(Partial) agonist/antagonist properties of novel diarylalkyl carbamates on histamine H3 receptors

Article abstract of DOI:10.1016/S0968-0896(00)00050-X

In the search for new ligands of the histamine H₃ receptor, novel diarylalkyl carbamates (1-19 were synthesized as derivatives of 3-(1H- imidazol-4-yl)propanol and -ethanol. Carbamates were built up via isocyanates either from corresponding amines by reaction with diphosgene or from related carboxylic acid/diphenylphosphoryl azide and the alcoholic component. Sterically hindered amines were prepared in a two-step reaction sequence from corresponding ketones. Some of the title compounds showed (partial) agonist activity at the histamine H₃ receptor in vitro and in vivo. Diphenylmethyl carbamate 2 was identified as a new lead structure (ED₅₀ = 5.3 ± 2.6 mg/kg po, α = 1.0). Aromatic substitution in ortho- or para-positions of 2 led to a loss of agonist activity. meta-Substitution was tolerated to some extent. These effects seemed to be caused by steric rather than electronic properties of the substituents. An investigation of exchange of one or both phenyl rings of 2 by heterocyclic rings led to the highly active and selective thienyl derivative 18 (ED₅₀ = 3.4 ± 1.4 mg/kg po, α = 1.0). These new (partial) agonists of the histamine H₃ receptor might serve as pharmacological tools for investigating molecular aspects of the H₃ receptor or as possible centrally acting therapeutic agents with oral bioavailability. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(00)00050-X

Bioorganic & Medicinal Chemistry 8 (2000) 1139±1149
(Partial) Agonist/Antagonist Properties of Novel Diarylalkyl
Carbamates on Histamine H3 Receptors
Astrid Sasse, a Holger Stark, a Xavier Ligneau, b Sigurd Elz, a Sibylle Reidemeister, a
C. Robin Ganellin, c Jean-Charles Schwartz d and Walter Schunack a,*
aInstitut fur Pharmazie, Freie Universitat Berlin, Konigin-Luise-Strasse 2+4, 14195 Berlin, Germany
È
È
È
bLaboratoire Bioprojet, 30 rue des Francs-Bourgeois, 75003 Paris, France
cDepartment of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street,
London WC1H 0AJ, UK
d
Â
Unite de Neurobiologie et Pharmacologie Moleculaire (U. 109), Centre Paul Broca de l'INSERM,
Â
Â
2ter rue d'Alesia, 75014 Paris, France
Received 28 September 1999; accepted 20 January 2000
AbstractÐIn the search for new ligands of the histamine H3 receptor, novel diarylalkyl carbamates (1±19) were synthesized as
derivatives of 3-(1H-imidazol-4-yl)propanol and -ethanol. Carbamates were built up via isocyanates either from corresponding
amines by reaction with diphosgene or from related carboxylic acid/diphenylphosphoryl azide and the alcoholic component. Steri-
cally hindered amines were prepared in a two-step reaction sequence from corresponding ketones. Some of the title compounds
showed (partial) agonist activity at the histamine H3 receptor in vitro and in vivo. Diphenylmethyl carbamate 2 was identi®ed as a
new lead structure (ED50=5.3‹2.6 mg/kg po, a=1.0). Aromatic substitution in ortho- or para-positions of 2 led to a loss of agonist
activity. meta-Substitution was tolerated to some extent. These e€ects seemed to be caused by steric rather than electronic proper-
ties of the substituents. An investigation of exchange of one or both phenyl rings of 2 by heterocyclic rings led to the highly active
and selective thienyl derivative 18 (ED50=3.4‹1.4 mg/kg po, a=1.0). These new (partial) agonists of the histamine H3 receptor
might serve as pharmacological tools for investigating molecular aspects of the H3 receptor or as possible centrally acting ther-
apeutic agents with oral bioavailability. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Classical agonists of the histamine H3 receptor, e.g., (R)-
a-methylhistamine6 and imetit7,8 (cf. Fig. 1), consist of an
imidazole nucleus, an alkyl spacer, and a basic moiety
which is protonated under physiological conditions.
Apart from this construction pattern, some partial ago-
nists lacking a second basic moiety have also been descri-
bed recently, e.g., iodoproxyfan9 and FUB 40710 (Fig. 1).
The histamine H3 receptor was discovered in 1983 by
Arrang et al. as an inhibitory presynaptic autoreceptor
modulating the synthesis and release of histamine.1,2 H3
heteroreceptors were also identi®ed on neurons releasing
other important neurotransmitters, e.g. dopamine, ser-
otonin, noradrenaline, glutamate, and acetylcholine.3
Therapeutic targets of histamine H3-receptor agonists
might be, e.g., neurogenic airway in¯ammation, migraine,
and sleep disorders.4 Very recently, the human hista-
mine H3 receptor cDNA has been cloned.5 Research
into the existence of receptor subtypes, species varia-
tions, and signal transduction of the histamine H3
receptor has now gained fresh impetus. Highly selective
and potent ligands, both agonists and antagonists, are
needed as pharmacological tools for such studies.
Depending on the test model, these compounds have
been described as antagonists, partial or even full
agonists.9 11 The aliphatic ether FUB 407 displays full
agonism under in vivo conditions after oral administra-
tion to Swiss mice,10 whereas iodoproxyfan is inactive in
this test system.11 Carbamates with partial agonist
activity in vitro and in vivo, e.g., FUB 475 (Fig. 1), have
also been described.10 Structure±activity relationships of
agonists lacking a second basic moiety do not seem to
follow a consistent line, as they are structurally diverse,
e.g., carbamates and ethers with aliphatic and aromatic
substituents (Fig. 1). Diphenylmethyl ethers have
been described as possessing combined histamine H1-
and H3-receptor antagonist properties without the
*Corresponding author. Tel.:+49-30-838-53278; fax:+49-30-838-
52242; e-mail: sieker@schunet1.pharmazie.fu-berlin.de
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00050-X

1140
A. Sasse et al. / Bioorg. Med. Chem. 8 (2000) 1139±1149
relationships are discussed. Additionally, heteroaro-
matic exchange of one or both phenyl rings of the
diphenylmethyl residue was investigated. For target
carbamates, two functional in vitro and one in vivo test
determining the modulatory activity at the histamine H3
receptor were conducted. Furthermore, the receptor
pro®le of selected compounds regarding histamine H1
and H2 receptors was determined.
Results and Discussion
Chemistry
Figure 1.
Target molecules (1±19) were prepared as shown in
Scheme 1. 2-(1H-Imidazol-4-yl)ethanol hydrochloride
(20) was obtained from 1,4-dihydroxybutanone and
formamidine acetate according to Dziuron and Schu-
nack.13 3-(1H-Imidazol-4-yl)propanol hydrochloride
(21) was prepared from urocanic acid as described by
Stark et al. in the triphenylmethyl protected form and
subsequently deprotected under acidic conditions.11
observation of any agonist activity.12 Due to this fact it
was surprising that related diphenylalkylcarbamates (1±
3) possessed (partial) agonist activity at histamine H3
receptors with high selectivity against H1 receptors.
With these initial results diphenylmethylcarbamate 2
was identi®ed as a new lead structure. In search of his-
tamine H3-receptor (partial) agonists, we have prepared
a series of substituted diphenylmethyl carbamates (8±
16). For these derivatives of the lead 2 structure±activity
Carbamates 1±4 and 6±19 were synthesized from the
corresponding amines (1c, 2c, 4c, 6c±19c) by reaction
Scheme 1. Synthesis of compounds 1±19. For residue R of the target molecules please refer to Tables 1 and 2, p=0 for 1, p=1 for 2±19; (i)
NH2OHÂHCl, Na2CO3, EtOH, re¯ux, 1±96 h; yield: 55±81%; (ii) Pd/C, H2 (3±4 bar), MeOH, rt, 2±4 h, yield: 33±70%; (iii) NaBH4/TiCl4, 1,2-
dimethoxyethane, 0 ꢀC!rt, 12±168 h, yield: 29±60%; (iv) 3-(1H-imidazol-4-yl)propanolÂHCl (21), diphenylphosphoryl azide, triethylamine, diox-
ane, re¯ux, 18 h, yield: 44%; (v) diphosgene, cat. charcoal, ethylacetate, 60 ꢀC, 4 h; (vi) triethylamine (cat.), acetonitrile, re¯ux, 12 h, yield: 3±92%; 1:
3-(1H-imidazol-4-yl)ethanolÂHCl (20), 2±19: 3-(1H-imidazol-4-yl)propanolÂHCl (21).

