Histamine H
3
-Receptor Ligands of Proxifan Series
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3341
4
3
-(3-Chloropropyl)-1-(triphenylmethyl)-1H-imidazole23 (10 mmol,
.86 g) dissolved in 5 mL of dry DMF was added and the
SO-d
H), 6.97 (m, 3H, OH*, Ph-3,5-H), 5.81 (s, 2H, NH
1H, CH), 4.06 (t, J ) 6.1 Hz, 2H, CH O), 2.83 (t, J ) 7.5 Hz,
2H, Im-CH ), 2.13 (m, 2H, Im-CH CH ), 1.42 (d, J ) 6.7 Hz,
3H, CH ). Anal. (C14 ‚2C ‚0.5H O) C, H, N.
6
) δ 8.68 (s, 1H, Im-2-H), 7.36 (m, 3H, Im-5-H, Ph-2,6-
2
*), 4.23 (m,
mixture heated to 75 °C for 3 days. The solvent was removed
under reduced pressure and the product purified by column
chromatography (eluent: EtOAc). Detritylation was achieved
in 20 mL of 2 N HCl and 40 mL of THF by heating to reflux
for 90 min. THF was evaporated under reduced pressure and
the aqueous residue washed with Et
was basified with K CO and extracted with Et
layer was separated and the solvent evaporated. The crude
product was subjected to column chromatography (eluent:
2
2
2
2
3
H
19
N
3
O
2
2
H
2
O
4
2
O-Meth yl (4-(3-(1H-Im id a zol-4-yl)p r op yloxy)p h en yl)-
eth a n on e Oxim e (16). FUB 37212 was treated with O-
2
O. The aqueous phase
O. The organic
methylhydroxylamine hydrochloride (2 equiv) for 4 h as
1
2
3
2
described in method B:
H NMR (Me SO-d ) δ 8.86 (s, 1H,
2
6
Im-2-H), 7.60 (d, J ) 8.8 Hz, 2H, Ph-2,6-H), 7.42 (s, 1H, Im-
5-H), 6.94 (d, J ) 8.9 Hz, 2H, Ph-3,5-H), 6.04 (s, 2H, Mal),
4.04 (t, J ) 6.2 Hz, 2H, CH O), 3.88 (s, 3H, OCH ), 2.80 (t, J
CH
hydrogen maleate from EtOH/Et
.86 (s, 1H, Im-2-H), 7.49 (d, J ) 8.5 Hz, 2H, Ph-2,6-H), 7.42
s, 1H, Im-5-H), 6.94 (d, J ) 8.6 Hz, 2H, Ph-3,5-H), 6.04 (s,
H, Mal), 4.05 (t, J ) 6.1 Hz, 2H, CH O), 3.43 (m, 4H,
pyrrolidine-2,5-H), 2.80 (t, J ) 7.6 Hz, 2H, Im-CH ), 2.08 (m,
), 1.84 (m, 4H, pyrrolidine-3,4-H). Anal.
‚0.5H O) C, H, N.
2 2
Cl /MeOH (90/10)). Pure fractions were crystallized as
2
3
1
2
O: H NMR (Me
2
SO-d
6
) δ
) 7.5 Hz, 2H, Im-CH ), 2.14 (s, 3H, CH ), 2.08 (m, 2H, Im-
2
3
8
(
2
CH CH ). Anal. (C H N O ‚C H O ) C, H, N.
2
2
15 19
3
2
4
4
4
(
4-(3-(1H -Im id a zol-4-yl)p r op yloxy)p h en yl)et h a n on e
2
12
Sem ica r ba zon e (18). FUB 372 (2.5 mmol, 0.61 g), semi-
2
carbazide hydrochloride (5 mmol, 0.58 g), and NaOAc (5 mmol,
2
H, Im-CH
2
CH
2
0
.40 g) were dissolved in 20 mL of dry EtOH and heated to
(C
17
H
21
N
3
O
2
‚C
4
H
4
O
4
2
reflux for 4 h. The crude product was concentrated under
reduced pressure, purified by column chromatography (elu-
ent: CH Cl /MeOH (90/10)), and crystallized as hydrogen
Gen er a l P r oced u r e for Oxim e F or m a tion . Meth od B.
