Substituted (pyrroloamino)pyridines: potential agents for the treatment of Alzheimer's disease.

Article abstract of DOI:10.1021/jm950644v

A novel series of substituted (pyrroloamino)pyridines was synthesized, and the compounds were evaluated for cholinomimetic-like properties in vitro (inhibition of [3H]quinuclidinyl benzilate binding) and in vivo (reversal of scopolamine-induced dementia)

Full text of DOI:10.1021/jm950644v

582
J . Med. Chem. 1996, 39, 582-587
Su bstitu ted (P yr r oloa m in o)p yr id in es: P oten tia l Agen ts for th e Tr ea tm en t of
Alzh eim er ’s Disea se
Larry Davis,* Gordon E. Olsen, J oseph T. Klein, Kevin J . Kapples, Francis P. Huger, Craig P. Smith,
Wayne W. Petko, Michael Cornfeldt, and Richard C. Effland
Hoechst-Roussel Pharmaceuticals Inc., Neuroscience Therapeutic Domain, Somerville, New J ersey 08876
Received August 30, 1995X
A novel series of substituted (pyrroloamino)pyridines was synthesized, and the compounds
were evaluated for cholinomimetic-like properties in vitro (inhibition of [3H]quinuclidinyl
benzilate binding) and in vivo (reversal of scopolamine-induced dementia) as potential agents
for the treatment of Alzheimer’s disease. Compounds displaying significant activity were more
broadly evaluated, which revealed the presence of a desirable adrenergic component of activity.
The synthesis and structure-activity relationships for this series is presented, along with the
biological profiles of selected compounds.
Sch em e 1a
In tr od u ction
Alzheimer’s disease (AD) is an age-related, chronic
neuronal degenerative disorder occurring in middle or
late life. The disease is characterized by a progressive
dementia, which is associated with both severe disability
in performing the activities of everyday life and a
reduced life expectancy after onset of the disease. The
well-known cholinergic hypothesis1,2 of AD was based
on accumulated evidence suggesting that enzymes
involved in the synthesis and/or hydrolysis of acetyl-
choline were deficient in brains of AD patients. This
breakdown of central cholinergic transmission resulted
in efforts to treat AD with cholinomimetic agents that
either augment the synthesis or inhibit the hydrolysis
of acetylcholine. On the basis of this approach, the
potent acetylcholinesterase inhibitors velnacrine3 (HP
029) and HP 290,4 discovered in our laboratories, were
advanced for clinical evaluation.
a
(a) KOH, hydroxylamine O-sulfonic acid, DMF, 0-30 °C, 3
h; (b) 4-chloropyridine hydrochloride, NMP, 80 °C, 5 h; (c) NaH,
R-X or dimethyl sulfate, DMF, 0-20 °C, 3 h; or acetic anhydride,
20 °C, 1 h; (d) NCS, THF, 5-20 °C, 20 h; (e) POCl3, DMF, DCE,
0-80 °C, 3 h.
lipophilic analogs, which resulted in the synthesis and
characterization of N-propyl-N-(4-pyridinyl)-1H-indol-
1-amine (besipirdine, 1).7,8 The synthesis and structure-
activity relationships of 8a and related (pyrroloamino)-
pyridine analogs constitute the subject of this paper,
while 1 and related analogs are described in our
companion paper.9
Neuropathological studies of brains from Alzheimer’s
patients and age-matched controls demonstrated that
other neurotransmitters are also affected in the disease
process, including catecholamines and particularly nor-
epinephrine. In addition to cholinomimetic agents, a
program was also initiated to discover compounds which
would mitigate multiple biochemical deficits associated
with AD5 and thus possibly be more effective in a
broader group of patients than pure cholinomimetics.
As a class, the aminopyridines were known to enhance
release of both acetylcholine and norepinephrine.6 Since
more lipophilic aminopyridine analogs had not been
extensively investigated, the synthesis of a series of
(pyrroloamino)pyridines was initiated. The compound
8a emerged as an early lead from this program, and the
biological profile of 8a shows a unique combination of
adrenergic and cholinomimetic-like properties. The
structural features of 8a led to investigation of more
Ch em istr y
As shown in Scheme 1, pyrrole (2) was N-aminated
with hydroxylamine O-sulfonic acid and subsequently
condensed with 4-chloropyridine to afford pyrroloami-
nopyridine 3a (R ) H). Alkylation of 3a with sodium
hydride and dimethyl sulfate or an alkyl halide provided
tertiary amines 3b-h , and standard acylation afforded
amide 3i (Table 1). Chlorination of 3a -d with N-
chlorosuccinimide gave ((2-chloropyrrolo)amino)pyridines
4a -d . The 2- and 3-pyrrolyl aldehydes 5a -e were
obtained by treatment of 3a ,b,d under Vilsmeier condi-
tions and chromatographic separation of the isomeric
aldehydes.
As shown in Scheme 2, 2-pyrrolyl aldehyde 5b was
reduced with NaBH4 to give the primary alcohol 6, and
X Abstract published in Advance ACS Abstracts, December 15, 1995.