A. Sasse et al. / Bioorg. Med. Chem. 8 (2000) 1139±1149
1141
with trichloromethyl chloroformate (diphosgene). The
intermediate isocyanate was carefully isolated from sol-
vent-diphosgene mixture by distillation and added to 20
resulting in 1, and to 21 yielding 2±4 and 6±19. Com-
pound 3 was prepared from the same amine (1c) as 1.
Appropriate amines were synthesized from correspond-
ing ketones by a two step reaction sequence (Scheme 1).
A direct reductive amination of ketones by heterogenous
catalysis to amines under standard conditions was not
successful (not shown), probably due to steric hindrance
of the diaryl ketone structure. Thus, ketones (8a±13a,
15a±18a) were transformed to oximes (8b±13b, 15b±18b)
with NH2OHÂHCl in good yields by standard proce-
dures. Oximes were reduced to amines by Pd/C catalyzed
hydrogenation under pressure or by using NaBH4/TiCl4.
The reduction procedure depended on the nature of
substitution of diphenylmethyl oximes. Chlorine-sub-
stituted diphenylmethanone oximes (12b, 13b, 15b), and
thienyl-substituted methanone oximes (18b, 19b) were
reduced by NaBH4/TiCl4 as they could not be prepared
by catalytic reduction. Utilizing Pd/C-catalyzed reduc-
tion, aromatic chlorine substituents (12b, 13b, 15b) were
cleaved o€ and thienyl containing methanone oximes
(18b, 19b) poisoned the catalyst. Methyl- (8b±11b),
¯uorosubstituted (16b) diphenylmethanone oximes, and
phenyl-(3-pyridyl)methanone oxime (17b) were hydro-
genated smoothly with Pd/C under pressure (3±4 bar).
Table 1. Chemical structures and potencies of 1±7 at histamine H3
receptors in vitro and in vivo in rodents
No. m R
EC50 (nM)a ab Ki (nM)c ED50 (mg/kg)d ab
‹SEM
‹SEM ‹SEM
1
2
3
4
5
0
1
1
1
1
>10,000
n.c.e > 1500 ꢁ20
ꢂ1
1.0
0.8
Ð
n.c.e
43‹27
n.c.e
0.20 26‹14
5.3‹2.6
0.28 17‹3
2.0‹0.3
0.22 29‹18 >10
A di€erent approach of carbamate synthesis was per-
formed for compound 5. Starting with the correspond-
ing carboxylic acid (5d), 5 was built up in a two-step,
one-pot reaction with diphenylphosphoryl azide
(DPPA) according to a modi®ed Curtius reaction, and
then with 21 (Scheme 1).14
Ðf ꢃ500
>10
Ð
Since pharmacological testing revealed no signi®cant
di€erences between mono- or disubstituted diarylmethyl
derivatives, separation into enantiomers of chiral com-
pounds was not considered worth while.
6
7
1
1
Ðf
Ðf
13‹8g >10
Ð
Ð
In vitro and in vivo potency on histamine H3 receptors in
rodents
13‹3 2.3‹0.5
Novel carbamates were tested in vitro on synaptosomes
of rat cerebral cortex on their ability to modulate K+-
evoked depolarization-induced [3H]histamine release
after preloading of synaptosomes with [3H]l-histidine.7
Modulation of in vivo Nt-methylhistamine (Nt-MeHA)
levels in cerebral cortex was determined after po
administration to Swiss mice.7 As activation of the his-
tamine H3 autoreceptor inhibits synthesis and release of
histamine, agonists decrease whereas antagonists
increase the level of Nt-MeHA, the main metabolite of
histamine in the central nervous system. Whereas chan-
ges in Nt-MeHA levels might re¯ect actions of the drugs
at targets other than the H3 receptor (e.g., histidine
decarboxylase or histamine N-methyltransferase), the
latter seem very unlikely taking into account their
structure and activity in vitro.
Imetith
2.8‹0.7i 1.0
1.0‹0.3i
1.0
aFunctional assay on synaptosomes of rat cerebral cortex;7 com-
pounds tested as agonists.
bIntrinsic activity.
cFunctional assay on synaptosomes of rat cerebral cortex; com-
7
pounds tested as antagonists.
dCentral assay with po administration of compounds to mice.
en.c.=not calculable.
fNo agonism evidenced.
g57% of maximum e€ect.
hRefs 7 and 8.
iRef 7.
anity for the histamine H3 receptor. 3-(1H-Imidazol-
4-yl)propyl homologue of 1, compound 3, displayed
calculable partial agonist activity on both test systems in
vitro and in vivo. When tested as an antagonist 3
showed high potency at the histamine H3 receptor
As shown in Table 1, compound 1 showed some agonist
activity in vitro as well as in vivo, which could not be
determined exactly due to low intrinsic activity and

1142
A. Sasse et al. / Bioorg. Med. Chem. 8 (2000) 1139±1149
(Ki=17 nM). Thus, all of the following compounds con-
tained 3-(1H-imidazol-4-yl)propyl as a central building
block. Further variations in chain length of the substituent
on the carbamate nitrogen (2 and 4) led to the diphe-
nylmethyl substituted lead compound 2, which showed full
intrinsic activity under in vivo conditions (ED50=5.3mg/
kg po, a=1.0). The corresponding 3,3-diphenylpropyl
homologue 4 was inactive under in vivo conditions.
in ortho- or para-positions led to the same pharmacolo-
gical e€ect, suggesting that steric rather than electronic
e€ects may be responsible for the low potency or inactivity
at the histamine H3 receptor. In agreement with this
hypothesis para,para-di¯uoro-substituted derivative 16
retained at least in vitro antagonist potency (Ki=54 nM).
However, no agonist activity was observed for 16.
Obviously, the rather small ¯uoro substituents did not
detract 16 from interaction with the receptor protein,
although induction of a large conformational change was
prevented, thus 16 showed purely antagonist behaviour.
Quaternization of the carbon atom next to the carba-
mate nitrogen of the new lead structure 2 by an addi-
tional methyl group led to in vitro and in vivo inactive 5
(Table 1). 1,2-Diphenylethyl substituted derivative 6
showed only antagonist behaviour in vitro; interestingly
the maximum antagonist e€ect reached was only 57%.
As this compound displays non-competitive antagonist
behaviour, terminal diaryl substitutition in this series
seemed to be important for either competitive antago-
nist or (partial) agonist activity. Increased rigidity of the
diphenylmethyl substituent of 2 as accomplished in 7 led
to pure antagonist behaviour.
meta-Substituted derivatives of 2, e.g., 9 and 13, showed
weak agonist activity under in vitro conditions. How-
ever, due to low intrinsic activities of 9 and 13 EC50-
values were not calculable. meta-Methyl-substituted 9
displayed weak agonist action in vivo, whereas the other
meta-substituted derivative 13 was not active. Aromatic
substitution of lead compound 2 in various positions led
in each case to a less active compound in vivo. Only
meta-substitution was tolerated as agonist activity was
retained to some extent (9).
Aromatic substitution of the diphenylmethyl residue of
2 with methyl (8±11), chloro (12±15), and ¯uoro (16)
groups led to interesting structure±activity relationships
(Table 2). Methyl substitution in ortho- or para-posi-
tions (8, 10 and 11) led to a dramatic decrease in H3-
receptor anity in vitro and inactivity under in vivo
conditions. The same e€ect was observed with chloro
substituted analogues (12, 14 and 15). The mesomeric as
well as the inductive e€ects of methyl and chloro sub-
stituents are clearly di€erent, nevertheless substitution
Replacement of one or both phenyl rings by heterocycles
was achieved with compounds 17±19. However, pyridyl-
substituted 17 displayed only antagonist properties in
vitro and in vivo. Introduction of thiophene (18, 19) led to
(partial) agonists in vitro and in vivo. Monothienyl sub-
stituted 18 was equipotent to 2 with full intrinsic activity
in vivo (ED50=3.4 mg/kg po, a=1). Partial agonist
activity was observed for the dithienyl derivative 19 in
vivo (ED50=3.0 mg/kg po, a=0.8).
Table 2. Chemical structures and potencies of lead compound 2 and analogues 8±19 at histamine H3 receptors in vitro and in vivo in rodents
No.
