Synthesis of potent non-imidazole histamine H3-receptor antagonists

Article abstract of DOI:10.1002/(SICI)1521-4184(199812)331:12<395::AID-ARDP395>3.0.CO;2-7

Histamine has been converted into a non-imidazole H₃-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N(α)-position followed by removal of the imidazole ring. The resulting compound, N-ethyl- N-(4-phenylbutyl)amine, remarkably has a Ki = 1.3 μM as an H₃ antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N- (5-phenoxypentyl)pyrrolidine (Ki = 0.18 ± 0.10 μM, for [³H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO₂ into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki= 39 ± 11 nM), ED₅₀ = 1.1 ± 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.

Full text of DOI:10.1002/(SICI)1521-4184(199812)331:12<395::AID-ARDP395>3.0.CO;2-7

Non-imidazole Histamine H3-Receptor Antagonists
395
Synthesis of Potent Non-imidazole Histamine H -Receptor Antagonists
3
b)
a)
a)
a)
b)
c)
C. Robin Ganellin *, Fabien Leurquin , Antonia Piripitsi , Jean-Michel Arrang , Monique Garbarg , Xavier Ligneau ,
d)
b)
Walter Schunack , and Jean-Charles Schwartz
a) Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London, WC1H OAJ, UK
b) Unité de Neurobiologie et Pharmacologie Moléculaire (U.109) de l’INSERM, Centre Paul Broca, 2 ter rue d’Alésia, 75014 Paris, France
c) Laboratoire Bioprojet, 9 rue Rameau, 75002 Paris, France
d) Institut für Pharmazie I, Freie Universität Berlin, Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany.
Key Words: H receptors; histamine antagonists; brain penetration
3
The prototype H antagonist is thioperamide (Chart 1)
Summary
3
which is very potent in vitro (K = 4.3 nM) but relatively high
i
doses are required in vivo to enhance histamine release in the
brain . This suggests that thioperamide has a limited brain
penetration, but the direct determination of penetrability
which has been reported is somewhat conflicting. Thus, when
[6]
Histamine has been converted into a non-imidazole H3-receptor
histamine antagonist by addition of a 4-phenylbutyl group at the
Nα-position followed by removal of the imidazole ring. The result-
ing compound, N-ethyl-N-(4-phenylbutyl)amine, remarkably has
a Ki = 1.3 µM as an H3 antagonist. Using this as a lead compound,
a novel series of homologous O and S isosteric tertiary amines was
synthesised and structure-activity studies furnished N-(5-phen-
oxypentyl)pyrrolidine (Ki = 0.18 ± 0.10 µM, for [3H]histamine
release from rat cerebral cortex synaptosomes) which, more im-
portantly, was active in vivo. Substitution of NO2 into the para
position of the phenoxy group gave N-(5-p-nitrophenoxypen-
tyl)pyrrolidine, UCL 1972 (Ki = 39 ± 11 nM), ED50 = 1.1 ±
0.6 mg/kg per os in mice on brain tele-methylhistamine levels.
given intravenously to rats, thioperamide was rather rapidly
[7]
eliminated and had low brain levels
but at higher doses,
given intraperitoneally, the results were more complex to
[8]
interpret
.
Brain penetration is greatly reduced by the presence ofpolar
[9,10]
acceptor or donor hydrogen-bonding groups
. Since
thioperamide contains an imidazole ring (strong H-bond ac-
ceptor and donor) anda thiourea moiety (two strongly H-bond
donating groups and one mild H-bond acceptor) it is likely
that these act to markedly reduce the penetrability of thiop-
eramide. Although brain penetration is assisted when com-
pounds are lipophilic this is not a sufficient criterion if the
compounds are also strong hydrogen bonders. Previous stud-
Introduction
ies in designing brain-penetrating H -receptor histamine an-
Histamine H receptors have been shown to be inhibitory
2
3
[11]
[1]
tagonists have served to emphasise these conclusions
. We
presynaptic autoreceptors which modulate the synthesis
[2]
therefore sought to devise non-imidazole containing com-
and release of histamine at histaminergic neurones in the
pounds as H antagonists which should have improved brain
central nervous system (CNS). Inhibition of the action of
3
penetration, aiming also to avoid thiourea and urea-type polar
groups.
histamine at the H receptor therefore increases the concen-
3
tration released of the histamine neurotransmitter. The H
3
[3]
All potent and selective H -receptor ligands possess a 4(5)-
receptors also occur as heteroreceptors
on non-histamin-
3
ergic neurones modulating the release of other neurotransmit- substituted imidazole ring. A few weakly active non-imida-
ters in the brain and periphery.
zole compounds have been described as H antagonists, e.g.
3
[12]
[13]
An H -receptor histamine antagonist entering the brain
betahistine
(K = 7 µM), phencyclidine
(K = 13 µM),
i
3
i
[14]
would lead to an increase in histamine transmission through
histaminergic pathways and thereby potentiate the role of
histamine in the CNS. Possible therapeutic applications of
dimaprit
eramide
(K = 3 µM), the pyridine analogue of thiop-
i
[15]
[16]
(K = 13 µM), and clozapine
(K = 0.7 µM).
i
i
Generally, however, replacement of the imidazole ring in H
3
[4,5]
such compounds which have been proposed
include
antagonists by other heterocycles is accompanied by a loss of
[17,18]
various CNS disorders such as memory and learning deficits,
Alzheimer’s disease, epilepsy, schizophrenia, sleep distur-
bance, and obesity.
activity
. It should be possible to obtain non-imidazole
antagonists using one of the foregoing compounds as a lead
even though they are only weakly active and, indeed, this
[19]
approach has very recently been reported in posters
starting from the compound sabeluzole
[20]
(Chart 1), which
is a benzothiazole derivative. However, it was attractive to
take a more fundamental line of reasoning, as follows.
It is possible to convert an agonist into an antagonist by
introducing additional groups into the molecule which can
[21]
locate binding sites in the vicinity of the receptor
.
Whether the resulting molecule will be a partial agonist, or a
pure antagonist, probably depends upon whether the agonist
Chart 1
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0365-6233/98/1212/0395 $17.50 +.50/0

396
Ganellin and co-workers
moieties continue to engage the receptor in the critical man- 4-(4-Fluorophenyl)butylamine was prepared in 5 steps from
[21]
ner required to elicit the receptor response
then the molecule will be an antagonist (see for example the acid by reduction of the ketone followed by reduction of the
. If they do not, the commercially available 3-(4-fluorobenzoyl)propanoic
[22]
structure-activity relationships for H -receptor ligands
)
acid, bromination of the resulting primary alcohol and a
2
and one may question whether the agonist moieties actually Gabriel synthesis to give the primary amine (Scheme 2).
[27]
make any useful contribution to the affinity. If the additional 3-Phenylthiopropylamine
groups are correctly positioned and interact appropriately amine
and 3-phenoxypropyl-
were prepared according to published procedures.
with the receptor, the resultant molecule should achieve a The tertiary amine 3 was made from 2 by alkylation using the
[28]
considerable increase in affinity.
Eschweiler-Clarke procedure.
For histamine, the thought arose that it might be possible to
convert histamine into an antagonist by addition of appropri-
ate groups, and then to remove the imidazole ring to yield a
non-imidazole antagonist molecule. It therefore seemed to be
worthwhile applying this analysis to the interaction of hista-
Scheme 3
mine at the H receptor. The difficulty of the approach resides
3
in finding out what may be appropriate groups to incorporate
into the histamine molecule and in which positions they
should be introduced to achieve a sufficient increase in affin-
ity.
The diethylamine derivatives 10 to 12 and 14 to 17
(Scheme 3) derive from the corresponding bromides:
1-bromo-3-phenoxypropane and 1-bromo-4-phenoxybutane
were commercially available; 1-bromo-3-phenylthio-
Of various attempts made, the one that appeared to hold
[29]
[29]
propane
phenoxypentane
, 1-bromo-4-phenylthiobutane
, 1-bromo-5-
α
promise was the finding that N -(4-phenylbutyl)histamine
[30]
[31]
, 1-bromo-6-phenoxyhexane
were
(1) was a pure antagonist of histamine at the H receptor with
3
synthesised according to the published methods. 1-Bromo-5-
[23]
a K = 0.63 µM
. Removal of the imidazole ring from this
i
phenylthiopentane was prepared in a similar way to its lower
structure led to the synthesis and testing of N-ethyl-N-(4-
[32]
homologues rather than as published
. The tertiary amines
phenylbutyl)amine (2) which, remarkably, was found to have
18 to 26 were also made from 1-bromo-5-phenoxypentane
(Scheme 4) but under somewhat different conditions.
