Side-chain modified analogues of histaprodifen: Asymmetric synthesis and histamine H1-receptor activity

Article abstract of DOI:10.1016/j.bmcl.2005.10.030

New analogues of histaprodifen with polar side chains have been stereoselectively synthesized and evaluated as histamine H₁-receptor agonists. As a key transformation the asymmetric aminohydroxylation has been used, which was successfully reali

Full text of DOI:10.1016/j.bmcl.2005.10.030

Bioorganic & Medicinal Chemistry Letters 16 (2006) 672–676
Side-chain modified analogues of histaprodifen:
Asymmetric synthesis and histamine H1-receptor activity
Rameshwar Patil,a Sigurd Elzb,* and Oliver Reisera,*
aInstitut fu¨r Organische Chemie, Universita¨t Regensburg, Universita¨tsstr. 31, 93053 Regensburg, Germany
bInstitut fu¨r Phamazie, Universita¨t Regensburg, Universita¨tsstr. 31, 93053 Regensburg, Germany
Received 11 September 2005; revised 7 October 2005; accepted 11 October 2005
Available online 2 November 2005
Abstract—New analogues of histaprodifen with polar side chains have been stereoselectively synthesized and evaluated as histamine
H1-receptor agonists. As a key transformation the asymmetric aminohydroxylation has been used, which was successfully realized
for the first time on an imidazolyl derivative. While all chiral analogues proved to be weak H1-receptor antagonists, an achiral keto
derivative of histaprodifen turned out to be the first 2-acylated histamine congener displaying partial H1-receptor agonism (relative
potency 12%).
Ó 2005 Elsevier Ltd. All rights reserved.
During the last 25 years, numerous histamine H1-recep-
tor mediated effects have been described1 emphasizing
X
NH2
NH2
N
the important physiological and pathophysiological role
of histamine (1) (Fig. 1). Although the search for highly
potent and subtype-selective H1-receptor agonists has
been an arduous task for several years,2 many deriva-
tives have arisen from the class of 2-substituted hista-
mines,3 which display improved potency and
selectivity.4,5 Recently histaprodifen (2, X, Y, and
Z = H)6 has been identified as a potent histamine
derivative offering a starting point for systematic devel-
opment of highly potent and selective histamine H1-re-
ceptor agonists. The aim of our present study was to
develop analogues of 2 (X, Y, and Z 5 H) to get addi-
tional information about structure–activity relationships
of histamine H1-receptor agonists. In particular, we
wanted to investigate the effect of additional polar
groups attached to the ethylamine side chain, posing
the additional challenge to introduce such groups in a
regio-, diastereo-, and enantioselective manner.
N
Y
Ph
N
N
H
H
Z
Ph
1 (Histamine)
2 (X,Y,Z=H: Histaprodifen)
Figure 1.
O
CO2Me
CO2Me
N
N
N
N
R
Me
4
3-R (R=H, Cbz, Tr, Ts)
Figure 2.
moiety could be introduced via an asymmetric amino-
hydroxylation (AA) reaction,7 which has proved to be
especially useful with cinnamates as substrates, but on
the other hand is also known to be problematic in the
presence of nitrogen containing heterocycles. Indeed, it
has been reported that various imidazolyl derivatives
3-R fail completely to give the AA.8 Moreover, our
attempts to utilize the N-oxides such as 4 for the AA,
which in the case of pyridineacrylates proved to be
the method of choice to achieve amino-9 and dihydro-
xylations,10 were also not successful.
As a suitable starting material toward side-chain modi-
fied derivatives of 1 and 2, we envisioned readily avail-
able urocanic acid methyl ester (3-H, Fig. 2). The
required amino group in b-position to the imidazole
Keywords: Histamine; Histaprodifen; Asymmetric aminohydroxyl-
ation; Urocanic acids; Imidazole.
