
and PPh3 (6.78 g, 25.48 mmol) in THF (35 mL) was added
diethyl azodicarboxylate (4.43 mL, 25.5 mmol). The coolant
was removed and the reaction stirred at 20 °C for 16 h. The
solvent was removed at reduced pressure and the residue was
purified by flash column chromatography (5/1 hexane/EtOAc)
to give 1,3′-bis(tert-butoxycarbonyl)-1-(1-pent-4-enyl)-2-methyl-
2-thiopseudourea as a colorless oil (6.23 g, 100%): 1H NMR
(300 MHz, CDCl3) 5.88-5.74 (m, 1H), 5.08-4.97 (m, 2H),
3.54-3.49 (m, 2H), 2.39 (s, 3H), 2.11-2.04 (m, 2H), 1.83-1.70
(m, 2H), 1.51 (s, 9H), 1.49 (s, 9H).
Step b. A solution of the product of step a (1.56 g, 4.36
mmol) and 4-chlorobenzylamine (1.20 mL, 9.83 mmol) in THF
(20 mL) and H2O (2 mL) was heated at reflux for 24 h. The
solution was diluted with EtOAc and washed sequentially with
H2O, 10% aqueous citric acid and brine. The organic phase

Non-Imidazole Histamine H3 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12 2369
1.84 (m, 4H), 1.72-1.62 (m, 2H), 1.48-1.41 (m, 2H), 1.36-
1.29 (m, 2H). Anal. (C18H29ClN4‚2HCl) C, H, N.
ylbutyl)amine bis-hydrochloride (655 mg, 62%): 1H NMR
(DMSO-d6) 11.00 (br s, 1H), 9.50 (br s, 2H), 7.61 (d, J ) 8.4
Hz, 2H), 7.48 (d, J ) 8.4 Hz, 2H), 4.11 (s, 2H), 3.44 (br s, 2H),
3.08-2.87 (m, 6H), 1.92 (br s, 4H), 1.73 (br s, 4H).
N-Cycloh exylm eth yl-N′-(5-pyr r olidin -1-ylpen tyl)gu an i-
d in e bis-h yd r och lor id e (22): 1H NMR (300 MHz, DMSO-
d6) 10.90 (br s, 1H), 7.78 (br s, 1H), 7.72 (br s, 1H), 7.45 (m,
2H), 3.50-3.44 (m, 2H), 3.17-2.90 (m, 8H), 1.99-1.83 (m, 4H),
1.70-1.63 (m, 7H), 1.51-1.31 (m, 5H), 1.20-1.06 (m, 3H),
0.95-0.87 (m, 2H). Anal. (C17H34N4‚2HCl) C, H, N.
N-Cycloh eptylm eth yl-N′-(5-pyr r olidin -1-ylpen tyl)gu an i-
d in e bis-h yd r och lor id e (23): 1H NMR (300 MHz, DMSO-
d6) 10.90 (br s, 1H), 7.78-7.74 (m, 2H), 7.46 (s, 2H), 3.50-
3.44 (m, 2H), 3.17-2.94 (m, 8H), 1.99-1.83 (m, 4H), 1.70-
1.38 (m, 17H), 1.19-1.09 (m, 2H). Anal. (C18H36N4‚2HCl‚4H2O)
C, H, N.
N-Ad a m a n ta n -1-ylm eth yl-N′-(5-p yr r olid in -1-ylp en tyl)-
gu a n id in e bis-h yd r och lor id e (24): 1H NMR (300 MHz,
DMSO-d6) 10.80 (br s, 1H), 7.84 (br s, 1H), 7.63 (br s, 1H),
7.49 (br s, 2H), 3.49-3.44 (m, 2H), 3.17-3.90 (m, 6H), 2.82 (d,
J ) 5.7 Hz, 2H), 1.94-1.86 (m, 7H), 1.73-1.49 (m, 16H), 1.40-
1.35 (m, 2H). Anal. (C21H38N4‚2HCl‚2.6H2O) C, H, N.
N-Ad a m a n ta n -1-ylm eth yl-N′-(5-p ip er id in -1-ylp en tyl)-
gu a n id in e bis-h yd r och lor id e (25): 1H NMR (300 MHz,
DMSO-d6) 10.40 (br s, 1H), 7.89 (br s, 1H), 7.68 (br s, 1H),
7.51 (br s, 2H), 3.32 (br s, 3H), 3.15 (q, J ) 6.3 Hz, 2H), 2.94
(m, 2H), 2.83 (m, 4H), 1.93 (br s, 3H), 1.83-1.45 (m, 20H),
1.34 (m, 3H). Anal. (C22H40N4‚2HCl‚4H2O) C, H, N.
N -Ad a m a n t a n -1-ylm e t h yl-N ′-(5-a ze p a n -1-ylp e n t yl)-
gu a n id in e bis-h yd r och lor id e (26): 1H NMR (DMSO-d6)
10.50 (br s, 1H), 7.88 (br s, 1H), 7.67 (br s, 1H), 7.50 (br s,
2H), 3.29 (br s, 2H), 3.15 (q, J ) 6.4 Hz, 2H), 3.02 (m, 4H),
2.83 (d, J ) 6 Hz, 2H), 1.94 (br s, 3H), 1.80-1.40 (m, 24H),
1.34 (m, 2H). Anal. (C23H42N4‚2HCl‚4H2O) C, H, N.