[24]
a K = 1.3 µM as an H -receptor histamine antagonist
.
i
3
Thus removal of the imidazole ring had led merely to a
twofold drop in affinity and had successfully produced the
necessary lead to generate a non-imidazole H -receptor his-
3
tamine antagonist.
Scheme 4
Chemical Synthesis
The substituted phenoxypentylpyrrolidines 27 to 29 and 31
to 35 were made from the appropriate substituted 1-bromo-
5-phenoxypentanes which had been synthesised from the
corresponding phenols by alkylation with 1,5-dibromopen-
tane (Scheme 4).
The ethylamines 2, 4 to 7, 9, and 13 were prepared from the
primary amine by acetylation followed by reduction of the
amide with borane or lithium aluminium hydride (Scheme 1).
The anilines 8 and 30 were obtained from the aromatic nitro
compounds 5 and 32 respectively by reduction with hydra-
zine hydrate or hydrogen in the presence of palladium on
carbon catalyst (Scheme 5).
Scheme 1
The requisite primary amines were obtained as follows. 4-(4-
Methoxyphenyl)butylamine was prepared in 3 steps from
4-(4-methoxyphenyl)butyric acid by conversion of the acid
to the acid chloride, reaction with ammonia and reduction of
Scheme 5
the amide with lithium aluminium hydride. 4-(4-Nitro-
[25]
Pharmacological Results and Discussion
phenyl)butylamine
and 4-(4-chlorophenyl)butyl-
[26]
amine
were prepared according to published procedures.
The compounds were tested for histamine antagonism at the
H -receptor in an in vitro functional assay on synaptosomes
3
[33]
of rat cerebral cortex
and, in vivo, given orally to mice for
[33]
their effect on brain tele-methylhistamine levels
. The
structures and activities of the compounds are given in Ta-
ble 1. N-Methylation to give the tertiary amine did not appear
to change affinity. Substituents were introduced into the para
position of the phenyl ring to probe for electronic effects and
were found to have some influence: OMe and NO groups
2
(compounds 4 and 5 respectively) did not alter the potency,
[34]
Scheme 2
whereas F, Cl, or NH markedly decreased potency (6–8)
.
2
Arch. Pharm. Pharm. Med. Chem. 331, 395–404 (1998)

Non-imidazole Histamine H3-Receptor Antagonists
397
Table 1. Structures and potencies of compounds as H -receptor histamine antagonists.
3
a) functional assay in vitro for [3H]histamine release from rat cerebral cortex synaptosomes; b) in vivo assay in mice for effect
on brain tele-methylhistamine levels, ED50 values calculated as mg free base per kg; c) measured on rat cerebral cortex slices;
d) n.d. = not determined.
Arch. Pharm. Pharm. Med. Chem. 331, 395–404 (1998)

398
Ganellin and co-workers
In retrospect it is of interest to note that compound 6 is a
partial structure of sabeluzole.
In order to improve the accessibility of compounds and
facilitate the structure-activity exploration, ether isosteres
were examined. The sulfur isostere (9) of 2 was not active
but, surprisingly, N-ethylation to give the tertiary amine 10
Conclusion
In the above structure-activity investigation, whichsuccess-
fully led to the design of a non-imidazole H antagonist, one
3
can see that the histamine substructure of compound 1 locates
the receptor and the additional group [Ph(CH ) ] contributes
2 4
to affinity. Since 1 is not a partial agonist, it appears that the
histamine substructure is no longer able to engage the recep-
tor in the productive manner required for stimulating it to
respond.
The imidazole group in 1 can be removed without substan-
tial loss of affinity and molecular manipulation has furnished
suitable affinity groups. Hence it now appears that the imida-
zole group in the antagonist is not even required for locating
the receptor so long as appropriate affinity groups have been
identified. In such antagonist structures it is therefore appar-
ent that one is no longer building on the affinity of the agonist.
The agonist structure merely served as a tool to probe for the
necessary binding sites at the receptor.
increased affinity by nearly an order of magnitude (K =
i
0.18 µM). Homologues (n = 4–5) were also examined (com-
pounds 11–12) and found to be similarly active in vitro and,
interestingly, compound 12 (n = 5) was active in vivo (ED
≈
50
[34]
15 mg/kg per os)
.
Similar results were obtained with the oxygen ether series.
The oxygen isostere (13) of 2 had some activity, and the
N-ethyl derivative (14) was approximately 30 fold more
potent (K = 0.15 µM). Homologues (n = 4–6) (15–17) were
i
similarly active in vitro (K = 0.11–0.23 µM) and 16 was
i
[34]
active in vivo (ED ≈ 17 mg/kg per os)
.
50
The phenoxypentylamine structure was then optimised for
activity with respect to the tertiary amino group. The amine
series NMe (18), NMeEt (19), NEt (16), NEtPr (20) showed
2
2
Acknowledgements
little variation in activity in vitro (K = 0.23–0.46 µM), but
i
This work was supported by the Commission of the European Communi-
ties under the Biomedical and Health Research Programmes Biomed 1
(CT92-1087) and Biomed 2 (BMH4-CT96-0204). We thank Ms Farah
Siddiqi for the synthesis of compounds 2 and 3 and we gratefully acknow-
ledge the excellent technical assistance of Mme N. Defontaine and Mr P.
Brugioti during the pharmacological testing.
NPr (21) was less active; 19, however, was also active in
2
vivo (ED ≈ 10 mg/kg per os). The compounds with pyr-
50
rolidino (22), piperidino (23), and homopiperidino (24)
groups were all of similar potencies in vitro (K = 0.12–0.18),
i
but the morpholino (25) and N-methylpiperazino (26) com-
pounds were distinctly less active. Most important, however,
was the finding that the pyrrolidino and piperidino com-
pounds were active orally in vivo, with the former being of
Experimental
special interest, having an ED value of 3.4 mg/kg. It is
apparent that the amino group is a determinant of in vivo
50
Chemistry
Melting points (open capillaries) were determined using an Electrother-
mal® electrically heated Cu block apparatus and are uncorrected. 1H NMR
spectra were recorded on a Varian XL-200 (200 MHz) or a Varian VXR-400
(400 MHz) spectrometer on the δ scale relative to TMS as internal reference.
Elemental analyses, C, H, N andCl (all within ± 0.4% of the calculated values
unless indicated) were determined by A.A.T. Stones and G.A. Maxwell in
the Department of Chemistry, University College London. Column chroma-
tography was performed on Merk silica gel 60 (70–230 mesh). Analytical
and preparative HPLC were performed on a Gilson HPLC apparatus fitted
with a Kromasil C18 5 µm reverse phase column 250 × 4.6 mm (analytical)
or 250 × 22 mm (preparative) with a flow rate of 1 mL min–1 (analytical) or
18 mL min–1 (preparative) and a detector at 215 nm. Fast atom bombardment
mass spectrometry was performed on a VG ZAB-SE double focussing mass
spectrometer by the Mass Spectrometry Service in the Department of Chem-
istry, University College London. All compounds were at least 98% pure by
analytical HPLC and their mass spectra were consistent with their attributed
structures. A few compounds retained an excess of oxalic acid (see Table 2).
activity; potency decreases in the order N(CH ) > N(CH )
2 4
2 5
> N(CH )C H > N(C H )C H > N(C H )C H but there is
3
2
5
2
5
2
5
3
7
2 5
no obvious overall correlation, either with carbon content or
size.
Substituents were then introduced into the phenoxy group
of the pyrrolidine derivative 22 and the compounds 27–35
were tested in vivo. Activity was found to be in the potency
order: p-NO > p-CN > p-NH > p-F > p-Cl > m-Cl ~ m-NO
2
2
2
~ m-CN > p-Me. The p-NO and p-CN compounds 32 and 34
2
being the most potent (ED = 1.1 and 1.9 mg/kg per os
50
respectively). This represents a very important finding since
the potency is similar to that of the standard reference H
3
[33]
antagonist, thioperamide (ED = 1.0 ± 0.5 mg/kg per os)
.
