Potent acetylcholinesterase inhibitors: Design, synthesis, and structure - Activity relationships of bis-interacting ligands in the galanthamine series

Article abstract of DOI:10.1016/S0968-0896(98)00133-3

New galanthamine derivatives, especially bis-interacting ligands 3-5 and 7-9 were prepared in order to interact with the catalytic and the peripheral sites of acetylcholinesterase (AChE). The synthesis, the anticholinesterase activities, and the structure-activity relationships of bis-interacting ligands are reported. Compounds 4d-e were found to be more potent than galanthamine and tacrine in inhibiting AChE. Copyright (C) 1998 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00133-3

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 1835±1850
Potent Acetylcholinesterase Inhibitors: Design, Synthesis, and
Structure±Activity Relationships of Bis-interacting Ligands in
the Galanthamine Series
Aude Mary, Dolor Za®arisoa Renko, Catherine Guillou* and Claude Thal
Institut de Chimie des Substances Naturelles, C.N.R.S., Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
Received 17 February 1998; accepted 18 May 1998
AbstractÐNew galanthamine derivatives, especially bis-interacting ligands 3±5 and 7±9 were prepared in order to
interact with the catalytic and the peripheral sites of acetylcholinesterase (AChE). The synthesis, the anticholinesterase
activities, and the structure±activity relationships of bis-interacting ligands are reported. Compounds 4d±e were found
to be more potent than galanthamine and tacrine in inhibiting AChE. # 1998 Elsevier Science Ltd. All rights reserved.
Introduction
In this paper, we report the synthesis and biological
activities of neutral or cationic bis-interacting ligands 3±
5 and 7±9.6 Our bis-ligand strategy is based on the
crystallographic structure of AChE from Torpedo cali-
fornica.7 The AChE active site contains a catalytic triad
(Ser200, His440, Glu327) located at the bottom of a
deep and narrow gorge, ꢀ 20 A long, lined with aro-
matic residues and a subsite, including Trp 84, located
near the bottom of the cavity. Trp 84 has been identi®ed
as the binding site of the quaternary group of acetyl-
choline, decamethonium, and edrophonium.8 In
addition, Trp 279 at the peripheral site, located at the
opening of the gorge, is involved in the binding of the
second quaternary group of decamethonium. The dis-
tance between these two tryptophan residues (84 and
279) is 12 A. We therefore presume that the bis-ligands
could simultaneously interact with the active and the
peripheral sites (Trp 84 and 279) and thereby optimize
the inhibiting potency. Recently, alkyl linked bis-tacrine
derivatives have been described to be highly potent
inhibitors of acetylcholinesterase.9
The cholinergic hypothesis postulates that memory
impairments in patients with Alzheimer's disease (AD)
result from a de®cit of cholinergic function in the brain.1
The most important changes observed in the brain of
AD patients are a decrease in hippocampal and cortical
levels of neurotransmitter acetylcholine and associated
enzymes (choline transferase and acetylcholinesterase).
One possible approach to treating this disease is to
restore the level of acetylcholine by inhibiting acetyl-
cholinesterase with reversible inhibitors. Clinical trials
indicate that AChE inhibitors such as tacrine and physo-
stigmine e€ectively improve memory in some patients.
Other cholinesterase inhibitors such as galanthamine 12
have received recent attention. This compound is less
potent, but also less toxic than tacrine and physo-
stigmine. Galanthamine, a centrally acting competitive
and reversible inhibitor, has been shown to produce
signi®cant improvement of cognitive performances in
AD patients.3 Moreover, Nivalin1 (galanthamine
hydrobromide) has recently received its ®rst approval
for the treatment of AD in Austria. A variety of syn-
thetic galanthamine derivatives have been previously
described including C-ring derivatives,4 quaternary
ammonium derivatives,4 or esters and carbamates of
6-O-demethylgalanthamine 65 (Scheme 1).
In order to synthesize bis-interacting ligands 3±5 and 7±
9, di€erent alkyl linkers (CH2)n with a terminal ammo-
nium or phthalimido group were connected to the
nitrogen of N-demethylgalanthamine (norgalanthamine)
210 and to the oxygen of 6-O-demethylgalanthamine
(sanguinine) 6. Both these modi®cations were con-
sidered because the binding mode of galanthamine to
the active site of AChE has not been elucidated.
*Corresponding author. Fax: (+31) 1 69 07 72 47; E-mail:
guillou@icsn.cnrs-gif.fr
0968-0896/98/$Ðsee front matter # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00133-3

1836
A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
Compounds 3 and 7 were also transformed into their
corresponding iminium salts 4 and 8 (Scheme 1). It was
hoped that this modi®cation could improve the anti-
cholinesterase activity of the galanthamine moiety of
bis-ligands 4 and 8, since the presence of a permanent
positive charge would favor interaction with Trp 84,
which is the binding site of the quaternary group of
acetylcholine. The greater inhibitory activity of galan-
thamine methiodide is consistent with this hypothesis.4
bromides 10 with potassium phthalimide or with tri-
methylamine a€orded phthalimido linkers 11 and
ammonium linkers 12, respectively.
Preparation of N-substituted derivatives 3±5. (Scheme 3
and Table 2) Preparation of N-substituted galanthamine
derivatives 3±5 requires an ecient N-selective de-
methylation of galanthamine 1 to norgalanthamine 2.
We have recently found that this transformation can be
selectively accomplished by a nonclassical Polonovski
reaction using iron salts.10
Chemical Results
Alkylation of norgalanthamine 2 with the phthalimido
linkers 11 or with the ammonium linkers 12 a€orded the
bis-ligands 3 and 5, respectively, in satisfactory yields.
Preparation of phthalimido linkers 11 and ammonium
linkers 12. (Scheme 2 and Table 1) Reaction of alkyl
Scheme 1.

A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
1837
Table 1.
n
Products (yield %)
3
12a (35)
4
11b*
11c (64)
11d (60)
11e (61)
11f (61)
6
12c (14)
12d (30)
12e (22)
12f (24)
8
10
12
*11b (n=4) commercially available.
carbon tetrachloride at room temperature (Method B).
The iminium salt 4f was prepared by reaction of iodine
with 3f (Method C).12
Scheme 2.
The iminium salts 4b±c were obtained in two steps from
the corresponding amino compounds 3b±c under Polo-
novski±Potier conditions.11 Thus, compounds 3b±c were
®rst converted into their corresponding N-oxides 3b0±c0
by reaction with m-chloroperbenzoic acid, and sub-
sequent treatment with tri¯uoroacetic anhydride in
dichloromethane at 0 ꢁC a€orded the iminium salts 4b±c
(Method A).
Preparation of O-substituted derivatives 7±9. (Scheme 4
and Table 3.) 6-Demethylgalanthamine 6 was used as the
precursor of the O-substituted derivatives 7±9. Com-
pound 6 was prepared in high yield (95%) by reaction of
galanthamine with l-selectride. This transformation has
been previously achieved in presence of NaSEt in 80%
yield.13
Alkylation of 6-O-demethylgalanthamine 6 with phthal-
imido linkers 11 or with ammonium linkers 12 in
dimethylformamide in the presence of cesium carbonate
The iminium salts 4d±e were obtained in one step from
compounds 3d±e by reaction of N-bromosuccinimide in
Scheme 3. Method A for 4b±c: (i) m-CPBA 1.1 equiv, CH2Cl2, 20 ꢁC, 1.5 h; (ii) (CF3CO)2O, CH2Cl2, 0 ꢁC, 6 h. Method B for 4d±e:
NBS-AIBN, CCl4, 20 ꢁC. Method C for 4f: (i) I2, NaOAc, EtOH, re¯ux, 1 h; (ii) HBr, 0.5% solution in water.

1838
A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
Table 2.
Table 3.
n
Products (yield %)
n
Products (yield %)
3
5a (76)
4
7b (70)
7d (45)
7e (48)
7f (67)
8b (60)
8d (57)
8e (56)
8f (54)
4
3b (88)
3c (80)
3d (86)
3e (84)
3f (81)
4b (38)*
4c (49)*
4d (52)
4e (45)
4f (28)
8
9d (59)
9e (51)
9f (50)
6
5c (71)
5d (65)
5e (55)
5f (63)
10
12
8
10
12
*Overall yield for the two steps: 3b±c!3b0±c0!4b±c.
Biological Results and Discussion
In vitro acetylcholinesterase inhibition was determined
using the spectroscopic method of Ellman et al.14 The
results are summarized in Table 5 as IC50 values. The
IC50 values of tacrine and galanthamine were deter-
mined to be 0.5‹0.04Â10 7 M and 3.6‹0.1Â10 7 M,
respectively.
a€orded compounds 7 and 9, respectively. Subsequent
treatment of O-substituted derivatives 7 with iodine and
sodium acetate in re¯uxing ethanol provided the corre-
sponding iminium salts 8 (Method C).
The bis-functional derivatives 13 which possess
a
phthalimido group at one end and a quaternary ammo-
nium function at the other were also prepared in order
to con®rm that the galanthamine moiety present in bis-
ligands 3±5 and 7±9 is essential for anticholinesterase
activity. Thus, reaction of phthalimido bromides 11
with trimethylamine in toluene a€orded the bis-func-
tional linkers 13 in practically quantitative yields
(Scheme 5 and Table 4).
As expected, the length of the alkyl linkers is a key fea-
ture for enhancing inhibitory potency. But the best
inhibitory activities, for the same length of alkyl chain,
depends on the function at the end of the linker as well
as on its locality. Thus, the inhibitory activities of the
N- and O-phthalimidoalkyl bis-interacting ligands were
optimal in compounds 3d and 7d with an eight methyl-
ene linker (n=8) and decrease when the alkyl chain is
further elongated, as in compounds 3e±f and 7e±f
Scheme 4.

A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
1839
Table 5. In vitro AChE inhibition
Compd
n
IC50‹SD (10 7 M)
3b
3c
4
20‹1.6
9.9‹2.0
2.8‹0.4
3.3‹0.2
14‹0.9
6
8
3d
3e
10
12
4
3f
4b
Scheme 5.
4.7‹0.4
0.4‹0.01
0.1‹0.02
0.2‹0.01
1.3‹0.09
124‹6.4
17‹2.7
4c
4d
6
8
4e
10
12
3
Table 4.
4f
5a
n
Products (yield %)
5c
5d
6
8
13d (98)
13e (96)
13f (97)
8
3.1‹0.2
1.2‹0.5
0.8‹0.1
161‹14
25‹1.5
10
12
5e
10
12
4
5f
7b
7d
7e
8
10
12
4
40‹2.1
46‹8.3
23‹3.5
7f
8b
(n=10 or 12). In comparison, the best inhibiting activ-
ities of the N- and O-alkylammonium bis-interacting
ligands were reached in compounds 5f and 9f with a
twelve methylene linker (n=12). We thus presume that
when the alkyl chain is of suitable length (from 8 to 12
CH2), the bis-interacting ligands are able to interact
with tryptophan residues Trp 84 and Trp 279. When the
alkyl chain is shorter (compounds 5a, n=3, 3b, 7b,
n=4) the phthalimido or the ammonium group prob-
ably hinder the optimal ®t of the molecule in the narrow
gorge, thereby negatively a€ecting the inhibitory activ-
ities of these compounds.
8d
8e
8
0.7‹0.1
0.5‹0.09
3.2‹0.1
97‹11
10
12
8
8f
9d
9e
10
12
8
41‹0.9
13‹1.1
9f
13d
9.0‹3.4
52.7‹3.1
30.3‹3.9
1.4‹0.2
3.6‹0.1
0.5‹0.04
13e
13f
1416
10
12
-
Galanthamine
Tacrine
N-Phthalimido compounds 3d (n=8) and 3e (n=10)
show an inhibitory activity comparable to galanth-
amine, whereas N-alkylammonium compounds 5d±f
(n=8, 10 and 12) are more potent. The inhibiting activ-
ities of the O-bis-interacting derivatives 7b±f and 9d±f
are lower than those of galanthamine and their corre-
sponding N-bis-interacting derivatives 3b±f and 5d±f.
These results reveal that linkage is more favorable on
the nitrogen atom, suggesting a di€erent binding mode
for the N and O-bis-interacting ligands to AChE
(Fig. 1(A): 3 versus 7). It is also interesting to note that
a quaternary ammonium function is more important in
determining potency than the phthalimido group
(Fig. 1(B): 5 versus 3). It seems likely that the ammo-
nium group makes close Van der Waals contact with the
`hydrophobic aromatic gorge'. Indeed, theoretical stu-
dies have shown that quaternary nitrogens interact pre-
ferentially with the p-electrons of aromatic residues,
especially Trp.7,15
moiety. Thus, compounds 13d±f were found to be less
active than the bis-interacting ligands 3d±f, 5d±f, having
the same number of methylenes. These results strongly
suggest that the galanthamine moiety is essential for the
anticholinesterase activity.
Concerning the iminium function, we have previously
observed that, incorporated on galanthamine itself (i.e.
compound 14),16 a signi®cant enhancement of enzyme
inhibition is obtained. Analogously, introducing this
cationic function on the neutral phthalimidoalkyl com-
pounds 3 and 7 conferred on them a substantial gain in
inhibitory activity. Thus, compounds 4 and 8 are more
active than their neutral parent compounds 3 and 7. The
e€ect of the length of the alkyl linker is similar to that
observed in the series of compounds 3 and 7. This per-
manent positive charge on the galanthamine nitrogen
atom constitutes the major factor in determining AChE
inhibition potency since for compounds 8, the less
favorable linkage to the oxygen atom is largely o€set by the
presence of the iminium function (Fig. 1(C): 8 versus 7).
Considering the good inhibitory activities of N-alkyl
compounds 3 and 5, the bis-functional linkers 13 were
needed to establish the in¯uence of the galanthamine

