Bis-cationic heteroaromatics as macrofilaricides: Synthesis of Bis- amidine and bis-guanylhydrazone derivatives of substituted imidazol[1,2- a]pyridines

Article abstract of DOI:10.1021/jm9803368

A series of guanylhydrazone, amidine, and hydrazone derivatives of 2- phenylimidazo[1,2-a]-pyridine have been prepared and evaluated for macrofilarial activity against Acanthocheilonema viteae and Brugia pahangi in jirds. Compounds with 4',6-bis-substitut

Full text of DOI:10.1021/jm9803368

J . Med. Chem. 1998, 41, 4317-4328
4317
Bis-Ca tion ic Heter oa r om a tics a s Ma cr ofila r icid es: Syn th esis of Bis-Am id in e
a n d Bis-Gu a n ylh yd r a zon e Der iva tives of Su bstitu ted Im id a zo[1,2-a ]p yr id in es
Richard J . Sundberg,* Sujay Biswas, Krishna Kumar Murthi, and Donna Rowe
Department of Chemistry, University of Virginia, McCormick Road, Charlottesville, Virginia 22901
J ohn W. McCall and Michael T. Dzimianski
Department of Parasitology, College of Veterinary Medicine, University of Georiga, Athens, Georgia 30602
Received J une 1, 1998
A series of guanylhydrazone, amidine, and hydrazone derivatives of 2-phenylimidazo[1,2-a]-
pyridine have been prepared and evaluated for macrofilarial activity against Acanthocheilonema
viteae and Brugia pahangi in jirds. Compounds with 4′,6-bis-substitution by cyclic guanylhy-
drazone groups show activity. 4′,6-Bis-amidines show some activity but are more toxic; 4′- or
6-monosubstituted compounds are inactive. 2,6-Bis-substituted compounds lacking the phenyl
ring are inactive. 4′,6-Bis-substituted compounds having additional double bonds inserted
between the heterocyclic ring and the phenyl ring or between the substituent and the ring
system show reduced activity.
Filarial infection is responsible for a number of
significant human pathologies in various parts of the
world.1 Onchocerca volvulus is responsible for “river-
blindness” which is endemic to large areas of Africa and
to more localized regions of Central and South America.2
Community-wide control programs based on diethyl-
carbamazine (DEC) and, more recently, ivermectin are
highly effective in reducing microfilarial infestations for
periods of several months to a year.3 While ivermectin
suppresses the fertility of adult O. volvulus, they retain
sufficient reproductive potential to cause reinfestation.4
As a result, development of an effective macrofilaricide
has been adopted as a WHO goal, and a screening
program based on Brugia pahangi and Acanthocheilone-
ma viteae infestation in jirds was initiated.5
examined. The substituents used were mainly guanyl-
hydrazones or amidines, although some hydrazones
were also prepared (Chart 1).
The guanylhydrazones were prepared from aldehyde
precursors while the amidines were prepared from
nitriles, making the corresponding aldehydes and ni-
triles the key synthetic intermediates. Halo-substituted
2-arylimidazo[1,2-a]pyridines were used as starting
materials. The preparation of 1b,c has already been
reported.9 The 6-substituted intermediates were pre-
pared from 6-iodo-2-phenylimidazo[1,2-a]pyridine by use
of cuprous cyanide displacement under traditional
CuCN substitution conditions.10 The 6-aldehyde was
obtained by formylation of the 6-lithio intermediate11
(Scheme 1).
While dinitrile 3b can be prepared using classical
CuCN substitution conditions, a Pd(Ph3P)4-catalyzed
procedure12 was much more convenient and avoided
handling large quantities of cyanide waste. Dialdehyde
3d was most effectively prepared from lithium/bromide
exchange of 3c followed by formylation with DMF
(Scheme 2).
In this paper we report the synthesis of a series of
bis-guanylhydrazones and bis-amidines derived from
substituted imidazo[1,2-a]pyridines and their evaluation
for macrofilaricidal activity. Bis-guanylhydrazones and
bis-amidines are normally considered to be included in
the DNA groove binding category and have frequently
been found to have activity against trypanosomes6 and
also against Pnuemocystis carinii.7 The lead compound
grew out of a program aimed at developing trypano-
cides.8
The truncated dialdehyde 4c was prepared starting
with ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate.
The iodine was effectively displaced by cyanide using
the Pd(Ph3P)4/CuI procedure. Selective reduction of
both the nitrile and ester group was accomplished by
DIBAL at -78 °C to give the dialdehyde 4c (Scheme
3).
Ch em istr y
Six separate series of compounds were investigated,
represented by structures 1-6. In addition to the 4′,6-
disubstituted compounds (series 3), the 4′- (1) and 6-
(2) monosubstituted analogues, a truncated series (4),
and two extended structures incorporating a double
bond between the imidazo[1,2-a]pyridine ring and phen-
yl substituent (5) or between the two substituents and
the 2-phenylimidazo[1,2-a]pyridine nucleus (6) were
The 2-styryl series (5) was synthesized starting with
6-iodoimidazo[1,2-a]pyridine-2-carboxaldehyde (4d ) and
diethyl 4-cyanobenzylphosphonate via a Wadsworth-
Emmons reaction giving 5a .13 The dinitrile 5b was
prepared by Pd(Ph3P)4/CuI cyanation. A good yield of
dialdehyde 5c was obtained by DIBAL reduction in CH2-
Cl2 at -78 °C (Scheme 4).
10.1021/jm9803368 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/18/1998

4318 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22
Sundberg et al.