50
Since these structures are generically phenylalkylamines or
phenoxy(thio)alkylamines, and various alkylamines are
known to act at biogenic amine receptors, it will be very
important to establish that the compounds have selectivity
General Method A
A solution of the appropriately substituted alkylamine (40 mmol) and
triethylamine (2 equiv.) in dry dichloromethane (60 mL) was stirred under
nitrogen and cooled to 0 °C. Acetyl chloride (1.5 equiv.) was added dropwise
and the resulting mixture was stirred at room temperature for 3 h. Water
(50 mL) was added and the organic layer was separated, washed with
aqueous HCl (4N), then with saturated NaCl, dried over magnesium sulfate
and concentrated under reduced pressure to give the crude amide. A solution
of the amide (23 mmol) in dry dichloromethane (50 mL) was added to a
molar solution of borane in THF (60 mL, 60 mmol) stirred at 0 °C under
nitrogen. The mixture was then heated under reflux for 16 h with stirring
under nitrogen. After cooling to 0 °C, an aqueous HCl solution (6N, 20 mL)
was slowly added and the resulting mixture was evaporated to dryness. The
crude hydrochloride salt was dissolved in water and the solution was basified
with an aqueous NaOH solution (10N). The free base was extracted with
towards histamine H receptors. Studies to determine selec-
3
tivity will certainly have to be undertaken before any of these
compounds or related structures can be considered as poten-
tial clinical candidates.
The p-NO and p-CN compounds 32 and 34 were also
2
examined in vitro and found to have approximately only one
fifth to one tenth (K = 19–39 nM) of the potency of thiop-
i
eramide in this test. Presumably, therefore, 32 and 34 are
inherently less active at the receptor than is thioperamide but,
since they are similarly active in vivo, it suggests that they,
indeed, have a better brain penetrability.
Arch. Pharm. Pharm. Med. Chem. 331, 395–404 (1998)

Non-imidazole Histamine H3-Receptor Antagonists
399
Table 2. Chemical and physical data on tested compounds.
——————————————————————————————————————————————
No.
Formulaa
Anal.
Yield
(%)
M.p.
(°C)
Cryst.
Synth.
solventb
scheme
——————————————————————————————————————————————
2
C12H19N; HCl
C,H,N,Cl
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,Nd
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N,Cl
C,H,N,Cl
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
56
44
18
26
21
23
15
5
152–154
110–112
178–180
183–185
203–205
A
A
A
B
C
B
D
C
C
C
C
C
C
C
C
C
D
C
D
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
1
1
1
1
1
1
5
1
3
3
3
1
3
3
3
3
4
4
4
4
4
4
4
4
4
4
4
4
5
4
4
4
4
4
3
C13H21N; C2H2O4
4
C
13H21NO; C2H2O4
C12H18N2O2; C2H2O4
C12H18FN; C2H2O4
5
6
7
C12H18ClN; C2H2O4
C12H20N2; 2.6 C2F3O2H
C11H17NS; C2H2O4
C13H21NS; C2H2O4
C14H23NS; C2H2O4
C15H25NS; 1.1 C2H2O4
C11H17NO; C2H2O4
C13H21NO; 1.6 C2H2O4
203–205
c
8
9
210–212
109–111
95–97
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
42
33
30
30
51
60
47
57
52
58
11
62
56
36
33
48
56
66
52
77
63
47
32
69
41
38
83–85
191–193
91–92
C
14H23NO; 1.05 C2H2O4
C15H25NO; C2H2O4
16H27NO; C2H2O4
111–113
107–109
88–91
C
C13H21NO; 2 C2H2O4; 2 H2O
C14H23NO; C2H2O4
C16H27NO; C2H2O4
C17H29NO; C2H2O4
C15H23NO; C2H2O4
129–130
122–124
90–91
112–114
153–155
143–145
132–134
166–168
208–210
149–150
139–141
131–132
120–122
138–140
145–147
130–131
129–130
119–120
C
16H25NO; C2H2O4
C17H27NO; C2H2O4
C15H23NO2; C2H2O4
C
16H26N2O; 2 HCl
C15H22FNO; C2H2O4
C15H22ClNO; C2H2O4
C15H22ClNO; C2H2O4
C15H24N2O; 2.1 C2H2O4
C16H25NO; C2H2O4
C
15H22N2O3; C2H2O4; 0.2 H2O
C15H22N2O3; C2H2O4
16H22N2O; 1.1 C2H2O4
C16H22N2O; C2H2O4
C
————————————————————————————————————————————————
a) C2H2O4 = oxalate; C2F3O2H = trifluoroacetate; b) A = ethanol:methanol (9:1); B = ethanol:methanol (1:1); C = ethanol;
D = isopropanol; c) hygroscopic glassy solid; d) N: calcd, 3.31; found, 3.87.
Arch. Pharm. Pharm. Med. Chem. 331, 395–404 (1998)

400
Ganellin and co-workers
4-(4-Methoxyphenyl)butanamide
diethyl ether (3×100 mL) and the combined extracts were dried over magne-
sium sulfate and concentrated to give the crude base as an oil. The base was
purified by column chromatography on silica gel eluting with a 9:1 mixture
of chloroform and methanol and the pure product was converted into the
oxalate salt by adding an ethanolic solution of oxalic acid (1.5 equiv.), and
the resulting oxalate was crystallised from the solvent indicated in Table 2.
A solution of 4-(4-methoxyphenyl)butanoic acid (24 g, 124 mmol) in
freshly distilled thionyl chloride (60 mL, 820 mmol) was stirred and heated
under reflux for 3 h. The excess thionyl chloride was distilled off to give the
crude acid chloride (26.28 g, 100%).– A solution of aqueous ammonia (δ =
0.88, 20 mL) was stirred and cooled to 0 °C and the acid chloride (18.43 g,
86.65 mmol) was added dropwise. The mixture was stirred at 0 °C for 30 min
and the crude amide collected by filtration (16.74 g, 100%).– 1H NMR
(CDCl3) δ = 7.26 (m, 2H), 6.83 (m, 2H), 3.70 (s, 3H), 3.34 (br, 2H), 2.48 (m,
2H), 2.02 (t, 7.5 Hz, 2H), 1.73 (m, 2H).
General Method B
A solution of the suitable bromoalkyl derivative (9 mmol) in a large excess
of diethylamine was heated at 50 °C for 48 h. The excess amine was removed
under reduced pressure and the residue dissolved in water (100 mL), the
solution basified with sodium hydroxide and the free base extracted into
diethyl ether (3×100 mL). The combined extracts were dried over magne-
sium sulfate and concentrated to give the crude base as an oil. The base was
purified by column chromatography on silica gel eluting with a 9:1 mixture
of chloroform and methanol and the pure product was converted into the
oxalate salt by adding an ethanolic solution of oxalic acid (1.5 equiv.).
4-(4-Methoxyphenyl)butylamine
A solution of 4-(4-methoxyphenyl)butanamide (16.7 g, 86.73 mmol) in dry
dichloromethane (10 mL) was added dropwise to an ice-cold solution of
lithium aluminium hydride (10 g, 260 mmol) in dry THF (50 mL) under
nitrogen. The resulting mixture was heated under reflux for 96 h. After
cooling to 0 °C, a saturated solution of sodium sulfate was cautiously added.
The resulting mixture was heated under reflux and the solution filtered hot.
The residue was extracted with boiling THF and filtered. The combined
filtrates were dried over magnesium sulfate and concentrated under reduced
pressure. The crude amine was purified by column chromatography on silica
gel eluting with 9/1 chloroform/methanol to give a yellow oil (2.2 g, 14%).–
1H NMR (DMSO d6) δ = 7.10 (m, 2H), 6.82 (m, 2H), 3.69 (s, 3H), 2.71 (t,
7.0 Hz, 2H), 2.49 (m, 2H), 1.52 (m, 2H).
General Method C
A solution of the suitable bromoalkyl derivative (1 mmol) and pyrrolidine
(10 equiv.) in absolute ethanol (10 mL) was stirred and heated under reflux
for 24 h. The solvent and excess amine were removed under reduced pres-
sure, the residue dissolved in water (40 mL) and sodium hydroxide was added
to reach a basic pH. The free base was extracted into diethyl ether (3×40 mL)
and the combined extracts were washed with water, dried over magnesium
sulfate and concentrated to give the crude base as a brown oil. The base was
converted into the oxalate salt by adding an ethanolic solution of oxalic acid
(1.5 equiv.).