1840
A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
Figure 1. In¯uence of di€erent parameters on the AChE inhibition as colog IC50 (i.e. -log IC50) versus chain length (n). (A) Linkage
e€ect: N-phthalimido compounds 3 versus O-phthalimido compounds 7. (B) Terminal group e€ect: N-alkylammonium derivatives 5
versus N-phthalimido derivatives 3. (C) Iminium function e€ect: charged O-phthalimido compounds 8 versus neutral parent com-
pounds 7.
The charged N-bis-interacting derivatives 4d and 4e are
more potent than galanthamine (36- and 18-fold,
respectively) and tacrine (5- and 2.5-fold, respectively),
whereas the charged O-bis-interacting derivatives 8d and
8e are nearly equipotent with tacrine.
than both galanthamine and tacrine. These results con-
®rm that introduction of an iminium function and N-
alkylation of the nitrogen of the galanthamine moiety
with a phthalimido alkyl linker (n=8 or 10) enhances
enzyme inhibition. Such bis-interacting ligands in the
galanthamine series constitute a possible new class of
potent therapeutic agents for Alzheimer's disease.
Conclusion
New O- and N-substituted galanthamine derivatives,
especially bis-interacting ligands, have been synthesized.
These compounds possess an alkyl side chain bearing a
terminal phthalimido or ammonium group allowing
them to interact simultaneously with the catalytic site
and the peripheral site of acetylcholinesterase. Two
compounds, 4d and 4e, were found to be more potent
Experimental
General
IR spectra were recorded on a Nicolet FT-IR spectro-
1
meter. H NMR spectra were recorded at 200, 250, and
300 MHz and 13C NMR spectra at 50.3, 62.9, and

A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
1841
75.4 MHz. Chemicals shifts are expressed in parts per
million (ppm), relative to tetramethylsilane (TMS) as an
internal standard. Coupling constants (J values) are in
Hertz. Multiplicities are designated as singlet (s), doub-
let (d), triplet (t), multiplet (m), or broad (br). All pur-
i®cations were carried out under ¯ash chromatographic
conditions on Merck silica gel 60 (70±230 mesh) at
medium pressure (200 mbar). TLC was performed on
Merck silica gel plates (60 F254) with a ¯uorescent indi-
cator. Elemental analyses were performed at the ICSN
(CNRS, Gif-sur-Yvette). HRMS spectra were recorded
with a KRATOS MS-80 instrument. Mass spectra were
recorded with a KRATOS MS-80 (FAB), or AEI MS-9
(CI), or AEI MS-50 (EI) instrument. Chemical ioniza-
tion mass spectra were recorded in the presence of iso-
butane gas. THF was distilled from sodium/
benzophenone complex. CH3CN was distilled from
CaH2, CH2Cl2 from P2O5 and NEt3 from KOH.
Organic extracts were washed with brine and dried with
anhydrous Na2SO4.
10-N-Demethyl-10-N-(40-phthalimidobutyl)-galanthamine
(3b). Reactants: (760 mg, 2.8 mmol) in CH3CN
2
(50 mL), 11b (942 mg, 3.3 mmol), and NEt3 (776 mL,
5.6 mmol) yielded 3b (1.17 g, 88%). IR (CHCl3) n: 3650,
3032, 2935, 1771, 1708 cm 1; EIMS 474 (M+Á) 286, 272;
1H NMR (300 MHz, CD3OD, d) 7.83±7.72 (4H, m,
phthalimido), 6.61 (1H, d, J=8, H7), 6.54 (1H, d,
J=8.0, H8), 6.14 (1H, d, J=10.5, H1), 5.91 (1H, dd,
J1=10.5, J2=4.7, H2), 4.53 (1H, br s, H4a), 4.15 (1H, d,
J=15.0, H9a), 4.13 (1H, br t, J=4.7, H3), 3.77 (1H, d,
J=15.0, H9b), 3.75 (3H, s, OCH3), 3.65 (2H, t, J=8.2,
H40), 3.34 (1H, br t, J=13.0, H11a), 3.14 (1H, dm,
J=13.0, H11b), 2.57±2.44 (3H, m, H10, H4a), 2.14±2.01
(2H, m, H12a, H4b), 1.63 (2H, m, H20), 1.59±1.48 (3H,
m, H30, H12b); 13C NMR (75.4 MHz, CDCl3) d 169.0
(CO), 146.9 (C6), 144.7 (C5a), 134.5 (CHar meta), 133.6
(C8b), 132.5 (Car), 128.6 (C8a), 127.9 (C2), 127.5 (C1),
123.2 (CHar ortho), 122.1 (C8), 112.2 (C7), 88.2 (C4a),
61.8 (C3), 57.5 (C9), 55.8 (OCH3), 51.9 (C11), 51.4
(C100), 47.8 (C4b), 37.8 (C40), 33.5 (C12), 30.7 (C4), 26.5
0
.
(C3 ), 24.4 (C2 ); Anal. calcd for C28H30N2O5 1/2H2O:
C, 69.57; H, 6.42; N, 5.80. Found: C, 69.51; H, 6.52; N
5.62.
Biological assays: in vitro inhibition of
acetylcholinesterase
The method of Ellman et al. was followed. The assay
solution consisted of a 0.1 M sodium phosphate bu€er
(pH 8.0), with 100 mL 5,50-dithiobis-2-nitrobenzoic acid
(DTNB, 10 mM), 200 mL acetylthiocholine iodide
(7.5 mM), 2 mL AChE (Sigma C 2888 from electrophorus
electricus) puri®ed on sephadex and 3.3 mL of the tested
compound. The ®nal assay volume was 3.305 mL.
Enzyme and drugs were added prior to substrate addi-
tion. Absorbance changes at 412 nm were monitored for
10-N-Demethyl-10-N-(60-phthalimidohexyl)-galanthamine
(3c). Reactants: 2 (1.17 g, 4.3 mmol) in CH3CN (40 mL),
11c (1.40 g, 4.5 mmol), and NEt3 (1.2 mL, 8.6 mmol)
produced 3c (1.73 g, 80%). IR (CHCl3) n: 3556, 3431,
3031, 2937, 2862, 1769, 1712, 1619, 1508, 1398,
1220 cm 1; EIMS 502 (M+Á), 485 (M-OH)+, 286, 272;
1H NMR (300 MHz, CDCl3, d) 7.83 (2H, m, Har
ortho), 7.71 (2H, m, Har meta), 6.66 (1H, d, J=8.3,
H7), 6.61 (1H, d, J=8.3, H8), 6.09 (1H, d, J=10.0, H1),
6.00 (1H, dd, J1=10.0, J2=4.8, H2), 4.61 (1H, br s,
H4a), 4.14 (1H, br t, J=4.8, H3), 4.12 (1H, d, J=15.5,
H9a), 3.83 (3H, s, OCH3), 3.80 (1H, d, J=15.5, H9b),
3.66 (2H, t, J=7.3, H60), 3.35 (1H, br t, J1=15.0,
J2=13.0, H11a), 3.16 (1H, br d, J=15.0, H11b), 2.68
(1H, dm, J=16.0, H4a), 2.52±2.39 (2H, m, H10), 2.10±
1.96 (2H, m, H12a, H4b), 1.72±1.60 (2H, m, H50), 1.54±
1.41 (3H, m, H12b, H20), 1.38±1.29 (4H, m, H40, H30);
13C NMR (75.4 MHz, CDCl3, d) 169.2 (CO), 146.5 (C6),
144.8 (C5a), 134.6 (CHar meta), 133.9 (C8b), 132.9
(Car), 130.1 (C8a), 128.3 (C2), 127.7 (C1), 123.9 (CHar
ortho), 122.8 (C8), 111.9 (C7), 89.4 (C4a), 62.8 (C3),
58.4 (C9), 56.6 (OCH3), 52.2 (C11), 51.6 (C10), 49.2
(C4b), 38.7 (C60), 33.7 (C12), 30.7 (C4), 29.3 (C50), 27.9
(C20), 27.6 (C40), 27.5 (C30); HMRS calcd for
C30H34N2O5, 502.2467; found, 502.2485.
120 s with
a Roucaire Shimadzu UV160 spectro-
photometer immediately after mixing at 25 ꢁC. Each
drug was evaluated at several concentrations (generally
between 10 4 M and 10 9 M). Values for percent inhi-
bition were calculated relative to a control sample, and
the IC50 values (concentration required to inhibit con-
trol activity by 50%) were determined by log-probit
analysis and represent the mean‹standard deviation
for three assays.
Chemistry
General Procedure for (3b±f). To a solution of norgal-
anthamine 2 in acetonitrile was added N-(bromoalkyl)-
phthalimide 11 (1.2 equiv) and NEt3 (2 equiv). The
reaction mixture was re¯uxed for 24 h. Evaporation of
the solvent gave a residue which was diluted with a
saturated aqueous solution of sodium carbonate and
extracted with CH2Cl2. After a general work up, the
combined organic extracts were evaporated. Flash
chromatography (elution with CH2Cl2/MeOH, 90/10)
of the residue gave the corresponding N-alkylated
compounds.
10-N-Demethyl-10-N-(80-phthalimidooctyl)-galanthamine
(3d). Reactants:
2 (250 mg, 0.9 mmol) in CH3CN
(35 mL), 11d (403 mg, 1.19 mmol), and NEt3 (255 mL,
1.55 mmol) yielded 3d (420 mg, 86%). IR (CHCl3) n:
3556, 3463, 3014, 2934, 2858, 1772, 1711 cm 1; CIMS
531 (MH)+, 513 (M-H2O)+; 1H NMR (300 MHz,