Ch a r t 1
Sch em e 1a
Sch em e 5a
a
Reagents: (i) CNCH2P(O(OEt)2/n-BuLi; (ii) (a) tBuN(Li)CHd
CHP(O)(OEt)2 (b) aq (CO2H)2.
a
Reagents: (i) CuCN/DMF; (ii) DIBALH; (iii) NCCH2PO(OEt)2/
n-BuLi; (iv) nBuLi, DMF.
purify. A Wadsworth-Emmons reaction using the
lithium salt of diethyl cyanomethylphosphonate14 was
much more satisfactory, giving 6b in 70% yield as the
pure trans-trans isomer (Scheme 5). Attempts to
convert 6b to 6c by Raney nickel reduction15 gave only
modest yields. The best route to 6c was from 3d . While
neither formylmethylenetriphenylphosphorane16 nor di-
ethyl diethoxymethylphosphonate17 worked well, good
results were achieved using the 2-(tert-butylamino)-
vinylphosphonate reagent developed by Meyers.18
Sch em e 2a
a
Reagents: (i) KCN, CuI, Pd(Ph3)4, 18-crown-6; (ii) nBuLi,
DMF.
The aldehyde and nitrile intermediates were used to
prepare guanylhydrazones, amidines, and substituted
hydrazones. The functional groups which were included
are designated in Chart 2. The guanylhydrazones were
prepared from the corresponding substituted hydra-
zines, as described previously.8 Some of the amidines
could be prepared efficiently by a standard Pinner
reaction (methods A-C).19 For others, a procedure
developed by Garigipati20 in which the amine is first
converted to an aluminum amide by trimethylaluminum
was more effective (method D). The cyclic amidines 1p -
5p and 1q-5q were prepared by heating the corre-
sponding ethyl imidate intermediates with ethylenedi-
amine or 1,3-diaminopropane.21 Hydrazones 3s-w
were prepared by warming 3d with the appropriate
hydrazine in ethanol. The vinylthiazolines 1x and 3x
were prepared by a Wadsworth-Emmons reaction using
diethyl 2-thiazolinylmethylphosphonate.22
Sch em e 3a
a
Reagents: (i) CuCN; (ii) ethyl pyruvate; (iii) KCN, CuI,
Pd(Ph3)4, 18-crown-6; (iv) DIBAL/-78 °C.
Sch em e 4a
Biologica l Eva lu a tion
a
Reagents: (d) DIBAL/-78 °C; (ii) diethyl cyanobenzylphos-
Biological activity was assayed using male Mongolian
jirds (Meriones unguiculatus) which were transplanted
subcutaneously with 10 (5 male, 5 female) adult A.
viteae worms. After 2 weeks, 20 (10 male, 10 female)
B. pahangi worms were transplanted into the peritoneal
cavity. These doubly infected jirds were treated accord-
ing to the doses of test compounds in Table 1 on five
successive days. A positive control using a dosage of
2.0 mg/day flubendazole for five successive days was run
phonate/NaH; (iii) KCN, CuI, Pd(Ph3)4, 18-crown-6; (iv) DIBAL/
-78 °C.
Efforts to obtain the bis-unsaturated nitrile 6b from
2-(4-iodophenyl)-6-iodoimidazo[1,2-a]pyridine by the Heck
reaction were only partially successful. The diiodo
compound gave up to 40% conversion to 6b using tri-
(o-tolyl)phosphine and Pd(OAc)2, but the product was a
mixture of cis and trans isomers which was difficult to

Bis-Cationic Heteroaromatics as Macrofilaricides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22 4319
Ch a r t 2
with each series. After 56 days, the jirds were killed
and the number of each species of worm was counted.
The percentage of worms was compared with the
negative control;5 60% reduction was considered to
constitute activity.
tional groups. Derivatives in which this distance was
shortened by removal of the phenyl ring or lengthened
by insertion of one or two double bonds were prepared.
The truncated compounds (4e-g) showed no activity.
The mono-extended guanylhydrazone 5f was active,
while 5e was not. The bis-extended guanylhydrazones
6e,f showed some activity but did not appear to be any
more potent than the parent analogues. Again the six-
membered guanylhydrazone appears to be more active
than the five-membered compound. The bis-extended
amidines 6m ,n were marginally active, effecting 50-
60% reduction at 12.5 mg/kg, but were more toxic than
the corresponding guanylhydrazones.
Resu lts
The initial observation of activity against A. viteae
was made with compound 3e. As shown in Table 1, it
caused 70-100% suppression of A. viteae at doses from
12.5 to 100 mg/day by sc administration for a period of
5 days. No significant suppression of B. pahangi was
observed. The first objective undertaken was to delin-
eate the scope of this activity. Several guanylhydra-
zones and amidines with single substituent group at C4′
or C6 were prepared, but no significant activity was
observed. Attention was then focused on disubstituted
analogues of the lead compound. Two additional gua-
nylhydrazones (3f,g), two amidines (3k ,p ), and several
hydrazones (3s-w ) were prepared. Both of the gua-
nylhydrazones showed significant activity. While 3g
showed evidence of toxicity, 3f appeared to be somewhat
more active than the lead compound with suppression
of 60-100% at dose rates from 1.56 to 100 mg/day (see
Table 1) for A. viteae.
Discu ssion
The compounds reported in this study are related to
a series of heteroaromatic guanylhydrazones synthe-
sized and examined for activity against African trypa-
nosomes.8 Compound 3e was synthesized at that time,
although it was not included in the published report.
This compound showed activity against A. viteae, and
the present study was undertaken to establish the
structural features required for activity and to search
for more active analogues.