N-Ethyl[4-(4-methoxyphenyl)butyl]amine oxalate (4)
Prepared according to general method A from 4-(4-methoxyphenyl)buty-
lamine.– 1H NMR (DMSO d6) δ = 7.11 (m, 2H), 6.84 (m, 2H), 3.71 (s, 3H),
2.89 (m, 2×2H), 2.52 (t, 2H), 1.57 (m, 2×2H), 1.16 (t, 7.3 Hz, 3H).
General Method D
A suspension of the appropriately substituted phenol (15 mmol), 1,5-di-
bromopentane (2 equiv.), and water (30 mL) was vigorously stirred and
heated under reflux. A solution of sodium hydroxide (1.5 equiv.) in water
(20 mL) was added dropwise and the mixture was then stirred and heated
under reflux for 4 h. After cooling, the organic layer was extracted into
chloroform (3 × 40 mL) and the combined extracts washed with water
(40 mL) and dried over magnesium sulfate. After removal of the solvent
under reduced pressure, the residue was distilled in vacuo (oil pump) to yield
first the excess of 1,5-dibromopentane and then the product as an oil.
N-Ethyl[4-(4-nitrophenyl)butyl]amine oxalate (5)
Prepared according to general method A from 4-(4-nitrophenyl)buty-
lamine [25].– 1H NMR (DMSO d6) δ = 8.15 (m, 2H), 7.51 (m, 2H), 2.90 (m,
2×2H), 2.74 (t, 7.6 Hz, 2H), 1.63 (m, 2×2H), 1.15 (t, 7.3 Hz, 3H).
4-(4-Fluorophenyl)butanoic acid
A mixture of zinc wool (162 g, 2.48 mol), mercury(II) chloride (12.8 g,
47 mmol) and concentrated hydrochloric acid (10 mL) in water (220 mL)
was stirred for 5 min. The liquid was then decanted and to the amalgam was
added water (70 mL), concentrated hydrochloric acid (150 mL), toluene
(90 mL) and 3-(4-fluorobenzoyl)propanoic acid (50 g, 255 mmol). The reac-
tion mixture was stirred and heated under reflux for 48 h with regular
additions of concentrated hydrochloric acid (50 mL) every 6 h. After cooling,
two layers separated. The aqueous layer was diluted with water (200 mL)
and extracted into diethyl ether (3 × 100 mL). The combined organic phases
were dried over magnesium sulfate and concentrated under reduced pressure.
The crude product was distilled in vacuo to give an orange oil (39.57 g,
85%).– 1H NMR (CDCl3) δ = 7.16 (m, 2H), 6.95 (m, 2H), 2.64 (t, 2H), 2.35
(t, 2H), 1.92 (m, 2H).
N-Ethyl(4-phenylbutyl)amine hydrochloride (2)
4-Phenylbutyl acetamide [35] (7.12 g, 37 mmol) was added dropwise to a
stirred suspension of lithium aluminium hydride (4.10 g, 110 mmol) in
25 mL dry THF kept at 0 °C under nitrogen. The mixture was subsequently
heated under reflux overnight with stirring under nitrogen. The reaction
vessel was then cooled in an ice and water bath and sodium sulfate decahy-
drate was added portionwise followed by 5 mL THF. After 2.5 h, the resulting
white suspension was filtered, dried over magnesium sulfate and the crude
product obtained after removal of the solvent was distilled in vacuo to yield
a colourless liquid (3.67 g, 56%, bp = 90–94 °C/ 0.3 Torr). N-(4-Phenyl-
butyl)ethylamine (1.08 g, 61 mmol) was converted into the hydrochloride
salt by adding a cooled ethanolic solution of HCl.– 1H NMR (DMSO
d6/TMS) δ = 9.10 (m, 2H), 7.25 (m, 5H), 2.86 (m, 2×2H), 2.61 (m, 2H), 1.67
(m, 2H), 1.22 (t, 8 Hz, 3H).
4-(4-Fluorophenyl)butan-1-ol
N-Ethyl-N-methyl(4-phenylbutyl)amine oxalate (3)
To a solution of borane (1 M) in THF (180 mL, 180 mmol) stirred at 0 °C
under nitrogen was slowly added a solution of 4-(4-fluorophenyl)butanoic
acid (25 g, 137 mmol) in dry dichloromethane (150 mL). The resulting
solution was then heated under reflux for 16 h. After cooling to 0 °C, a 1:1
mixture of water and THF (75 mL) was cautiously added, the aqueous phase
was saturated with potassium carbonate, the organic layer separated and the
product extracted into diethyl ether (6 × 100 mL). The combined organic
phases were dried over magnesium sulfate and the solvent removed under
reduced pressure to leave an oil that was purified by column chromatography
on silica gel eluting with chloroform to give a colourless oil (10.19 g, 44%).–
1H NMR (CDCl3) δ = 7.16 (m, 2H), 6.94 (m, 2H), 3.63 (t, 2H), 2.59 (t, 7.4
Hz, 2H), 1.62 (m, 2×2H).
To N-ethyl(4-phenylbutyl)amine (see compound 2, 2.03 g, 11 mmol) was
added formic acid (2.75 g, 60 mmol), and formaldehyde (37% aqueous
solution, 1.1 g, 40 mmol). The mixture was heated to 65–70 °C in a water
bath with stirring for 4.5 h. After cooling, the mixture was poured into an ice
and water mixture and made strongly basic by adding sodium hydroxide
pellets. The base was extracted into diethyl ether and the crude product
obtained after concentration was distilled in vacuo (1.23 g, 56%, bp = 90–
94 °C/0.8 Torr). N-Methyl-N-4-phenylbutyl)ethylamine (1.00 g, 4.4 mmol)
was converted into the oxalate salt by adding an ethanolic solution of oxalic
acid (432 mg, 4.8 mmol).– 1H NMR (DMSO d6/TMS) δ = 7.27 (m, 5H), 3.02
(m, 2 × 2H), 2.67 (m, 2H+3H), 1.60 (m, 2×2H), 1.18 (t, 8 Hz, 3H).
Arch. Pharm. Pharm. Med. Chem. 331, 395–404 (1998)

Non-imidazole Histamine H3-Receptor Antagonists
401
1-Bromo-4-(4-fluorophenyl)butane
N,N-Diethyl(3-phenylthiopropyl)amine oxalate (10)
To a solution of 4-(4-fluorophenyl)butan-1-ol (4.98 g, 29.6 mmol) in dry
dichloromethane (200 mL) stirred at 0 °C under nitrogen was added drop-
wise a solution of phosphorus tribromide (6 mL, 17.1 g, 63.2 mmol). The
reaction mixture was then heated at 60 °C for 14 h. After cooling to 0 °C,
water was cautiously added and the organic phase separated. The product
was extracted into dichloromethane (3 × 50 mL) and the combined organic
solutions were dried over magnesium sulfate. The solvent was removed
under reduced pressure to leave an oil that was purified by column chroma-
tography on silica gel eluting with chloroform to give a yellow oil (3.62 g,
53%).– 1H NMR (CDCl3) δ = 7.10 (m, 2H), 6.95 (m, 2H), 3.40 (t, 2H), 2.60
(t, 7.4 Hz, 2H), 1.62 (m, 2×2H).
Prepared according to general method B from 1-bromo-3-phenylthio-
propane [29].– 1H NMR (D2O) δ = 7.29 (m, 5H), 2.99 (m, 4×2H), 1.79 (m,
2H), 1.08 (t, 7.3 Hz, 2×3H).
N,N-Diethyl(4-phenylthiobutyl)amine oxalate (11)
Prepared according to general method B from 1-bromo-4-phenylthiobu-
tane [29].– 1H NMR (D2O) δ = 7.27 (m, 5H), 3.01 (t, 7.3 Hz, 2H), 2.91 (m,
3×2H), 1.59 (m, 2×2H), 1.04 (t, 7.3 Hz, 2×3H).
1-Bromo-5-phenylthiopentane [32]
A mixture of thiophenol (1.82 g, 16.6 mmol), 1,5-dibromopentane (9.28
g, 40.4 mmol), sodium hydroxide ( 1.05 g, 26.3 mmol), water (50 mL),
toluene (50 mL) and a 40% aqueous solution of tetrabutylammonium hy-
droxide (1 mL) was stirred at room temperature under nitrogen for 25 min.