0022-2623/96/1839-0582$12.00/0 © 1996 American Chemical Society

Substituted (Pyrroloamino)pyridines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2 583
Ta ble 1. Substituted (Pyrroloamino)pyridinesa
compd
R
X
start. mat.
mp, °C
% yieldb
recrystnc solvent
formula
C9H9N3
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
5a
5b
5c
5d
5e
6
7a
7b
8a
8b
9a
9b
10
H
CH3
H
H
H
H
H
H
H
H
2
153-154
226-227
224-225
232-233
178-179
210-211
218-219
230-231
220-222
172-173
230-231
206-207
210-211
165-166
118-119
139-140
144-146
95-97
32
55
59
58
60
43
59
57
80
65
23
22
19
23
58
11
28
25
77
72
55
22
69
49
61
71
A
B
B
B-C
B
D-C
B-C
B
E-C
B-C
B-C
B-C
B-C
B
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3a
3b
3b
3d
3d
5b
5b
5c
5b
5b
8a
8b
5b
C10H11N3‚HCl
C11H13N3‚HCl
C12H15N3‚HCl
C13H17N3‚HCl
C12H15N3‚HCl
C12H13N3‚HCl
C12H11N3‚HCl
C11H11N3O‚HCl
C9H8ClN3‚HCl
C10H10ClN3‚HCl
C11H12ClN3‚HCl
C12H14ClN3‚HCl
n-C2H5
n-C3H7
C4H9
CH2C6H5
CH2CHdCH2
CH2CtCH
COCH3
H
H
2-Cl
2-Cl
2-Cl
2-Cl
2-CHO
2-CHO
3-CHO
3-CHO
2-CHO
CH3
C2H5
n-C3H7
H
d
C
10H9N3O‚C4H4O4
d
d
d
d
CH3
CH3
B
B
C11H11N3O‚C4H4O4
C11H11N3O‚C4H4O4
C13H15N3O‚C4H4O4
C13H15N3O‚C4H4O4
C11H13N3O
n-C3H7
n-C3H7
CH3
B-C
B-C
B-F
B-C
C
B-C
B-C
B-C
D-C
B
2-CH2OH
150-151
118-119
95-96
d
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2-CH(OH)CH3
3-CH(OH)CH3
2-CHdCH2
2-CHdCHC6H5
2-C2H5
C12H15N3O‚C4H4O4
C12H15N3O
C12H13N3‚C4H4O4
C18H17N3‚HCl
C12H15N3‚HCl
C18H19N3‚HCl
C11H10N4‚HCl
d
87-88
244-245
197-198
173-174
251-252
2-(CH2)2C6H5
2-CN
a
All compounds exhibited IR, MS, and 1H-NMR spectra consistent with the structure, and elemental analyses (C,H,N) were within
(0.4%. Isolated yield; yields were not optimized. c A ) benzene; B ) 2-propanol; C ) ethyl ether; D ) absolute ethanol; E ) methanol;
F ) petroleum ether. Acid maleate salt.
b
d
Sch em e 2a
quent dehydration with benzenesulfonyl chloride gave
the ((2-cyanopyrrolo)amino)pyridine 10.
Biologica l Resu lts a n d Discu ssion
One goal of our research was the discovery of agents
which would mitigate multiple biochemical deficits
associated with AD, and compounds displaying a com-
bination of cholinomimetic and adrenergic properties
were considered highly desirable. As shown in Table
2, the majority of the compounds from this series
displayed moderate to weak affinities for central mus-
carinic binding sites as evidenced by inhibition of [3H]-
quinuclidinyl benzilate ([3H]QNB) binding in vitro.10
Zinc and other heavy metals or sulfhydryl reagents were
shown to increase the affinity of [3H]QNB binding sites
for cholinergic agonists (e.g. oxotremorine).11 In our
laboratory a muscarinic agonist-like profile for a com-
pound is associated with a ratio of [3H]QNB IC50 values
equal to or greater than 3 obtained in the absence (-Zn)
and presence (+Zn) of zinc.12 As shown in Table 2, the
enhancement in binding affinity observed in the pres-
ence of zinc suggested that many of these compounds
might be cholinergic agonists. Most of these compounds
were also active in vivo with respect to antagonizing
scopolamine-induced deficits in the scopolamine demen-
tia dark avoidance paradigm (SDDA).13 However, only
compounds 7b and 8a significantly antagonized tetra-
benazine-induced ptosis (TBZ),14 which is a property
associated with many clinically efficacious antidepres-
sants that augment central adrenergic mechanisms.
These compounds represented early leads in our search
a
(a) NaBH4, i-C3H7OH, 20 °C, 20 h; (b) CH3MgBr, THF, 5-20
°C, 3 h; (c) n-BuLi, CH3P(C6H5)3Br or C6H5CH2P(C6H5)3Cl, DCM,
0 °C, 1 h; (d) 10% Pd/C, H2, C2H5OH, 20 °C, 1 h; (e) H2NOH-HCl,
pyridine, 20 °C, 1 h; (f) benzenesulfonyl chloride, 90 °C, 0.5 h.
addition of methylmagnesium bromide to 5b or the
3-pyrrolyl aldehyde 5c provided secondary alcohols 7a ,b,
respectively. Wittig olefination of 5b with n-butyl-
lithium and methyltriphenylphosphonium bromide or
benzyltriphenylphosphonium chloride afforded alkenes
8a ,b, which were catalytically reduced to alkanes 9a ,b.