The corresponding free base of the aldehyde or ketone (2.5
2
2
1
mmol), 2-20 equiv of (substituted) hydroxylamine hydrochlo-
maleate from EtOH/Et O: H NMR (Me SO-d ) δ 9.20 (s, 1H,
2
2
6
ride (5-50 mmol), and 2-20 equiv of Na
2
CO
3
(5-50 mmol,
CONH*), 8.86 (s, 1H, Im-2-H), 7.75 (d, J ) 8.7 Hz, 2H, Ph-
0
.53-5.3 g) were dissolved in 20 mL of dry EtOH and heated
2,6-H), 7.42 (s, 1H, Im-5-H), 6.88 (d, J ) 8.6 Hz, 2H, Ph-3,5-
to reflux for 4-18 h. After filtration of inorganic salts, the
solvent was evaporated under reduced pressure. The product
H), 6.43 (br, 2H, NH *), 6.04 (s, 2H, Mal), 4.03 (t, J ) 6.1 Hz,
2
2H, CH O), 2.66 (t, J ) 7.5 Hz, 2H, Im-CH ), 2.13 (s, 3H, CH ),
2
2
3
was purified by column chromatography (eluent: CH
MeOH (90/10)) and crystallized as free base from EtOH or as
hydrogen maleate from EtOH/Et O. Compounds 11, 12, 14,
6, 17, 19-24, and 26-30 were prepared by this method.
-(3-(1H-Im ida zol-4-yl)pr opyloxy)ben za ldeh yde Oxim e
2
Cl
2
/
2.07 (m, 2H, Im-CH CH ). Anal. (C H N O ‚C H O ‚0.5H O)
2
2
15 19
5
2
4
4
4
2
C, H, N.
2
5
-(4-(3-(1H-Im idazol-4-yl)pr opyloxy)ph en yl)-5-(h ydr ox-
1
yim in o)va ler ic Acid (25). 5-(4-(3-(1H-Imidazol-4-yl)propy-
loxy)phenyl)-5-oxovalerianic acid12 (0.63 mmol, 0.20 g) and
hydroxylamine hydrochloride (1.89 mmol, 0.13 g) were dis-
solved in 15 mL of dry pyridine and heated to reflux for 3 h.
The solvent was removed under reduced pressure and the
residue taken up in 10 mL of 2 N HCl. The pH was adjusted
4
1
2
(
11). 4-(3-(1H-Imidazol-4-yl)propyloxy)benzaldehyde was
treated with hydroxylamine hydrochloride (2 equiv) for 4 h as
described in method B: H NMR (Me SO-d ) δ 10.96 (s, 1H,
2 6
OH*), 8.86 (s, 1H, Im-2-H), 8.06 (s, 1H, CH), 7.94 (d, J ) 8.7
Hz, 2H, Ph-2,6-H), 7.53 (s, 1H, Im-5-H), 6.94 (d, J ) 8.5 Hz,
2
1
with K
ambient temperature. The precipitate was filtered off and
washed carefully with MeOH: 1H NMR (Me
SO-d ) δ 10.98*
2 3
CO to 5-6, then the mixture was stirred for 12 h at
H, Ph-3,5-H), 6.04 (s, 2H, Mal), 4.04 (t, J ) 6.0 Hz, 2H,
CH
CH
2
O), 2.80 (t, J ) 7.5 Hz, 2H, Im-CH
2
), 2.08 (m, 2H, Im-
O) C, H, N.
2
6
2
CH ). Anal. (C13 ‚C ‚0.5H
2
H
15
N
3
O
2
4
H
4
O
4
2
(s, 1H, NOH*), 7.58 (d, J ) 8.4 Hz, 2H, Ph-2,6-H), 7.52 (s, 1H,
Im-2-H), 6.92 (d, J ) 8.4 Hz, 2H, Ph-3,5-H), 6.77 (s, 1H, Im-
N-Hyd r oxy-4-(3-(1H-im id a zol-4-yl)p r op yloxy)ben za m i-
d in e (13). 4-(3-(1H-Imidazol-4-yl)propyloxy)benzonitrile19 (1
mmol, 0.21 g), hydroxylamine hydrochloride (2 mmol, 0.14 g),
5-H), 4.01 (t, J ) 6.0 Hz, 2H, CH O), 2.68 (m, 4H, C(NOH)-
2
CH
Im-CH
0.5H O) C, H, N.
2
, Im-CH
2
), 2.26 (m, 2H, C(NOH)CH
2
CH
2 2
CH ), 2.03 (m, 2H,
and Na
2
CO
3
(2 mmol, 0.21 g) were dissolved in 20 mL of EtOH
2
CH ), 1.68 (m, 2H, C(NOH)CH
2
2
CH
2
). Anal. (C17H N O ‚
21 3 4
and heated to reflux for 24 h. After filtration of inorganic salts,
the solvent was evaporated under reduced pressure. The
2
(2-F lu or o-4-(3-(1H-im id a zol-4-yl)p r op yloxy)p h en yl)e-
th a n on e Oxim e (30). (2-Fluoro-4-(3-(1H-imidazol-4-yl)pro-
product was purified by column chromatography (eluent: CH
Cl /MeOH (90/10)) and crystallized as hydrogen maleate from
EtOH/Et
H, Im-2-H), 7.60 (d, J ) 8.6 Hz, 2H, Ph-2,6-H), 7.36 (s, 1H,
Im-5-H), 6.92 (d, J ) 8.7 Hz, 2H, Ph-3,5-H), 6.04 (br, 4H, Mal,
NH *), 4.03 (t, J ) 6.1 Hz, 2H, CH O), 2.78 (t, J ) 7.5 Hz, 2H,
Im-CH ), 2.08 (m, 2H, Im-CH CH ). Anal. (C13 ‚C
.5H O) C, H, N.