*
Corresponding authors. Tel.: +499419434631; fax: +499419434121;
e-mail: Oliver.Reiser@chemie.uni-regensburg.de
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.10.030

R. Patil et al. / Bioorg. Med. Chem. Lett. 16 (2006) 672–676
673
In an important contribution by Pyne and co-workers it
was demonstrated that N-protected urocanic ethers hav-
ing an acetyl group in 2-position are amenable toward
osmium-catalyzed asymmetric dihydroxylations.11 Keep-
ing the side chain in 2-position of histaprodifen in mind,
we therefore envisioned 7–9 as a starting point for asym-
metric aminohydroxylation reactions (Scheme 1).
alklated regioisomers, from which 5, being the major
one, could be separated by chromatography. Subse-
quently, metallation with LDA and trapping with the
Weinreb amide 6 gave rise to 7 in moderate yield. Alter-
natively, 5 could be reduced to the corresponding allylic
alcohol, into which after protection the side chain was
introduced again via 6 to yield 8 and 9, respectively.
Thus, treatment of 3-H with 2-methoxyethoxymethyl
chloride (MEM-Cl) gave rise to a 9:1 mixture of N-
Indeed, 7–9 could be utilized as substrates for the osmi-
um-catalyzed aminohydroxylation (Table 1) with mod-
erate results, nevertheless, succeeding for the first time
with imidazolyl derivatives in this transformation. In
agreement with the general trend observed in AA reac-
tions with aromatic substrates, in the presence of
(DHQ)2PHAL the amino group is preferentially intro-
duced in the benzylic position (regioisomer B, entries
1, 4). To obtain a better ratio of regioisomers with
respect to the desired histamine analogues A, the
pseudoenantiomeric ligand (DHQD)2AQN was em-
ployed. Although the ratio of regioisomers could not
be reversed as it is known in the case of cinnamates, at
least the formation of A was somewhat improved (Table
1, entries 2, 3, and 7). Changing the solvent to acetoni-
trile/water considerably improved the rate and yield of
the reaction with 7, as well as the enantioselectivity of
CO2Me
CO2Me
N
N
a
N
H
N
MEM
3-H
5
Ph
O
CH3
b
c
Ph
N
OMe
6
CO2Me
OR
N
N
N
Ph
Ph
N
O
O
MEM
MEM
Ph
Ph
7
8: R = H
9: R = Bn
OH
OH
NHBoc
NH2
Scheme 1. Reagents and conditions: (a) NaH, MEM-Cl, DMSO, 0–
80 °C, 6 h, 72%; (b) LDA (2 equiv), 6, THF, 0 °C ! rt, 2 h, 48%; (c)
Synthesis of 8: i—DIBAL-H, CH2Cl2, 0 °C ! rt, 12 h, 86%; ii—
TBDMS-Cl, imidazole, DMF, rt, 1 h, 96%; iii—n-BuLi, THF, ꢀ78 °C,
1 h, then 6, ꢀ78 °C 1 h, then rt, 1 h, 69%; iv—TBAF, THF, rt, 1.5 h,
92%; Synthesis of 9: i—DIBAL-H, CH2Cl2, 0 °C ! rt, 12 h, 86%; ii—
NaH, benzyl bromide, DMF, 0 °C ! rt, 16 h, 82%; iii—n-BuLi, THF,
ꢀ78 °C, 1 h, then 6, ꢀ78 °C 1 h, then rt, 1 h, 67%.
N
N
a)
CO2Me
CO2Me
• 2HCl
Ph
Ph
N
N
H
O
O
MEM
Ph
Ph
17
16
Scheme 2. Reagents and conditions: (a) i—HCl (aq), MeOH, reflux
1 h; ii—H2SO4 (cat), MeOH, reflux, 30 h, 75% (over two steps).