Conversion of 5b to the oxime derivative and subse-

584 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2
Davis et al.
Ta ble 2. Biological Data for Substituted (Pyrroloamino)pyridinesa
QNBb
IC50 (µM)
ratio
-Zn/+Zn
TBZc ED50
(mg/kg, ip)
SDDAd A, NA,
or NT, mg/kg, sc (% response)
compd
-Zn
184
+Zn
3a
3b
3c
3d
3e
3f
43
(33-55)
13
(7-21)
9.5
(4.7-18.8)
6.5
(4.8-8.7)
4.0
(1.4-11)
3.5
(2.1-4.6)
6.9
(5.9-8.2)
9.0
(4-20)
NT
13
(7.6-20)
6.9
(4.8-10)
5.4
(2.3-13)
2.6
(2.0-3.3)
86
(52-142)
24
(15-38)
33
(25-40)
11
(8.7-14)
14
(5.7-33)
26
(13-51)
23
(18-29)
11
(6.1-19)
8.8
(5.1-15)
1.6
(0.53-46)
6.4
(4.9-8.3)
3.0
(1.3-5.9)
24
(16-35)
0.94
(0.56-1.6)
0.66
(0.43-1.0)
4.3
5.4
12
>20
>20
>20
>20
>20
>20
>20
>20
A (4/8)
(98-343)
0.31 (21), 0.63 (21), 2.5 (47), 5.0 (36)
70
A (1/6)
5.0 (29)
NA
(54-90)
120
(91-152)
21.5
(11.6-39.6)
12.5
(6.7-23)
13.5
(8.2-20.2)
27
(22-34)
76.4
3.3
3.1
3.9
3.9
8.5
A (3/6)
0.16 (33), 0.63 (27), 2.5 (27)
A (1/6)
0.63 (20)
A (1/6)
0.16 (20)
A (2/6)
0.16 (20), 0.63 (20)
A (4/6)
3g
3h
(40-147)
>1000
0.02 (20), 0.04 (27), 0.16 (47), 0.31 (27)
NT
NA
3i
4a
76.2
(56-104)
43
(34-56)
33
(25-45)
8.6
(4.2-17.4)
721
(567-916)
52
(34-78)
185
(110-311)
138
(91-208)
51
(30-88)
39
(20-74)
173
(101-296)
24
(12-48)
18
(14-23)
17
(8.2-33)
22
5.9
6.2
6.1
3.3
8.4
2.2
5.6
12.5
3.6
1.5
7.5
2.2
2.0
10.6
3.4
2.7
12.3
3.2
4.2
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
4b
4c
4d
5a
5b
5c
5d
5e
6
NA
A (3/6)
0.63 (20), 1.25 (36), 2.5 (27)
A (1/6)
2.5 (27)
A (4/6)
0.16 (20), 0.31 (27), 0.63 (43), 1.25 (20)
A (6/6)
0.16 (50), 0.31 (53), 0.63 (27), 1.25 (60), 2.5 (50), 5.0 (31)
A (4/6)
0.31 (20), 0.63 (33), 1.25 (29), 5.0 (47)
NT
NA
NT
NA
7a
7b
8a
8b
9a
9b
10
1
10
(9.4-12)
8.3
(7.8-9.0)
>20
A (3/6)
0.16 (20), 0.31 (20), 1.25 (27)
A (6/6)
0.16 (27), 0.31 (33), 0.63 (33), 1.25 (33), 2.5 (27), 5.0 (20)
A (2/6)
2.5 (20), 5.0 (33)
A (2/6)
0.63 (20), 5.0 (27)
A (1/6)
0.31 (33)
A (2/6)
1.25 (40), 5.0 (20)
A (5/6)
>20
>20
>20
(17-29)
8.1
(6.5-9.9)
295
(181-480)
3.0
(1.9-4.6)
2.7
3.1
(2.9-3.4)
0.02 (24), 0.04 (30), 0.08 (33), 0.16 (27), 0.63 (40)
oxotremorine
amitriptyline
(2.2-3.7)
0.3
1.5
(0.29-0.32)
(1.0-2.1)
a
IC50 and ED50 values are corrected for the percentage of base compound in the case of salts. Numbers in parentheses are 95% confidence
limits unless otherwise noted. Inhibition of [3H]quinuclidinyl benzilate (QNB) binding, rat forebrain membranes, in the absence (-Zn)
b
and presence (+Zn) of zinc. c Prevention of tetrabenazine-induced (TBZ) ptosis by intraperitoneal compound administration in mice.
d
Antagonism of scopolamine-induced behavioral deficits in mice in the scopolamine dementia dark avoidance (SDDA) paradigm. A cutoff
was defined for the scopolamine-vehicle group as the value for the animal with the second longest latency time. Results are reported as
active (A), not active (NA) or not tested (NT) with the number of active (g20% response) dosages versus the total number of dosages
evaluated in parentheses. For active compounds, the second line of data represents the active doses (mg/kg, sc) with the percent response
(i.e. the percent of animals in the scopolamine-drug group with latencies greater than the cutoff time) in parentheses.