1842
A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
CDCl3, d) 7.84 (2H, m, Har ortho), 7.71 (2H, m, Har
meta), 6.66 (1H, d, J=8.0, H7), 6.61 (1H, d, J=8.0,
H8), 6.08 (1H, d, J=10.0, H1), 6.00 (1H, dd, J1=10.0,
J2=4.5, H2), 4.61 (1H, br s, H4a), 4.14 (1H, br t,
J=4.5, H3), 4.13 (1H, d, J=15.0, H9a), 3.83 (3H, s,
OCH3), 3.80 (1H, d, J=15.0, H9b), 3.66 (2H, t, J=7.0,
H80), 3.35 (1H, br t, J1=14.5, J2=13.0, H11a), 3.17
(1H, br d, J=14.5, H11b), 2.68 (1H, dm, J=15.5, H4a),
2.46 (2H, m, H10), 2.40 (1H, br s, OH), 2.08±1.97 (2H,
m, H12a, H4b), 1.65 (2H, m, H70), 1.54±1.43 (3H, m,
H12b, H20), 1.31 (4H, br s, H60, H30), 1.26 (4H, m, H40,
H50); 13C NMR (75.4 MHz, CDCl3, d) 168.2 (CO), 145.6
(C6), 143.8 (C5a), 133.6 (CHar meta), 132.9 (C8b),
131.9 (Car), 129.2 (C8a), 127.4 (C2), 126.8 (C1), 122.9
(CHar ortho), 121.8 (C8), 111.0 (C7), 88.5 (C4a), 61.9
(C3), 57.5 (C9), 55.7 (OCH3), 51.3 (C10, C11), 48.2
(C4b), 37.8 (C80), 32.7 (C12), 29.8 (C4), 29.1 (C40), 28.9
(C30), 28.3 (C70), 27.1 (C20), 27.0 (C50), 26.6 (C60); Anal.
calcd for C32H38N2O5: C, 72.43; H, 7.22; N, 5.28.
Found: C, 72.09; H, 7.66; N, 4.91.
H8), 6.09 (1H, d, J=10.0, H1), 6.00 (1H, dd, J1=10.0,
J2=5.0, H2), 4.61 (1H, br s, H4a), 4.14 (1H, br t,
J=4.5, H3), 4.13 (1H, d, J=15.0, H9a), 3.83 (3H, s,
OCH3), 3.82 (1H, d, J=15.0, H9b), 3.67 (2H, t, J=7.0,
H120), 3.36 (1H, br t, J1=15.0, J2=13.0, H11a), 3.18
(1H, br d, J=15.0, H11b), 2.68 (1H, dm, J=15.5, H4a),
2.46 (3H, m, OH, H10), 2.07 (1H, m, H12a), 2.00 (1H,
ddd, J1=15.5, J2=5.0, J3=2.5, H4b), 1.66 (2H, m,
H110), 1.54±1.45 (3H, m, H12b, H20), 1.31 (2H, m,
H100), 1.24 (14H, br s, H30, H40, H50, H60, H70, H80,
H90); 13C NMR (75.4 MHz, CDCl3, d) 167.9 (CO), 145.3
(C6), 143.5 (C5a), 133.3 (CHar meta), 132.6 (C8b),
131.7 (Car), 128.8 (C8a), 127.1 (C2), 126.5 (C1), 122.6
(CHar ortho), 121.5 (C8), 110.7 (C7), 88.2 (C4a), 61.5
(C3), 57.2 (C9), 55.4 (OCH3), 51.1±51.0 (C10, C11), 47.9
(C4b), 37.5 (C120), 32.5 (C12), 29.5 (C4), 29.0 (C40, C50,
C60, C70, C80, C90), 28.6 (C30), 28.1 (C110), 26.9 (C20),
26.3 (C100); HRMS calcd for C36H47N2O5, 587.3473;
found, 587.3498.
General procedure for (4b±c). To a solution of 3b or 3c
in dry CH2Cl2 was added m-CPBA (1.1 equiv). The
reaction mixture was stirred at room temperature for
1.5 h and evaporated. Flash chromatography (elution
with CH2Cl2/MeOH, 90/10; then CH2Cl2/MeOH/NH3,
90/9/1) of the residue a€orded the corresponding N-
oxide as a white powder after trituration with ether.
10-N-Demethyl-10-N-(100-phthalimidodecyl)-galanthamine
(3e). Reactants: 2 (103 mg, 0.38 mmol) in CH3CN
(15 mL), 11e (166 mg, 0.45 mmol), and NEt3 (105 mL,
0.75 mmol) produced 3e (177 mg, 84%). IR (CHCl3) n:
3557, 3464, 3012, 2932, 2857, 1771, 1712 cm 1; CIMS
559 (MH)+, 541 (M-H2O)+; 1H NMR (300 MHz,
CDCl3, d) 7.82 (2H, m, Har ortho), 7.70 (2H, m, Har
meta), 6.66 (1H, d, J=8.0, H7), 6.61 (1H, d, J=8.0,
H8), 6.09 (1H, d, J=10.0, H1), 5.99 (1H, dd, J1=10.0,
J2=5.0, H2), 4.61 (1H, br s, H4a), 4.14 (1H, br s, H3),
4.13 (1H, d, J=15.0, H9a), 3.82 (3H, s, OCH3), 3.81
(1H, d, J=15.0, H9b), 3.66 (2H, t, J=7.0, H100), 3.35
(1H, br t, J1=15.0, J2=13.5, H11a), 3.17 (1H, br d,
J=15.0, H11b), 2.67 (1H, dm, J=14.0, H4a), 2.47 (2H,
m, H10), 2.07 (1H, m, H12a), 2.01 (1H, ddd, J1=14.0,
J2=5.0, J3=2.5, H4b), 1.66 (2H, m, H90), 1.51 (1H, dm,
J=15.0, H12b), 1.46 (2H, m, H20), 1.31 (2H, m, H80),
1.25 (10H, br s, H30, H40, H50, H60, H70); 13C NMR
(75.4 MHz, CDCl3, d) 168.9 (CO), 146.3 (C6), 144.5 (C5a),
134.3 (CHar meta), 133.6 (Car), 132.6 (C8b), 129.9
(C8a), 128.1 (C2), 127.5 (C1), 123.6 (CHar ortho), 122.5
(C8), 111.7 (C7), 89.2 (C4a), 62.5 (C3), 58.2 (C9), 56.4
(OCH3), 52.1±52.0 (C10, C11), 48.9 (C4b), 38.5 (C100),
33.4 (C12), 30.5 (C4), 30.0±29.6 (C30, C40, C50, C60, C70),
29.0 (C90), 27.8 (C20), 27.3 (C80); HRMS calcd for
C34H43N2O5 (MH)+, 559.3161; found, 559.3170.
10-N-Demethyl-10-N-(40-phthalimidobutyl)-galanthamine
N-oxide (3b0). Reactants: 3b (203 mg, 0.43 mmol) in
CH2Cl2 (10 mL) and m-CPBA (116 mg, 0.67 mmol)
yielded 3b0 (180 mg, 86%). IR (CHCl3) n: 3406, 3031,
2937, 1775, 1712, 1219 cm 1; EIMS: 490 (M+Á), 474 (M-
1
O), 286, 272; H NMR (300 MHz, CDCl3, d) 7.80 (2H,
m, Har ortho), 7.72 (2H, m, Har meta), 6.63 (2H, m,
H8, H7), 6.08 (2H, br s, H2, H1), 4.84 (1H, br d,
J=14.0, H9a), 4.69 (1H, br s, H4a), 4,41 (1H, d,
J=14.0, H9b), 4.18 (1H, br t, J=5.0, H3), 4.06 (1H, m,
H11a), 3.82 (3H, s, OCH3), 3.71±3.62 (3H, m, H11b,
H40), 3.11 (2H, m, H10), 2.71 (1H, dm, J=15.0, H4a),
2.08±1.90 (5H, m, H12, H4b, H20), 1.67 (2H, m, H30);
13C NMR (75.4 MHz, CDCl3, d) 168.3 (CO), 146.3 (C6,
C5a), 134.0 (CHar meta), 131.9 (C8b), 129.9 (C2, C1),
124.4 (Car), 123.7 (C8), 123.2 (CHar ortho), 119.3
(C8a), 112.0 (C7), 88.7 (C4a), 73.5 (C9), 67.6 (C11), 61.4
(C3), 55.9 (OCH3), 50.1 (C10), 46.3 (C4b), 37.3 (C40),
33.9 (C12), 30.1 (C4), 25.8 (C20), 19.1 (C30); HRMS
calcd for C28H31N2O6 (MH)+, 491.2174; found,
491.2147.
10-N-Demethyl-10-N-(120-phthalimidododecyl)-galanthamine
(3f). Reactants: 2 (102 mg, 0.37 mmol) in CH3CN
(15 mL), 11f (177 mg, 0.45 mmol), and NEt3 (104 mL,
0.75 mmol) yielded 3f (177 mg, 81%). IR (CHCl3) n:
3563, 3032, 2932, 1772, 1709, 1588, 1055 cm 1; CIMS:
587 (MH)+, 569 (M-H2O)+; 1H NMR (300 MHz,
CDCl3, d) 7.84 (2H, m, Har ortho), 7.70 (2H, m, Har
meta), 6.66 (1H, d, J=8.0, H7), 6.61 (1H, d, J=8.0,
10-N-Demethyl-10-N-(60-phthalimidohexyl)-galanthamine
N-oxide (3c0). Reactants: 3c (55 mg, 0.11 mmol) in
CH2Cl2 (5 mL) and m-CPBA (30 mg, 0.17 mmol) pro-
duced 3c0 (48 mg, 85%). EIMS 518 (M+Á), 502 (M-O),
286, 272; 1H NMR (200 MHz, CD3OD, d) 7.85±7.75
(4H, m, phthalimido), 6.82 (2H, m, H8, H7), 6.23 (1H,

A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
1843
br d, J=10.0, H1), 6.03 (1H, dd, J1=10.0, J2=4.0, H2),
4.71 (1H, br d, J=14.3, H9a), 4.66 (1H, br s, H4a), 4.38
(1H, br d, J=14.3, H9b), 4.19 (1H, br s, H3), 3.98 (1H,
m, H11a), 3.79 (3H, s, OCH3), 3.76 (1H, m, H11b), 3.60
(2H, br t, J=7.0, H60), 3.06 (2H, m, H10), 2.54 (1H, dm,
J=15.5, H4a), 2.14 (1H, ddd, J1=15.5, J2=5.5,
J3=3.5, H4b), 2.02±1.76 (4H, m, H12, H50), 1.61 (2H,
m, H20), 1.29 (4H, br s, H40, H30).
NMR (75.4 MHz, CDCl3, d) 168.5 (CO), 168.3 (C9),
162.9 (COCF3), 153.2 (C6), 146.5 (C5a), 137.0 (C8b),
136.0 (C8), 134.0 (CHar meta), 132.0 (Car), 130.3 (C2),
126.0 (C1), 123.2 (CHar ortho), 114.7 (C8a), 113.0 (C7),
88.9 (C4a), 65.3 (C10), 61.0 (C3), 56.7 (OCH3), 52.2
(C11), 46.8 (C4b), 37.3 (C60), 31.8 (C12), 29.7 (C4), 28.2
(C50), 28.0 (C20), 25.9 (C40), 25.4 (C30).
General procedure for compounds (4d±e). To a solution
of compound 3 in CCl4 shielded from light was added
N-bromosuccinimide (1.3 equiv) and 5% AIBN at room
temperature. After 24 h, water was added and was
extracted with CH2Cl2. After general workup, the com-
bined organic extracts were evaporated. Puri®cation by
preparative TLC (elution with CH2Cl2/MeOH/0.5%
HBr, 91/9/0.1) of the residue provided the correspond-
ing iminium salts.
To a solution of N-oxide 3b0 or 3c0 in CH2Cl2 was added
freshly distilled tri¯uoroacetic anhydride. The mixture
was stirred at 0 ꢁC for 6 h then allowed to come to room
temperature. Evaporation of the solvent gave a residue
which was puri®ed by ¯ash chromatography (elution
with CH2Cl2/MeOH/NH3, 95/5/1) to provide the corre-
sponding iminium salts.
9-Dehydro-10-N-demethyl-10-N-(40 -phthalimidobutyl)-
galanthaminium tri¯uoroacetate (4b). Reactants: 3b0
(178 mg, 0.36 mmol) in CH2Cl2 (10 mL) and (CF3CO)2O
(154 mL, 1.09 mmol) yielded 4b (79 mg, 44%). IR
(CHCl3) n: 3408, 3021, 2931, 2856, 1775, 1712,
1609, 1394, 1225, 1141 cm 1; EIMS 473 (M)+, 454
(M-H2O)+; 1H NMR (250 MHz, CDCl3+CF3COOH,
d) 8.77 (1H, s, H9), 7.83 (2H, m, Har ortho), 7.74 (2H,
m, Har meta), 7.59 (1H, d, J=8.7, H8), 7.02 (1H, d,
J=8.7, H7), 6.14 (1H, dd, J1=10.0, J2=4.7, H2), 5.62
(1H, d, J=10.0, H1), 4.81 (1H, br s, H4a), 4.38 (1H, br
t, J=4.7, H3), 4.14 (2H, m, H11), 3.98 (3H, s, OCH3),
3.77 (2H, br t, J=6.7, H40), 2.78 (1H, dm, J=16.0,
H4a), 2.26 (2H, m, H10), 2.18±2.09 (2H, m, H12a, H4b),
2.00 (2H, m, H20), 1.88±1.66 (3H, m, H30, H12b). 13C
NMR (62.9 MHz, CDCl3+CF3COOH, d) 169.0 (CO),
168.0 (C9), 160.3 (COCF3), 153.5 (C6), 146.7 (C5a),
136.2 (C8), 134.5 (CHar meta), 134.4 (C8b), 131.8 (Car),
129.4 (C2), 126.8 (C1), 123.6 (CHar ortho), 114.5 (C8a),
113.3 (C7), 88.7 (C4a), 64.5 (C10), 61.5 (C3), 56.9
(OCH3), 52.5 (C11), 50.5 (C4b), 36.5 (C40), 31.7 (C12),
28.9 (C4), 25.6 (C20), 25.2 (C30); HRMS calcd for
C28H29N2O5, 473.2069; found, 473.2061.
9-Dehydro-10-N-demethyl-10-N-(80 -phthalimidooctyl)-
galanthaminium bromide (4d). Reactants: 3d (72 mg,
0.13 mmol) in CCl4 (2 mL) with NBS (32 mg, 0.18 mmol)
and AIBN (1 mg, 0.007 mmol) yielded 4d (43 mg, 52%).
IR (CHCl3) n: 3450, 3020, 2937, 2856, 1710, 1609, 1137,
1117 cm 1; FABMS 529 (M)+; 1H NMR (300 MHz,
CDCl3, d) 10.09 (1H, s, H9), 8.03 (1H, d, J=8.5, H8),
7.83 (2H, m, Har ortho), 7.71 (2H, m, Har meta), 6.90
(1H, d, J=8.5, H7), 6.19 (1H, dd, J1=10.0, J2=5.0,
H2), 5.85 (1H, d, J=10.0, H1), 4.78 (1H, br s, H4a),
4.44±4.34 (3H, m, H10, H11a), 4.23 (1H, br t, J=4.5,
H3), 4.15 (1H, dm, J1=17.0, J2=4.0, H11b), 3.95 (s,
3H, OCH3), 3.65 (2H, t, J=7.0, H80), 2.74 (1H, dm,
J=16.0, H4a), 2.23 (2H, m, H12), 2.09 (1H, dm,
J1=16.0, J2=5.0, J3=2.0, H4b), 1.92 (2H, m, H20), 1.65
(2H, m, H70), 1.42 (2H, m, H30), 1.33 (6H, m, H40, H50
H60); 13C NMR (75.4 MHz, CDCl3, d) 168.9 (CO, C9),
153.0 (C6), 146.7 (C5a), 137.4 (C8b), 136.6 (C8), 134.5
(CHar meta), 132.6 (Car), 130.7 (C2), 127.1 (C1), 123.7
(CHar ortho), 115.8 (C8a), 111.8 (C7), 89.3 (C4a), 65.4
(C10), 61.5 (C3), 57.3 (OCH3), 53.0 (C11), 47.4 (C4b),
38.4 (C80), 32.5 (C12), 30.0 (C4), 29.5±29.3 (C40, C50),
29.1±29.0 (C20, C70), 27.1 (C60), 26.7 (C30); HRMS calcd
for C32H37N2O5, 529.2702; found, 529.2699.
9-Dehydro-10-N-demethyl-10-N-(60 -phthalimidohexyl)-
galanthaminium tri¯uoroacetate (4c). Reactants: 3c0
(48 mg, 0.09 mmol) in CH2Cl2 (5 mL), (CF3CO)2O
(52 mL, 0.37 mmol). 4c (28 mg, 58%). IR (CHCl3) n:
3462, 3022, 2937, 2862, 1775, 1712, 1609, 1512, 1398,
1225 cm 1; FABMS 501 (M)+; 1H NMR (300 MHz,
CDCl3+CF3COOH, d) 8.95 (1H, s, H9), 7.85 (2H, m,
Har ortho), 7.78 (2H, m, Har meta), 7.69 (1H, d, J=8.5,
H8), 7.02 (1H, d, J=8.5, H7), 6.15 (1H, dd, J1=10.0,
J2=5.0, H2), 5.60 (1H, d, J=10.0, H1), 4.78 (1H, br s,
H4a), 4.25 (1H, br t, H3), 4.11 (2H, m, H11), 3.98 (3H,
s, OCH3), 3.66 (2H, t, J=7.0, H60), 2.77 (1H, dm,
J=16.0, H4a), 2.25 (2H, m, H10), 2.12 (1H, dm,
J=16.0, H4b), 1.95 (2H, m, H50), 1.78±1.63 (3H, m,
H12a, H20), 1.52±1.35 (5H, m, H12b, H40, H30); 13C
9-Dehydro-10-N-demethyl-10-N-(100-phthalimidodecyl)-
galanthaminium bromide (4e). Reactants: 3e (89 mg,
0.16 mmol) in CCl4 (2.5 mL), NBS (37 mg, 0.21 mmol),
AIBN (1 mg, 0.008 mmol). 4e (46 mg, 45%). IR (CHCl3)
1
n: 3408, 3020, 2935, 2865, 1710, 1609, 1137, 1116 cm
;
FABMS 557 (M)+; 1H NMR (300 MHz, CDCl3, d) 10.7
(1H, s, H9), 8.06 (1H, d, J=8.5, H8), 7.83 (2H, m, Har
ortho), 7.71 (2H, m, Har meta), 6.91 (1H, d, J=8.5,
H7), 6.19 (1H, dd, J1=10.0, J2=5.0, H2), 5.81 (1H, d,
J=10.0, H1), 4.78 (1H, br s, H4a), 4.45±4.33 (3H, m,
H10, H11a), 4.23 (1H, br s, H3), 4.13 (1H, dm, J=17.0,
H11b), 3.97 (3H, s, OCH3), 3.66 (2H, t, J=7.0, H100),
2.75 (1H, dm, J=16.0, H4a), 2.23 (2H, m, H12), 2.09