R1
R2
m
n
X
Y
EC50 (nM)a
‹ SEM
ab
Ki (nM)c
‹ SEM
ED50 (mg/kg)d
‹ SEM
ab
2
8
9
H
H
H
H
CH3
H
H
H
Cl
F
H
1
1
1
1
1
1
1
1
1
1
1
0
0
1
1
1
1
1
1
1
1
1
1
1
1
0
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
S
n.c.e
>10,000
n.c.e
0.2
Ð
0.21
Ðf
Ð
Ðf
0.10
Ðf
Ðf
Ðf
Ðf
0.27
26‹14
ꢃ1500
5.3‹2.6
>10
1.0
Ð
ꢁ1
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
1.0
0.8
ortho-CH3
meta-CH3
para-CH3
para-CH3
ortho-Cl
meta-Cl
para-Cl
para-Cl
para-F
H
31‹10
279‹140
>1500
380‹100
21‹5
ꢁ30
10
11
12
13
14
15
16
17
18
19
>10
>10
>10,000
n.c.e
>10
>10
>10
>10
137‹36
258‹61
54‹22
96‹35
14‹4
ꢁ10
H
H
H
>10
3.4‹1.4
3.0‹1.9
H
H
S
S
557‹196
n.d.g
n.d.g
aFunctional assay on synaptosomes of rat cerebral cortex;7 compounds tested as agonists.
bIntrinsic activity.
cFunctional assay on synaptosomes of rat cerebral cortex; 7 compounds tested as antagonists.
dCentral assay with po administration of compounds to mice.
en.c.=not calculable.
fNo agonism evidenced.
gn.d.=not determined.

A. Sasse et al. / Bioorg. Med. Chem. 8 (2000) 1139±1149
1143
Steric requirements for (partial) agonists of dia-
rylmethyl carbamates at the histamine H3 receptor seem
to be very distinct. Aromatic substitution or increasing
rigidity of the lead diphenylmethyl carbamate 2 was not
tolerated well, except for meta-substitution (9, 13),
which retained some agonist activity. Phenylthie-
nylmethyl exchange (18) of the diphenylmethyl moiety
of 2 was tolerated, however. Partial agonist activity was
observed for dithienylmethyl substituted 19 in vivo.
presence of diarylalkyl moieties did not generally lead to
low selectivity (H3 versus H1). Highest potency on his-
tamine H1-receptors was observed for 4 (pA2=6.5).
Most compounds showed non-competitive antagonist
behaviour on histamine H1 and H2 receptors (pD02
ꢂ5.4). Highest selectivity was determined for the new
lead compound 2 and its monothienyl analogue 18
(440:1, 1000:1, respectively) for H3 versus H1 and H2
receptors.
Since partial agonists generally cause lower receptor
down regulation or desentization, these novel receptor
activating agents might display potential bene®cial
e€ects from a therapeutic point of view.15
Conclusions
Novel carbamates with diarylalkyl structure were syn-
thesized. Some of the new compounds showed (partial)
agonist activity in vitro and in vivo at the histamine H3
receptor despite their structural di€erence to classical
H3-receptor agonists. Diphenylmethyl carbamate 2 was
identi®ed as a new lead (ED50=5.3‹2.6 mg/kg po,
a=1.0). Increased rigidity of the diphenylmethyl sub-
stituent (7) led to a loss of agonist activity. Substitution
in ortho- and para-position of the diphenylmethyl moiety
revealed that steric rather than electronic e€ects were
responsible for the decreased antagonist anity and lost
agonist activity at the histamine H3 receptor. Only meta-
substitution was tolerated as decreased partial agonist
activity was maintained. Replacement of one or both
phenyl rings by thiophene (18, 19) led to equie€ective
derivatives of 2 in vivo. Full agonism was observed for
monothienyl substituted 18 (ED50=3.4‹1.4 mg/kg po,
a=1.0). Under in vitro conditions on synaptosomes of
rat cerebral cortex partial agonism was observed for 2
and 18. Selectivity of (partial) agonists 2 and 18 for H3
receptors was high with respect to histamine H1 and H2
receptors. These diphenylmethyl and phenylthienylmethyl
carbamates seem to be the parent compounds for a new
class of histamine H3-receptor (partial) agonists as phar-
macological tools and as possible therapeutic agents with
central activity after po administration.
Histamine receptor pro®le of selected compounds
The receptor pro®le regarding other histamine receptors
(H1 and H2) of selected compounds was determined on
functional models of the guinea pig (Table 3).16 For
determination of histamine H3 receptor modulation a
second functional in vitro model on guinea pig ileum
was conducted (Table 3).17,18 With this peripheral
model no partial agonism was evidenced with any of the
new compounds. These di€erences in pharmacological
action in vivo (mouse) and in vitro (rat, guinea pig)
might be caused by a varying receptor reserve or species
variants of the histamine H3-receptor protein as well as
by di€erent experimental conditions within the assays.
Comparable antagonist potencies were observed for
most compounds in these two functional H3-receptor
models (jpA2 (guinea pig) pKi (rat)j ꢂ 0.4 log units).
Only 4, 6, and meta-substituted 9 and 13 showed di€er-
ent antagonist potencies in the two test models. Similar
discrepancies in the two functional test models of the
histamine H3 receptor have been observed for alkyl
cabamates.19 Structural similarity of the new com-
pounds to histamine H1-receptor antagonists3 due to the
Table 3. Receptor pro®le of selected compounds (1±7, 9, 12±15 and
18)
Experimental
Chemistry
H3
H2
H1
pD02
pD02
b
c
d
No.
pKia
pA2
General procedures. Melting points were determined on
an Electrothermal IA 9000 digital or a Buchi 512 appa-
ratus and are uncorrected. For all compounds 1H NMR
spectra were recorded on a Bruker DPX 400 Avance
(400 MHz) spectrometer. Chemical shifts are expressed
1
2
3
4
5
6
7
9
12
13
14
15
18
<5.8
7.6
7.8
6.2
7.2
7.5
6.7
6.3
6.4
7.8
6.8
6.1
6.9
6.8
6.3
8.0
4.9
4.6
5.1
5.3
5.2
5.0
4.9
4.7
4.5
4.7
7.5
6.5e
4.9
1
<6.3
7.9f
7.9
7.5
6.4
7.7
6.9
6.6
7.9
in ppm down®eld from internal TMS as reference. H
5.0
NMR data are reported in the following order: multi-
plicity (br, broad; s, singlet; d, doublet; t, triplet; m,
multiplet; *, exchangeable by D2O; Im, imidazole; Mal,
maleic acid; Ph, phenyl; Pyr, Pyridyl; Th, thienyl), num-
ber of protons, and approximate coupling constants in
hertz (Hz). Mass spectra were obtained on a Finnigan
MAT CH7A (EI±MS) and a Finnigan MAT CH5DF
(FAB±MS). IR spectra were recorded with a 1420
Ratio-Recording or a 297 spectral photometer (Perkin±
Elmer) in KBr (br, broad; m, medium; s, strong). Ele-
mental analyses (C, H, N) for all compounds were
measured on Perkin±Elmer 240 B or Perkin±Elmer 240
5.4e
5.0
5.1e
5.0e
5.4
5.0
<5.0e
<5.0e
5.1
5.0
4.8
5.4
4.6
aH3-receptor assay on synaptosomes of rat cerebral cortex.7
bH3-receptor assay on guinea pig ileum.17,18
cH2-receptor test on guinea pig atrium.16
dH1-receptor test on guinea pig ileum.16
epA2-value.
f57% of maximum e€ect.

1144
A. Sasse et al. / Bioorg. Med. Chem. 8 (2000) 1139±1149
C instruments and were within 0.4% of theoretical
values. Preparative, centrifugally accelerated, rotatory
chromatography was performed using a Chromatotron
7924T (Harrison Research) and glass rotors with 4 mm
layers of silica gel 60 PF254 containing gypsum (Merck).
(3-Chlorophenyl)phenylmethanone oxime (13b). Synthe-
sized, as described for 8b from (3-chlorophenyl)phe-
nylmethanone. Reaction was stopped after 15 h. 13b
crystallized from hot ethanol (69%). Mp 109±114 ꢀC.21
1H NMR (DMSO-d6) d 11.51* (s, 1H, ˆN±OH), 7.48±
7.21 (m, 9H, 9Ph±H); MS (70 eV), m/z (%) 231 ([M+],
100); IR (cm 1) 3234br (n[OH]), 1622m (n[CˆN]). Anal.