for agents with broader biochemical profiles, and 8a was
selected for further evaluation.
binding, and both compounds were comparatively weaker
with respect to affinity for R1-adrenergic binding sites
as evidenced by inhibition of [3H]WB4101 binding.17
With respect to biogenic amine uptake, 8a was a
considerably weaker inhibitor of norepinephrine,18
dopamine,18 and serotonin19 uptake than 1. Although
8a has affinity for central muscarinic receptors as
The biological profile of 8a is summarized in Table 3
and compared with compound 1, which was selected
from a later series. In vitro both 8a and 1 displayed
affinity for central R2-adrenergic receptors as evidenced
by inhibition of [3H]clonidine15 and [3H]yohimbine16

Substituted (Pyrroloamino)pyridines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2 585
Ta ble 3. Biological Profiles of 8a and 1
IC50 (µM)a
in vitro assays
8a
1
Receptor Binding: Adrenergic
[3H]clonidine (R2, cortex)b
[3H]yohimbine (R2, cortex)b
[3H]WB4101 (R1, whole brain)c
Biogenic Amine Uptaked
[3H]norepinephrine (whole brain)
[3H]dopamine (striatum)
[3H]serotonin (whole brain)
Receptor Binding: Cholinergic
[3H]QNB (muscarinic, forebrain)e
+Zn2+
0.21 (0.08-0.59)
0.95 (0.58-1.6)
5.9 (3.4-10)
0.33 (0.22-0.51)
0.25 (0.18-0.33)
10 (6.4-17)
14 (1-20)
>20
>20
0.43 (0.29-1.7)
0.41 (0.23-0.73)
2.6 (1.4-5.0)
18 (14-23)
8.8 (5.1-15)
5.1 (2.5-10)
3.0 (1.9-4.6)
0.94 (0.56-1.6)
1.3 (1.0-1.8)
[3H]pirenzepine (M1, cortex)b
AChE Inhibition
acetylthiocholine (striatum)f
>100
>100
in vivo assays
8a
1
TBZg ED50 (mg/kg, ip)
SDDAh (mg/kg, sc)
8.3 (7.8-9.0)
active at 0.16, 0.31, 0.63, 1.25, 2.5, 5.0
3.1 (2.9-3.4)
active at 0.02, 0.04, 0.08, 0.16, 0.63
a
IC50 and ED50 values are corrected for the percentage of base compound in the case of salts. Numbers in parentheses are 95% confidence
limits. Compounds 8a and 1 were evaluated as maleate salts. Rat cortical membranes. c Rat whole brain minus cerebella. Rat brain
b
d
synaptosomes. e Inhibition of [3H]quinuclidinyl benzilate (QNB) binding, rat forebrain membranes. f Acetylcholinesterase (AChE) inhibition
g
h
(rat striatum) using acetylthiocholine as substrate. Prevention of tetrabenazine-induced (TBZ) ptosis (mice). Scopolamine dementia
dark avoidance (SDDA) paradigm (mice).
evidenced by inhibition of [3H]QNB and [3H]piren-
were determined on a Thomas-Hoover capillary apparatus and
zepine20 binding, the compound was less potent than 1.
are uncorrected. HPLC separations were performed on a
Waters Prep LC/System 500A using a Prep Pak-500/Silica
cartridge. Elemental analyses were performed by Micro-Tech
Laboratories, Skokie, IL.
Neither 8a nor 1 significantly inhibited striatal acetyl-
cholinesterase (AChE).21 In vivo, both 8a and 1 were
active with respect to reversing scopolamine-induced
deficits in the SDDA paradigm and both compounds
enhanced adrenergic mechanisms as evidenced by pre-
vention of tetrabenazine-induced ptosis. However, 1
N-Am in op yr r ole. To a solution of pyrrole (10.7 g, 0.16 mol,
2) in 150 mL of DMF at 0 °C was added milled KOH (40 g, 0.8
mol), followed by hydroxylamine O-sulfonic acid (20 g, 0.18
mol) added portionwise over 30 min. After stirring at ambient
displayed a broader, more robust profile with respect
to adrenergic and cholinomimetic-like effects than 8a ,
and 122 was advanced to clinical trials.
temperature for 1 h, the mixture was filtered, and the filtrate
was poured into 1 L of ice-water and extracted with ethyl
acetate (3 × 100 mL). The organic layer was washed with
water and saturated NaCl solution, dried (MgSO4), and
filtered, and the filtrate was concentrated in vacuo. The
resultant oil was eluted on a silica gel column with dichlo-
romethane (DCM) via HPLC to give N-aminopyrrole as a clear
oil: 5 g (38%); 1H-NMR (CDCl3) δ 6.20 (t, 2H, J ) 8 Hz), 6.70
Con clu sion s
A series of (pyrroloamino)pyridine analogs was syn-
thesized and evaluated as potential agents for the
treatment of Alzheimer’s disease. Compound 8a was
selected for further evaluation. The compound dis-
played affinity for central R2-adrenergic and muscarinic
receptors but was weakly active with respect to inhibi-
tion of biogenic amine uptake. Compound 8a does not
inhibit acetylcholinesterase but is active in vivo with
respect to antagonizing scopolamine-induced deficits in
the SDDA paradigm, suggesting potential utility for
Alzheimer’s disease. In addition, 8a augments adren-
ergic mechanisms as suggested by weak in vitro inhibi-
tion of norepinephrine uptake and in vivo prevention
of tetrabenazine-induced ptosis.