Compounds such as 3e,f are similar in general
structural features to various aromatic bis-cationic
compounds. This broad group includes bis-amidines
The final structure variable explored was the rela-
tionship between activity and separation of the func-

4320 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22
Ta ble 1. Macrofilarial Reduction
Sundberg et al.
macrofilarial reduction
dose (sc)
macrofilarial reduction
dose (sc)
compd
(mg/kg) × 5 days
B. pahangi
A. viteae
compd
(mg/kg) × 5 days
B. pahangi
A. viteae
1e
1f
1g
1i
1k
1l
1m
1p
1q
1r
1x
2e
2f
2k
2m
2p
3e
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
50
0
0
0
12
36
15
29
8
0
18
0
0
0
25, 0
12
42
11, 18
0, 0
28, 0
0
0, 9
0
0
60
0
47
0
0
0
0
20
0
28
0
20
30
60, 27
0
3g
3j
3k
3p
3s
3t
3u
3v
3w
3x
4e
4f
4g
5e
5f
100, 100a
100
3.12
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
50
0,0a
32
0
35
5
0
38
8
16
0
5
5
5
60, 73a
100
39
0
24
0
0
0
0
0
13
0
0
4
24
32
toxic
toxic
toxic
18
41, 12
38
13
38
0
100
toxic
toxic
toxic
71
100, 64
100
73
50
72
50
57
0
5k
5o
5p
6e
6f
100, 78
100, 100
73, 82
82
100, 100
100
25
12.5
100
75
50
25
12.5
6.25
3.12
1.56
3f
25
100
6g
6k
6m
6n
12.5
6.25
12.5
12.5
0
100, 100
64, 100
100, 75
88
0, 34
0, 39
11
16
0
0
63
a
Toxicity noted at this dosage.
such as berenil, pentamidine, and furamidine. Many
Bis-cations have activity in mitochondria as evidenced
by generation of petite mutants in S. cerevisae.33
The observation that certain bis-cations inhibit the
filarial nematode A. viteae is, so far as we are aware, a
novel result. This activity appears to have a much
higher degree of structural specificity than the trypano-
cidal activity of bis-cations, and indeed, the minimal
effect of the present compounds on B. pahangi also
indicates a considerable degree of species specificity. In
considering mechanisms by which the bis-guanylhydra-
zones might function, we can remark on one possibility.
Both trypanosomes and nematodes utilize posttransla-
tional trans-splicing of m-RNA, involving the addition
of spliced leader sequences in processing of pre-mRNA.
While trans-splicing is, along with RNA editing, a
universal part of RNA processing in trypanosomes,34 it
is also prevalent in some nematodes.35 It is known that
certain cationic antibiotics and drugs inhibit RNA
processing. Specific examples include the inhibition of
group I intron splicing in P. carinii by pentamidine and
dibenzimidazole bis-amidine.36 Other basic compounds,
including arginine peptides37 and tuberactinomycin
antibiotics,38 are known to inhibit RNA splicing. While
it would be premature to indicate RNA processing is the
target of the activity of 3e,f, the susceptibility of
trypanosomes, P. carinii, and certain nematodes to bis-
cations suggests RNA processing is at least one of the
possibilities that might be investigated.
such bis-cations possess trypanocidal activity.6 These
and related bis-cationics also show activity against P.
carinii.7 Heteroaromatic bis-guanylhydrazones have
shown similar profiles of activity.23 We are unaware of
previous reports that bis-cationics have macrofilaricidal
activity. Compounds which have previously been dem-
onstrated to have macrofilaricidal activity include ben-
zimidazole-2-carbamates1,24 and benzothiazoles.25 More
preliminary indications of activity have been observed
with aminoisoquinolines26 and â-carbolines.27
Several bis-cations have been shown to bind to oligo-
nucleotides in the minor groove and have been classified
as groove binders.28 Bis-cations also bind to RNA29 and
to DNA-RNA triple helices.30 Precisely how (or if) this
binding affects the viability of the protozoa has not been
established. Bis-cations have demonstrated a range of
other biological activities, including inhibition of RNA-
protein interactions31 and inhibition of topoisomerase.32
Exp er im en ta l Section
2-(4′-Iod op h en yl)im id a zo[1,2-a ]p yr id in e (1a ). A solu-
tion of 2-aminopyridine (9.27 g, 98.5 mmol) and 2-bromo-4′-
iodoacetophenone (32 g, 98.5 mmol) in dry acetone (230 mL)
was stirred under reflux for 12 h. A white solid precipitated.
After being cooled, it was filtered and resuspended in methanol
(200 mL) containing 48% HBr (30 mL). The reaction mixture

Bis-Cationic Heteroaromatics as Macrofilaricides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22 4321
was then stirred and refluxed for 2 h. After cooling to room
temperature, the mixture was neutralized (pH 7) with 10%
NaOH. The solid was filtered and dried in air to furnish 1a
(26.6 g) as a white solid: 83%; 1H NMR (CDCl3) δ 8.11 (d, J )
6.6 Hz, 1H), 7.86 (s, 1H), 7.75 (d, J ) 8.4 Hz, 2H), 7.69 (d, J
) 8.4 Hz, 2H), 7.64 (d, J ) 9.0 Hz, 1H), 7.18 (t, J ) 9.0 Hz,
1H), 6.81 (t, J ) 6.6 Hz, 1H).