(C13H10ClNO) calcd C: 67.4, H: 4.35, N: 6.05; found C:
67.3, H: 4.35, N: 5.99.
Synthesis of oximes (8b±13b, 15b±18b)
(2-Methylphenyl)phenylmethanone Oxime (8b). A solu-
tion of (2-methylphenyl)phenylmethanone (3.9 g,
20 mmol), NH2OHÂHCl (4.2 g, 60 mmol) and Na2CO3
(6.4 g, 60 mmol) in 50 mL of ethanol was heated to
re¯ux for 72 h. The solvent was evaporated under
reduced pressure, the residue dissolved in an aqueous
solution of K2CO3 and ®ltered. The crystalline residue
was dissolved in CH2Cl2, ®ltered, and the solvent eva-
porated. Crude 8b was crystallized from hot ethanol.
(72%). Mp 108 ꢀC.20 1H NMR (DMSO-d6) d 11.28* (s,
Bis(4-chlorophenyl)methanone oxime (15b). Synthesized,
as described for 8b from bis(4-chlorophenyl)methanone.
Reaction was stopped after 72 h. 15b crystallized from
hot ethanol (55%). Mp 138 ꢀC.24 1H NMR (DMSO-d6)
d 11.59* (s, 1H, ˆN±OH), 7.53 (d, 2H, J=8.3 Hz, 2Ph±
3,5±H), 7.44 (d, 2H, J=8.6 Hz, 2Ph-30,50-H), 7.38 (d,
2H, J=8.6 Hz, 2Ph±2,6±H), 7.33 (d, 2H, J=8.3 Hz,
2Ph-20,60-H); MS (70 eV), m/z (%) 265 ([M+], 66); IR
1
1H, ˆN-OH), 7.35±7.01 (m, 9H, 9Ph±H), 2.08 (s, 3H,
(cm
)
3279br (n[OH]), 1655m (n[CˆN]). Anal.
1
CH3); MS (70 eV), m/z (%) 211 ([M+], 75); IR (cm
)
(C13H9Cl2NO) calcd C: 58.7, H: 3.41, N: 5.26; found C:
58.7, H: 3.47, N: 5.17.
3398br (n[OH]), 1626m (n[CˆN]). Anal. (C14H13NO)
calcd C: 79.6, H: 6.20, N: 6.63; found C: 79.6, H: 6.20,
N: 6.62.
Bis(4-¯uorophenyl)methanone oxime (16b). Synthesized,
as described for 8b from bis(4-¯uorophenyl)methanone.
Reaction was stopped after 6ꢀh. 16b crystallized from
hot methanol (68%). Mp 142 C.25 1H NMR (DMSO-
(3-Methylphenyl)phenylmethanone oxime (9b). Synthe-
sized, as described for 8b from (3-methylphenyl)phe-
nylmethanone. Reaction was stopped after 6 h. 9b
crystallized from hot methanol (78%). Mp 114/139ꢀC.20
1H NMR (DMSO-d6) d 11.26*/11.25* (2s, 1H, ˆN±OH),
7.39±7.04 (m, 9H, 9Ph±H), 2.33±2.27 (2s, 3H, CH3); MS
(70 eV), m/z (%) 211 ([M+], 100); IR (cm 1) 3250br (n
[OH]), 1629m (n[CˆN]). Anal. (C14H13NO) calcd C:
79.6, H: 6.20, N: 6.63; found C: 79.4, H: 6.17, N: 6.63.
d6) d 11.43* (s, 1H, ˆN±OH), 7.43±7.18 (m, 8H, 8Ph±
1
H); MS (70 eV), m/z (%) 233 ([M+], 100); IR (cm
)
3414br (n[OH]), 1620m (n[CˆN]). Anal. (C13H9F2NO)
calcd C: 67.0, H: 3.89, N: 6.01; found C: 66.8, H: 3.86,
N: 5.97.
Phenyl-(3-pyridyl)methanone oxime (17b). Synthesized,
as described for 8b from phenyl(3-pyridyl)methanone.
Reaction was stopped after 1 h. 17b crystallized from
hot methanol (78%). Mp 142/165 ꢀC.26 1H NMR
(DMSO-d6) d 11.66*/11.62* (2s, 1H, ˆN±OH), 8.63 (m,
1H, Pyr-6-H), 8.51 (m, 1H, Pyr-2-H), 7.74 (m, 1H, Pyr-
4-H), 7.53±7.49 (m, 6H, 5Ph±H, Pyr-5-H); MS (70 eV),
m/z (%) 198 ([M+], 61); IR (cm 1) 3406br (n[OH]),
1625m (n[CˆN]). Anal. (C12H10N2O) calcd C: 72.7, H:
5.08, N: 14.1; found C: 72.7, H: 5.22, N: 14.1.
(4-Methylphenyl)phenylmethanone oxime (10b). Synthe-
sized, as described for 8b from (4-methylphenyl)phe-
nylmethanone. Reaction was stopped after 6 h. 10b
crystallized from hot methanol (75%). Mp 142 ꢀC.21 1
H
NMR (DMSO-d6) d 11.28* (s, 1H, ˆN±OH), 7.50±7.20
(m, 9H, 9Ph±H), 2.40±2.35 (m, 3H, CH3); MS (70 eV), m/z
(%) 211 ([M+], 100); IR (cm 1) 3234br (n[OH]), 1611 m
(n[CˆN]). Anal. (C14H13NO) calcd C: 79.6, H: 6.20, N:
6.63; found C: 79.6, H: 6.18, N: 6.58.
Phenyl-(2-thienyl)methanone oxime (18b). Synthesized,
as described for 8b from phenyl(2-thienyl)methanone.
Reaction was stopped after 96 h. 18b crystallized from
hot ethanol (62%). Mp 95 ꢀC.21 1H NMR (DMSO-d6) d
12.22/11.28* (s, 1H, ˆN±OH), 7.81 (m, 1H, Th±H-),
7.47 (s, 5H, 5Ph±H), 7.10 (m, 2H, 2Th±H); MS (70 eV),
m/z (%) 203 ([M+], 100); IR (cm 1) 3239br (n[OH]),
1604m (n[CˆN]). Anal. (C11H9NOS) calcd C: 65.0, H:
4.46, N: 6.89; found C: 65.0, H: 4.50, N: 6.82.
Bis(4-methylphenyl)methanone oxime (11b). Synthesized,
as described for 8b from bis(4-methylphenyl)methanone.
Reaction was stopped after 6 h. 11b crystallized from hot
methanol (81%). Mp 168 ꢀC.22 1H NMR (DMSO-d6) d
11.13* (s, 1H, ˆN±OH), 7.26 (s, 4H, 4Ph-3,30,5,50-H),
7.17 (s, 4H, 4Ph-2,20,6,60-H), 2.35±2.30 (s, 6H, 2ÂCH3);
MS (70 eV), m/z (%) 225 ([M+], 100); IR (cm 1) 3275br
(n[OH]), 1631m (n[CˆN]). Anal. (C15H15NO) calcd C:
80.0, H: 6.71, N: 6.22; found C: 80.0, H: 6.67, N: 6.14.
Synthesis of amines (8c±13c, 15c±19c)
(2-Chlorophenyl)phenylmethanone oxime (12b). Synthe-
sized, as described for 8b from (2-chlorophenyl)phe-
nylmethanone. Reaction was stopped after 16 h. 12b
(RS)-(2-Methylphenyl)phenylmethylamine (8c). A solu-
tion of 8b (3.2 g, 15 mmol), Pd/C (10%, 200 mg) in
50 mL of methanol was hydrogenated under pressure at
3±4 bar for 2 h. The catalyst was ®ltered and the residue
concentrated under reduced pressure. The crude pro-
duct was dissolved in 2 N HCl and washed with ethyl
acetate. The aqueous layer was alkalized with K2CO3
and extracted with ethyl acetate. The organic layer was
crystallized from hot ethanol (73%). Mp 126 ꢀC.23 1
H
NMR (DMSO-d6) d 11.55* (s, 1H, ˆN±OH), 7.62±7.30
(m, 9H, 9Ph±H); MS (70 eV), m/z (%) 231 ([M+], 100);
IR (cm 1) 3253br (n[OH]), 1621m (n[CˆN]). Anal.