(t, 2H, J ) 8 Hz), 8.30 (broad s, 2H); IR (CHCl3) 3325 cm-1
NH2; EI-MS m/e 82. Anal. (C4H6N2) C, H, N.
,
4-(1H-P yr r ol-1-yla m in o)p yr id in e (3a ). To 150 mL of
N-methyl-2-pyrrolidinone were added N-aminopyrrole (18 g,
0.22 mol) and 4-chloropyridine hydrochloride (17 g, 0.14 mol),
and the mixture was stirred at 80 °C for 5 h. After cooling,
the mixture was poured into 300 mL of water, basified with
Na2CO3, and extracted with ethyl acetate (3 × 150 mL). The
organic layer was washed with water and saturated NaCl
solution, dried (MgSO4), and filtered. The filtrate was evapo-
rated in vacuo and the resultant oil eluted on a silica gel
column with ethyl acetate via HPLC to give 12 g of a light tan
solid, mp 150 °C. A sample was recrystallized from benzene
to give 3a as light tan crystals: mp 153-154 °C; 1H-NMR
(CDCl3) δ 6.20 (t, 2H, J ) 8 Hz), 6.30 (d, 2H, J ) 10 Hz), 6.70
(t, 2H, J ) 8 Hz), 8.30 (d, 2H, J ) 10 Hz), 8.40 (broad s, 1H);
IR (CHCl3) 3270 cm-1, NH; EI-MS m/e 159. Properties of 3a
are included in Table 1.
Exp er im en ta l Section
All structures are supported by their IR (Perkin-Elmer 547),
MS (Finnigan 4000 GC-MS equipped with an INCOS data
system), and 1H-NMR (Varian XL-200) spectra. Melting points
4-[N-Meth yl-N-(1H-p yr r ol-1-yl)a m in o]p yr id in e Hyd r o-

586 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2
Davis et al.
ch lor id e (3b). To a suspension of NaH (50% oil dispersion,
1.5 g, 0.030 mol) in 5 mL of DMF at 0 °C, was added a solution
of 3a (4g, 0.025 mol) in 10 mL of DMF. After warming to 50
°C for 30 min, the solution was cooled to 0 °C, and a solution
of dimethyl sulfate (3.8 g, 0.03 mol) in 5 mL of DMF was slowly
added. After 30 min, the mixture was stirred with 300 mL of
ice-water and extracted with DCM (3 × 100 mL). The organic
extract was washed with water and saturated NaCl solution,
dried (MgSO4), and filtered. The filtrate was evaporated in
vacuo to give 4 g of a yellow oil, which was eluted on a silica
gel column with ethyl acetate via HPLC to afford 3.5 g of a
yellow oil. The oil was dissolved in 2-propanol and converted
to the hydrochloride salt by addition of ethereal HCl to give
3b as white crystals: 3.1 g; mp 226-227 °C; 1H-NMR (CDCl3)
δ 3.70 (s, 3H), 6.30 (t, 2H, J ) 3 Hz), 6.60 (broad s, 2H), 6.75
(t, 2H, J ) 3 Hz), 8.30 (broad s, 2H), 15.80 (broad s, 1H); EI-
MS m/e 174. Properties of 3b, and of 3c-h prepared in a
similar manner using the appropriate alkylhalide, are included
in Table 1.
MS m/e 201. Further elution afforded 2.0 g of the 3-carbox-
aldehyde as a light brown oil. This oil was converted to the
maleate salt and recrystallized from 2-propanol to give 1.9 g
1
of 5c as white crystals: mp 139-140 °C; H-NMR (CDCl3) δ
3.76 (s, 3H), 6.35 (s, 2H), 6.70 (d, 2H, J ) 3 Hz), 6.88 (d, 2H,
J ) 1 Hz), 7.50 (d, 1H, J ) 1 Hz), 8.50 (d, 2H, J ) 3 Hz), 9.87
(s, 1H), 13.20 (broad s, 2H); IR (CHCl3) 1640 cm-1, CHO; EI-
MS m/e 201. Properties of 5b,c, and 5a ,d ,e prepared in a
similar manner, are included in Table 1.
1-[N-Meth yl-N-(4-pyr idin yl)am in o]-1H-pyr r ole-2-m eth a-
n ol (6). To a solution of 5b (8 g, 0.04 mol) in 100 mL of
2-propanol was added NaBH4 (3g, 0.08 mol). After stirring
for 2 h at ambient temperature, water was added, and the
mixture was extracted with ethyl acetate (3 × 100 mL). The
organic layer was washed with water and saturated NaCl
solution, dried (MgSO4), and filtered. The filtrate was evapo-
rated in vacuo to give 7.6 g of a pale yellow oil, which was
purified by HPLC (silica, 5% MeOH/EtOAc) to afford 6.2 g of
a pale yellow solid, mp 145-148 °C. A 4 g portion of this solid
was recrystallized from 2-propanol/petroleum ether (1:10) to
give 2.3 g of 6 as white crystals: mp 150-151 °C; 1H-NMR
(CDCl3) δ 2.68 (broad s, 1H), 3.46 (s, 3H), 4.40 (dd, 2H, J ) 4,
8 Hz), 6.20 (d, 2H, J ) 2 Hz), 6.22 (m, 2H), 6.67 (m, 1H), 8.23
(d, 2H, J ) 2 Hz); IR (CHCl3) 3240 cm-1, OH; EI-MS m/e 203.