2-(4′-Cya n op h en yl)im id a zo[1,2-a ]p yr id in e (1b). A mix-
ture of 2-(4′-iodophenyl)imidazo[1,2-a]pyridine (10.3 g, 32.2
mmol) and CuCN (3.45 g, 38.6 mmol) in dry DMF (200 mL)
was refluxed for 48 h. The hot reaction mixture was poured
into 1:4 ethylenediamine-water mixture (1000 mL) and
extracted with CHCl3 (5 × 100 mL). The combined extracts
were washed with water and brine, dried over MgSO4, and
concentrated. Excess DMF was azeotropically removed with
benzene until the volume was reduced to ∼20 mL. The
product was precipitated with hexane. The solid was collected,
and the mother liquor was subjected to the same procedure
twice to afford the desired nitrile 1b as a white solid: 5.1 g,
72%; mp 215-7 °C (recrystallized from CH2Cl2); 1H NMR
(CDCl3) δ 8.13 (d, J ) 6.9 Hz, 1H), 8.04 (d, J ) 8.4 Hz, 2H),
7.95 (s, 1H), 7.70 (d, J ) 8.4 Hz, 2H), 7.63 (d, J ) 9.0 Hz, 1H),
7.23 (t, J ) 9.0 Hz, 1H), 6.83 (t, J ) 6.9 Hz, 1H). Anal.
(C14H9N3), C, H, N.
2-(4′-F or m ylp h en yl)im id a zo[1,2-a ]p yr id in e (1c). To a
stirred solution of 2-(4′-cyanophenyl)imidazo[1,2-a]pyridine
(3.0 g, 13.64 mmol) in toluene (60 mL) at 0 °C was slowly added
DIBAL (11 mL, 1.5 M in toluene, 16.4 mmol). The reaction
mixture was stirred at room temperature for 3 h, quenched
with methanol (1 mL), and stirred for 10 min. Then cold 10%
H2SO4 (50 mL) was added, and the reaction mixture was
stirred at room temperature for 30 min. A white solid
precipitated and was filtered. It was dissolved in hot water
and basified (pH 12) with 10% NaOH. The aldehyde was
isolated by filtration and dried in air to provide 1c as a white
solid: 2.31 g, 77%; mp 208-9 °C (recrystallized from CHCl3);
1H NMR (CDCl3) δ 10.04 (s, 1H), 8.16 (d, J ) 6.6 Hz, 1H),
8.12 (d, J ) 8.1 Hz, 2H), 7.98 (s, 1H), 7.94 (d, J ) 8.1 Hz, 2H),
7.65 (d, J ) 9.0 Hz, 1H), 7.23 (t, J ) 9.0 Hz, 1H), 6.83 (t, J )
6.6 Hz, 1H). This compound was also prepared by a metal-
halogen exchange reaction from the corresponding iodo com-
pound 1a following the procedure described for 2c. Anal.
(C14H10N2O) C, H, N.
2-[4′-(2-Cya n oeth en yl)p h en yl]im id a zo[1,2-a ]p yr id in e
(1d ). To a stirred solution of diethyl cyanomethylphosphonate
(5.8 g, 33 mmol) in THF (100 mL) was added n-BuLi (13.2
mL, 2.5 M in hexane, 33 mmol) at 5-10 °C. After the addition,
stirring was continued at 10 °C for 15 min and then at room
temperature for 1.5 h. A solution of 1c (5.0 g, 22.5 mmol) in
THF (50 mL) was added to the lithium enolate solution at 0
°C. The resulting reaction mixture was stirred at 0 °C for 30
min and then at room temperature for 2 h. Saturated NH4Cl
was added to the reaction mixture. After the organic layer
was separated, the aqueous layer was extracted with CHCl3
(3 × 70 mL). The organic solutions were combined, extensively
washed with water and brine, and dried over MgSO4. After
removal of solvent, the crude solid was recrystallized from
absolute EtOH to furnish 1d as a brown solid: 4.1 g, 74%; 1H
NMR (DMSO-d6) δ 8.80 (s, 1H), 8.78 (br d, J ) 8 Hz, 1H), 8.02
(d, J ) 8.4 Hz, 2H), 7.81 (d, J ) 8.4 Hz, 2H), 7.84 (m, 2H),
7.65 (d, J ) 16.8 Hz, 1H), 7.38 (t, J ) 6.6 Hz, 1H), 6.58 (d, J
) 16.8 Hz, 1H).
1H), 7.97 (d, J ) 7.2 Hz, 2H), 7.71 (d, J ) 9.3 Hz, 1H), 7.47 (d,
J ) 7.8 Hz, 1H), 7.43 (t, J ) 7.8 Hz, 2H), 7.33 (t, J ) 7.5 Hz,
1H). This compound was also prepared by palladium-
catalyzed cyanation from 2a as described for 3b. Anal.
(C14H9N3) C, H, N.