(C13H10ClNO) calcd C: 67.4, H: 4.35, N: 6.05; found C:
67.3, H: 4.37, N: 5.95.

A. Sasse et al. / Bioorg. Med. Chem. 8 (2000) 1139±1149
1145
dried with Na2SO4 and evaporated under reduced pres-
sure. Compound 8c was crystallized aꢀs hydrochloride
salt from EtOH/Et2O (40%). Mp 268 C (decomp.).20
1H NMR (DMSO-d6) d 9.09* (s, 3H, NH3+), 7.67±7.22
(m, 9H, 9Ph±H), 5.70 (s, 1H, CH), 2.26 (s, 3H, CH3);
FAB+±MS (Xe, MeOH/glycerol), m/z (%) 198
([M+H+], 13); IR (cm 1) 3431br (n[NH]), 3181s
(n[NH+3 ]). Anal. (C14H15NÂHCl) calcd C: 71.9, H:
6.90, N: 5.99; found C: 72.0, H: 6.81, N: 5.91.
calcd C: 61.4, H: 5.16, N: 5.51; found C: 61.4, H: 5.43,
N: 5.47.
Bis(4-chlorophenyl)methylamine (15c). Synthesized, as
described for 12c from 15b (43%). Mp 262 ꢀC
(decomp.).27 1H NMR (DMSO-d6) d 9.25* (s, 3H,
NH+3 ), 7.55 (d, J=8.7 Hz, 4H, 4Ph-3,30,5,50-H), 7.51 (d,
J=8.6 Hz, 4H, 4Ph-2,20,6,60-H), 5.72 (s, 1H, CH); MS
(70 eV), m/z (%) 251 ([M+], 17); IR (cm 1) 3433br
(n[NH]), 3024br (n[NH+3 ]). Anal. (C13H11Cl2NÂHCl)
calcd C: 54.1, H: 4.19, N: 4.85; found C: 53.9, H: 4.45,
N: 4.71.
(RS)-(3-Methylphenyl)phenylmethylamine (9c). Synthe-
sized, as described for 8c from 9b (70%). Mp 268 ꢀC
(decomp.).20 1H NMR (DMSO-d6) d 9.17* (s, 3H,
NH+3 ), 7.55±7.15 (m, 9H, 9Ph±H), 5.56 (s, 1H, CH),
2.30 (s, 3H, CH3); MS (70 eV), m/z (%) 197 ([M+], 72);
IR (cm 1) 3422br (n[NH]), 3190s (n[NH+3 ]). Anal.
(C14H15NÂHCl) calcd C: 71.9, H: 6.90, N: 5.99; found
C: 71.8, H: 6.94, N: 5.88.
Bis(4-¯uorophenyl)methylamine (16c). Synthesized, as
described for 8c from 16b (63%). Mp 250 ꢀC
(decomp.).28 1H NMR (DMSO-d6) d 9.25* (s, 3H,
NH+3 ), 7.37 (m, 4H, 4Ph-2,20,6,60-H), 7.22 (m, 4H, 4Ph±
3,30,5,50-H), 5.71 (s, 1H, CH); MS (70 eV), m/z (%) 219
([M+], 25); IR (cm 1) 3395br (n[NH]), 2911br (n[NH3]).
Anal. (C13H11F2NÂHCl) calcd C: 61.0, H: 4.73, N:
5.48; found C: 61.0, H: 4.87, N: 5.30.
(RS)-(4-Methylphenyl)phenylmethylamine (10c). Synthe-
sized, as described for 8c from 10b (33%). Mp 250 ꢀC
(decomp.).20 1H NMR (DMSO-d6) d 9.08* (s, 3H,
NH+3 ), 7.50±7.23 (m, 9H, 9Ph±H), 5.57 (s, 1H, CH),
2.29 (s, 3H, CH3); MS (70 eV), m/z (%) 197 ([M+], 53);
IR (cm 1) 3426br (n[NH]), 3150s (n[NH+3 ]). Anal.
(C14H15NÂHCl) calcd C: 71.9, H: 6.90, N: 5.99; found
C: 71.9, H: 7.00, N: 5.88.
(RS)-Phenyl-(2-pyridyl)methylamine (17c). Synthesized,
as described for 8c from 17b. The reaction was stopped
after 4 h (72%). Mp 230 ꢀC (decomp.).26 1H NMR
(DMSO-d6) d 9.17* (s, 3H, NH+3 ), 8.96* (s, 1H, Pyr+-
H), 8.66 (d, J=4.0 Hz, 1H, Pyr-6-H), 7.90 (m, 1H, Pyr-
4-H), 7.56±7.34 (m, 7H, 5Ph-H, 2Pyr-3,5-H), 5.75 (d,
J=5.4 Hz, 1H, CH); MS (70 eV), m/z (%) 184 ([M +],
40); IR (cm 1) 3428br (n[NH]), 3261s (n[NH+3 ]). Anal.
(C12H12N2Â2 HCl) calcd C: 56.1, H: 5.49, N: 10.9;
found C: 56.0, H: 5.58, N: 10.7.
Bis(4-methylphenyl)methylamine (11c). Synthesized, as
described for 8c from 11b. The reaction was stopped
after 4 h (43%). Mp 246 ꢀC (decomp.).20 1H NMR
(DMSO-d6) d 9.02* (s, 3H, NH+3 ), 7.37 (d, J=8.0 Hz,
4H, 4Ph-2,20,6,60-H), 7.22 (d, J=8.0 Hz, 4H, 4Ph-
3,30,5,50-H), 5.53 (d, J=5.1 Hz, 1H, CH), 2.29 (s, 6H,
(RS)-Phenyl-(2-thienyl)methylamine (18c). Synthesized,
as described for 12c from 18b. The reaction was stopped
after 48 h (60%). Mp 200 ꢀC (decomp.).29 1H NMR
(DMSO-d6) d 9.23* (s, 3H, NH+3 ), 7.61±7.36 (m, 7H,
2ÂCH3); MS (70 eV), m/z (%) 211 ([M+], 38); IR
1
(cm
)
3397br (n[NH]), 3034s (n[NH+3 ]). Anal.
(C15H17NÂHCl) calcd C: 72.7, H: 7.32, N: 5.65; found
C: 72.8, H: 7.33, N: 5.53.
5Ph±H, 2Th-3,5-H), 7.08 (m, 1H, Th-4-H), 5.91 (s, 1H,
1
CH); MS (70 eV), m/z (%) 189 ([M+], 100); IR (cm
)
(RS)-(2-Chlorophenyl)phenylmethylamine (12c). To a
3428br (n[NH]), 2946br (n[NH+3 ]). Anal. (C11H11
NSÂHCl H2O) calcd C: 57.4, H: 5.47, N: 6.08; found
1
solution of 12b (2.3 g, 10 mmol) in 10 mL of 1,2-dime-
thoxyethane, NaBH4 (1.59 g, 41 mmol) was added.
TiCl4 (4.0 g, 21 mmol) was added slowly under nitrogen
atmosphere at 0 ꢀC. The mixture was warmed up to
room temperature and stirred for 24 h. 100 mL of cold
water was added, the solution alkalized with ammonia,
and extracted with ethyl acetate. The organic layer was
washed with a saturated solution of NaCl, dried over
Na2SO4, and evaporated under reduced pressure. 12c
was crystallized as hydrochloride salt from EtOH/Et2O
(29%). Mp 246 ꢀC (decomp.).27 1H NMR (DMSO-d6) d
9.34* (s, 3H, NH+3 ), 7.99±7.34 (m, 9H, 9Ph±H), 5.82 (s,
C: 57.6, H:45.51, N: 6.00.
Bis(2-thienyl)methylamine (19c). Synthesized, as descri-
bed for 12c from bis(2-thienyl)methanone oxime. The
reaction was stopped after 168 h (34%). Mp 146 ꢀC
(decomp.). 1H NMR (DMSO-d6) d 9.27* (s, 3H, NH+3 ),
7.60 (dd, J=5.1 Hz, J=1.1 Hz, 2H, 2Th-5,50-H), 7.42
(d, J=3.4 Hz, 2H, 2Th-3,30-H), 7.10 (dd, 3J=5.0 Hz,
4J=3.6 Hz, 2H, 2Th-4,40-H), 6.27 (s, 1H, CH); MS (70
eV), m/z (%) 195 ([M+], 79); IR (cm 1) 3434br
(n[NH]), 2975br (n[NH+3 ]). Anal. (C9H9NS2ÂHCl)
calcd C: 46.6, H: 4.35, N: 6.04; found C: 46.6, H: 4.26,
N: 5.92.