Properties of 6 are included in Table 1.
N-(4-P yr id in yl)-N-(1H-p yr r ol-1-yl)a cet a m id e Hyd r o-
ch lor id e (3i). A solution of 3a (4 g, 0.025 mol) in 25 mL of
acetic anhydride was stirred at ambient temperature for 1 h
and then evaporated in vacuo to an oil. This oil was stirred
with water, basified with Na2CO3, and extracted with DCM
(3 × 100 mL). The organic layer was washed with water and
saturated NaCl solution, dried (MgSO4), and filtered. The
filtrate was evaporated in vacuo to a solid (6 g), which was
purified by flash chromatography (silica, 20% EtOAc/DCM) to
give 5 g of a white solid, mp 103-105 °C. This solid was
converted to the hydrochloride salt and recrystallized from
methanol-ether (1:10) to give 4.8 g of 3i as a white solid: mp
1-{1-[N -Me t h yl-N -(4-p yr id in yl)a m in o]p yr r ol-2-yl}-
eth a n ol Ma lea te (7a ). To a cooled solution of 5b (3g, 0.015
mol) in 50 mL of THF was slowly added CH3MgBr (3.2 M in
ether, 5.1 mL, 0.0164 mol). After stirring for 2 h at ambient
temperature, the mixture was stirred with 300 mL of NH4Cl
solution and extracted with ethyl acetate (3 × 100 mL). The
organic layer was washed with water and saturated NaCl
solution, dried (MgSO4), and filtered. The filtrate was evapo-
rated in vacuo to give 3.4 g of a yellow oil. This oil was purified
by HPLC (silica, 5% MeOH/DCM) to afford 3.0 g of a clear oil,
which was converted to the maleate salt and recrystallized
from 2-propanol/ether (1:10) to give 3.6 g of 7a as white
crystals: mp 118-119 °C; 1H-NMR (DMSO-d6) δ 1.35 (d, 3H,
J ) 3 Hz), 3.60 (s, 3H), 4.30 (m, 1H), 6.08 (s, 2H), 6.10-6.22
(m, 2H), 6.52 (d, 2H, J ) 2 Hz), 6.95 (t, 1H, J ) 2 Hz), 8.42 (d,
2H, J ) 2 Hz); IR (KBr) 3240 cm-1, OH; EI-MS m/e 217.
Properties of 7a , and of 7b prepared in a similar manner, are
included in Table 1.
1
220-222 °C dec; H-NMR (DMSO-d6) δ 2.04 (s, 3H), 6.35 (t,
2H, J ) 3 Hz), 7.24 (t, 2H, J ) 3 Hz), 7.48 (d, 2H, J ) 4 Hz),
8.80 (d, 2H, J ) 4 Hz); IR (KBr) 1660 cm-1, C(dO)N; EI-MS
m/e 201. Properties of 3i are included in Table 1.
4-[N-(2-Ch lor o-1H -p yr r ol-1-yl)-N-m et h yla m in o]p yr i-
d in e Hyd r och lor id e (4b). To a solution of 3b (7.7 g, 0.044
mol) in 300 mL of THF at 5 °C was added N-chlorosuccinimide
(6.1 g, 0.046 mol). After stirring at ambient temperature for
60 h, the mixture was stirred with an aqueous solution of
NaHSO3 and extracted with ether (3 × 100 mL), and the
organic layer was washed with water and saturated NaCl
solution, dried (MgSO4), and filtered. The filtrate was evapo-
rated in vacuo to give a brown oil, 9.5 g. The oil was purified
by HPLC (silica, EtOAc) to give 4.4 g (48%) of a yellow oil,
which was eluted by column chromatography (alumina, ether)
to provide 2.4 g of an oil. This oil was converted to the
hydrochloride salt in 2-propanol, diluting with ether to give
4b as white crystals: 2.5 g; mp 230-231 °C; 1H-NMR (CDCl3)
δ 3.70 (s, 3H), 6.30-6.50 (m, 3H), 6.80 (s, 1H), 7.20 (broad s,
1H), 8.40 (broad s, 2H), 16.40 (broad s, 1H); EI-MS m/e 207.
Properties of 4b, and of 4a ,c,d prepared in a similar manner,
are included in Table 1.
1-[N-Meth yl-N-(4-p yr id in yl)a m in o]p yr r ole-2-ca r boxa l-
d eh yd e Ma lea te (5b) a n d 1-[N-Meth yl-N-(4-p yr id in yl)-
a m in o]p yr r ole-3-ca r boxa ld eh yd e Ma lea te (5c). To cold
DMF (7 g, 0.096 mol) was slowly added POCl3 (14.7 g, 0.096
mol), and the resultant clear complex was stirred 1 h at
ambient temperature and then dissolved in 25 mL of dichlo-
roethane (DCE). To this was slowly added a solution of 3b
(15 g, 0.087 mol) in 25 mL of DCE. After stirring 12 h at 95
°C, the mixture was cooled, and a solution of sodium acetate
trihydrate (60 g, 0.44 mol) in 200 mL of water was slowly
added. The mixture was stirred 1 h at 95 °C, cooled, stirred
with 500 mL of water, and then basified with Na2CO3 solution.