2-P h en yl-6-for m ylim id a zo[1,2-a]p yr id in e (2c). To a
stirred suspension of 2-phenyl-6-iodoimidazo[1,2-a]pyridine (8
g, 25 mmol) and TMEDA (5.7 mL, 37.5 mmol) in toluene (200
mL) was added dropwise n-BuLi (15 mL of 2.5 M solution in
hexane, 37.5 mmol) at -78 °C. The brown-colored thick
reaction mixture was allowed to slowly warm to -20 °C and
then stirred at -20 °C for 30 min. A solution of DMF (6 mL,
75 mmol) in toluene (20 mL) was added dropwise to the
reaction mixture at -20 °C. Stirring was continued at -20
°C for 30 min, and then the mixture was allowed to slowly
warm to room temperature and stirred overnight. Saturated
NH4Cl (50 mL) was added to the reaction mixture at 0 °C,
and it was stirred for 10 min. Then it was poured into a
biphasic mixure of CHCl3 (100 mL) and saturated NaHCO3
(100 mL). After the organic layer was separated, the aqueous
layer was extracted with CHCl3 (3 × 50 mL). The combined
CHCl3 extract was washed with water and brine and then
dried over MgSO4. Removal of solvent under reduced pressure
provided a crude brownish solid which was recrystallized from
CH2Cl2 to furnish aldehyde 2c as a yellow solid: 4.05 g, 73%;
mp 219-20 °C (recrystallized from CHCl3); 1H NMR (DMSO-
d6) δ 9.92 (s, 1H), 9.27 (s, 1H), 8.58 (s, 1H), 7.97 (d, J ) 8.1
Hz, 2H), 7.67 (d, J ) 9.3 Hz, 1H), 7.58 (d, J ) 9.3 Hz, 1H),
7.44 (t, J ) 7.8 Hz, 2H), 7.33 (t, J ) 7.2 Hz, 1H). This
compound was also prepared starting with nitrile 2b by partial
reduction using DIBAL following the procedure described for
5c. Anal. (C14H10N2O) C, H, N.
6-Iod o-2-(4′-iod op h en yl)im id a zo[1,2-a ]p yr id in e (3a ).
Following the procedure described for 1a , 2-amino-5-iodopy-
ridine39 (8.1 g, 36.9 mmol) and 2-bromo-4′-iodoacetophenone
(12 g, 36.9 mmol) in dry acetone (70 mL) gave diiodo derivative
3a as a cream-colored solid: 18 g, 90%; 1H NMR (CDCl3) δ
8.38 (s, 1H), 7.80 (s, 1H), 7.75 (d, J ) 8.7 Hz, 2H), 7.66 (d, J
) 8.7 Hz, 2H), 7.41 (d, J ) 9.3 Hz, 1H), 7.33 (d, J ) 9.3 Hz,
1H).
6-Cyan o-2-(4′-cyan oph en yl)im idazo[1,2-a ]pyr idin e (3b).
A mixture of 6-iodo-2-(4′-iodophenyl)imidazo[1,2-a]pyridine
(446 mg, 1 mmol), powdered dry KCN (390 mg, 6 mmol), CuI
(1.14 g, 6 mmol), Pd[PPh3]4 (25 mg, 0.02 mmol), and 18-crown-6
(50 mg, 0.18 mmol) in dry DMF (2 mL) was stirred at room
temperature for 20 min under a nitrogen atmosphere.12 The
thick dark-green reaction mixture was refluxed in a preheated
oil bath (195 °C). The solution was stirred under reflux for 2
h and then cooled to room temperature. The thick dark-gray
mass was suspended in concentrated NH4OH (80 mL) and
stirred overnight. The solid was isolated by filtration, thor-
oughly washed with water, and then dried in air. This solid
was stirred under reflux with CHCl3 (80 mL) overnight and
then filtered hot to remove undissolved material. Removal of
CHCl3 under reduced pressure afforded a crude gray solid
which was recrystallized from absolute ethanol to furnish the
desired dinitrile 3b as a yellowish brown solid: 150 mg, 60%;
1
mp 257-9 °C; H NMR (CDCl3) δ 8.60 (s, 1H), 8.07 (d, J ) 8
Hz, 2H), 8.04 (s, 1H), 7.76 (d, J ) 8 Hz, 2H), 7.71 (s, 1H), 7.33
(m, 1H). This compound was also prepared by treating diiodo
derivative 3a with CuCN by the procedure described for 1b.
Anal. (C15H8N4‚0.5H2O) C, H, N.
2-P h en yl-6-iod oim id a zo[1,2-a]p yr id in e (2a ). Following
the procedure described for 1a , 2-amino-5-iodopyridine39 (10
g, 45.5 mmol) and 2-bromoacetophenone (9.05 g, 45.5 mmol)
in dry acetone (100 mL) gave 2a as a white solid: 13.52 g,
93%; 1H NMR (DMSO-d6) δ 8.86 (s, 1H), 8.27 (s, 1H), 7.91 (d,
J ) 8.4 Hz, 2H), 7.39 (m, 4H), 7.28 (t, J ) 7.2 Hz, 1H); MS
(CI) 321 (M + 1).
6-Br om o-2-(4′-br om oph en yl)im idazo[1,2-a ]pyr idin e (3c).
Following the procedure for 1a , 2-amino-5-bromopyridine40
(8.58 g, 45.5 mmol) and 2,4′-dibromoacetophenone (15.6 g, 45.5
mmol) in dry acetone (120 mL) gave 3c as a white solid: 15.5
g, 88%; 1H NMR (CDCl3) δ 8.26 (d, J ) 1.8 Hz, 1H), 7.79 (d, J
) 8.4 Hz, 2H), 7.81 (s, H), 7.54 (d, J ) 8.4 Hz, 2H), 7.51 (d, J
) 9.6 Hz, 1H), 7.23 (dd, J 1 ) 9.6 and J 2 ) 1.8 Hz, 1H).