-(3-(1H-Imidazol-4-yl)propyloxy)phenylethanone Oxime
2
-
pyloxy)phenyl)ethanone12 was treated with hydroxylamine
2
1
1
2
O: H NMR (Me
2
SO-d
6
) δ 9.59 (s, 1H, OH*), 8.75 (s,
hydrochloride (5 equiv) for 4 h as described in method B:
NMR (Me SO-d
7.39 (m, 2H, Im-5-H, Ph-6-H), 6.79 (m, 2H, Ph-3,5-H), 6.04 (s,
2H, Mal), 4.05 (t, J ) 6.2 Hz, 2H, CH O), 2.79 (t, J ) 7.5 Hz,
, Im-CH CH ). Anal. (C14
H
1
2
6
) δ 11.22 (s, 1H, OH*), 8.87 (s, 1H, Im-2-H),
2
2
2
2
2
2
H
16
N
4
O
2
4
H
4
O
4
‚
2H, Im-CH
FN ‚C
2
4
), 2.08 (m, 5H, CH
) C, H, N.
3
2
2
H
16
-
0
2
3
O
2
4
H
O
4
4
Sin gle-Cr ysta l X-r a y An a lysis of 14. The X-ray diffraction
experiments were executed on a Siemens four-circle diffrac-
tometer (AED) equipped with a N gas stream cooling device.
2
1
2
(
14). FUB 372 was treated with hydroxylamine hydrochloride
1
(
2 equiv) for 4 h as described in method B: H NMR (Me
) δ 10.97 (s, 1H, OH*), 8.85 (s, 1H, Im-2-H), 7.57 (d, J ) 8.7
Hz, 2H, Ph-2,6-H), 7.42 (s, 1H, Im-5-H), 6.91 (d, J ) 8.9 Hz,
H, Ph-3,5-H), 6.04 (s, 2H, Mal), 4.03 (t, J ) 6.2 Hz, 2H,
CH O), 2.80 (t, J ) 7.4 Hz, 2H, Im-CH ), 2.10 (s, 3H, CH ),
.06 (m, 2H, Im-CH CH ). Anal. (C14 ‚C ‚0.5H O)
C, H, N.
-(3-(4-(1-(Hyd r oxya m in o)eth yl)p h en oxy)p r op yl)-1H-
2
SO-
d
6
Precise lattice parameters and three-dimensional intensity
data were collected at a low temperature of 193 °K using Nb-
filtered Mo KR radiation (λ ) 0.71068 Å). The intensity data
were corrected for Lorentz and polarization effects but not for
absorption. Phase determination was made with direct meth-
2
2
2
3
2
2
2
H
17
N
3
O
2
4
H
4
O
4
2
3
7
ods (program SHELXS 97 ), and refinement was done with
3
7
the corresponding least-squares program of the SHELXL 97
program system. All hydrogens were located from difference
syntheses. After convergence R-values of R ) 5.1% and wR
13.4% (based on F ) were obtained. No significant peaks or
holes were seen in a final difference Fourier map.
4
im id a zole (15). Compound 14 (free base, 2 mmol, 0.52 g),
methyl orange (pH indicator, 2 mg), and sodium cyanohydri-
doborate (6 mmol, 0.38 g) were dissolved in 20 mL of dry THF
and stirred at ambient temperature for 5 min. After 5 min, a
solution of 4 N HCl in dioxane was added dropwise in order
to maintain the pH at 3-4. When a steady red color was
obtained, the mixture was poured into 50 mL of water, basified
with 1 N NaOH, and extracted with Et
was washed with water, dried (Na SO
chromatography (eluent: CH Cl /MeOH (90/10)), and cystal-
lized as hydrogen oxalate from EtOH/Et
1
2
2
)
In the course of structure determination and refinement, it
turned out that the present modification of the title molecule
crystallizes with one molecule of maleic acid and in addition
also with one molecule of methanol in the asymmetric unit
(obtained from different methanol/diethyl ether mixtures).
During the crystallization experiments a second, methanol-
free, crystalline modification was found (space group mono-
2
O. The organic layer
2
4
), purified by column
2
2
1
2
2
O: H NMR (Me -