Table 1. Asymmetric aminohydroxylation of imidazolyl derivatives 7–9a
OH
NHCbz
OH
NHCbz
+
R
N
N
N
AA
R
R
Ph
Ph
Ph
N
N
N
O
O
Ph
O
MEM
MEM
MEM
Ph
Ph
A
B
7: R = CO2Me
8: R = CH2OH
9: R = CH2OBn
10: R = CO2Me
12: R = CH2OH
14: R = CH2OBn
11: R = CO2Me
13: R = CH2OH
15: R = CH2OBn
Entry Substrate Ligand
Solvent
Reaction time [h] Product ratio of regioisomersb Yieldc [%]
% eed
A
B
1
2
3
4
5
6
7
7
7
7
8
9
9
9
(DHQ)2PHAL n-PrOH/H2O (1.5:1) 30
(DHQD)2AQN n-PrOH/H2O (1.5:1) 30
ent-(10/11) = 1:3
10/11 = 1:1
10/11 = 1:1
52
56
72
63
56
65
67
56
54
75
0
53
52
87
nd
nd
nd
(DHQD)2AQN MeCN/H2O (3:1)
(DHQD)2AQN MeCN/H2O (1.5:1)
4
1
1
1
1
12/13 = 1:3
(DHQ)2PHAL
(DHQD)2AQN n-PrOH/H2O (1.5:1)
n-PrOH/H2O (1.5:1)
ent-(14/15) = 1:3.3
14/15 = 1:3
14/15 = 1:1.5
nd
nd
48e nd
(DHQD)2AQN MeCN/H2O (3:1)
a Reagents and conditions: K2OsO2(OH)4 (4 mol %), ligand (5 mol %), BnOC(O)NNaCl (5 mol %) at 25 °C.
b Ratio determined by 1H NMR, for substrate 8 and 9 ratio determined after N-Cbz to N-Boc conversion.
c Isolated yields as a mixture of regioisomers.
d Determined by HPLC on ChiracelTM OD/ODH (nd, not determined).
e Determined after conversion to 19 by HPLC on ChiracelTM OD/ODH.

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R. Patil et al. / Bioorg. Med. Chem. Lett. 16 (2006) 672–676
the products (Table 1, entries 2, 3). Surprisingly, the al-
lyl alcohol 8 and allyl ether 9 were considerably more
reactive than the ester 7, however, with the former sub-
strates the undesired regioisomer B was always favored,
even when the AQN ligand was employed. Moreover,
only racemic products were obtained with the allyl alco-
hol 8 (entry 4). Preparatively most useful appeared to be
the formation of 10 and 11 mediated by (DHQD)2AQN
(entry 3), giving useful yields and selectivities that al-
lowed us to arrive at regio- and enantiomerically pure
products at the next stage in the reaction sequence.
OH
NHBoc
OH
NHBoc
N
N
+
Ph
Ph
OR
OR
N
N
O
O
MEM
MEM
Ph
Ph
Single-step exchange12 of the nitrogen protecting group
on the mixture of 10/11 from Cbz to Boc (10% Pd/C, H2,
MeOH, Boc2O, rt, 3 h, 96% yield) allowed the facile sep-
aration of 16 by column chromatography, which was
obtained enantiomerically pure in 40% yield after recrys-
tallization (28% yield starting from 7), along with the
corresponding regioisomer being obtained in 48% yield.
The structure of 16 could be confirmed by X-ray analy-
sis.13 Finally, deprotection of 16 was achieved by treat-
ment with HCl, resulting also in partial cleavage of the
methyl ester, which was subsequently remedied by ree-
sterification with MeOH to give rise to 1714 (Scheme 2).
18: R = Bn
20: R = H
19: R = Bn
21: R = H
a)
b)
OH
NH2
OH
N
Ph
Ph
N
H
• 2HCl
O
22
Scheme 3. Reagents and conditions: (a) 10% Pd/C, H2, THF, 40 bar,
40 °C, 48 h, 62%; (b) i—NaIO4, 1,4-dioxane, H2O, rt, 2.5 h, 87% based
on 18; ii—HCl (aq), MeOH, reflux 1 h, 95%.
Similarly, the mixture of 14/15 was converted to the N-
Boc derivatives 18/19 (94% yield). However, at this stage
separation of the regioisomers was still not possible.