2-P h en yl-6-cya n oim id a zo[1,2-a]p yr id in e (2b). Follow-
ing the procedure for 1b, 2-phenyl-6-iodoimidazo[1,2-a]pyridine
(8 g, 25 mmol) and CuCN (5 g) in dry DMF (80 mL) provided
2b as an off-white solid: 3.72 g, 68%; mp 247-9 °C (recrystal-
lized from CHCl3); 1H NMR (DMSO-d6) δ 9.29 (s, 1H), 8.46 (s,
6-F or m yl-2-(4′-for m ylp h en yl)im id a zo[1,2-a ]p yr id in e
(3d ). Following the procedure for 2c, 6-bromo-2-(4′-bromophe-
nyl)imidazo[1,2-a]pyridine, 3c (3.52 g, 10 mmol), and TMEDA
(4.5 mL, 30 mmol) in toluene (75 mL) were treated dropwise
at -78 °C with n-BuLi (15 mL of 2 M solution in toluene, 30

4322 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22
Sundberg et al.
mmol). After the mixture slowly warmed to -20 °C, additional
toluene (20 mL) was added and stirring was continued at -20
°C for 30 min. A solution of DMF (4.6 mL, 58.6 mmol) in
toluene (5 mL) was added dropwise to the reaction mixture.
Stirring was continued at -20 °C for 30 min; then the mixture
was allowed to slowly warm to room temperature and stirred
overnight. Saturated NH4Cl (50 mL) was added at 0 °C and
stirred for 10 min. The mixture was poured into a biphasic
mixure of CHCl3 (80 mL) and saturated NaHCO3 (80 mL). The
sparingly soluble dialdehyde was recovered from the CHCl3
extract and CHCl3 extraction of the filtered solid. Evaporation
of the CHCl3 afforded a brown solid which was purified by
recrystallization from CH2Cl2 to furnish desired dialdehyde
3d (1.2 g) as a yellow solid: mp 203-5 °C. Additional product
was obtained by chromatography of the mother liquor using
6-Iod oim id a zo[1,2-a]p yr id in e-2-ca r boxa ld eh yd e (4d ).
Following the procedure described for 4c, 2-carbethoxy-6-
iodoimidazo[1,2-a]pyridine (7.28 g, 23 mmol) in CH2Cl2 (100
mL) was added dropwise to DIBAL (30.4 mL, 1.5 M in toluene,
45.6 mmol) at -78 °C. The reaction mixture was stirred at
this temperature for 1.5 h. Excess DIBAL was decomposed
with methanol (2 mL), and stirring continued for 10 min. A
standard workup gave a crude solid which was purified by
recrystallization from EtOAc to provide 4d as a cream-colored
1
crystalline solid: 4 g, 63%; H NMR (CDCl3) δ 10.15 (s, 1H),
8.45 (s, 1H), 8.08 (s, 1H), 7.47 (m, 2H).
6-Iod o-2-(4′-cya n op h en ylet h en yl)im id a zo[1,2-a ]p yr i-
d in e (5a ). To a stirred suspension of NaH (60% dispersion
in mineral oil, 1.06 g, 22 mmol) that had been washed with
hexane (2 × 5 mL) in THF (15 mL) was added dropwise a
solution of diethyl 4-cyanobenzylphosphonate13 (4.83 g, 19
mmol) in THF (13 mL) at 0 °C. The reaction mixture was
stirred at room temperature for 3 h. The resulting dark-
greenish sodium enolate solution was added to the suspension
of aldehyde 4d (4 g, 14.7 mmol) in THF (20 mL) at 0 °C. The
reaction mixture was stirred at room temperature for 30 min
and then heated under reflux with stirring for 2 h. After being
cooled, the mixture was poured into crushed ice-water mixure.
The brown solid which precipitated was filtered, dried, and
recrystallized from CHCl3 to provide desired iodonitrile 5a as
a cystalline off-white solid: 4.9 g, 90%; 1H NMR (CDCl3) δ 8.35
(s, 1H), 7.61 (m, containing a singlet at 7.62 and a doublet at
7.60, J ) 9 Hz, 5H), 7.38 (m, 2H), 7.22 (d, J ) 16.5 Hz, 2H).
6-Cya n o-2-(4′-cya n op h en yleth en yl)im id a zo[1,2-a ]p yr i-
d in e (5b). Following the procedure for 3b, a mixture of
compound 5a (1 g, 2.69 mmol), CuI (1.6 g, 8.4 mmol), freshly
dry powdered KCN (0.55 g, 8.4 mmol), Pd[PPh3]4 (0.095 g, 0.08
mmol 3 mol %), and 18-crown-6 (67 mg, 0.25 mmol) in dry
DMF (2 mL) was stirred at room temperature for 20 min and
then immediately brought to reflux in an oil bath preheated
to about 200 °C for 2 h. The reaction was worked up as
described for 3b to give 5b as a dark-brown solid: 700 mg,
96%; mp 265-7 °C (recrystallized from CHCl3); 1H NMR
(CDCl3) δ 8.54 (s, 1H), 7.64 (m, 5H), 7.37 (s, 1H), 7.32 (m, 1H),
7.23 (d, J ) 17 Hz, 2H).
6-F or m yl-2-(4′-for m ylp h en yleth en yl)im id a zo[1,2-a ]p y-
r id in e (5c). To a stirred solution of dinitrile 5b (0.56 g, 2.07
mmol) in CH2Cl2 (50 mL) was added DIBAL (8.3 mL, 1.5 M in
toluene, 12.44 mmol) slowly at -78 °C. Stirring was continued
at this temperature for 10 min. After the reaction mixture
was quenched with methanol (1 mL) at -78 °C, it was
immediately poured into a vigorously stirred cold (0 °C)
biphasic mixture of 5% KHSO4 (65 mL, 24.8 mmol) and CHCl3
(100 mL). The resulting mixture was stirred at 0 °C for 30
min and at room temperature overnight. Insoluble material
was removed by passing through a Celite bed. After the
organic layer was separated, the aqueous layer (pH ∼ 6) was
extracted with CHCl3 (3 × 20 mL). The combined organic
layers were washed with water and brine and dried over
MgSO4. Evaporation of solvent afforded a crude solid which
was purified by flash chromatography of silica gel using 10%
EtOAc in CHCl3 as the eluant to furnish 5c as a yellow solid:
280 mg, 45%; mp 238-42 °C dec (recrystallized from CHCl3);
1H NMR (CDCl3) δ 10.01 (s, 1H), 9.96 (s, 1H), 8.65 (s, 1H),
7.89 (d, J ) 8.5 Hz, 2H), 7.77 (s, 1H), 7.68 (m, containing a
doublet at 7.71, J ) 8.5 Hz, 4H), 7.30 (d, J ) 15.87 Hz, 2H).