N -Ad a m a n t a n -1-ylm e t h yl-N ′-(5-a zoca n -1-ylp e n t yl)-
gu a n id in e bis-h yd r och lor id e (27): 1H NMR (300 MHz,
DMSO-d6) 10.50 (br s, 1H), 7.88 (br s, 1H), 7.66 (br s, 1H),
7.50 (br s, 2H), 3.30 (br s, 2H), 3.16-2.98 (m, 6H), 2.83 (d, J
) 6 Hz, 2H), 1.94 (br s, 3H), 1.83-1.40 (m, 26H), 1.34 (m, 2H).
Anal. (C24H44N4‚2HCl‚4H2O) C, H, N.
N-(4-Ch lor ob en zyl)-N-(4-p yr r olid in -1-ylb u t yl)gu a n i-
d in e Bis-h yd r och lor id e (28). Step a . To a stirred solution
of 4-chlorobenzylamine (9.86 g, 69.6 mmol) in 1,4-dioxan (100
mL) was added dropwise a solution of di-tert-butyl dicarbonate
(15.2 g, 69.6 mmol) in 1,4-dioxan (50 mL). The solution was
stirred at 20 °C for 45 min and then the solvent was
evaporated at reduced pressure. The residue was suspended
in hexane and the solid recovered by filtration. The solid was
washed with further hexane and dried in vacuo at 50 °C to
give (4-chlorobenzyl)carbamic acid tert-butyl ester (13.5 g,
80%): 1H NMR (300 MHz, CDCl3) 7.31-7.20 (m, 4H), 4.80 (br
s, 1H), 4.27 (d, J ) 5.7 Hz, 2H), 1.46 (s, 9H).
Step b. To an ice-cooled stirred solution of the product from
step a (725 mg, 3.00 mmol) in DMF (9 mL) was added, in a
single portion, sodium hydride (60% dispersion in mineral oil,
144 mg, 3.60 mmol). The coolant was removed and the
suspension was stirred at 20 °C for 30 min. The suspension
was cooled in ice and 1,5-dibromobutane (1.23 mL, 9.03 mmol)
was added in three portions. The coolant was removed and
the reaction mixture was stirred at 20 °C for 18 h. The reaction
was quenched with H2O and then extracted with EtOAc. The
aqueous phase was discarded and the organic phase washed
with brine (×2). The organic phase was dried (MgSO4) and
the filtrate evaporated at reduced pressure. The residue was
purified by flash column chromatography (5/1 hexane/EtOAc)
to afford (4-bromo-butyl)(4-chlorobenzyl)carbamic acid tert-
butyl ester.
Step c. To a stirred solution of the product from step b in
acetonitrile (4 mL) was added pyrrolidine (1.27 mL, 15.2 mmol)
and the resultant solution was stirred at 20 °C for 18 h. The
reaction mixture was diluted with EtOAc, washed sequentially
with H2O and brine, and dried (MgSO4). The filtrate was
evaporated at reduced pressure and the residue treated with
hydrogen chloride in 1,4-dioxan (4 M, 10 mL, 40 mmol). The
solution was stirred at 20 °C for 1 h and the solvent removed
at reduced pressure to afford (4-chlorobenzyl)(4-pyrrolidin-1-
Step d . To an ice-cooled suspension of the product of step c
(1.24 g, 3.65 mmol) in DCM (30 mL) were added sequentially
NEt3 (2.54 mL, 18.3 mmol), 1,3-bis(tert-butoxycarbonyl)-2-
methyl-2-thiopseudourea (1.16 g, 4.00 mmol) and mercury(II)
chloride (1.09 g, 4.00 mmol). The coolant was removed and
the resultant solution was stirred at 20 °C for 18 h to give a
suspension. The suspension was filtered through a plug of
Celite and the filter-cake was washed with further DCM. The
filtrate was washed sequentially with H2O and brine. The
organic phase was dried (MgSO4) and the filtrate was evapo-
rated at reduced pressure. The crude residue was purified by
flash column chromatography (100/10/1 DCM/MeOH/NH4OH)
to afford N,N-bis(tert-butyoxycarbonyl)-N′′-(4-chlorobenzyl)-N′′-
(4-pyrrolidin-1-ylbutyl)guanidine (1.19 g, 64%): 1H NMR (300
MHz, CDCl3) 9.97 (br s, 1H), 7.32-7.22 (m, 4H), 4.67 (s, 2H),
3.34-3.29 (m, 2H), 2.51-2.36 (m, 6H), 1.76-1.70 (m, 4H),
1.50-1.41 (m, 22H).