3
4
1H, CH); MS (70 eV), m/z (%) 217 ([M+], 50); IR
1
(cm
)
3441br (n[NH]), 3150m (n[NH+3 ]). Anal.
(C13H12ClNÂHCl) calcd C: 61.4, H: 5.16, N: 5.51;
found C: 61.3, H: 5.22, N: 5.44.
Synthesis of carbamates (1±19)
(RS)-(3-Chlorophenyl)phenylmethylamine (13c). Synthe-
sized, as described for 12c from 13b (45%). Mp 251 ꢀC
(decomp.).27 1H NMR (DMSO-d6) d 9.13* (s, 3H,
NH+3 ), 7.65±7.36 (m, 9H, 9Ph-H), 5.69 (s, 1H, CH); MS
(70 eV), m/z (%) 217 ([M+], 28); IR (cm 1) 3429br
(n[NH]), 3183m (n[NH+3 ]). Anal. (C13H12ClNÂHCl)
2-(1H-Imidazol-4-yl)ethyl N-(2,2-Diphenylethyl)carbamate
(1). To a solution of trichloromethyl chloroformate
(1.2 g, 6 mmol) and a catalytic amount of charcoal in
30 mL of dry ethyl acetate was added rapidly 2,2-
diphenylethylamine (1c) (1.0 g, 5 mmol). The reaction
mixture was heated to re¯ux for 4 h. Then the black

1146
A. Sasse et al. / Bioorg. Med. Chem. 8 (2000) 1139±1149
Table 4. Physical properties and elemental analysis of target carbamates (1±19)
Calcd (%)
H
Found (%)
H
Compound no.
Formula
Mw
(g/mol)
Mp
(ꢀC)
C
N
C
N
1
2
3
4
5
6
7
8
C
20H21N3O2ÂC4H4O4
451.5
456.0
465.5
479.5
444.0
470.0
454.0
439.5
439.5
426.0
379.5
459.9
468.9
468.9
520.4
492.0
345.4
431.5
428.5
136
127
106
126
132
140
175
134
132
131
134
135
107
104
147
141
141
121
126
63.9
65.2
64.5
65.1
62.2
63.9
63.5
62.9
62.9
63.7
65.1
57.5
56.4
56.4
55.4
58.6
66.1
55.7
49.9
5.58
5.64
5.85
6.10
5.79
5.90
5.22
5.73
5.73
5.94
6.10
4.82
4.94
4.94
4.45
4.81
6.13
4.91
4.42
9.31
9.22
9.03
8.76
9.46
8.94
9.26
9.56
9.56
9.86
8.76
9.14
8.96
8.96
8.07
8.54
63.7
65.5
64.5
65.2
62.4
64.0
63.3
62.9
62.8
63.8
65.0
57.3
56.5
56.6
55.2
58.5
66.4
55.6
50.1
5.77
5.64
5.75
6.20
5.80
5.83
5.23
5.76
5.97
5.75
6.06
4.96
5.06
4.91
4.58
4.83
5.97
4.91
4.60
9.13
9.19
8.94
8.85
9.46
8.96
9.38
9.61
9.61
9.69
8.70
9.16
8.83
8.85
8.12
8.43
1
4
C
20H21N3O2ÂC4H4O4Â H2O
C21H23N3O2ÂC4H4O4
C
22H25N3O2ÂC4H4O4
1
C21H23N3O2ÂC2H2O4Â4 H2O
1
C21H23N3O2ÂC4H4O4Â H2O
4
1
C
20H19N3O2ÂC4H4O4Â H2O
4
C21H23N3O2ÂC2H2O4
9
C
21H23N3O2ÂC2H2O4
1
4
10
11
12
13
14
15
16
17
18
19
C21H23N3O2Â0.8 C2H2O4Â H2O
C
22H25N3O2ÂC4H4O4
C20H20ClN3O2ÂC2H2O4
1
C20H20ClN3O2ÂC2H2O4Â H2O
2
1
C
20H20ClN3O2ÂC2H2O4Â H2O
2
C20H19Cl2N3O2ÂC4H4O4
1
C
20H19F2N3O2ÂC4H4O4Â H2O
4
1
C19H20N4O2Â H2O
16.2
9.74
9.81
16.1
9.55
9.82
2
C18H19N3O2SÂC2H2O4
C
16H17N3O2S2Â0.9 C2H2O4
solution was cooled, ®ltered, and the solvent was eva-
porated under reduced pressure. The freshly prepared
isocyanate was dissolved in 30 mL of dry acetonitrile and
added to 2-(1H-imidazol-4-yl)ethanolÂHCl13 (20) (0.7 g,
5 mmol) in 10 mL of dry acetonitrile. The solution was
heated to re¯ux for 4 h and concentrated in vacuo. The
residue was puri®ed by rotatory chromatography (elu-
ent: CH2Cl2:MeOH (gradient from 99:1 to 90:10),
ammonia atmosphere]. The pure fractions were con-
centrated in vacuo and dried (40%). The yellow oil was
crystallized as hydrogenmaleate. 1H NMR (DMSO-d6) d
8.83 (s, 1H, Im-2-H), 7.32±7.19 (m, 12H, 10Ph-H+Im-5-
H+CONH), 6.06 (s, 2H, Mal), 4.20±4.10 (m, 3H,
NHCH2CH), 3.62 (m, 2H, CH2O), 2.87 (t, J=6.3 Hz,
2H, Im-CH2); MS (70 eV), m/z (%) 335 ([M+], 2); IR
(cm 1) 1720s (n[CˆO]).
nylpropylamin and 2111 (61%). 1H NMR (DMSO-d6) d
8.89 (s, 1H, Im-2-H), 7.40 (s, 1H, Im-5-H), 7.29±7.17
(m, 11H, 10Ph-H+CONH), 6.07 (s, 2H, Mal), 3.98±
3.94 (m, 3H, CH2O+CH), 2.89 (m, 2H, NHCH2), 2.68
(t, J=7.5 Hz, 2H, Im-CH2), 2.17 (m, 2H, CH2CH), 1.89
(m, 2H, Im-CH2CH2); MS (70 eV), m/z (%) 363 ([M+],
47); IR (cm 1) 1718s (n[CˆO]).
3-(1H-Imidazol-4-yl)propyl N-(1,1-diphenylethyl)carba-
mate (5). A mixture of 2,2-diphenylpropionic acid (1.1 g,
5 mmol), triethylamine (0.5g, 5 mmol), and diphenylpho-
sphoryl azide (1.4g, 5 mmol) was stirred for 45min in
30mL of dry acetonitrile at room temperature. The reac-
tion mixture was heated to re¯ux for 30min, 2111 (0.8 g,
5 mmol) was added, and the solution was re¯uxed for 4 h.
The solvent was removed under reduced pressure, the
residue dissolved in Et2O and extracted with a saturated
solution of K2CO3 and NaHCO3. After concentration
of the combined organic fractions the residue was pur-
i®ed by rotatory chromatography [eluent: CHCl3/
MeOH (gradient from 95/5 to 90/10), ammonia atmo-
sphere]. The combined fractions were concentrated,
dried, and crystallized as hydrogenoxalate (44%). 1H
NMR (DMSO-d6) d 8.64 (s, 1H, Im-2-H), 7.75 (s, 1H,
Im-5-H), 7.33±7.19 (m, 11H, 10Ph-H+CONH), 3.87 (t,
J=7.5 Hz, 2H, CH2O), 2.65 (m, 2H, Im-CH2), 1.98 (s,
3H, CH3), 1.84 (m, 2H, Im-CH2CH2); MS (70 eV), m/z
(%) 349 ([M+], 29); IR (cm 1) 1722s (n[CˆO]).
3-(1H-Imidazol-4-yl)propyl N-(diphenylmethyl)carbamate
(2). Synthesized as described for 1 with diphenylmethy-
lamine and 3-(1H-imidazol-4-yl)propanolÂHCl11 (21)
1
(85%). H NMR (DMSO-d6) d 8.87 (s, 1H, Im-2-H),
8.29* (d, J=9.2 Hz, 1H, CONH), 7.39±7.20 (m, 11H,
10Ph-H+Im-5-H), 6.05 (s, 2H, Mal), 5.86 (d, J=9.2Hz,
1H, CH), 4.01 (t, J=6.4Hz, 2H, CH2O), 2.69 (m, 2H, Im-
CH2), 1.91 (m, 2H, Im-CH2CH2); MS (70 eV), m/z (%)
335 ([M+], 26); IR (cm 1) 1722s (n[CˆO]).