6-(2-Cya n oeth en yl)-2-[4′-(2-cya n oeth en yl)p h en yl]im i-
d a zo[1,2-a ]p yr id in e (6b). To a stirred solution of diethyl
cyanomethylphosphonate (2.12 g, 11.96 mmol) in THF (20 mL)
was added n-BuLi at 5-10 °C. Stirring was continued at 10
°C for 15 min and then at room temperature for 1.5 h. The
resulting lithium enolate was added to a suspension of
dialdehyde 3d (1.0 g, 4 mmol) in THF (30 mL) at 0 °C. The
reaction mixture was stirred at 0 °C for 30 min and then at
room temperature for 18 h. It was then decomposed with
saturated NH4Cl. After the organic layer was separated, the
aqueous layer was extracted with CHCl3 (3 × 50 mL). After
drying and removal of solvent, the gray solid was recrystallized
from absolute EtOH to furnish 6b as a brown solid: 830 mg,
1
silica gel: total yield 1.4 g, 56%; H NMR (CDCl3) δ 10.06 (s,
1H), 9.99 (s, 1H), 8.72 (s, 1H), 8.16 (d, J ) 8 Hz, 2H), 8.11 (s,
1H), 7.99 (d, J ) 8 Hz, 2H), 7.75 (m, 2H). Anal. (C15H10N2O2)
C, H, N.
2-Am in o-5-cya n op yr id in e (7c). Following the procedure
described for 1b, a suspension of 2-amino-5-iodopyridine39 (60
g, 272 mmol) and CuCN (36.5 g, 407 mmol) in dry DMF (600
mL) was refluxed for 48 h. The crude product was purified
by recrystallization from ethanol to furnish 7c as a light-
greenish white solid: 24.5 g, 77%; 1H NMR (CDCl3) δ 8.31 (d,
J ) 2.1 Hz, 1H), 7.54 (dd, J 1 ) 8.7 and J 2 ) 2.1 Hz, 1H), 6.47
(d, J ) 8.7 Hz, 1H), 5.27 (br s, 2H). This compound was also
obtained by palladium-catalyzed cyanation from iodo com-
pound 7b following the procedure described for 3b.
2-Car beth oxy-6-iodoim idazo[1,2-a ]pyr idin e (4a). A mix-
ture of 2-amino-5-iodopyridine39 (5 g, 23 mmol) and ethyl
bromopyruvate (4.9 g, 23 mmol) in ethanol was refluxed for
18 h. The solvent was evaporated under reduced pressure,
and the residue was dissolved in a minimum volume of 10%
HCl. The acidic suspension was neutralized to pH 8 with
saturated NaHCO3. The precipitate was filtered, dried in air,
and purified by recrystallization from EtOAc to give 4a as a
cream-colored solid: 4.6 g, 65%; 1H NMR (CDCl3) δ 8.40 (s,
1H), 8.10 (s, 1H), 7.46 (d, J ) 9.3 Hz, 1H), 7.38 (dd, J 1 ) 9.3
and J 2 ) 0.9 Hz, 1H), 4.44 (q, J ) 7.2 Hz, 2H), 1.43 (t, J ) 7.2
Hz, 3H).
2-Ca r beth oxy-6-cya n oim id a zo[1,2-a]p yr id in e (4b).
A
solution of 2-amino-5-cyanopyridine (24 g, 200 mmol) and ethyl
bromopyruvate (39 g, 200 mmol) in ethanol (300 mL) was
stirred under reflux for 15 h. The solvent was evaporated,
and the residue was dissolved in a minimum volume of 10%
HCl. The solution was neutralized (pH 8) with saturated
NaHCO3. The precipitate was filtered and dried in air to give
cyano ester 4b as a creamy solid: 25.8 g, 59%; 1H NMR (CDCl3)
δ 8.62 (s, 1H), 8.27 (s, 1H), 7.76 (d, J ) 9.3 Hz, 1H), 7.33 (dd,
J 1 ) 9.3 and J 2 ) 1.5 Hz, 1H), 4.43 (q, J ) 7.2 Hz, 2H), 1.44
(t, J ) 7.2 Hz, 3H). This compound was also prepared by
palladium-catalyzed cyanation from iodo compound 4a follow-
ing the procedure described for 3b.