Therefore, the mixture was debenzylated and subse-
quently treated with NaIO4 to cleave the diol in the
undesired regioisomer 21 (Scheme 3). This way, 20 could
be obtained as a single diastereomer with moderate
enantiomeric excess (48% ee), which was subsequently
deprotected to 22.15
As the missing link to allow a meaningful assessment of
the influence of the modified ethylamine side chain in 17
and 22 with respect to 2, the histaprodifen analogue 25
being acylated instead of alkylated in 2-position could
be synthesized in a straightforward way (Scheme 4).16
All new compounds were screened in vitro for functional
interaction with histamine H1-receptors of guinea-pig
ileum according to standard procedures (Table 2).17
Neither (rac)-17 nor the enantiopure 17 or the diastereo-
merically pure 22 elicited ileal contractions (Table 2).
Only at higher concentrations (30–100 lM), these com-
Scheme 4. Reagents and conditions: (a) i—10% Pd/C, H2, MeOH, rt,
16 h, 98%; ii—LiOH, THF/MeOH/H2O [3:1:1], 0 °C ! rt, 6 h, 95%;
(b) i—(COCl)2, CH2Cl2, 0 °C ! rt 3 h; ii—TMS-N3, CH2Cl2,
0 °C ! rt, 5 h; iii—BnOH, toluene, reflux, 120 °C, 18 h , 86% over
three steps; iv—10% Pd/C, H2, MeOH, rt, 16 h, 86%; (c) concd HCl/
MeOH/H2O [1:1:1], reflux, 1.5 h, 97%.
Table 2. Interaction with histamine H1-receptors (guinea-pig ileum)a
Compound
Agonism
Affinityb
pD0
SEM
Nc
Emax SEM
pEC50 SEM
Rel potency [%]
2
(rac)-17
17
0
0
0
0
—
—
—
—
3.80 0.09
4.61 0.12
4.08 0.14
5.05 0.12
nd
9.07 0.03e
6.04 0.05f
—
7
9
6
4
9
22
24
—
—
—
—
25
75
0
3
5.78 0.08
—
12
Mepyramined
—
34
34g
2d
1
100
100
6.74 0.02
6.70 0.02
111
100
>95
a Experimental protocol and definition of parameters see Ref. 6 and literature cited therein.
b Determined at 10–100 lM unless otherwise indicated.
c Number of experiments for agonism or affinity determination.
d Data from Ref. 6.
e pA2 value, determined at 0.3–100 nM.
f pKP value, determined at 3–30 lM.
g N = 12 for affinity measurement.

R. Patil et al. / Bioorg. Med. Chem. Lett. 16 (2006) 672–676
675
References and notes
100
80
60
40
20
0
1
SEM
1. Hill, S. J.; Ganellin, C. R.; Timmerman, H.; Schwartz, J.-
C.; Shankley, N. P.; Young, J. M.; Schunack, W.; Levi,
R.; Haas, H. L. Pharmacol. Rev. 1997, 49, 253.
2. Pertz, H. H.; Elz, S.; Schunack, W. Mini-Rev. Med. Chem.
2004, 4, 935.
3. Black, J. W.; Ganellin, C. R. Experientia 1974, 30, 111.
4. Dziuron, P.; Schunack, W. Eur. J. Med. Chem. Chim.
Ther. 1975, 10, 129.
25
25
versus
mepyramine (2 nM)
5. Leschke, C.; Elz, S.; Garbarg, M.; Schunack, W. J. Med.
Chem. 1995, 38, 1287.
6. Elz, S.; Kramer, K.; Pertz, H. H.; Detert, H.; ter Laak, A.
-8
-7
-6
-5
-4
-3
log10 c (agonist)
M.; Kuhne, R.; Schunack, W. J. Med. Chem. 2000, 43, 1071.
¨
7. Leading reviews: (a) Kolb, H. C.; Sharpless, K. B.. In
Transition Metals for Organic Synthesis; Beller, M., Bolm,
C., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, p 309; (b)
Bolm, C.; Hildebrand, J. P.; Muniz, K. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: Wein-
heim, 2000; p 399–428; (c) Nilov, D.; Reiser, O. Adv.