Step e. A solution of the product of step d (1.18 g, 2.31
mmol) in chloroform (10 mL) was treated with hydrogen
chloride-dioxan (4 M, 10 mL, 40 mmol) and the reaction
stirred at 20 °C for 16 h. The solvent was removed at reduced
pressure and the residue was evaporated twice from CHCl3
(×2) to give the title compound as a foam (889 mg, 100%): 1H
NMR (300 MHz, DMSO-d6) 11.00 (br s, 1H), 7.73 (br s, 4H),
7.46 (d, J ) 6 Hz, 2H), 7.27 (d, J ) 6 Hz, 2H), 4.64 (s, 2H),
3.47-3.28 (m, 4H), 3.05-2.89 (m, 4H), 1.95-1.86 (m, 4H),
1.62-1.58 (m, 4H). Anal. (C16H25ClN4‚2HCl‚2H2O) C, H. N.
The following compounds (29-32) were prepared in a
similar manner utilizing the appropriate dibromide in step b.
N-(4-Ch lor oben zyl)-N-(5-p yr r olid in -1-ylp en tyl)gu a n i-
d in e bis-h yd r och lor id e (29): 1H NMR (300 MHz, DMSO-
d6) 10.90 (br s, 1H), 7.67-7.61 (br m, 4H), 7.46 (d, J ) 6 Hz,
2H), 7.27 (d, J ) 6 Hz, 2H), 4.62 (s, 2H), 3.46-3.44 (m, 2H),
3.27-3.24 (m, 2H), 3.03-2.90 (m, 4H), 1.96-1.86 (m, 4H),
1.65-1.52 (m, 4H), 1.30-1.27 (m, 2H). Anal. (C17H27ClN4‚
2HCl‚2H2O) C, H, N.
N-(4-Ch lor ob en zyl)-N-(6-p yr r olid in -1-ylh exyl)gu a n i-
d in e bis-h yd r och lor id e (30): 1H NMR (300 MHz, DMSO-
d6) 11.00 (br s, 1H), 7.68 (br s, 4H), 7.47 (d, J ) 9 Hz, 2H),
7.27 (d, J ) 9 Hz, 2H), 4.62 (s, 2H), 3.48-3.38 (m, 2H), 3.29-
3.24 (m, 2H), 3.05-2.88 (m, 4H), 1.98-1.80 (m, 4H), 1.66-
1.58 (m, 2H), 1.50 (br s, 2H), 1.27-1.26 (m, 4H). Anal.
(C18H29ClN4‚2HCl‚1.5H2O) C, H, N.
N-(4-Ch lor oben zyl)-N-(7-p yr r olid in -1-ylh ep tyl)gu a n i-
d in e bis-h yd r och lor id e (31): 1H NMR (300 MHz, DMSO-
d6) 11.10 (br s, 1H), 7.72 (br s, 4H), 7.46 (d, J ) 9 Hz, 2H),
7.27 (d, J ) 9 Hz, 2H), 4.62 (s, 2H), 3.48-3.41 (m, 2H), 3.26
(t, J ) 7.5 Hz, 2H), 3.05-2.86 (m, 4H), 1.98-1.82 (m,
4H), 1.64 (m, 2H), 1.48 (br m, 2H), 1.24 (br s, 6H). Anal.
(C19H31ClN4‚2HCl‚2H2O) C, H, N.
N-(4-Ch lor ob en zyl)-N-(8-p yr r olid in -1-yloct yl)gu a n i-
d in e bis-h yd r och lor id e (32): 1H NMR (300 MHz, DMSO-
d6) 10.90 (br s, 1H), 7.62 (br s, 4H), 7.47-7.43 (m, 2H), 7.26-
7.24 (m, 2H), 4.60 (s, 2H), 3.46-3.44 (m, 2H), 3.28-3.23 (m,
2H), 3.04-2.92 (m, 4H), 1.95-1.85 (m, 4H), 1.64 (br s, 2H),
1.48 (br s, 2H), 1.23 (br s, 8H). Anal. (C20H33ClN4‚2HCl‚
1.55H2O) C, H, N.
σ1 Bin d in g Assa y. Guinea-pig cerebral cortical homoge-
nates24 membranes (400 µL, 10 mg mL-1 original weight) were
incubated for 48 h at 21 ( 3 °C in a final volume of 500 µL
with 20 mM Hepes-NaOH buffer containing [3H]-(+)-penta-
zocine (50 µL, 10 nmol) and the test compound. Total and
nonspecific binding of [3H]-(+)-pentacozine were defined using
50 µL of Hepes-NaOH buffer and 50 µL of 100 µM 1,3-di(2-
tolyl)guanidine (DTG), respectively. The assay was terminated
by rapid filtration through presoaked (0.1% PEI) Whatman
GF/B filters using a Brandell cell harvester. Bound radioactiv-
ity was determined by liquid scintillation counting. Competi-
tion experiments were analyzed and KI’s were determined
using the equation KI ) IC50/1 + ([ligand]/KD). The Kd is the

2370 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12
Linney et al.
equilibrium dissociation constant of [3H]-(+)-pentazocine (pKd
) 9.00 ( 0.12) determined by saturation analysis in the cortex.
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