(1H-Imidazol-4-yl)propyl N-(2,2-diphenylethyl)carbamate
(3). Synthesized as described for 1 from 1c and 2111
1
(61%). H NMR (DMSO-d6) d 8.87 (s, 1H, Im-2-H),
(RS)-3-(1H-Imidazol-4-yl)propyl N-(1,2-diphenylethyl)-
carbamate (6). Synthesized as described for 1 from 1,2-
7.35±7.17 (m, 12H, 10Ph-H+Im-5-H+CONH), 6.06 (s,
2H, Mal), 4.20 (m, 1H, CH), 3.93 (t, J=6.4 Hz, 2H,
CH2O), 3.63 (m, 2H, NHCH2), 2.61 (t, J=7.5 Hz, 2H,
Im-CH2), 1.83 (m, 2H, Im-CH2CH2); MS (70 eV), m/z
(%) 349 ([M+], 19); IR (cm 1) 1690s (n [CˆO])
1
diphenylethylamine and 2111 (70%). H NMR (DMSO-
d6) d 8.85 (s, 1H, Im-2-H), 7.80* (d, J=8.9Hz, 1H,
CONH), 7.33±7.15 (m, 11H, 10Ph-H+Im-5-H), 6.05 (s,
2H, Mal), 4.74 (m, 1H, CH), 3.85 (t, J=6.4 Hz, 2H,
CH2O), 2.92 (t, J=7.6Hz, 2H, CHCH2), 2.58 (t,
J=7.5Hz, 2H, Im-CH2), 1.81 (m, 2H, Im-CH2CH2); MS
(70 eV), m/z (%) 349 ([M+], 8); IR (cm 1) 1690s (n [CˆO]).
3-(1H-Imidazol-4-yl)propyl N-(3,3-diphenylpropyl)carba-
mate (4). Synthesized as described for 1 from 3,3-diphe-

A. Sasse et al. / Bioorg. Med. Chem. 8 (2000) 1139±1149
1147
N-(9-Fluorenyl)3-(1H-imidazol-4-yl)propylcarbamate (7).
Synthesized as described for 1 from 9-¯uorenylamine
and 2111 (49%). 1H NMR (DMSO-d6) d 8.87 (s, 1H, Im-
2-H), 7.85±7.31 (m, 10H, 8Ph-H+Im-5-H+CONH),
6.05 (s, 2H, Mal), 5.70 (d, J=8.5 Hz, 1H, CH), 4.12 (t,
J=6.5 Hz, 2H, CH2O), 2.72 (t, J=7.5 Hz, 2H, Im-CH2),
1.97 (m, 2H, Im-CH2CH2); MS (70 eV), m/z (%) 333
([M+], 39); IR (cm 1) 1690s (n[CˆO]).
(RS)-N-[(3-Chlorophenyl)phenylmethyl]3-(1H-imidazol-
4-yl)propylcarbamate (13). Synthesized as described for 1
from 13c and 2111 (92%). The product was crystallized as
hydrogenoxalate from EtOH/Et2O. 1H NMR (DMSO-d6)
d 8.41 (m, 1H, Im-2-H), 8.30* (d, J=8.2 Hz, 1H, CH),
7.39±7.15 (m, 10 H, 9Ph-H+Im-5-H), 5.86 (d, J=9.2 Hz,
1H, CH), 3.98 (t, J=6.4 Hz, 2H, CH2O), 2.63 (t, J=8.0 Hz,
2H, Im-CH2), 1.88 (m, 2H, Im-CH2CH2); MS (70 eV), m/z
(%) 369 ([M+], 18); IR (cm 1) 1699s (n[CˆO]).
(RS)-3-(1H-Imidazol-4-yl)propyl N-[(2-methylphenyl)-
phenylmethyl]carbamate (8). Synthesized as described
for 1 from 8c and 2111 (13%). The product was crystal-
(RS)-N-[(4-Chlorophenyl)phenylmethyl]3-(1H-imidazol-4
-yl)propylcarbamate (14). Synthesized as described for 1
from (4-chlorophenyl)phenylmethylamine and 2111
(57%). The product was crystallized as hydrogenoxalate
1
lized as hydrogenoxalate from EtOH/Et2O. H NMR
(DMSO-d6) d 8.88 (s, 1H, Im-2-H), 8.17* (d, J=8.1 Hz,
1H, CONH), 7.32±7.12 (m, 10 H, 9Ph-H+Im-5-H), 6.02
(d, J=8.7 Hz, 1H, CH), 3.99 (m, 2H, CH2O), 2.63 (m,
2H, Im-CH2), 2.25 (s, 3H, CH3), 1.88 (m, 2H, Im-
CH2CH2); MS (70 eV), m/z (%) 349 ([M+], 48); IR
(cm 1) 1713s (n[CˆO]).
1
from EtOH/Et2O. H NMR (DMSO-d6) d 8.51 (s, 1H,
Im-2-H), 8.29* (d, J=8.4 Hz, 1H, CH), 7.40±7.21 (m,
10H, 9Ph-H+Im-5-H), 5.87 (d, J=8.8 Hz, 1H, CH),
4.01 (m, 2H, CH2O), 2.66 (m, 2H, Im-CH2), 1.90 (m,
2H, Im-CH2CH2); MS (70 eV), m/z (%) 369 ([M+], 19);
IR (cm 1) 1701s (n[CˆO]).
(RS)-3-(1H-Imidazol-4-yl)propyl N-[(3-methylphenyl)-
phenylmethyl]carbamate (9). Synthesized as described
for 1 from 9c and 2111 (11%). The product was crystal-
N-[Bis(4-chlorophenyl)methyl]3-(1H-imidazol-4-yl)pro-
pylcarbamate (15). Synthesized as described for 1 from
15c and 2111 (33%). 1H NMR (DMSO-d6) d 8.81 (s, 1H,
Im-2-H), 8.31* (d, J=8.8 Hz, 1H, CH), 7.39 (d, J=8.5Hz,
4H, 4Ph-3,30,5,50-H), 7.39 (s, 1H, Im-5-H), 7.32 (d,
J=8.5Hz, 4H, 4Ph-2,20,6,60-H), 6.04 (s, 2H, Mal), 5.88 (d,
J=9.2Hz, 1H, CH), 4.00 (t, J=6.5Hz, 2H, CH2O), 2.86
(m, 2H, Im-CH2), 1.90 (m, 2H, Im-CH2CH2); MS (70 eV),
m/z (%) 403 ([M+], 8); IR (cm 1) 1696s (n[CˆO]).
1
lized as hydrogenoxalate from EtOH/Et2O. H NMR
(DMSO-d6) d 8.48 (s, 1H, Im-2-H), 8.24* (d, J=8.6 Hz,
1H, CONH), 7.31±7.03 (m, 10 H, 9Ph-H+Im-5-H), 5.80
(d, J=9.3 Hz, 1H, CH), 3.99 (t, J=6.2 Hz, 2H, CH2O),
2.65 (t, J=7.3 Hz, 2H, Im-CH2), 2.26 (s, 3H, CH3), 1.88
(m, 2H, Im-CH2CH2); MS (70 eV), m/z (%) 349 ([M+],
62); IR (cm 1) 1702s (n[CˆO]).
(RS)-3-(1H-Imidazol-4-yl)propyl N-[(4-methylphenyl)-
phenylmethyl]carbamate (10). Synthesized as described
for 1 from 10c and 2111 (40%). The product was crystal-
N-[Bis(4-¯uorophenyl)methyl]3-(1H-imidazol-4-yl)propyl-
carbamate (16). Synthesized as described for 1 from 16c
and 2111 (75%). Mp 141 ꢀC. H NMR (DMSO-d6) d
1
1
lized as hydrogenoxalate from EtOH/Et2O. H NMR
8.83 (s, 1H, Im-2-H), 8.29* (d, J=9.0 Hz, 1H, CONH),
7.34 (m, 5H, 4Ph-2,20,6,60-H+Im-5-H), 7.16 (m, 4H,
4Ph-3,30,5,50-H), 6.04 (s, 2H, Mal), 5.88 (d, J=9.1 Hz,
1H, CH), 4.00 (t, J=6.5 Hz, 2H, CH2O), 2.68 (m, 2H,
Im-CH2), 1.91 (m, 2H, Im-CH2CH2); MS (70 eV), m/z
(%) 371 ([M+], 41); IR (cm 1) 1704s (n[CˆO]).