Synth. Catal. 2002, 344, 1169; (d) Bodkin, J. A.; McLeod,
M. D. J. Chem. Soc., Perkin Trans. 1 2002, 2733.
8. Dong, L.; Miller, M. J. J. Org. Chem. 2002, 67, 4759.
9. Raatz, D.; Innertsberger, C.; Reiser, O. Synlett 1999, 1907.
10. (a) Feng, Z.-X.; Zhou, W.-S. Tetrahedron Lett. 2003, 44,
493; (b) Heimga¨rtner, G.; Raatz, D.; Reiser, O. Tetra-
hedron 2005, 61, 643.
Figure 3. Contraction of guinea-pig ileum by 1 (n, N = 9) and 25 in the
absence (Ç, Emax = 75 3%, N = 9) and presence (Æ, 47 4%, N = 5)
of mepyramine (2 nM). Rel potency of 25 was 12% (95% conf limits 9–
17%), pA2 of mepyramine was 9.08 0.11. Data from three animals.
For protocol, see Ref. 6.
pounds depressed the effect of 1 without producing a
rightward shift of the agonist curve. Thus, in contrast
to the potent reference antagonist mepyramine (nano-
molar affinity, pA2 = 9.07), they have to be classified
as weak non-competitive H1-receptor blockers (pD02
<
11. Cliff, M. D.; Pyne, S. G. J. Org. Chem. 1995, 60, 2378.
12. Boger, D. L.; Lee, R. J.; Bounaud, P.-Y.; Meier, P. J. Org.
Chem. 2000, 65, 6770.
13. Details on the X-ray structure of 16 can be obtained from
the Cambridge Crystallographic Data Center quoting
CCDC 286008.
5).
Compared with the lead 2, the new antagonists are en-
dowed with several chemical modifications. It was of
special interest to understand the influence of the car-
bonyl group attached to C2 of the imidazole, since 2-
acylated histamine derivatives have never been studied
so far. To our surprise compound 25, a Ôketo histaprod-
ifen,Õ turned out to be a moderate partial H1-receptor
agonist, displaying approximately 12% relative potency
compared with its parent compound 2. The contractile
effect was mediated by H1-receptors since mepyramine
(2 nM), a reference H1-receptor antagonist, successfully
blocked the effect of 25 (Fig. 3) with the expected
nanomolar affinity. The N1-protected precursor of 25,
24, failed to stimulate H1-receptors which is in agree-
ment with the current concept of H1-receptor agonist
SAR.2
14. Analytical data for 17: Rf = 0.16 (SiO2, ethyl acetate/
22
methanol 7:3); white solid; mp 147–154 °C; ½aꢁD ꢀ14.3 (c
0.6, CH2Cl2); 1H NMR (300 MHz CD3OD) d: 3.73 (s, 3 H,
CO2CH3), 3.79 (dd, J = 1.89, 7.82 Hz, 2H, CH2CO), 3.87
(d, J = 3.60 Hz, 1H, CHNH2), 4.75 (t, J = 7.82 Hz, 1H,
CHCH2), 5.11 (dd, J = 0.72, 3.60 Hz, 1H, CHOH), 7.09–
7.31 (m, 11H, aromatic); 13C NMR (75.5 MHz, CD3OD)
d: 44.5, 47.6, 52.8, 60.3, 70.3, 118.0 , 127.4, 128.9, 129.0,
~
128.5, 145.6, 145.6, 146.3, 174.5, 190.4; IR (neat) m: 3300–
2500 (broad), 1754, 1715, 1599, 1495, 1219, 1039, 747, 698,
613 cmꢀ1
Found: 393.1688.
15. Analytical data for 22: Rf = 0.27 (SiO2, CH2Cl2/MeOH/
; HRMS: calcd for C22H23N2O4: 393.1689.