1844
A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
(1H, dm, J1=16.0, J2=5.0, J3=2.0, H4b), 1.91 (2H, m,
H20), 1.65 (2H, m, H90), 1.41 (2H, m, H30), 1.30±1.26
(10H, m, H40, H50, H60, H70, H80); 13C NMR
(75.4 MHz, CDCl3, d) 169.2 (CO), 169.0 (C9), 153.2
(C6), 146.8 (C5a), 137.5 (C8b), 136.8 (C8), 134.6 (CHar
meta), 132.8 (Car), 130.8 (C2), 127.3 (C1), 123.8 (CHar
ortho), 116.0 (C8a), 113.3 (C7), 89.5 (C4a), 65.6 (C10),
61.7 (C3), 57.4 (OCH3), 53.2 (C11), 47.6 (C4b), 38.7
(C100), 32.7 (C12), 30.2 (C4), 30.0±29.7 (C40, C50, C60,
C70), 29.3±29.2 (C20, C90), 27.4 (C80), 26.9 (C30); HRMS
calcd for C34H41N2O5, 557.3015; found, 557.3024.
the residue by preparative TLC (elution with CH2Cl2/
MeOH/H2O, 50/40/10) provided the corresponding
alkylated compound as a white solid.
10-N-Demethyl-10-N-(30-trimethylammoniumpropyl) gal-
anthamine bromide (5a). Reactants: 2 (39 mg, 0.14 mmol)
in CH3CN (5 mL) and Na2CO3 (38 mg, 0.36 mmol) with
12a (41 mg, 0.16 mmol) yielded 5a (49 mg, 76%). IR n:
3396, 3031, 2938, 2837, 1622, 1508, 1224 cm 1; FABMS
373 (M)+, 314 (M-N(CH3)3)+; 1H NMR (250 MHz,
CD3OD, d) 6.78 (2H, s, H8, H7), 6.19 (1H, d, J=10.0,
H1), 5.95 (1H, dd, J1=10.0, J2=4.5, H2), 4.59 (1H, br
s, H4a), 4.42 (1H, d, J=15.0, H9a), 4.17 (1H, br s, H3),
4.06 (1H, d, J=15.0, H9b), 3.81 (3H, s, OCH3), 3.57±
3.37 (4H, m, H11, H30), 3.18 (9H, s, N(CH3)3), 2.82 (2H,
br t, J=7.0, H10), 2.49 (1H, dm, J=16.0, H4a), 2.20±
2.03 (4H, m, H12a, H4b, H20), 1.71 (1H, dm, J=14.5,
H12b); 13C NMR (62.9 MHz, CD3OD, d) 147.8 (C6),
145.5 (C5a), 134.4 (C8b), 130.1 (C8a), 128.7 (C2), 128.3
(C1), 122.9 (C8), 113.1 (C7), 89.1 (C4a), 66.3 (C30), 62.5
(C3), 58.2 (C9), 56.7 (OCH3), 53.7 (N(CH3)3), 53.6
(C10), 52.9 (C11), 49.1 (C4b), 34.7 (C12), 31.6 (C4), 21.7
(C20); HRMS calcd for C22H33N2O5, 373.2491; found,
373.2491.
9-Dehydro-10-N-demethyl-10-N-(120-phthalimidododecyl)-
galanthaminium bromide (4f). To a solution of 3f (73 mg,
0.12 mmol) in EtOH (5 mL) was added sodium acetate
(13 mg, 0.16 mmol) and iodine (63 mg, 0.25 mmol). The
reaction mixture was re¯uxed for 1 h, then cooled to
room temperature. A 10% aq solution of sodium
bisul®te was added. The solvents were removed in
vacuo. Saturated solution of sodium carbonate was
added to the residue and the mixture was extracted with
CH2Cl2. The combined organic extracts were washed
with a 0.5% aq solution of HBr. After a general
workup, the combined organic extracts were evapo-
rated. Flash chromatography (elution with CH2Cl2/
MeOH/1% HBr, 80/19/1) of the residue a€orded 4f
(23 mg, 28%) as a yellow oil. IR (CHCl3) n: 3575,
3025, 2933, 1711, 1609 cm 1; FABMS 585 (M)+, 567
10-N-Demethyl-10-N-(60-trimethylammoniumhexyl) gal-
anthamine bromide (5c). Reactants: 2 (39 mg, 0.14 mmol)
in CH3CN (5 mL), Na2CO3 (38 mg, 0.36 mmol), and 12c
(48 mg, 0.16 mmol) produced 5c (50 mg, 71%). IR n:
3394, 3022, 2937, 2856, 1626, 1224 cm 1; FABMS: 415
(M)+; 1H NMR (250 MHz, CD3OD, d) 6.80 (1H, d,
J=8.5, H7), 6.75 (1H, d, J=8.5, H8), 6.18 (1H, d,
J=10.5, H1), 5.97 (1H, dd, J1=10.5, J2=4.5, H2), 4.61
(1H, br s, H4a), 4.45 (1H, d, J=15.0, H9a), 4.17 (1H, br
t, J=4.5, H3), 4.11 (1H, d, J=15.0, H9b), 3.81 (3H, s,
OCH3), 3.59 (1H, br t, J=13.0, H11a), 3.46±3.36 (3H,
m, H11b, H60), 3.13 (9H, s, N(CH3)3), 2.84 (2H, m,
H10), 2.49 (1H, dm, J=16.0, H4a), 2.24±2.08 (2H, m,
H12a, H4b), 1.84±1.63 (5H, m, H12b, H50, H20), 1.28
(4H, br s, H30, H40); 13C NMR (62.9 MHz, CDCl3, d)
147.9 (C6), 146.2 (C5a), 134.4 (C8b), 129.8 (C8a), 128.9
(C2), 128.0 (C1), 123.6 (C8), 113.3 (C7), 88.9 (C4a), 67.6
(C60), 62.3 (C3), 58.3 (C9), 56.7 (OCH3), 53.7 (C10), 53.6
(N(CH3)3), 53.1 (C11), 49.7 (C4b), 34.1 (C12), 31.5 (C4),
27.5 and 26.8 (C30, C40), 26.5 (C20), 23.7 (C50); HRMS
calcd for C25H39N2O5, 415.2961; found, 415.2956.
1
(M-H2O)+, 515; H NMR (300 MHz, CDCl3, d) 10.03
(1H, s, H9), 8.03 (1H, d, J=8.5, H8), 7.83 (2H, m, Har
ortho), 7.71 (2H, m, Har meta), 6.90 (1H, d, J=8.5,
H7), 6.18 (1H, dd, J1=10.0, J2=5.0, H2), 5.86 (1H, d,
J=10.0, H1), 4.78 (1H, br s, H4a), 4.47±4.34 (3H, m,
H10, H11a), 4.22 (1H, br s, H3), 4.18 (1H, dm, J=17.0,
H11b), 3.96 (3H, s, OCH3), 3.66 (2H, t, J=7.0, H120),
2.74 (1H, dm, J=16.0, H4a), 2.39 (1H, br s, OH), 2.23
(2H, m, H12), 2.10 (1H, dm, J1=16.0, J2=5.0, J3=2.0,
H4b), 1.91 (2H, m, H20), 1.66 (2H, m, H110), 1.40±1.30
(4H, m, H30, H100), 1.23 (12H, br s, H40, H50, H60, H70,
H80, H90); 13C NMR (75.4 MHz, CDCl3, d) 168.3 (CO),
168.1 (C9), 152.3 (C6), 145.9 (C5a), 136.6 (C8b), 136.1
(C8), 133.7 (CHar meta), 132.0 (Car), 130.0 (C2), 126.4
(C1), 123.0 (CHar ortho), 115.1 (C8a), 112.5 (C7), 88.7
(C4a), 64.8 (C10), 60.9 (C3), 56.5 (OCH3), 52.3 (C11),
46.7 (C4b), 37.9 (C120), 31.8 (C12), 29.2 (C4), 29.1±29.0
(C40, C50, C60, C70, C80), 28.5 (C110, C20), 26.6 (C90),
26.1 (C30); HRMS calcd for C36H45N2O5, 585.3328;
found, 585.3328.
10-N-Demethyl-10-N-(80-trimethylammoniumoctyl) gal-
anthamine bromide (5d). Reactants: 2 (41 mg, 0.15 mmol)
in CH3CN (5 mL), Na2CO3 (40 mg, 0.37 mmol), and 12d
(55 mg, 0.16 mmol) produced 5d (51 mg, 65%). IR n:
3385, 3031, 2938, 2837, 1626, 1509, 1223 cm 1; FABMS:
443 (M)+; 1H NMR (250 MHz, CD3OD, d) 6.80 (1H, d,
J=8.3, H7), 6.74 (1H, d, J=8.3, H8), 6.19 (1H, d,
J=10.5, H1), 5.96 (1H, dd, J1=10.5, J2=5.0, H2), 4.61
(1H, br s, H4a), 4.39 (1H, d, J=15.0, H9a), 4.18 (1H,
General procedure for bromoalkyl trimethylammonium
bromide (5a) and (5c±e). To a solution of norgalanth-
amine 2 in acetonitrile was added Na2CO3 (2.5 equiv)
and N-(bromoalkyl)-trimethylammonium bromide 12
(1.1 equiv). After stirring at 50 ꢁC for 20 h, the reaction
mixture was cooled to room temperature and ®ltered.
The ®ltrate was evaporated to dryness. Puri®cation of