The organic layer was separated, washed with 10% aqueous sodium hydrox-
ide, water and dried over magnesium sulfate. After removal of the solvent
under reduced pressure, the oil was distilled in vacuo (2.28 g, 53%).–
1H NMR (CDCl3) δ = 7.23 (m, 5H), 3.39 (t, 2H), 2.90 (t, 2H), 1.72 (m, 3×2H).
N-[4-(4-Fluorophenyl)butyl]phthalimide
Potassium phthalimide (8 g, 43.2 mmol) was added to a solution of
1-bromo-4-(4-fluorophenyl)butane (6.64 g, 28.74 mmol) in anhydrous DMF
(200 mL) under nitrogen. The reaction mixture was then heated at 90 °C for
16 h. After cooling to room temperature, chloroform (200 mL) was added,
followed by water (200 mL). The two layers separated and the product was
extracted into chloroform(3 × 100 mL), the combined organic solutions were
dried over magnesium sulfate and the solvent was removed under reduced
pressure to leave a white solid. The crude product was purified by column
chromatography on silica gel elutingwithchloroform togivethe pure product
N,N-Diethyl(5-phenylthiopentyl)amine oxalate (12)
1
Prepared according to general method B from 1-bromo-5-phenylthiopen-
as a white solid (5.55 g, 65%).– H NMR (CDCl3) δ = 7.82 (m, 4H), 7.20
1
tane.– H NMR (DMSO d6) δ = 7.24 (m, 5H), 3.00 (m, 4×2H), 1.50 (m,
(m, 2H), 7.05 (m, 2H), 3.58 (t, 2H), 2.57 (t, 2H), 1.52 (m, 2×2H).
3×2H), 1.15 (t, 7.3 Hz, 2×3H).
4-(4-Fluorophenyl)butylamine
N-Ethyl(3-phenoxypropyl)amine oxalate (13)
A mixture of N-[4-(4-fluorophenyl)butyl]phthalimide (5.03 g, 17 mmol),
glacial acetic acid (150 mL) and concentrated hydrochloric acid (150 mL)
was stirred and heated under reflux for 36 h. The mixture was evaporated to
dryness, the white residue was dissolved in water, anhydrous potassium
carbonate was added and the free base extracted into chloroform (3 ×
100 mL). The combined extracts were dried over magnesium sulfate and the
solvent removed under reduced pressure to leave the product as a yellow oil
(1.17 g, 7 mmol).– 1H NMR (DMSO d6) δ = 7.17 (m, 4H), 3.58 (t, 2H), 2.50
(m, 2H), 1.52 (m, 2×2H).
Prepared according to general method A from 3-phenoxypropylamine
[28].– 1H NMR (DMSO d6) δ = 7.28 (m, 2H), 6.93 (m, 3H), 4.03 (t, 6.1 Hz,
2H), 2.98 (m, 4H), 2.04 (m, 2H), 1.17 (t, 7.2 Hz, 3H).
N,N-Diethyl(3-phenoxypropyl)amine oxalate (14)
Prepared according to general method B from 1-bromo-3-phe-
noxypropane.– 1H NMR (D2O) δ = 7.25 (m, 2H), 6.90 (m, 3H), 4.03 (t, 2H),
3.12 (m, 3×2H), 2.04 (m, 2H), 1.15 (t, 7.3 Hz, 2×3H).
N-Ethyl[4-(4-fluorophenyl)butyl]amine oxalate (6)
N,N-Diethyl(4-phenoxybutyl)amine oxalate (15)
Prepared according to general method A from 4-(4-fluorophenyl)buty-
1
Prepared according to general method B from 1-bromo-4-phenoxybu-
tane.– 1H NMR (D2O) δ = 7.24 (m, 2H), 6.90 (m, 3H), 3.98 (t, 5.9 Hz, 2H),
3.07 (m, 3×2H), 1.71 (m, 2×2H), 1.13 (t, 7.3 Hz, 2×3H).
lamine.– H NMR (DMSO d6) δ = 7.23 (m, 2H), 7.09 (m, 2H), 2.88 (m,
2×2H), 2.57 (t, 2H), 1.56 (m, 2×2H), 1.14 (t, 7.3 Hz, 3H).
N-Ethyl[4-(4-chlorophenyl)butyl]amine oxalate (7)
N,N-Diethyl(5-phenoxypentyl)amine oxalate (16)
Prepared according to general method A from 4-(4-chlorophenyl)buty-
lamine [26].– 1H NMR (DMSO d6) δ = 7.32 (m, 2H), 7.24 (m, 2H), 2.89 (m,
2×2H), 2.59 (t, 2H), 1.58 (m, 2×2H), 1.16 (t, 7.3 Hz, 3H).
Prepared according to general method B from 1-bromo-5-phenoxypentane
[30].– 1H NMR (D2O) δ = 7.24 (m, 2H), 6.93 (m, 3H), 3.95 (t, 6.3 Hz, 2H),
3.00 (m, 3×2H), 1.62 (m, 2×2H), 1.36 (m, 2H), 1.12 (t, 7.3 Hz, 2×3H).
N-Ethyl[4-(4-aminophenyl)butyl]amine trifluoroacetate (8)
N,N-Diethyl(6-phenoxyhexyl)amine oxalate (17)
N-Ethyl[4-(4-nitrophenyl)butyl]amine (770 mg, 3.47 mmol) was dis-
solved in absolute ethanol (30 mL) and the solution heated to 50 °C. Palla-
dium (5%) on carbon (100 mg) was added followed by hydrazine hydrate
(4.12 g, 82.3 mmol) in 0.5 mL portions over 10 minutes. Additional palla-
dium (5%) on carbon (100 mg) was added and the mixture was stirred at
50 °C for 72 h. After cooling, the catalyst was filtered off and the solution
concentrated to dryness. The base was purified by preparative HPLC eluting
with 90% water and 10% methanol, both containing 0.1% TFA. After
concentration, the product was dissolved in isopropanol, filtered and concen-
Prepared according to general method B from 1-bromo-6-phenoxyhexane
[31].– 1H NMR (D2O) δ = 7.23 (m, 2H), 6.89 (m, 3H), 3.93 (t, 6.4 Hz, 2H),
2.99 (m, 3×2H), 1.58 (m, 2×2H), 1.31 (m, 2×2H), 1.11 (t, 7.3 Hz, 2×3H).
N,N-Dimethyl(5-phenoxypentyl)amine oxalate (18)
1-Bromo-5-phenoxypentane (200 mg, 0.82 mmol) was added to a solution
of dimethylamine (2M) in THF (20 mL, 40 mmol) and the mixture was
heated at 55 °C for 48 h. After cooling, the solvent and excess amine were
removed under reduced pressure and the residue dissolved in water (100 mL),
the solution basified with sodium hydroxide and the free base extracted into
diethyl ether (3×100 mL). The combined extracts were dried over magne-
sium sulfate and concentrated to give the crude base as a yellow oil (151 mg,
94%). The base was purified by column chromatography on silica gel eluting
with a 3:2 mixture of chloroform and methanol and the pure product (147 mg,
0.71 mmol) was converted into the oxalate salt by adding an ethanolic
solution of oxalic acid (126 mg, 1.4 mmol).– 1H NMR (D2O) δ = 7.23 (m,
1
trated to give the product as a hygroscopic brown glassy solid.– H NMR
(DMSO d6) δ = 8.37 (br, 2H), 7.16 (m, 2H), 7.00 (m, 2H), 2.90 (m, 2×2H),
2.54 (t, 6.7 Hz, 2H), 1.54 (m, 2×2H), 1.14 (t, 7.3 Hz, 3H).
N-Ethyl(3-phenylthiopropyl)amine oxalate (9)
Prepared according to general method A from 3-phenylthiopropylamine
[27].– 1H NMR (DMSO d6) δ = 7.27 (m, 5H), 2.97 (m, 3×2H), 1.85 (m, 2H),
1.14 (t, 7.3 Hz, 3H).