22
NH3 7:3:0.2); white glassy solid; mp 122–127 °C; ½aꢁD ꢀ4.8
1
(c 0.6, MeOH, 48% ee); H NMR (600 MHz, DMSO) d:
3.43 (dd, J = 5.97, 11.10 Hz, 1H, CHHOH), 3.47 (m, 1H,
CHNH3), 3.55 (dd, J = 3.93, 11.10 Hz, 1H, CHHOH),
3.87 (dd, J = 7.77, 17.15 Hz, 1H, CHHCO), 3.93 (dd,
J = 7.77, 17.15 Hz, 1H, CHHCO), 4.68 (dd, J = 7.77,
7.77 Hz, 1H, CHCH2), 4.85 (d, J = 6.98 Hz, 1H, CHOH),
4.98 (s, very broad, 2H, imidazole NH and CH2OH), 7.12–
7.35 (m, 10H, Ph-H), 7.51 (s, 1H, imidazole 5-H), 8.06 (s,
broad 3H, CHNH3); 13C NMR (150.9 MHz, DMSO) d:
43.2, 45.4, 56.5, 58.3, 63.2, 121.0, 126.1, 127.5, 128.3,
It is concluded that the lack of H1-receptor agonist
activity observed for aminohydroxylation products
structurally related to 2 ((rac)-17, 17, 21) is due to the
additional oxygen-containing polar functionalities at-
tached to the ethylamine side chain of 2. The keto deriv-
ative 25 is the first 2-acyl derivative of 1 reported which
is capable of stimulating histamine H1-receptors. This
finding may be of importance since 2-acyl congeners of
1 are available much more conveniently than their 2-al-
kyl counterparts.
128.5, 139.9, 142.5, 144.0, 187.2; IR (neat) m: 3400–3020
~
(broad), 2890, 1703, 1676, 1599, 1493, 1396, 1223, 1044,
; HRMS: calcd for
1022, 990, 731, 699, 613 cmꢀ1
C21H23N3O3: 365.1739. Found: 365.1732.
16. Analytical data for 25: Rf = 0.13 (SiO2, CH2Cl2/MeOH/
NH3 10:1:0.2); white solid; mp 180–182 °C; 1H NMR
(300 MHz, DMSO) d: 2.97 (t, J = 7.25 Hz, 2H,
CH2CH2N), 3.13 (tq, J = 7.25, 6.03 Hz, 2H, CH2NH3),
3.93 (d, J = 7.68 Hz, CH2CO), 4.68 (t, J = 7.68 Hz, 2H,
CHCH2CO), 5.1–6.5 (s, very broad, imidazole NH), 7.12–
7.41 (m, 10H, Ph-H), 7.54 (s, 1H, imidazole 5-H), 8.24 (s,
broad 3H, CH2NH3); 13C NMR (75.5 MHz, DMSO) d:
Acknowledgments
This work was supported by the Deutsche Forschungs-
gemeinschaft (Graduiertenkolleg Medizinische Chemie
760) and the Fonds der Chemischen Industrie. The con-
tribution of C. Braun and K. Ro¨hrl to in vitro pharma-
cology is acknowledged.

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R. Patil et al. / Bioorg. Med. Chem. Lett. 16 (2006) 672–676
23.5, 37.6, 43.5, 45.3, 121.5, 126.3, 127.6, 128.4, 141.4,
~
TyrodeÕs solution. In the continuous presence of the
anticholinergic blocker atropine (100 nM), concentra-
tion–effect curves for 1 or compounds under study were
recorded in a cumulative manner in the absence and
presence of either reference or potential H1-receptor
antagonist. For details, see Ref. 6.
144.1, 186.3; IR (KBr) m: 3448, 3029, 1699, 1495, 1213,
1034, 749, 702, 567 cmꢀ1; HRMS: calcd for C20H21N3O:
319.1685. Found: 319.1685.
17. In brief, isolated whole segments of guinea-pig ileum were
mounted under isotonic conditions (preload 0.5 g) in