A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
1845
br t, J=5.0, H3), 4.07 (1H, d, J=15.0, H9b), 3.82 (3H,
s, OCH3), 3.55 (1H, br t, J1=15.0, J2=12.8, H11a),
3.42±3.36 (3H, m, H11b, H80), 3.15 (9H, s, N(CH3)3),
2.77 (2H, m, H10), 2.49 (1H, dm, J=16.0, H4a), 2.22±
2.10 (2H, m, H12a, H4b), 1.85±1.70 (3H, m, H70,
H12b), 1.64 (2H, m, H20), 1.38 (8H, m, H30, H40, H50,
H60); 13C NMR (62.9 MHz, CDCl3, d) 147.9 (C6), 146.3
(C5a), 134.4 (C8b), 129.1 (C2), 127.9 (C1), 125.2 (C8a),
123.8 (C8), 113.4 (C7), 88.9 (C4a), 67.8 (C80), 62.2 (C3),
58.3 (C9), 56.7 (OCH3), 54.1 (C10), 53.6 (N(CH3)3), 53.2
(C11), 48.9 (C4b), 34.1 (C12), 31.5 (C4), 30.0, 29.9, 27.9
and 27.1 (C30, C40, C50, C60), 26.6 (C20), 23.8 (C70);
HRMS calcd for C27H43N2O3, 443.3274; found,
443.3279.
(75.4 MHz, CD3OD, d) 147.8 (C6), 145.9 (C5a), 134.4
(C8b), 128.7 (C2), 128.3 (C1), 127.2 (C8a), 123.4 (C8),
113.2 (C7), 89.0 (C4a), 67.8 (C120), 62.3 (C3), 58.3 (C9),
56.6 (OCH3), 53.7 (C10), 53.6 (N(CH3)3), 53.0 (C11),
49.1 (C4b), 34.2 (C12), 31.5 (C4), 30.5±30.4 and 30.2
(C40, C50, C60, C70, C80, C90), 28.2 (C30), 27.3 (C20), 27.2
(C100), 24.9 (C110); HRMS calcd for C31H51N2O3,
499.3900; found, 499.3872.
6-O-Demethylgalanthamine (6). To a solution of galan-
thamine 1 (507 mg, 1.77 mmol) in THF (20 mL) was
added l-selectride1 (1 M solution in tetrahydrofuran
8 mL, 7.95 mmol) at room temperature. The reaction
mixture was re¯uxed for 20 h, then diluted with AcOEt
at 0 ꢁC and quenched slowly with water. Evaporation of
the combined aq layers a€orded a residue, which was
puri®ed by ¯ash chromatography (elution with CH2Cl2/
MeOH/NH3, 90/9/1) and crystallized in acetone to pro-
vide 6-Oꢁ-demethylgalanthamine 6 (460 mg, 95%). Mp
228±230 C; CIMS 274 (MH)+; 1H NMR (250 MHz,
CD3OD, d) 6.57 (1H, d, J=8.0, H8), 6.52 (1H, d,
J=8.0, H7), 6.11 (1H, d, J=10.5, H1), 5.91 (1H, dd,
J1=10.5, J2=5.0, H2), 4.52 (1H, br s, H4a), 4.15 (1H,
br t, J=4.5, H3), 4.06 (1H, d, J=15.0, H9a), 3.64 (1H,
d, J=15.0, H9b), 3.22 (1H, br t, J=12.5, H11a), 3.01
(1H, dm, J=14.5, H11b), 2.49 (1H, dm, J=16.0, H4a),
2.38 (3H, s, NCH3), 2.10 (1H, ddd, J1=16.0, J2=5.0,
J3=3.0, H4b), 2.05 (1H, m, H12a), 1.65 (1H, dm,
J=14.5, H12b); 13C NMR (75.4 MHz, CD3OD, d) 146.8
(C6), 142.6 (C5a), 134.2 (C8b), 128.6 (C2), 128.1 (C1),
128.0 (C8a), 123.1 (C8), 116.7 (C7), 88.8 (C4a), 62.6
(C3), 61.6 (C9), 55.2 (C11), 47.9 (C4b), 43.1 (NCH3),
35.5 (C12), 31.3 (C4); Anal. calcd for C16H19NO3: C,
70.31; H, 7.01; N, 5.12. Found: C, 70.39; H, 7.01; N,
4.86.
10-N-Demethyl-10-N-(100-trimethylammoniumdecyl) gal-
anthamine bromide (5e). Reactants: 2 (43 mg, 0.16 mmol)
in CH3CN (5 mL), Na2CO3 (42 mg, 0.39 mmol), and 12e
(62 mg, 0.17 mmol) yielded 5e (48 mg, 55%). IR (CHCl3)
1
n: 3423, 3025, 2934, 2858, 1168, 1133, 1110, 1055 cm
;
FABMS 471 (M)+; 1H NMR (250 MHz, CD3OD, d)
6.79 (1H, d, J=8.3, H7), 6.72 (1H, d, J=8.3, H8), 6.18
(1H, d, J=10.3, H1), 5.96 (1H, dd, J1=10.2, J2=4.5,
H2), 4.60 (1H, br t, H4a), 4.37 (1H, d, J=14.8, H9a),
4.17 (1H, br t, J=4.5, H3), 4.03 (1H, d, J=14.8, H9b),
3.82 (3H, s, OCH3), 3.53 (1H, br t, J1=15.0, J2=3.0,
H11a), 3.39±3.33 (3H, m, H11b, H100), 3.14 (9H, s,
N(CH3)3), 2.75±2.69 (2H, m, H10), 2.49 (1H, dm,
J=16.0, H4a), 2.20±2.09 (2H, m, H12a, H4b), 1.84±1.70
(3H, m, H90, H12b), 1.61 (2H, m, H20), 1.37 (4H, br s,
H80, H30), 1.32 (8H, m, H40, H50, H60, H70); 13C NMR
(75.4 MHz, CD3OD, d) 148.8 (C6), 147.0 (C5a), 135.4
(C8b), 129.9 (C2), 129.1 (C1), 127.2 (C8a), 124.6 (C8),
114.3 (C7), 89.9 (C4a), 68.8 (C100), 63.3 (C3), 59.2 (C9),
57.7 (OCH3), 54.9 (C10), 54.6 (N(CH3)3), 54.1 (C11),
49.1 (C4b), 35.1 (C12), 32.5 (C4), 31.3 and 31.0 (C40,
C50, C60, C70), 29.0 (C30), 28.2 (C80), 27.8 (C20), 24.9
(C90); HRMS calcd for C29H47N2O3, 471.3587; found,
471.3587.
General procedure for compounds (7b) and (7d±f). To a
solution of 6-O-demethylgalanthamine 6 in dimethyl-
formamide was added Cs2CO3 (1 equiv) and N-(bromo-
alkyl)-phthalimide 11 (1 equiv). The reaction mixture
was re¯uxed for 24 h. Evaporation of the solvent gave a
residue which was taken up with a saturated aqueous
solution of sodium carbonate and extracted with
CH2Cl2. After a general workup, the combined organic
extracts were evaporated. Flash chromatography (elu-
tion with CH2Cl2/MeOH, 90/10) of the residue a€orded
the corresponding O-alkylated compounds in good
yields.
10-N-Demethyl-10-N-(120 -trimethylammoniumdodecyl)
galanthamine bromide (5f). Reactants:
2
(50 mg,
0.18 mmol) in CH3CN (5 mL), Na2CO3 (49 mg,
0.46 mmol), and 12f (78 mg, 0.20 mmol) produced 5f
(67 mg, 63%). IR n: 3392, 3021, 2933, 2857, 1626, 1509,
1225 cm 1; FABMS 499 (M)+; 1H NMR (300 MHz,
CD3OD, d) 6.76 (1H, d, J=8.3, H7), 6.67 (1H, d,
J=8.3, H8), 6.17 (1H, d, J=10.3, H1), 5.93 (1H, dd,
J1=10.3, J2=4.8, H2), 4.56 (1H, br s, H4a), 4.24 (1H, d,
J=15.8, H9a), 4.17 (1H, br t, J=4.8, H3), 3.89 (1H, d,
J=15.8, H9b), 3.81 (3H, s, OCH3), 3.46±3.24 (4H, m,
H11, H120), 3.15 (9H, s, N(CH3)3), 2.56 (2H, m, H10),
2.48 (1H, dm, J=16.0, H4a), 2.18±2.02 (2H, m, H12a,
H4b), 1.77 (2H, m, H110), 1.63 (1H, dm, J=14.5,
H12b), 1.52 (2H,0 m, H20), 01.38 0(4H,0 br s, H30, H100),
1.27 (12H, m, H4 , H50, H6 , H7 , H8 , H90); 13C NMR
6-O-Demethyl-6-O-(40 -phthalimidobutyl)-galanthamine
(7b). Reactants: 6 (79 mg, 0.29 mmol) in DMF (3 mL),
Cs2CO3 (94 mg, 0.29 mmol), and 11b (82 mg, 0.29 mmol)
a€orded 7b (95 mg, 70%). IR (CHCl3) n: 3427, 3037,
2944, 1775, 1712, 1609, 1227 cm 1; EIMS 474 (M+Á),
456 (M-H2O)+, 272 (M-(CH2)4Pht)+, 202, 160; 1H
NMR (300 MHz, CDCl3, d) 7.84 (2H, m, Har ortho),