Arch. Pharm. Pharm. Med. Chem. 331, 395–404 (1998)

402
Ganellin and co-workers
give the crude base as an oil. The base was converted into the oxalate salt by
adding an ethanolic solution of oxalic acid (400 mg, 4.4 mmol).– 1H NMR
(DMSO d6) δ = 7.27 (m, 2H), 6.93 (m, 3H), 3.96 (t, 6.3 Hz, 2H), 3.20 (br,
2×2H), 3.04 (m, 2H), 1.77 (m, 2×2H), 1.72 (m, 2×2H), 1.59 (br, 2×2H), 1.42
(m, 2H).
2H), 6.88 (m, 3H), 3.95 (t, 6.3 Hz, 2H), 2.99 (t, 2H), 2.71 (s 2×3H), 1.65 (m,
2×2H), 1.37 (m, 2H).
N-Ethyl-N-methyl(5-phenoxypentyl)amine oxalate (19)
A solution of 1-bromo-5-phenoxypentane (511 mg, 2.1 mmol) in N-
methylethylamine (1.24 g, 21 mmol) was stirred at room temperature for
48 h. The excess amine was removed under reduced pressure, the residue
dissolved in water (40 mL) and sodium hydroxide was added to reach a basic
pH. The free base was extracted into diethyl ether (3×40 mL) and the
combined extracts were washed with water, dried over magnesium sulfate
and concentrated to give the crude base as a yellow oil. The base was
converted into the oxalate salt by adding an ethanolic solution of oxalic acid
(180 mg, 2 mmol).– 1H NMR (DMSO d6) δ = 7.28 (m, 2H), 6.92 (m, 3H),
3.95 (t, 6.3 Hz, 2H), 3.05 (q, 7.2 Hz, 2H), 2.98 (m, 2H), 2.66 (s, 3H), 1.70
(m, 2×2H), 1.44 (m, 2H), 1.18 (t, 7.2 Hz, 3H).
4-(5-Phenoxypentyl)morpholine oxalate (25)
A solution of 1-bromo-5-phenoxypentane (785 mg, 3.2 mmol) in mor-
pholine (3.06 g, 35 mmol) was stirred and heated under reflux for 48 h. The
excess amine was removed under reduced pressure, the residue dissolved in
water (40 mL) and sodium hydroxide was added to reach a basic pH. The
free base was extracted into diethyl ether (3×40 mL) and the combined
extracts were washed with water, dried over magnesium sulfate and concen-
trated to give the crude base as a brown oil. The base was purified by column
chromatography on silica gel eluting with a 1:1 mixture of chloroform and
methanol. After removal of the solvents, the pure product was converted into
the oxalate salt by adding an ethanolic solution of oxalic acid (225 mg,
2.5 mmol).– 1H NMR (DMSO d6) δ = 7.26 (m, 2H), 6.90 (m, 3H), 3.95 (t,
6.3 Hz, 2H), 3.75 (br, 2×2H), 3.02 (br, 2×2H), 2.90 (m, 2H), 1.70 (m, 2×2H),
1.42 (m, 2H).
N-Ethyl-N-propyl(5-phenoxypentyl)amine oxalate (20)
A solution of 1-bromo-5-phenoxypentane (360 mg, 1.5 mmol) and N-
ethylpropylamine (1 g, 11 mmol) in absolute ethanol (10 mL) was stirred and
heated under reflux for 48 h. The excess amine and the solvent were removed
under reduced pressure, the residue diluted with aqueous sodium hydroxide
(40 mL) and the free base was extracted into diethyl ether (3×40 mL). The
combined extracts were washed with water, dried over magnesium sulfate
and concentrated to give the crude base as a brown oil. The base was
converted into the oxalate salt by adding an ethanolic solution of oxalic acid
(150 mg, 1.7 mmol).– 1H NMR (DMSO d6) δ = 7.27 (m, 2H), 6.92 (m, 3H),
3.95 (t, 6.2 Hz, 2H), 3.06 (m, 2H), 2.96 (m, 2×2H), 1.68 (m, 3×2H), 1.44 (m,
2H), 1.16 (t, 7.1 Hz, 3H), 0.89 (t, 7.3 Hz, 3H).
4-Methyl-1-(5-phenoxypentyl)piperazine dihydrochloride (26)
A solution of 1-bromo-5-phenoxypentane (510 mg, 2.1 mmol) in N-
methylpiperazine (2.2 g, 22 mmol) was stirred and heated under reflux for
48 h. The mixture was diluted with aqueous sodium hydroxide (40 mL), the
free base was extracted into diethyl ether (3×40 mL) and the combined
extracts were washed with water, dried over magnesium sulfate and concen-
trated to give the crude base as a brown oil. The base was converted into the
1
hydrochloride salt by adding aqueous 4N HCl (5 mL).– H NMR (DMSO
d6) δ = 7.28 (m, 2H), 6.93 (m, 3H), 3.96 (t, 6.3 Hz, 2H), 3.44 (br, 4×2H), 3.12
(br, 2H), 2.81 (br, 3H), 1.76 (m, 2×2H), 1.45 (m, 2H).
N,N-Dipropyl(5-phenoxypentyl)amine oxalate (21)
Prepared according to general method B from 1-bromo-5-phenoxypen-
tane, using dipropylamine and heating at 110 °C for 48 h.– 1H NMR (D2O)
δ = 7.24 (m, 2H), 6.89 (m, 3H), 3.96 (t, 6.3 Hz, 2H), 2.96 (m, 3×2H), 1.53
(m, 5×2H), 1.31 (m, 2×2H), 0.80 (t, 7.4 Hz, 2×3H).
1-Bromo-5-(4-fluorophenoxy)pentane
Prepared according to general method D from 4-fluorophenol.– bp:
~140 °C/1 Torr.– 1H NMR (CDCl3) δ = 6.94 (m, 2H), 6.81 (m, 2H), 3.90 (t,
6.3 Hz, 2H), 3.42 (t, 6.7 Hz, 2H), 1.92 (m, 2H), 1.78 (m, 2H), 1.60 (m, 2H).
1-(5-Phenoxypentyl)pyrrolidine oxalate (22)
A solution of 1-bromo-5-phenoxypentane (788 mg, 3.24 mmol) in pyr-
rolidine (2.56 g, 36 mmol) was stirred and heated under reflux for 24 h. The
excess amine was removed under reduced pressure, the residue dissolved in
water (40 mL) and sodium hydroxide was added to reach a basic pH. The
free base was extracted into diethyl ether (3×40 mL) and the combined
extracts were washed with water, dried over magnesium sulfate and concen-
trated to give the crude base as a yellow oil. The base was converted into the
oxalate salt by adding an ethanolic solution of oxalic acid (303 mg,
3.4 mmol).– 1H NMR (DMSO d6) δ = 7.27 (m, 2H), 6.92 (m, 3H), 3.95 (t,
6.3 Hz, 2H), 3.21 (br, 2×2H), 3.07 (m, 2H), 1.91 (m, 2×2H), 1.70 (m, 2×2H),
1.42 (m, 2H).
1-[5-(4-Fluorophenoxy)pentyl]pyrrolidine oxalate (27)
Prepared according to general method C from 1-bromo-5-(4-fluorophe-
noxy)pentane.– 1H NMR (DMSO d6) δ = 7.11 (m, 2H), 6.94 (m, 2H), 3.94
(t, 6.3 Hz, 2H), 3.23 (br, 2×2H), 3.09 (m, 2H), 1.92 (br, 2×2H), 1.71 (m,
2×2H), 1.44 (m, 2H).
1-Bromo-5-(4-chlorophenoxy)pentane [36]
Prepared according to general method D from 4-chlorophenol.– 1H NMR
(CDCl3) δ = 7.23 (m, 2H), 6.82 (m, 2H), 3.93 (t, 6.3 Hz, 2H), 3.44 (t, 6.7 Hz,
2H), 1.94 (m, 2H), 1.80 (m, 2H), 1.62 (m, 2H).
1-(5-Phenoxypentyl)piperidine oxalate (23)
1-[5-(4-Chlorophenoxy)pentyl]pyrrolidine oxalate (28)
A solution of 1-bromo-5-phenoxypentane (780 mg, 3.2 mmol) in piperid-
ine (2.93 g, 34 mmol) was stirred and heated under reflux for 48 h. The excess
amine was removed under reduced pressure, the residue dissolved in water
(40 mL) and sodium hydroxide was added to reach a basic pH. The free base
was extracted into diethyl ether (3×40 mL) and the combined extracts were
washed with water, dried over magnesium sulfate and concentrated to give
the crude base as a yellow oil. The base was converted into the oxalate salt
by adding an ethanolic solution of oxalic acid (288 mg, 3.2 mmol).– 1H NMR
(DMSO d6) δ = 7.26 (m, 2H), 6.90 (m, 3H), 3.94 (t, 6.3 Hz, 2H), 3.06 (br,
2×2H), 2.95 (m, 2H), 1.70 (m, 4×2H), 1.52 (br, 2H), 1.42 (m, 2H).