An oil separated and was extracted with DCM (3 × 100 mL).
The organic phase was washed with water and saturated NaCl
solution, dried (MgSO4), and filtered. The filtrate was evapo-
rated in vacuo to give a brown oil, 18 g. The oil was purified
by HPLC (silica, EtOAc) to afford 10.2 g of the 2-carboxalde-
hyde as a light brown solid, mp 71-74 °C. A 2.5 g portion of
the solid was converted to the maleate salt and recrystallized
from 2-propanol to give 3.4 g of 5b as white crystals: mp 118-
119 °C; 1H-NMR (CDCl3) δ 3.65 (s, 3H), 6.30 (s, 2H), 6.40-
6.60 (m, 3H), 7.15 (broad s, 2H), 8.20 (d, 2H, J ) 4 Hz), 9.58
(s, 1H), 16.35 (broad s, 2H); IR (CHCl3) 1640 cm-1, CHO; EI-
N -(2-E t h e n y l-1H -p y r r o l-1-y l)-N -m e t h y l-4-p y r id in -
a m in e Ma lea te (8a ). To n-BuLi (2.1 M in hexane, 25 mL,
0.052 mol), diluted with 50 mL of ether and cooled with an
ice-bath, was slowly added methyltriphenylphosphonium bro-
mide (18 g, 0.050 mol), followed by addition of a solution of 5b
(8 g, 0.040 mol) in 100 mL of ether. After stirring with cooling
for 1 h, water was added, and the aqueous layer was extracted
with DCM (2 × 100 mL). The combined organic layer was
washed with water and saturated NaCl solution, dried (Mg-
SO4), and filtered. The filtrate was evaporated in vacuo to a
brown oil, which was purified by HPLC (silica, EtOAc) to give
a yellow oil, 5.4 g. The oil was converted to the maleate salt
and recrystallized from 2-propanol/ether (1:10) to give 8a as
white crystals: 2.7 g; mp 87-88 °C; 1H-NMR (DMSO-d6) δ 3.55
(s, 3H), 5.05 (d, 1H, J ) 3 Hz), 5.50 (d, 1H, J ) 3 Hz), 6.08 (s,
2H), 6.28 (t, 1H, J ) 2 Hz), 6.35 (d, 1H, J ) 2 Hz), 6.57 (d, 2H,
J ) 3 Hz, broad s, 1H), 7.07 (s, 1H), 8.45 (d, 2H, J ) 2 Hz),
14.20 (broad s, 2H); EI-MS m/e 199. Properties of 8a , and 8b
prepared in a similar manner, are included in Table 1.
N-(2-E t h yl-1H -p yr r ol-1-yl)-N-m et h yl-4-p yr id in a m in e
Hyd r och lor id e (9a ). A solution of 8a (5.2 g, 0.026 mol) in
250 mL of ethanol containing PtO2 (350 mg) was hydrogenated
in a Parr apparatus at 50 psi for 3 h at ambient temperature.
After filtering, the solvent was evaporated in vacuo to a yellow
oil (5 g), which was purified by flash chromatography (silica,
25% DCM/EtOAc) to give 3.9 g of a pale yellow oil. This oil
was converted to the hydrochloride salt and recrystallized from
2-propanol/ether (1:10) to afford 3.0 g of 9a as white crystals:
mp 197-198 °C; 1H-NMR (CDCl3) δ 1.20 (t, 3H, J ) 6 Hz),
2.25-2.35 (m, 2H), 3.64 (s, 3H), 6.00 (m, 3H), 6.28 (dd, 1H, J
) 4, 2 Hz), 6.64 (d, 1H, J ) 2 Hz), 8.20 (broad s, 1H), 8.50

Substituted (Pyrroloamino)pyridines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2 587
(5) Santucci, A. C.; Haroutunian, V.; Tsuboyama, G. K.; Kanof, P.
D.; Davis, K. L. Therapeutics of Alzheimer’s disease for clinical
and pre-clinical issues. In Alzheimer’s Disease and Related
Disorders; Alan R. Liss, Inc.: New York, 1989; pp 1111-1120.
(6) Thesleff, S. Aminopyridines and synaptic transmission. Neuro-
science 1980, 5, 1413-1419.
(7) Klein, J . T.; Davis, L.; Olsen, G. E.; Cornfeldt, M. L.; Huger, F.
P.; Smith, C. P.; Petko, W. W.; Wilker, J .; Blitzer, R.; Landau,
E.; Haroutunian, V.; Effland, R.C. Synthesis and SAR of HP 749
and related analogs: Potential therapeutic agents for Alz-
heimer’s Disease. Abstracts of Papers, 201st ACS National
Meeting, Atlanta, GA, April 1991, MEDI 66.