1846
A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
7.72 (2H, m, Har meta), 6.72 (1H, d, J=8.3, H7), 6.67
(1H, d, J=8.3, H8), 6.10 (1H, dd, J1=10.0, J2=5.0,
H2), 5.93 (1H, d, J=10.0, H1), 4.65 (1H, br s, H4a),
4.17 (1H, br s, H3), 4.08 (1H, br d, J=15.0, H9a), 4.06
(2H, m, H10), 4.01 (1H, d, J=15.0, H9b), 3.70 (2H, t,
J=7.0, H40), 3.62 (1H, br t, J1=15.0, J2=13.0, H11a),
3.33 (1H, m, J=15.0, H11b), 2.72 (1H, dm, J=16.0,
H4a), 2.59 (3H, s, NCH3), 2.13 (1H, dm, J=13.5,
H12a), 2.01 (1H, ddd, J1=16.0, J2=5.0, J3=2.5, H4b),
1.86 (1H, m, H12b), 1.79 (2H, m, H20), 1.59 (2H, m,
H30); 13C NMR (62.9 MHz, CDCl3, d) 168.7 (CO), 146.3
(C6), 143.7 (C5a), 137.1 (C8b), 134.2 (CHar meta),
133.9 (Car), 132.4 (C8a), 128.0 (C2), 127.1 (C1), 123.5
(CHar ortho), 122.4 (C8), 113.5 (C7), 88.8 (C4a), 68.6
(C10), 62.3 (C3), 60.8 (C9), 54.0 (C11), 48.4 (C4b), 42.2
(NCH3), 37.8 (C40), 33.9 (C12), 30.1 (C4), 26.8 (C20),
25.3 (C30).
H100), 3.32 (1H, br t, J1=15.0, J2=13.0, H11a), 3.06
(1H, br d, J=14.5, H11b), 2.68 (1H, dm, J=15.5, H4a),
2.48 (1H, br s, OH), 2.41 (3H, s, NCH3), 2.11 (1H, dm,
J=13.5, H12a), 2.00 (1H, ddd, J1=15.5, J2=5.0,
J3=2.3, H4b), 1.75 (2H, m, J=7.0, H20), 1.70±1.53 (3H,
m, H90, H12b), 1.39 (2H, m, H30), 1.28 (10H, br s, H40,
H50, H60, H70, H80); 13C NMR (75.4 MHz, CDCl3, d)
167.9 (CO), 145.7 (C6), 143.1 (C5a), 133.3 (CHar meta),
132.6 (Car), 131.7 (C8b), 116.6 (C8a), 127.2 (C2), 126.3
(C1), 122.7 (CHar ortho), 121.6 (C8), 112.4 (C7), 88.0
(C4a), 68.6 (C10), 61.6 (C3), 60.0 (C9), 53.3 (C11), 47.7
(C4b), 41.5 (NCH3), 37.5 (C100), 33.2 (C12), 29.4 (C4),
28.9 (C20), 28.8±28.7 and 28.6 (C50, C60, C70, C80), 28.1
(C90), 26.3 (C40), 25.3 (C30); HRMS calcd for
C34H43N2O5, 559.3161; found, 559.3155.
6-O-Demethyl-6-O-(120-phthalimidododecyl)-galanthamine
(7f). Reactants: 6 (55 mg, 0.20 mmol) in DMF (3 mL),
Cs2CO3 (66 mg, 0.20 mmol), 11f (79 mg, 0.20 mmol). 7f
(79 mg, 67%). IR (CHCl3) n: 3027, 2930, 2856, 1775,
1711, 1612, 1398, 1225 cm 1; CIMS 587 (MH)+, 569
6-O-Demethyl-6-O-(80 -phthalimidooctyl)-galanthamine
(7d). Reactants: 6 (110 mg, 0.40 mmol) in DMF (4 mL),
Cs2CO3 (132 mg, 0.40 mmol), and 11d (137 mg,
1
0.40 mmol) a€orded 7d (97 mg, 45%). IR (CHCl3) n:
(MH-H2O)+; H NMR (200 MHz, CDCl3, d) 7.84 (2H,
1
3535, 3033, 2930, 2857, 1771, 1711, 1268, 1234 cm
;
m, Har ortho), 7.70 (2H, m, Har meta), 6.67 (1H, d,
J=8.3, H7), 6.60 (1H, d, J=8.3, H8), 6.06 (1H, d,
J=10.5, H1), 5.98 (1H, m, H2), 4.61 (1H, br s, H4a),
4.14 (1H, br s, H3), 4.12 (1H, d, J=15.0, H9a), 3.97
(2H, m, H10), 3.71 (1H, d, J=15.0, H9b), 3.67 (2H, t,
J=7.0, H120), 3.30 (1H, br t, J1=14.5, J2=13.0, H11a),
3.07 (1H, br d, J=14.5, H11b), 2.76 (1H, dm, J=16.0,
H4a), 2.54 (1H, br s, OH), 2.42 (3H, s, NCH3), 2.12
(1H, dm, J=13.5, H12a), 2.00 (1H, ddd, J1=16.0,
J2=5.0, J3=2.3, H4b), 1.75 (2H, m, J=7.0, H20), 1.61
(3H, m, H110, H12b), 1.31 (2H, m, H30), 1.26 (14H, br s,
H40, H50, H60, H70, H80, H90, H100); HRMS calcd for
C36H47N2O5, 587.3473; found, 587.3460.
CIMS 531 (MH)+, 513 (MH-H2O)+; 1H NMR
(300 MHz, CDCl3, d) 7.83 (2H, m, Har ortho), 7.70 (2H,
m, Har meta), 6.65 (1H, d, J=8.0, H7), 6.58 (1H, d,
J=8.0, H8), 6.05 (1H, d, J=10.5, H1), 5.99 (1H, m,
H2), 4.59 (1H, br s, H4a), 4.12 (1H, br t, H3), 4.08 (1H,
d, J=15.0, H9a), 3.95 (2H, m, H10), 3.67 (1H, d,
J=15.0, H9b), 3.66 (2H, t, J=6.5, H80), 3.26 (1H, br t,
J1=15.0, J2=13.0, H11a), 3.04 (1H, br d, J=14.5,
H11b), 2.83 (1H, br s, OH), 2.68 (1H, dm, J=15.5,
H4b), 2.39 (3H, s, NCH3), 2.11 (1H, dm, J=13.5,
H12a), 1.99 (1H, dm, J=15.5, H4a), 1.83 (5H, m, H20,
H70, H12b), 1.42 (2H, m, H30), 1.33 (6H, br s, H40, H50,
H60); 13C NMR (75.4 MHz, CDCl3, d) 168.9 (CO), 146.7
(C6), 144.0 (C5a), 134.3 (CHar meta), 133.6 (Car), 132.6
(C8b), 129.5 (C8a), 128.1 (C2), 127.3 (C1), 123.6 (CHar
ortho), 122.5 (C8), 113.4 (C7), 89.0 (C4a), 69.6 (C10),
62.6 (C3), 61.0 (C9), 54.3 (C11), 48.6 (C4b), 42.5
(NCH3), 38.5 (C80), 34.2 (C12), 30.4 (C4), 29.6 (C20),
29.5 (C60, C50), 29.0 (C70), 27.3 (C40), 26.3 (C30); HRMS
calcd for C32H39N2O5, 531.2849; found, 531.2846.
General procedure for compounds (8b) and (8d±f). To a
solution of compound 7 in absolute ethanol was added
iodine (2 equiv) and NaOAc (1.3 equiv). The reaction
mixture was re¯uxed for 1 h, then cooled to room tem-
perature. A 10% aqueous solution of sodium thiosul-
phate was added dropwise. The solvents were removed
in vacuo. The residue was taken up with water and
extracted with CH2Cl2. The organic layers were washed
6-O-Demethyl-6-O-(100-phthalimidodecyl)-galanthamine
(7e). Reactants: 6 (110 mg, 0.40 mmol) in DMF (4 mL),
Cs2CO3 (131 mg, 0.40 mmol), and 11e (148 mg,
0.40 mmol) yielded 7e (108 mg, 48%). IR (CHCl3) n:
3556, 3031, 2932, 2858, 1772, 1712, 1616, 1509, 1398,
1225 cm 1; CIMS 559 (MH)+, 541 (MH-H2O)+; 1H
NMR (300 MHz, CDCl3, d) 7.84 (2H, m, Har ortho),
7.70 (2H, m, Har meta), 6.66 (1H, d, J=8.0, H7), 6.60
(1H, d, J=8.0, H8), 6.06 (1H, d, J=10.3, H1), 6.00 (1H,
dd, J1=10.3, J2=4.5, H2), 4.60 (1H, br s, H4a), 4.12
(1H, br t, H3), 4.10 (1H, br d, J=14.5, H9a), 3.97 (2H,
m, H10), 3.69 (1H, d, J=14.5, H9b), 3.67 (2H, t, J=7.0,
successively with a saturated aqueous solution of
sodium carbonate and with a 0.5% aqueous solution of
HBr. After a general work up, the combined organic
layers were evaporated. Puri®cation of the residue by
preparative TLC (elution with CH2Cl2/EtOH/0.5%
HBr, 90/10/0.1) provided the corresponding iminium
salt as a yellow solid.
9-Dehydro-6-O-demethyl-6-O-(40-phthalimidobutyl)-gal-
anthaminium bromide (8b). Reactants: 7b (80 mg,
0.17 mmol) in EtOH (8 mL), I2 (86 mg, 0.34 mmol), and
NaOAc (18 mg, 0.22 mmol) produced 8b (56 mg, 60%).

A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
1847
FABMS 473 (M)+, 456 (M-OH)+; 1H NMR (300 MHz,
CDCl3 with two drops of CD3OD, d) 9.40 (1H, s, H9),
7.83 (2H, m, Har ortho), 7.74 (2H, m, Har meta), 6.97
(2H, s, H7, H8), 6.20 (1H, dd, J1=10.0, J2=4.5, H2),
5.78 (1H, d, J=10.0, H1), 4.80 (1H, br s, H4a), 4.30
(1H, br t, J=13.0, H11a), 4.23 (1H, br s, H3), 4.14±4.05
(3H, m, H10, H11b), 4.02 (3H, s, NCH3), 3.77 (2H, t,
J=7.0, H40), 2.75 (1H, dm, J=16.0, H4a), 2.28 (1H, m,
H12a), 2.19 (1H, m, H12b), 2.07 (1H, dm, J=16.0,
H4b), 1.88 (4H, br s, H20, H30).
J3=2.0, H4b), 1.83 (2H, m, J=7.0, H20), 1.67 (2H, m,
H90), 1.42 (2H, m, H30), 1.30 (10H, br s, H40, H50, H60,
H70, H80); 13C NMR (75.4 MHz, CD3OD, d) 170.6
(CO), 170.1 (C9), 154.4 (C6), 148.2 (C5a), 139.1 (C8b),
137.7 (C8), 136.0 (CHar meta), 134.0 (Car), 132.0 (C2),
128.3 (C1), 125.1 (CHar ortho), 116.6 (C8a), 115.5 (C7),
90.5 (C4a), 72.0 (C10), 63.0 (C3), 56.5 (C11), 54.3
(NCH3), 48.6 (C4b), 40.0 (C100), 33.2 (C12), 31.3 (C4),
31.1±31.0 (C40, C50, C60, C70), 30.7 (C20), 30.5 (C90),
28.7 (C80), 27.6 (C30); HRMS calcd for C34H41N2O5,
557.3015; found, 557.3007.
9-Dehydro-6-O-demethyl-6-O-(80-phthalimidooctyl)-gal-
anthaminium bromide (8d). Reactants: 7d (64 mg,
0.12 mmol) in EtOH (4 mL), I2 (62 mg, 0.24 mmol), and
NaOAc (13 mg, 0.16 mmol) a€orded 8d (42 mg, 57%).
IR (CHCl3) n: 3556, 3011, 2931, 2858, 1772, 1709, 1619,
1266, 1235 cm 1; FABMS 529 (M)+, 512 (M-OH)+; 1H
NMR (300 MHz, CDCl3, d) 9.40 (1H, s, H9), 7.84 (2H,
m, Har ortho), 7.77 (1H, d, J=9.0, H8), 7.73 (2H, m,
Har meta), 6.96 (1H, d, J=9.0, H7), 6.16 (1H, dd,
J1=10.0, J2=5.0, H2), 5.79 (1H, d, J=10.0, H1), 4.77
(1H, br s, H4a), 4.32 (1H, br t, J1=17.0, J2=13.0,
H11a), 4.22 (1H, br t, J=5.0, H3), 4.15±4.09 (3H, m,
H10, H11b), 4.02 (3H, s, NCH3), 3.68 (2H, t, J=7.0,
H80), 2.76 (1H, dm, J=16.0, H4a), 2.30 (1H, tm,
J1=15.0, J2=13.0, J3=3.0, H12a), 2.16 (1H, dm,
J=15.0, H12b), 2.10 (1H, ddd, J1=16.0, J2=5.5,
J3=2.0, H4b), 1.83 (2H, m, J=7.0, H20), 1.68 (2H, m,
H70), 1.43 (2H, m, H30), 1.36 (6H, br s, H40, H50, H60);
13C NMR (75.4 MHz, CD3OD, d) 169.2 (CO), 168.6
(C9), 153.1 (C6), 146.9 (C5a), 137.7 (C8b), 136.2 (C8),
134.6 (CHar meta), 132.5 (Car), 130.6 (C2), 126.8 (C1),
123.7 (CHar ortho), 115.1 (C8a), 114.1 (C7), 89.0 (C4a),
70.5 (C10), 61.4 (C3), 55.0 (C11), 52.8 (NCH3), 47.2
(C4b), 38.5 (C80), 31.8 (C12), 29.9 (C4), 29.6±29.5 (C40,
C50), 29.3 (C20), 29.0 (C70), 27.2 (C60), 26.2 (C30);
HRMS calcd for C32H37N2O5, 529.2702; found,
529.2710.
9-Dehydro-6-O-demethyl-6-O-(120-phthalimidododecyl)-
galanthaminium bromide (8f). Reactants: 7f (65 mg,
0.11 mmol) in EtOH (4 mL), I2 (56 mg, 0.22 mmol), and
NaOAc (12 mg, 0.14 mmol) yielded 8f (40 mg, 54%). IR
(CHCl3) n: 3550, 3030, 2938, 2857, 1769, 1711, 1609,
1237 cm 1; FABMS 585 (M)+; 1H NMR (200 MHz,
CDCl3, d) 9.46 (1H, s, H9), 7.86 (2H, m, Har ortho),
7.77 (1H, d, J=8.5, H8), 7.73 (2H, m, Har meta), 6.96
(1H, d, J=8.5, H7), 6.18 (1H, dd, J1=10.0, J2=5.0,
H2), 5.78 (1H, d, J=10.0, H1), 4.75 (1H, br s, H4a),
4.32 (1H, m, H11a), 4.22 (1H, br s, H3), 4.13 (2H, t,
J=6.5, H10), 4.08 (1H, m, H11b), 4.03 (3H, s, NCH3),
3.68 (2H, t, J=7.0, H120), 2.75 (1H, dm, J=16.0, H4a),
2.28 (1H, tm, J1=15.0, J2=11.5, J3=3.0, H12a), 2.17
(1H, dm, J=15.0, H12b), 2.10 (1H, ddd, J1=16.0,
J2=4.5, J3=2.0, H4b), 1.85 (2H, m, H20), 1.68 (2H, m,
H110), 1.42 (2H, m, H30), 1.31 (14H, br s, H40, H50, H60,
H70, H80, H90, H100); HRMS calcd for C36H45N2O5,
585.3328; found, 585.3319.
General procedure for compounds (9d±f). A mixture of 6-
O-demethylgalanthamine 6 and Cs2CO3 (1 equiv) in
anhydrous DMF was stirred for 30 min at rt. Bromo-
alkyl-trimethylammonium bromide 12 (1.1 equiv) was
added and the mixture was heated at 130 ꢁC under
argon for 2 h. The precipitate was ®ltered o€ and the
®ltrate was evaporated. Puri®cation of the residue by
¯ash chromatography (elution with H2O/EtOH/
CH2Cl2, 4/36/60) provided the expected product.
9-Dehydro-6-O-demethyl-6-O-(100-phthalimidodecyl)-gal-
anthaminium bromide (8e). Reactants: 7e (72 mg,
0.13 mmol) in EtOH (4 mL), I2 (66 mg, 0.26 mmol), and
NaOAc (14 mg, 0.17 mmol) a€orded 8e (46 mg, 56%).
IR (CHCl3) n: 3560, 3411, 3022, 2935, 2858, 1768, 1711,
1608, 1140 cm 1; FABMS 557 (M)+, 540 (M-OH)+,
272 (M-Pht(CH2)10)+; 1H NMR (300 MHz, CDCl3 with
two drops of CD3OD, d) 9.44 (1H, s, H9), 7.84 (2H, m,
Har ortho), 7.78 (1H, d, J=8.5, H8), 7.72 (2H, m, Har
meta), 6.95 (1H, d, J=8.5, H7), 6.17 (1H, dd, J1=10.0,
J2=5.0, H2), 5.80 (1H, d, J=10.0, H1), 4.77 (1H, br s,
H4a), 4.33 (1H, br t, J1=17.0, J2=13.0, H11a), 4.22
(1H, br t, J=5.0, H3), 4.14 (2H, t, J=6.5, H10), 4.12
(1H, m, H11b), 4.03 (3H, s, NCH3), 3.67 (2H, t, J=7.0,
H100), 2.74 (1H, dm, J=16.0, H4a), 2.30 (1H, tm,
J1=15.0, J2=12.0, J3=3.0, H12a), 2.16 (1H, dm,
J=15.0, H12b), 2.10 (1H, ddd, J1=16.0, J2=5.0,
6-O-Demethyl-6-O-(80-trimethylammoniumoctyl) galanth-
amine bromide (9d). Reactants: 6 (208 mg, 0.76 mmol)
in DMF (6 mL), Cs2CO3 (248 mg, 0.76 mmol), and 12d
(277 mg, 0.84 mmol) yielded 9d (236 mg, 59%). IR
(CHCl3) n: 3392, 3012, 2937, 2861, 1625, 1506, 1174,
1125 cm 1; FABMS 443 (M)+; 1H NMR (250 MHz,
CD3OD, d) 6.74 (1H, d, J=7.5, H7), 6.64 (1H, d,
J=7.5, H8), 6.13 (1H, d, J=9.5, H1), 5.93 (1H, dd,
J1=9.5, J2=4.2, H2), 4.54 (1H, br s, H4a), 4.16 (1H, br
t, H3), 4.13 (1H, d, J=14.0, H9a), 4.00 (2H, t, J=6.0,
H10), 3.70 (1H, d, J=14.0, H9b), 3.36 (2H, m, H80), 3.27
(1H, br t, J1=13.5, J2=12.0, H11a), 3.14 (9H, s,
N(CH3)3), 3.04 (1H, br d, J=13.5, H11b), 2.48 (1H, dm,
J=14.5, H4a), 2.41 (3H, s, NCH3), 2.15±2.05 (2H, m,