Prepared according to general method C from 1-bromo-5-(4-chlorophe-
noxy)pentane.– 1H NMR (DMSO d6) δ = 7.30 (m, 2H), 6.94 (m, 2H), 3.95
(t, 6.3 Hz, 2H), 3.20 (br, 2×2H), 3.06 (m, 2H), 1.90 (br, 2×2H), 1.70 (m,
2×2H), 1.42 (m, 2H).
1-Bromo-5-(3-chlorophenoxy)pentane
Prepared according to general method D from 3-chlorophenol.– bp: 145-
150 °C/1 Torr.–1H NMR (CDCl3) δ = 7.19 (t, 8.1 Hz, 1H), 6.92 (dd, 0.8 and
8.9 Hz, 1H), 6.89 (dd, 2.1 and 2.4 Hz, 1H), 6.78 (ddd, 0.8 and 2.4 and 8.4
Hz, 1H), 3.96 (t, 6.3 Hz, 2H), 3.45 (t, 6.8 Hz, 2H), 1.94 (m, 2H), 1.82 (m,
2H), 1.63 (m, 2H).
1-(5-Phenoxypentyl)homopiperidine oxalate (24)
A solution of 1-bromo-5-phenoxypentane (520 mg, 2.1 mmol) in ho-
mopiperidine (2.64 g, 26.6 mmol) was stirred and heated under reflux for 4 h.
The mixture was diluted with aqueous sodium hydroxide (40 mL), the free
base was extracted into diethyl ether (3×40 mL) and the combined extracts
were washed with water, dried over magnesium sulfate and concentrated to
1-[5-(3-Chlorophenoxy)pentyl]pyrrolidine oxalate (29)
Prepared according to general method C from 1-bromo-5-(3-chlorophe-
noxy)pentane.– 1H NMR (DMSO d6) δ = 7.28 (t, 8.1 Hz, 1H), 6.98 (m, 2H),
Arch. Pharm. Pharm. Med. Chem. 331, 395–404 (1998)

Non-imidazole Histamine H3-Receptor Antagonists
403
1-Bromo-5-(3-cyanophenoxy)pentane
6.89 (dd, 2.3 and 8.4 Hz, 1H), 3.98 (t, 6.3 Hz, 2H), 3.21 (br, 2×2H), 3.07 (m,
2H), 1.90 (br, 2×2H), 1.70 (m, 2×2H), 1.42 (m, 2H).
Prepared according to general method D from 3-hydroxybenzonitrile.–
1H NMR (CDCl3) δ = 7.36 (dd, 7.5 and 7.2 Hz, 1H), 7.23 (ddd, 7.6 and 1.2
and 1.2 Hz, 1H), 7.13 (m, 2H), 3.98 (t, 6.3 Hz, 2H), 3.45 (t, 6.7 Hz, 2H), 1.92
(m, 2H), 1.84 (m, 2H), 1.64 (m, 2H).
1-[5-(4-Aminophenoxy)pentyl]pyrrolidine dioxalate (30)
A solution of 1-[5-(4-nitrophenoxy)pentyl]pyrrolidine oxalate (see com-
pound 32, 210 mg, 0.57 mmol) in a mixture of methanol (10 mL) and
absolute ethanol (10 mL) was vigorously stirred at room temperature under
hydrogen in the presence of palladium (5%) on carbon (100 mg) for 3 h. The
catalyst was filtered off and the solvents removed under reduced pressure.
The residue was dissolved in methanol and oxalic acid was added (100 mg,
1.1 mmol).– 1H NMR (DMSO d6) δ = 6.70 (m, 4H), 6.50 (br, 2H), 3.85 (t,
6.3 Hz, 2H), 3.27 (br, 2×2H), 3.10 (m, 2H), 1.92 (br, 2×2H), 1.60 (m, 2×2H),
1.42 (m, 2H).
1-[5-(3-Cyanophenoxy)pentyl]pyrrolidine oxalate (35)
Prepared according to general method C from 1-bromo-5-(3-cyanophe-
noxy)pentane.– 1H NMR (DMSO d6) δ = 7.49 (dd, 7.8 and 7.9 Hz, 1H), 7.40
(m, 2H), 7.28 (m, 1H), 4.05 (t, 6.4 Hz, 2H), 3.23 (br, 2×2H), 3.10 (m, 2H),
1.92 (br, 2×2H), 1.77 (m, 2H), 1.69 (m, 2H), 1.45 (m, 2H).
Pharmacology. General Procedures
1-Bromo-5-(4-methylphenoxy)pentane
In vitro
Prepared according to general method D from para cresol.– 1H NMR
(CDCl3) δ = 7.09 (m, 2H), 6.81 (m, 2H), 3.96 (t, 6.3 Hz, 2H), 3.45 (t, 6.8 Hz,
2H), 2.30 (s, 3H), 1.95 (m, 2H), 1.81 (m, 2H), 1.63 (m, 2H).
Compounds were tested for their potencies as histamine H3-receptor
antagonists in an assay using K+-evoked depolarization-induced release of
[3H] histamine from synaptosomes of rat cerebral cortex as described [33]
.
1-[5-(4-Methylphenoxy)pentyl]pyrrolidine oxalate (31)
In vivo
The compounds were tested in vivo by administration as the salt form
indicated in Table 2 as a suspension in 1% methylcellulose per os to groups
Prepared according to general method C from 1-bromo-5-(4-methylphe-
noxy)pentane.– 1H NMR (DMSO d6) δ = 7.05 (m, 2H), 6.79 (m, 2H), 3.90
(t, 6.3 Hz, 2H), 3.20 (br, 2×2H), 3.06 (m, 2H), 1.90 (br, 2×2H), 1.68 (m,
2×2H), 1.42 (m, 2H).
of at least six male Swiss mice (weighing 18–22g) as described [33]
.
References
1-Bromo-5-(4-nitrophenoxy)pentane [36]
[1] J.-M. Arrang, M. Garbarg, J.-C. Schwartz, Neuroscience 1987, 23,
Prepared according to general method D from 4-nitrophenol.– bp: 196–
198 °C/2 Torr.– 1H NMR (CDCl3) δ = 8.21 (m, 2H), 6.95 (m, 2H), 4.07 (t,
6.3 Hz, 2H), 3.46 (m, 2H), 1.92 (m, 2×2H), 1.62 (m, 2H).
149–157.
[2] J.-M. Arrang, M. Garbarg, J.-C. Schwartz, Nature (London) 1983, 302,
832–837.
[3] E. Schlicker, B. Malinowska, , M. Kathmann, M. Göthert, Fundam.
Clin. Pharmacol. 1994, 8, 128–137.
1-[5-(4-Nitrophenoxy)pentyl]pyrrolidine oxalate (32)
Prepared according to general method C from 1-bromo-5-(4-nitrophe-
noxy)pentane.– 1H NMR (DMSO d6) δ = 8.19 (m, 2H), 7.13 (m, 2H), 4.12
(t, 6.3 Hz, 2H), 3.19 (br, 2×2H), 3.07 (m, 2H), 1.90 (br, 2×2H), 1.76 (m,
2×2H), 1.44 (m, 2H).
[4] R. Leurs, P. Blandina, C. Tedford, H. Timmerman, Trends Pharmacol.
Sci. 1998, 19, 177–183.
[5] H. Stark, E. Schlicker, W. Schunack, Drugs Future 1996, 21, 507–520.
[6] J.-M. Arrang, M. Garbarg, J.-C. Lancelot, J.-M. Lecomte, H. Pollard,
M. Robba, W. Schunack, J.-C. Schwartz, Nature (London) 1987, 327,
117–123.