(8) Davis, L.; Kapples, K. J .; Klein, J . T.; Olsen, G. E.; Cornfeldt,
M. L.; Huger, F. P.; Smith, C. P.; Petko, W. W.; Wilker, J .;
Effland, R. C. Synthesis and SAR of heteroaryl analogs of the
4-pyridinyl-1H-indol-1-amine HP 749: Potential agents for the
treatment of Alzheimer’s Disease. Ibid. MEDI 104.
(9) Klein, J . T.; Davis, L.; Olsen, G. E.; Wong, G. S.; Huger, F. P.;
Smith, C. P.; Petko, W. W.; Cornfeldt, M.; Wilker, J . C.; Blitzer,
R. D.; Landau, E.; Haroutunian, V.; Martin, L. L.; Effland, R.
C. Synthesis and structure-activity relationships of N-propyl-
N-(4-pyridinyl)-1H-indol-1-amine (besipiridine) and related ana-
logs as potential therapeutic agents for Alzheimer’s disease. J .
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(broad s, 1H), 16.35 (broad s, 1H); EI-MS m/e 201. Properties
of 9a , and 9b prepared in a similar manner, are included in
Table 1.
N -(2-C y a n o -1H -p y r r o l-1-y l)-N -m e t h y l-4-p y r i d i n -
a m in e Hyd r och lor id e (10). To a solution of 5b (9.5 g, 0.047
mol) in 50 mL of pyridine was added H2N-OH‚HCl (10 g, 0.14
mol). After stirring at ambient temperature for 1 h, the
solvent was evaporated in vacuo, and the residue was stirred
with water and extracted with ether (3 × 100 mL). The ether
layer was washed with water and saturated NaCl solution,
dried (MgSO4), and filtered. The filtrate was evaporated in
vacuo to a yellow oil (13 g), which was purified by HPLC (silica,
EtOAc) to give 9.2 g of an isomeric mixture of oximes: IR
(CHCl3) 3240, NOH, 1640 cm-1, CdN; EI-MS m/e 216.
To a solution of the oximes (4.3 g, 0.024 mol) in 50 mL of
ether was added pyridine (2g, 0.024 mol) followed by
benzenesulfonyl chloride (4.2 g, 0.024 mol). After warming
on a steam bath to dryness (30 min), the residue was cooled,
stirred with water, basified with Na2CO3, and extracted with
ethyl acetate (2 × 100 mL). The organic extract was washed
with water and saturated NaCl solution, dried (MgSO4), and
filtered. The filtrate was evaporated in vacuo to a brown waxy
residue (4 g), which was purified by HPLC (silica, EtOAc) to
give a white solid, 3.2 g, mp 88-90 °C. This material was
converted to the hydrochloride salt and recrystallized from
2-propanol to give 10 as white crystals: 3.3 g; mp 251-252
°C; 1H-NMR (DMSO-d6) δ 3.75 (s, 3H), 6.48 (t, 1H, J ) 3 Hz),
6.85 (broad s, 2H), 7.06-7.15 (m, 1H), 7.32 (d, 1H, J ) 3 Hz),
8.55 (d, 1H, J ) 3 Hz); IR (KBr) 2250 cm-1; CtN; EI-MS m/e
198. Properties of 10 are included in Table 1.
(10) Yamamura, H. I.; Snyder, S. H. Muscarinic cholinergic binding
in rat brain. Proc. Nat. Acad. Sci. U.S.A. 1974, 71, 1725-1729.
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(12) Smith, C. P. and Huger, F. P. Effect of zinc on [3H]QNB
displacement by cholinergic agonists and antagonists. Biochem.
Pharmacol. 1983, 32, 377.
Biologica l Meth od s. Procedural details for in vitro dis-
placement of [3H]quinuclidinyl benzilate (QNB),12 [3H]cloni-
dine,15 [3H]yohimbine,16 [3H]WB4101,17 and [3H]pirenzepine20
binding; in vitro inhibition of biogenic amine uptake;18,19 in
vitro inhibition of acetylcholinesterase21 (AChE); and in vivo
prevention of tetrabenazine (TBZ) induced ptosis14 and rever-
sal of scopolamine-induced dementia dark avoidance13 (SDDA)
were previously reported.
(13) Rush, D. K. Scopolamine amnesia of passive avoidance: A deficit
of information acquisition. Behav. Neur. Biol. 1988, 50, 255-
274.
(14) Benesova, O.; Nahunek, K. Correlation between the experimen-
tal data from animal studies and therapeutical effects of
antidepressant drugs. Psychopharmacologia 1971, 10, 337-347.
(15) U’Prichard, D. C.; Greenberg, D. A.; Snyder, S. H. Binding
characteristics of a radiolabeled agonist and antagonist at
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Pharmacol. 1977, 13, 454-473.
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presynaptic R-adrenoreceptors by yohimbine. Eur. J . Pharmacol.
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noradrenergic receptor binding in mammalian brain: Dif-
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19, 69-76.
Ack n ow led gm en t. The authors express their ap-
preciation to Anastasia R. Linville and Sandra H.
Anselmo for spectral data, to Dianne M. Saumsiegle for
typing the manuscript, and to Lawrence L. Martin for
his many helpful suggestions.
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J M950644V