1848
A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
H4b, H12a), 1.80±1.65 (5H, m, H12b, H20, H70), 1.42
(8H, br s, H60, H50, H40, H30); 13C NMR (62.9 MHz,
CD3OD, d) 147.9 (C6), 144.8 (C5a), 134.4 (C8b), 129.0
(C8a), 128.6 (C2), 128.4 (C1), 123.2 (C8), 114.6 (C7),
88.9 (C4a), 70.2 (C10), 67.7 (C80), 62.4 (C3), 61.3 (C9),
55.1 (C11), 53.5 (N(CH3)3), 48.6 (C4b), 43.1 (NCH3),
35.5 (C12), 31.5 (C4), 30.3 (C20), 30.1 (C30), 30.0 (C40),
27.1 (C50), 26.8 (C60), 23.8 (C70); HRMS calcd for
C27H43N2O3, 443.3274; found, 443.3269.
(C110); HRMS calcd for C31H51N2O3, 499.3900; found,
499.3892.
General procedure for compounds (11c±f). To a boiling
solution of alkyl dibromide 10 (2 equiv) in acetone was
added potassium phthalimide in four equal portions
over a 4 h period. The resulting mixture was re¯uxed for
24 h, then cooled to rt and ®ltered. The ®ltrate was eva-
porated to dryness. Puri®cation by ¯ash chromato-
graphy (elution with CH2Cl2/heptane, 90/10; then 50/
50) of the residue provided the corresponding com-
pound as a white powder.
6-O-Demethyl-6-O-(100-trimethylammoniumdecyl) galanth-
amine bromide (9e). Reactants: 6 (27 mg, 0.10 mmol) in
DMF (1 mL), Cs2CO3 (32 mg, 0.10 mmol), and 12e
(39 mg, 0.11 mmol) produced 9e (28 mg, 51%). IR
(CHCl3) n: 3399, 3020, 2934, 2864, 1622, 1139,
1127 cm 1; FABMS 471 (M)+; 1H NMR (250 MHz,
CD3OD, d) 6.77 (1H, d, J=7.6, H7), 6.70 (1H, d,
J=7.6, H8), 6.16 (1H, d, J=9.5, H1), 5.96 (1H, dd,
J1=9.5, J2=4.2, H2), 4.58 (1H, br s, H4a), 4.34 (1H, d,
J=13.6, H9a), 4.18 (1H, br t, J=4.0, H3), 4.01 (2H, t,
J=6.0, H10), 3.89 (1H, d, J=13.6, H9b), 3.51±3.33 (3H,
m, H11a, H100), 3.23±3.15 (10H, m+s, H11b,
N(CH3)3), 2.58 (3H, s, NCH3), 2.50 (1H, dm, J=14.5,
H4a), 2.20±2.10 (2H, m, H4b, H12a), 1.82±170 (5H, m,
H90, H20, H12b), 1.39 (6H, br s, H80, H70 H60), 1.36 (6H,
br s, H50, H40, H30); 13C NMR (62.9 MHz, CD3OD, d)
148.1(C6), 145.3 (C5a), 134.4 (C8b), 128.9 (C2), 128.0
(C1), 126.7 (C8a), 123.6 (C8), 114.7 (C7), 88.8 (C4a),
70.3 (C10), 67.8 (C100), 62.4 (C3), 61.1 (C9), 55.3 (C11),
53.6 (N(CH3)3), 48.8 (C4b), 43.3 (NCH3), 35.3 (C120),
31.5 (C4), 30.3±30.1 (C20, C30, C40, C50, C60), 27.2 (C70),
27.0 (C80), 23.9 (C90); HRMS calcd for C29H47N2O3,
471.3587; found, 471.3596.
N-(6-Bromohexyl)-phthalimide (11c). Reactants: 10c
(11.2 g, 45.8 mmol) in acetone (100 mL) and PhtK
(4.24 g, 22.9 mmol) produced 11c (4.55 g, 64%). Mp 50±
52 ꢁC; IR (CHCl3) n: 3028, 3012, 2941, 2861, 1772,
1
1712 cm 1; EIMS 311 and 309 (M+Á), 230 (M-Br)+; H
NMR (250 MHz, CDCl3, d) 7.85 (2H, m, Har ortho),
7.72 (2H, m, Har meta), 3.69 (2H, t, J=7.2, H1), 3.40
(2H, t, J=7.0, H6), 1.86 (2H, m, H5), 1.70 (2H, m, H2),
1.47 (2H, m, H4), 1.37 (2H, m, H3); 13C NMR
(62.9 MHz, CDCl3, d) 168.4 (CO), 133.9 (CHar meta),
132.1 (Car), 123.1 (CHar ortho), 37.8 (C1), 33.8 (C6),
28.4 (C2), 27.7 (C5), 27.3 (C4), 26.0 (C3).
N-(8-Bromooctyl)-phthalimide (11d). Reactants: 10d
(5.87 g, 21.6 mmol) in acetone (80 mL), PhtK (2.00 g,
10.8 mmol). 11d (2.55 g, 60%). Mp 52±54 ꢁC; EIMS 339
and 337 (M+Á), 258 (M-Br)+; 1H NMR (250 MHz,
CDCl3, d) 7.86 (2H, m, Har ortho), 7.72 (2H, m, Har
meta), 3.69 (2H, t, J=7.5, H1), 3.41 (2H, t, J=7.0, H8),
1.86 (2H, m, J=7.0, H7), 1.69 (2H, m, J=7.0, H2), 1.43
(2H, m, H6), 1.35 (6H, br s, H3, H4, H5); 13C NMR
(75.4 MHz, CDCl3) 168.6 (CO), 134.0 (CHar meta),
132.3 (Car), 123.3 (CHar ortho), 38.1 (C1), 34.1 (C8), 32.8
(C2), 29.0 (C7), 28.7, 28.6, 28.2 and 26.8 (C4, C3, C5, C6).
6-O-Demethyl-6-O-(120-trimethylammoniumdodecyl) gal-
anthamine bromide (9f). Reactants: 6 (104 mg, 0.38 mmol)
in DMF (5 mL), with Cs2CO3 (124 mg, 0.38 mmol), and
12f (162 mg, 0.42 mmol) produced 9f (111 mg, 50%). IR
(CHCl3) n: 3388, 3020, 2932, 2864, 1629, 1138,
1127 cm 1; FABMS 499 (M)+; 1H NMR (300 MHz,
CD3OD, d) 6.76 (1H, d, J=8.0, H7), 6.70 (1H, d,
J=8.0, H8), 6.16 (1H, d, J=10.0, H1), 5.96 (1H, dd,
J1=10.0, J2=4.5, H2), 4.58 (1H, br s, H4a), 4.33 (1H, d,
J=14.6, H9a), 4.18 (1H, br t, J=4.5, H3), 4.01 (2H, t,
J=6.5, H10), 3.88 (1H, d, J=14.6, H9b), 3.50±3.35 (3H,
m, H11a, H120), 3.23±3.16 (10H, m+s, H11b,
N(CH3)3), 2.57 (3H, s, NCH3), 2.50 (1H, dm, J=15.5,
H4a), 2.18±2.10 (2H, m, H4b, H12a), 1.80±1.70 (5H, m,
H110, H20, H12b), 1.45±1.38 (8H, m, H100, H90, H80,
H70), 1.33 (8H, br s, H60, H50, H40, H30); 13C NMR
(75.4 MHz, CD3OD, d) 148.0 (C6), 145.3 (C5a), 134.4
(C8b), 128.9 (C2), 128.0 (C1), 126.8 (C8a), 123.5 (C8),
114.7 (C7), 88.8 (C4a), 70.3 (C10), 67.8 (C120), 62.3 (C3),
61.1 (C9), 55.3 (C11), 53.6 (N(CH3)3), 49.0 (C4b),
43.3 (NCH3), 35.3 (C12), 31.4 (C4), 30.5±30.1 (C20, C30,
C40, C50, C60, C70, C80), 27.3 (C90), 27.0 (C100), 23.9
N-(10-Bromodecyl)-phthalimide (11e). Reactants: 10e
(6.48 g, 21.6 mmol) in acetone (80 mL), PhtK (2.00 g,
10.8 mmol). 11e (2.22 g, 61%). Mp 60±61 ꢁC; IR
1
(CHCl3) n: 3031, 2932, 2858, 1772, 1712, 1398 cm
;
EIMS 367 and 365 (M+Á); H NMR (250 MHz, CDCl3,
d) 7.84 (2H, m, Har ortho), 7.71 (2H, m, Har meta),
3.68 (2H, t, J=7.2, H1), 3.40 (2H, t, J=7.0, H10), 1.84
(2H, m, J=7.0, H9), 1.67 (2H, m, H2), 1.41 (2H, m,
H8), 1.34±1.23 (10H, m, H3, H4, H5, H6, H7); HRMS
calcd for C18H25BrNO2 (MH)+, 366.1063; found,
366.1086.
1
N-(12-Bromododecyl)-phthalimide (11f). Reactants: 10f
(7.08 g, 21.6 mmol) in acetone (80 mL), PhtK (2.00 g,
10.8 mmol). 11f (2.42 g, 61%). Mp 65±66 ꢁC; IR
(CHCl3) n: 3030, 2930, 2857, 1772, 1711 cm 1; CIMS
396 and 394 (MH)+; 1H NMR (250 MHz, CDCl3, d)
7.85 (2H, m, Har ortho), 7.71 (2H, m, Har meta), 3.67