(DMSO-d6) d 8.36 (s, 1H, Im-2-H), 8.21* (d, J=8.9 Hz,
1H, CONH), 7.31±7.11 (m, 10 H, 9Ph-H+Im-5-H), 5.81
(d, J=9.2 Hz, 1H, CH), 4.00 (t, J=6.4 Hz, 2H, CH2O),
2.62 (t, J=6.6 Hz, 2H, Im-CH2), 2.26 (s, 3H, CH3), 1.89
(m, 2H, Im-CH2CH2); MS (70 eV), m/z (%) 349 ([M+],
46); IR (cm 1) 1699s (n[CˆO]).
(RS)-3-(1H-Imidazol-4-yl)propyl N-[phenyl(3-pyridyl)me-
thyl]carbamate (17). Synthesized as described for 1 from
17c and 2111 (23%). The product was crystallized as free
N-[Bis(4-methylphenyl)methyl]3-(1H-imidazol-4-yl)pro-
pylcarbamate (11). Synthesized as described for 1 from
11c and 2111 (73%). 1H NMR (DMSO-d6) d 8.83 (s, 1H,
Im-2-H), 8.15* (d, J=9.3Hz, 1H, CONH), 7.37 (s, 1H,
Im-5-H), 7.16 (d, J=8.1 Hz, 4H, 4Ph-2,20,6,60-H), 7.10 (d,
J=8.1Hz, 4H, 4Ph-3,30,5,505-H), 6.04 (s, 2H, Mal), 5.75
(d, J=9.4Hz, 1H, CH), 3.99 (t, J=6.3 Hz, 2H, CH2O),
2.67 (m, 2H, Im-CH2), 2.25 (s, 6H, 2CH3), 1.90 (m, 2H,
Im-CH2CH2); MS (70 eV), m/z (%) 363 ([M+], 53); IR
(cm 1) 1696s (n[CˆO]).
1
base. H NMR (DMSO-d6) d 8.56 (s, 1H, Im-2-H), 8.44
(m, 1H, Pyr-6-H), 8.36* (d, J=8.7 Hz, 1H, CONH), 7.71
(m, 1H, Pyr-4-H), 7.50 (s, 1H, Pyr-2-H), 7.37±7.23 (m, 9H,
8Ph-H+Pyr-4-H), 6.73 (s, 1H, Im-5-H), 5.94 (d,
J=9.1Hz, 1H, CH), 4.00 (t, J=6.5Hz, 2H, CH2O), 2.54
(m, 2H, Im-CH2), 1.85 (m, 2H, Im-CH2CH2); MS (70 eV),
m/z (%) 339 ([M+], 21); IR (cm 1) 1692s (n[CˆO]).
(RS)-3-(1H-Imidazol-4-yl)propyl N-[phenyl(2-thienyl)me-
thyl]carbamate (18). Synthesized as described for 1 from
18c and 2111 (29%). The product was crystallized as
(RS)-N-[(2-Chlorophenyl)phenylmethyl]3-(1H-imidazol-
4-yl)propylcarbamate (12). Synthesized as described for
1 from 12c and 2111 (22%). The product was crystal-
1
hydrogenoxalate from EtOH/Et2O. H NMR (DMSO-
1
lized as hydrogenoxalate from EtOH/Et2O. H NMR
d6) 8.50 (m, 1H, Im-2-H), 8.42* (d, J=8.6 Hz, 1H, CH),
7.71-7.21 (m, 7 H, 5Ph-H+Im-5-H+Th-5-H), 6.94 (m,
1H, Th-4-H), 6.79 (m, 1H, Th-3-H), 6.04 (d, J=9.2 Hz,
1H, CH), 4.00 (m, 2H, CH2O), 2.66 (m, 2H, Im-CH2),
1.91 (m, 2H, Im-CH2CH2); MS (70 eV), m/z (%) 341
([M+], 35); IR (cm 1) 1700s (n[CˆO]).
(DMSO-d6) d 8.33 (m, 2H, Im-2-H+CONH), 7.53±7.13
(m, 10 H, 9Ph-H+Im-5-H), 6.22 (d, J=9.1 Hz, 1H,
CH), 3.99 (t, J=6.3 Hz, 2H, CH2O), 2.63 (t, J=7.2 Hz,
2H, Im-CH2), 1.88 (m, 2H, Im-CH2CH2); MS (70 eV),
m/z (%) 369 ([M+], 13); IR (cm 1) 1704s (n[CˆO]).

1148
A. Sasse et al. / Bioorg. Med. Chem. 8 (2000) 1139±1149
N-[Bis(2-thienyl)methyl]3-(1H-imidazol-4-yl)propylcarba-
mate (19). Synthesized as described for 1 from 19c and
2111 (3%). The product was crystallized as hydro-
Histamine H3-receptor agonist/antagonist potency in
vivo in mouse. In vivo testing was performed after per-
oral administration to Swiss mice as described by Gar-
barg et al.7 Brain histamine turnover was assessed by
measuring the level of the main metabolite of histamine,
Nt-MeHA. Mice were fasted for 24 h before po treat-
ment. Animals were decapitated 90 min after treatment,
and the cerebral cortex was prepared out. The cortex
was homogenized in 10 vol of ice-cold perchloric acid
(0.4 M). The Nt-MeHA level was measured by radio-
immunoassay.34 By treatment with 10 mg/kg of thio-
peramide or imetit the maximum/minimum Nt-MeHA
levels were obtained and related to the level reached
with the administered antagonist/agonist. The ED50
value was calculated as mean with SEM.32
1
genoxalate from EtOH/Et2O. H NMR (DMSO-d6) d
8.51 (m, 1H, CONH), 8.35 (m, 1H0, Im-2-H), 7.45 (dd,
3J=4.6 Hz, 4J=1.4 Hz, 2H, 2Th-5,5 -H), 7.13 (s, 1H, Im-
5-H), 6.98 (m, 4H, 4Th-3,4-H), 6.30 (d, J=9.0 Hz, 1H,
CH), 4.02 (t, J=6.5 Hz, 2H, CH2O), 2.64 (m, 2H, Im-
CH2), 1.90 (m, 2H, Im-CH2CH2); MS (70 eV), m/z (%)
347 ([M+], 34); IR (cm 1) 1701s (n[CˆO]).
Pharmacology
Histamine H3-receptor assay on synaptosomes of rat cer-
ebral cortex. Compounds were tested for their H3-
receptor agonist/antagonist activity in an assay with
K+-evoked depolarization-induced release of [3H]hista-
mine from rat synaptosomes according to Garbarg et
al.7 A synaptosomal fraction from rat cerebral cortex
prepared according to the method of Whittaker30 was
preincubated for 30min with l-[3H]histidine (0.4 mM) at
37ꢀC in a modi®ed Krebs-Ringer solution. The synapto-
somes were washed extensively, resuspended in fresh
2 mM K+ Krebs-Ringer's medium, and incubated for
2 min with 2 or 30mM K+ (®nal concentration).
Antagonists and 1 mM histamine or the agonist in
increasing concentrations were added 5 min before depo-
larization stimulus. Incubations were stopped by rapid
centrifugation, and [3H]histamine levels were determined
after puri®cation by liquid scintillation spectrometry.7 Ki
values were determined according to the Cheng±Prusso€
equation.31 The data presented are given as mean values
with standard error of the mean (SEM)32 for a mini-
mum of three separate determinations each. The intrin-
sic activity (a) of agonists was expressed as percent of
the maximal e€ect of the compounds over the maximal
e€ect of histamine.
In vitro screening at other histamine receptors. Selected
compounds were screened for histamine H2-receptor
activity on the isolated spontaneously beating guinea pig
right atrium as well as for H1-receptor activity on the iso-
lated guinea pig ileum by standard methods described by
Hirschfeld et al.16 The given values represent the mean.
Acknowledgements
We gratefully thank Dr. K. Purand for the preparation
of compound 2. This work was supported by the Bio-
medical & Health Research Programme (BIOMED) of
the European Union and the Fonds der Chemischen
Industrie, Verband der Chemischen Industrie, Frank-
furt/Main, Germany.
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