1-Bromo-5-(3-nitrophenoxy)pentane
Prepared according to general method D from 3-nitrophenol. Heated under
reflux for 6 h.– bp: 190–196 °C/1 Torr.– 1H NMR (CDCl3) δ = 7.76 (ddd,
8.1 and 1.3 and 0.8 Hz, 1H), 7.67 (dd, 2.3 and 2.3 Hz, 1H), 7.38 (dd, 8.2 and
8.2 Hz, 1H), 7.18 (ddd, 8.2 and 3.3 and 2.5 Hz, 1H), 4.01 (t, 6.3 Hz, 2H),
3.42 (t, 6.7 Hz, 2H), 1.93 to 1.78 (m, 4H), 1.62 (m, 2H).
[7] E. Sakurai, E. Gunji, Y. Iizuka, N. Hikichi, K. Maeyama, T. Watanabe,
J. Pharm. Pharmacol. 1994, 46, 209–212.
[8] F. Bordi, S. Rivara, A. Caretta, V. Ballabeni, E. Barocelli, P.V Plazzi,
Farmaco, 1997, 52, 457–462.
[9] W.D. Stein, The Movement of Molecules Across Cell Membranes;
Academic Press: New York, 1967, pp 65–91.
1-[5-(3-Nitrophenoxy)pentyl]pyrrolidine oxalate (33)
[10] H.S. Chadha, M.H. Abraham, R.C. Mitchell, Bioorg. Med. Chem. Lett.
1994, 4, 2511–2516.
Prepared according to general method C from 1-bromo-5-(3-nitrophe-
noxy)pentane.– 1H NMR (DMSO d6) δ = 7.81 (dd, 2.2 and 8.1 Hz, 1H), 7.70
(dd, 2.3 and 2.3 Hz, 1H), 7.58 (dd, 8.2 and 8.2 Hz, 1H), 7.42 (dd, 2.4 and 8.3
Hz, 1H), 4.11 (t, 6.4 Hz, 2H), 3.23 (br, 2×2H), 3.10 (m, 2H), 1.92 (br, 2×2H),
1.78 (m, 2H), 1.71 (m, 2H), 1.47 (m, 2H).
[11] R.C. Young, R.C. Mitchell, T. H. Brown, C.R. Ganellin, R. Griffiths,
M. Jones, K.K. Rana, D. Saunders, I.R. Smith, N.E. Sore, T.J. Wilks.
J. Med. Chem. 1988, 31, 656–671.
[12] J.-M. Arrang, M. Garbarg, T.T. Quach, M.D.T. Tuong, E. Yeramian,
1-Bromo-5-(4-cyanophenoxy)pentane [36]
J.-C. Schwartz, Eur. J. Pharmacol. 1985, 111, 73–84.
[13] J.-M. Arrang, N. Defontaine, J.-C. Schwartz, Eur. J. Pharmacol. 1988,
157, 31–35.
Prepared according to general method D from 4-hydroxybenzonitrile.–
1H NMR (CDCl3) δ = 7.58 (m, 2H), 6.93 (m, 2H), 4.02 (t, 6.3 Hz, 2H), 3.45
(t, 6.7 Hz, 2H), 1.93 (m, 2H), 1.84 (m, 2H), 1.64 (m, 2H).
[14] J.-C. Schwartz, J.-M. Arrang, M. Garbarg, H. Pollard, Agents Actions
1990, 30, 13–23.
1-[5-(4-Cyanophenoxy)pentyl]pyrrolidine oxalate (34)
[15] C.R. Ganellin, D. Jayes, Y.S. Khalaf, W. Tertiuk, J.-M. Arrang, N.
Defontaine, J.-C. Schwartz, Coll. Czech. Chem. Commun. 1991, 56,
2448–2455.
Prepared according to general method C from 1-bromo-5-(4-cyanophe-
noxy)pentane.– 1H NMR (DMSO d6) δ = 7.50 (m, 2H), 7.09 (m, 2H), 4.06
(t, 6.3 Hz, 2H), 3.20 (br, 2×2H), 3.07 (m, 2H), 1.90 (br, 2×2H), 1.75 (m, 2H),
1.66 (m, 2H), 1.43 (m, 2H).
[16] M. Kathmann, E. Schlicker, M. Göthert, Psychopharmacol. 1994, 116,
464–468.
Arch. Pharm. Pharm. Med. Chem. 331, 395–404 (1998)

404
Ganellin and co-workers
[17] K. Kiec-Kononowicz, X. Ligneau, H. Stark, J.-C. Schwartz, W.
[26] F.E. Ali, P.A. Dandridge, J.G. Gleason, R.D. Krell, C.H. Kruse, P.G.
Schunack, Arch. Pharm. Pharm. Med. Chem. 1995, 328, 445–450.
Lavanchy, K.M. Snader, J. Med. Chem. 1982, 25, 947–952.
[27] D.H. Boschelli, D.T. Connor, M.E. Lesch, D.J. Schrier, Bioorg. Med.
Chem. 1996, 4, 557–562.
[18] K. Kiec-Kononowicz, X. Ligneau, J.-C. Schwartz, W. Schunack, Arch.
Pharm. Pharm. Med. Chem. 1995, 328, 469–472.
[28] O.W. Lever, L.N. Bell, H.M. McGuire, R. Ferone, J. Med. Chem. 1985,
28, 1870–1874.
[19] W.M.P.B. Menge, G. Romeo, S. Gobbi, B. Limmen, C. Enguehard, H.
Timmerman, Poster P 111; K. Walczynski, R. Guryn, H. Timmerman,
O.P. Zuiderveld, Poster P 119, 15th EFMC International Symposium
on Medicinal Chemistry, Edinburgh, Scotland, 6–10 September 1998.
[29] P. Bakuzis, M.L.F. Bakuzis, C.C. Fortes, R. Santoa, J. Org. Chem.
1976, 41, 2769–2770.
[30] P. Gaubert, R.P. Linstead, H.N. Rydon, J. Chem. Soc. 1937, 1974–
[20] L. Werbrouck, A.A.H.P. Megens, R.A. Stokbroekx, C.J.E. Niemegeers,
1979.
Drug Dev. Res. 1991, 24, 41–51.
[31] F.J. Buckle, F.L. Pattison, B.C. Saunders, J. Chem. Soc. 1949, 1471–
[21] E.J.Ariens, A.M. Simonis, Arch. Int. Pharmacodyn. 1960, 127, 479–
1479.
496.
[32] R.D. Westland, J.L. Holmes, M.L. Mouk, D.D. Marsh, R.A. Cooley Jr,
[22] D.G. Cooper, R.C. Young, G.J. Durant, C.R. Ganellin in Comprehen-
sive Medicinal Chemistry, 1990, 3, pp 350–364, Ed. J.C. Emmett,
Pergamon: Oxford.
J.R. Dice, J. Med. Chem. 1968, 11, 1190–1201.
[33] C.R. Ganellin, A. Fkyerat, B. Bang-Andersen, S. Athmani, W. Tertiuk,
M. Garbarg, X. Ligneau, J.-C. Schwartz, J. Med. Chem. 1996, 39,
3806–3813.
[23] R. Lipp, W. Schunack, J.-M. Arrang, M. Garbarg, J.-C. Schwartz,
Poster P 119, 10th EFMC International Symposium on Medicinal
Chemistry, Budapest, Hungary, August 1988. H. Stark, R. Lipp, J.-M.
Arrang, M. Garbarg, J.-C. Schwartz, W. Schunack, Eur. J. Med. Chem.
1994, 29, 695–700.
[34] A. Piripitsi, Synthesis and Structure-Activity Studies of Novel Com-
pounds Acting at Histamine H3 Receptors. Ph.D. Thesis, University of
London, 1996.
[35] V.G Devries, J.D. Bloom, M.D. Dutia, A.S. Katocs, E.E. Largis, J. Med.
Chem. 1989, 32, 2318–2325.
[24] Y.S. Khalaf. Synthesis and Structure-Activity Studies of Novel H3-Re-
ceptor Histamine Antagonists. Ph.D Thesis, University of London,
1990, p 101.
[36] J. Marquet, E. Cayón, X. Martin, F. Casado, I. Gallardo, M. Moreno,
J.M. Lluch, J. Org. Chem. 1995, 60, 3814–3825.
[25] W.A. Denny, B.F. Cain, G.J. Atwell, C. Hansch, A. Panthananickal, A.
Leo, J. Med. Chem. 1982, 25, 276–315.
Received: October 5, 1998 [FP339]
Arch. Pharm. Pharm. Med. Chem. 331, 395–404 (1998)