A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
1849
(2H, t, J=7.5, H1), 3.41 (2H, t, J=7.0, H12), 1.85 (2H,
m, J=7.0, H11), 1.66 (2H, m, H2), 1.41 (2H, m, H10),
1.32 (2H, m, H3), 1.26 (12H, br s, H4, H5, H6, H7, H8,
H9); HRMS calcd for C20H29BrNO2, 394.1375; found,
394.1355.
Mp 130±132 ꢁC; IR (CHCl3) n: 3399, 3020, 2935, 2859,
1488, 1478, 1237, 1139, 1116 cm 1; FABMS 280 and 278
(M)+; 1H NMR (250 MHz, CDCl3, d) 3.64 (2H, m, H1),
3.47 (9H, s, N(CH3)3), 3.42 (2H, t, J=7.0, H10), 1.85
(2H, m, J=7.0, H9), 1.80±1.70 (2H, m, H2), 1.47±1.29
(12H, m, H3, H4, H5, H6, H7, H8); 13C NMR
(75.4 MHz, CDCl3, d) 66.6 (C1), 53.2 (N(CH3)3), 34.0
(C10), 32.5 (C2), 29.0 (C9, C3, C8), 28.4 (C4), 27.8 (C7),
25.9 (C5), 23.0 (C6); HRMS calcd for C13H29NBr,
278.1483; found, 278.1481.
General procedure for compounds (12a±e). To a solution
of dihalide 10 (1.2 equiv) in toluene or ether was added
dropwise Me3N (33% in EtOH, 1 equiv) at room tem-
perature and the reaction mixture was kept for 2 days in
the dark. After precipitation of the product with ether,
the precipitate was ®ltered and washed with Et2O and
then with dichloromethane. The crude product was
taken up in acetone and the undissolved material was
removed by ®ltration. Evaporation of the ®ltrate pro-
vided the corresponding bromoalkyl trimethylammo-
nium bromide.
N-(12-Bromododecyl)-trimethylammonium bromide (12f).
Reactants: 10f (3.28 g, 10 mmol) in toluene (20 mL),
Me3N (2 mL of a 33% in EtOH solution). 12f (794 mg,
24%). Mp 181±183 ꢁC; IR (CHCl3) n: 3392, 3010, 2932,
2857, 1488, 1478, 1238, 1139 cm 1; FABMS 308 and 306
(M)+; 1H NMR (250 MHz, D2O, d) 3.53 (2H, t, J=7.0,
H12), 3.36 (2H, m, H1), 3.15 (9H, s, N(CH3)3), 1.89
(2H, m, J=7.0, H11), 1.81 (2H, m, H2), 1.52±1.34 (16H,
m, H3, H4, H5, H6, H7, H8, H9, H10); 13C NMR
(50.3 MHz, CDCl3, d) 66.9 (C1), 53.4 (N(CH3)3), 34.2
(C12), 32.8 (C2), 29.3 (C9, C3, C4, C10, C11), 28.7 (C5),
28.1 (C8), 26.2 (C6), 23.2 (C7); HRMS calcd for
C15H33NBr, 306.1796; found, 306.1796.
N-(3-Bromopropyl)-trimethylammonium bromide (12a).
Reactants: 10a (1 mL, 10 mmol) in toluene (10 mL),
Me3N (2 mL of a 33% in EtOH solution). 12a (786 mg,
35%). Mp 210±214 ꢁC; IR (CHCl3) n: 3415, 2950, 1476,
1136, 1115 cm 1; FABMS 182 and 180 (M)+; 1H NMR
(250 MHz, D2O, d) 3.53±3.46 (4H, m, H1, H3), 3.26
(9H, s, N(CH3)3), 2.43 (2H, m, H2); 13C NMR
(75.4 MHz, CD3OD, d) 66.5 (C1), 53.8 (N(CH3)3), 29.4
(C3), 27.2 (C2); HRMS calcd for C6H15NBr, 180.0388;
found, 180.0395.
General procedure for compounds (13d±f). To a solution
of 11 (1.2 equiv) in toluene (20 mL) was added dropwise
Me3N (33% in EtOH) at room temperature and the
reaction mixture was kept for 2 days in the dark. After
precipitation of the product with ether, the mixture was
®ltered and the precipitate was washed with Et2O and
then with CH2Cl2. The crude product was taken up in
acetone and the undissolved material was removed by
®ltration. Evaporation of the ®ltrate provided the corre-
sponding phthalimidoalkyl trimethylammonium bromide.
N-(6-Bromohexyl)-trimethylammonium bromide (12c).
Reactants: 10c (3 mL, 20 mmol) in Et2O (50 mL), Me3N
(1 mL of a 33% in EtOH solution). 12c (174 mg, 14%).
Mp 110±112 ꢁC; IR (CHCl3) n: 3390, 2946, 1488, 1478,
1
1237, 1132, 1117 cm 1; FABMS 224 and 222 (M)+; H
NMR (300 MHz, D2O, d) 3.52 (2H, t, J=6.5, H6), 3.32
(2H, m, H1), 3.11 (9H, s, N(CH3)3), 1.94±1.76 (4H, m,
H5, J=6.5, H2), 1.56±1.48 (2H, m, J=6.5, H4), 1.45±
1.35 (2H, m, H3); HRMS calcd for C6H21NBr,
222.0857; found, 222.0868.
8-(Phthalimidooctyl)-trimethylammonium bromide (13d).
Reactants: 11d (503 mg, 1.49 mmol) in toluene (3 mL),
Me3N (1.77 mL of a 33% in EtOH solution). 13d
(577 mg, 98%); IR (CHCl3) n: 3391, 3020, 2943,
2861, 1772, 1710, 1616, 1398 cm 1; mp 168±171 ꢁC;
FABMS 317 (M)+, 160 (M-((CH2)7N(Me3)3))+; 1H
NMR (250 MHz, CDCl3, d) 7.82 (2H, m, Har ortho),
7.73 (2H, m, Har meta), 3.67 (2H, t, J=7.0, H8), 3.59
(2H, m, H1), 3.48 (9H, s, N(CH3)3), 1.77 (2H, m, H2),
1.67 (2H, m, H7), 1.36 (8H, br s, H3, H4, H5, H6);
HRMS calcd for C19H29N2O2, 317.2229; found,
317.2247.
N-(8-Bromooctyl)-trimethylammonium bromide (12d).
Reactants: 10d (1.85 mL, 10 mmol) in toluene (20 mL),
Me3N (2 mL of a 33% in EtOH solution). 12d (850 mg,
30%). Mp 78±80 ꢁC; IR (CHCl3) n: 3389, 2940, 2861,
1488, 1478, 1239,1139 cm 1; FABMS 252 and 250
(M)+; 1H NMR (250 MHz, CDCl3, d) 3.65 (2H, m, H1),
3.47 (9H, s, N(CH3)3), 3.42 (2H, t, J=6.5, H8), 1.91±
1.72 (4H, m, H7, H2), 1.49±1.29 (8H, m, H3, H4, H5,
H6); 13C NMR (75.4 MHz, CDCl3, d) 66.7 (C1), 53.3
(N(CH3)3), 34.0 (C8), 32.5 (C2), 28.9 (C7), 28.3 (C3),
27.8 (C6), 25.9 (C4), 23.0 (C5); HRMS calcd for
C11H25NBr, 250.1170; found, 250.1170.
10-(Phthalimidodecyl)-trimethylammonium bromide (13e).
Reactants: 11e (491 mg, 1.34 mmol) in toluene (5 mL),
Me3N (6.4 mL of a 33% in EtOH solution). 13e
(545 mg, 96%). IR (CHCl3) n: 3400, 3031, 2935,
2859, 1771, 1712, 1617, 1398 cm 1; mp 153±155 ꢁC;
FABMS 345 (M)+; 1H NMR (300 MHz, CDCl3, d) 7.84
(2H, m, Har ortho), 7.72 (2H, m, Har meta), 3.67 (2H, t,
N-(10-Bromodecyl)-trimethylammonium bromide (12e).
Reactants: 10e (3 g, 10 mmol) in toluene (20 mL), Me3N
(2 mL of a 33% in EtOH solution). 12e (680 mg, 22%).

1850
A. Mary et al./Bioorg. Med. Chem. 6 (1998) 1835±1850
J=7.0, H10), 3.59 (2H, m, H1), 3.49 (9H, s, N(CH3)3),
1.76 (2H, m, H2), 1.66 (2H, m, H9), 1.31 (12H, m, H3,
H4, H5, H6, H7, H8); HRMS calcd for C21H33N2O2,
345.2542; found, 345.2544.
5. Bores, G. M.; Kosley, Jr. R. W. Drugs of the Future 1996,
21, 621.
6. Thal, C.; Guillou, C.; Mary, A.; Renko, D. Z.; Potier, P.;
Christen, Y. PCT E.U.Int. Appl. WO 97 03,987, 1996.
7. Sussman, J. L.; Harel, M.; Frolow, F.; Oefner, C.; Gold-
man, A.; Toker, L.; Silman, I. Science 1991, 253, 872.
12-(Phthalimidododecyl)-trimethylammonium
bromide
(13f). Reactants: 11f (500 mg, 1.27 mmol) in toluene
(3 mL), Me3N (604 mL of a 33% in EtOH solution). 13f
(557 mg, 97%). IR (CHCl3) n: 3399, 3020, 2932,
2858, 1771, 1711, 1614, 1398 cm 1; mp 156±157 ꢁC;
FABMS 373 (M)+; 1H NMR (300 MHz, CDCl3, d) 7.84
(2H, m, Har ortho), 7.71 (2H, m, Har meta), 3.67 (2H, t,
J=7.0, H12), 3.57 (2H, m, H1), 3.48 (9H, s, N(CH3)3),
1.75 (2H, m, H2), 1.67 (2H, m, H11), 1.32 (16H, m, H3,
H4, H5, H6, H7, H8, H9, H10); HRMS calcd for
C23H37N2O2, 373.2855; found, 373.2845.
8. Harel, M.; Schalk, I.; Ehret-Sabatier, L.; Bouet, F.; Goeld-
ner, M.; Hirth, C.; Axelsen, P. H.; Silman, I.; Sussman, J. L.
Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 9031.
9. (a) Pang, Y. P.; Quiram, P.; Jelacic, T.; Hong, F.; BrimiJoin,
S. J. Biol. Chem. 1996, 271, 23646; (b) Pang, Y. P.; Hong, F.;
Quiram, P.; Jelacic, T.; BrimiJoin, S. J. Chem. Soc., Perkin 1
1997, 171.
10. Mary, A.; Renko, D. Z.; Guillou, C.; Thal, C. Tetrahedron
Lett. 1997, 38, 5151.
11. (a) Grierson, D. Org. React. 1990, 39, 85; (b) Monkovic, I.;
Wong, H.; Bachand, C. Synthesis 1985, 770.
12. Lete, E.; Sotomayor, N.; Dominguez, E. Tetrahedron 1995,
51, 12721.
Acknowledgements
13. Kosley, Jr. R. W.; Davis, L.; Taberna, V. PCT E. U. Appl.
WO 0649846A1.
The authors would like to thank Professor P. Potier for
his interest in this work, Ipsen±Beaufour Laboratory
(Paris) for ®nancial support, and R. Dodd for careful
reading of the manuscript and helpful comments.
14. Ellman, G. L.; Courtney, K. D.; Andres, V.; Featherstone,
R. M. Biochem. Pharmacol. 1961, 7, 88.
15. (a) Dougherty, D. A.; Stau€er, D. A. Science 1990, 250,
1558; (b) Dougherty, D. A. Science 1996, 271, 163.
References and Notes
16. Compound 14 was prepared as described in reference 6.
1. (a) Perry, E. K. Br. Med. Bull. 1986, 42, 63; (b) Bartus, R.
T.; Dean, L. D.; Beer, B.; Lippa, A. S. Science 1982, 217, 408.
2. Harvey, A. L. Pharmacol. Ther. 1995, 68, 113.
3. (a) Sweeney, T.; Kewitz, H. Life Sci. 1990, 46, 1553; (b)
Thomsen, T.; Bickel, U.; Fischer, J. P.; Kewitz, H. Eur. J. Clin.
Pharmacol. 1990, 39, 603.
4. Han, S. Y.; Sweeney, J. E.; Bachman, E. S.; Schweiger, E. J.;
Forloni, G.; Coyle, J. T.; Davis, B. M.; Joullie, M. M. Eur. J.
Med. Chem. 1992, 27, 673.