Im id a zo[1,2-a ]p yr id in e-2,6-d ica r boxa ld eh yd e (4c). To
a solution of 2-carbethoxy-6-cyanoimidazo[1,2-a]pyridine (5 g,
23 mmol) in CH2Cl2 (200 mL) was added dropwise DIBAL (62
mL, 1.5 M in toluene, 93 mmol) at -78 °C. Stirring was
continued at -78 °C for 30 min. The reaction mixture was
quenched with cold methanol and then stirred for 10 min. The
resulting mixture was poured into a biphasic mixture of
saturated NaHCO3 (100 mL) and CHCl3 (150 mL) and allowed
to warm to room temperature with occasional stirring. It was
then passed through a Celite bed to remove a gelatinous mass,
and the bed was thoroughly washed with CHCl3. After the
organic layer was separated, the aqueous layer was extracted
with CHCl3 (3 × 50 mL). The combined filtrate and extracts
were washed with water and brine, dried over MgSO4, and
concentrated under reduced pressure. The crude solid was
purified by recrystallization from EtOAc to provide 4c as an
off-white crystalline solid: 2.5 g, 62%; mp 226-8 °C (recrystal-
1
lized from EtOAc); H NMR (CDCl3) δ 10.19 (s, 1H), 10.0 (s,
1H), 8.73 (s, 1H), 8.29 (s, 1H), 7.78 (br s, 2H).

Bis-Cationic Heteroaromatics as Macrofilaricides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22 4323
1
1
70%; mp 214-6 °C dec (recrystallized from EtOH); H NMR
(CDCl3) δ 8.22 (s, 1H), 8.00 (d, J ) 8 Hz, 2H), 7.95 (s, 1H),
7.68 (d, J ) 9.7 Hz, 1H), 7.54 (d, J ) 8 Hz, 2H), 7.43 (d, J )
16.48 Hz, 1H), 7.34 (m, containing a doublet J ) 16.48 Hz,
2H), 5.93 (d, J ) 16.48 Hz, 1H), 5.89 (d, J ) 16.48 Hz, 1H).
Anal. (C19H12N4‚0.25H2O) C, H, N.
1g: 50%; H NMR (DMSO-d6) δ 11.36 (s, 1H), 8.89 (s, 1H),
8.84 (d, J ) 6.6 Hz, 1H), 8.44 (s, 1H), 8.10 (d, J ) 8.4 Hz, 2H),
8.00 (d, J ) 8.4 Hz, 2H), 7.91 (t, J ) 7.2 Hz, 1H), 7.44 (t, J )
7.2 Hz, 1H), 3.47 (s, 4H), 1.94 (s, 4H); MS (CI) 333 (M + 1).
Anal. (C19H2ON6‚2HBr‚2H2O) C, H, N, Br.
1
1i: 56%; H NMR (DMSO-d6) δ 11.69 (s, 1H), 8.89 (s, 1H),
8.84 (d, J ) 6.6 Hz, 1H), 8.42 (s, 1H), 8.31(s, 1H), 8.10 (d, J )
8.4 Hz, 2H), 8.03 (d, J ) 8.1 Hz, 2H), 7.91 (t, J ) 8.7 Hz, 1H),
7.45 (t, J ) 6.6 Hz, 1H), 3.69 (m, 4H), 3.56 (m, 4H); MS (CI)
349 (M + 1). Anal. (C19H20N6‚2HBr‚2H2O) C, H, N, Br.
6-(3-Oxo-1-p r op en yl)-2-[4′-(3-oxo-1-p r op en yl)p h en yl]-
im id a zo[1,2-a ]p yr id in e (6c). To a cooled and stirred solu-
tion of lithium diisopropylamide prepared from diisopropy-
lamine (3.5 mL, 25.2 mmol) and n-BuLi (10.1 mL of 2.5 M in
hexane, 25.2 mmol) in THF (15 mL) at -78 °C under nitrogen
1
2e: 60%; H NMR (DMSO-d6) δ 12.46 (s, 1H), 9.08 (s, 1H),
41
8.65 (s, 1H), 8.26 (s, 1H), 8.24 (d, 1H), 7.95 (d, J ) 7.5 Hz,
2H), 7.84 (d, J ) 9.3 Hz, 1H), 7.51 (t, J ) 7.2 Hz, 2H), 7.45 (t,
J ) 7.2 Hz, 1H), 3.75 (s, 4H); MS (CI) 305 (M + 1). Anal.
(C17H16N6‚2HBr‚0.5H2O) C, H, N, Br.
atmosphere was added acetaldehyde N-tert-butylimine (1.6
mL, 12 mmol). Stirring was continued at -78 °C for 30 min,
and then a solution of distilled diethyl chlorophosphate (2.08
g, 12 mmol) in THF (2 mL) was added. After addition was
complete, the reaction mixture was stirred at -78 °C for 2 h
and then allowed to warm to -10 °C over a period of 5 h. The
resulting yellow solution of lithioenaminophosphonate18 was
stirred at -10 °C for 20 min, then again cooled to -40 °C,
and added through a cannula to the cold suspension of
dialdehyde 3d (1 g, 4 mmol) in THF (80 mL) at -78 °C. The
reaction mixture was stirred at this temperature for 30 min
and then slowly allowed to warm to room temperature.
Stirring was continued at room temperature overnight, and a
clear red-colored solution resulted. The reaction mixture was
then treated with aqueous oxalic acid (3.45 g in 80 mL water,
27.3 mmol) followed by addition of benzene (80 mL). The
biphasic mixture was stirred at room temperature, and after
3 h a yellow solid started to separate out from the reaction
mixture. Stirring was continued at room temperature for
overnight. The yellow solid was filtered through Celite bed
and then washed with water. The yellow solid along with
Celite was boiled under reflux with CHCl3. Then this mixture
was again passed through a Celite bed. The filtrate was
washed with water and brine and then dried over MgSO4.
Removal of solvent provided pure 6c as a yellow solid which
was directly used for making hydrazones without further
purification. After separating the organic layer from the
original filtrate, the aqueous layer was made alkaline (pH 9)
with 10% NaOH and then extracted with CHCl3 (3 × 30 mL).
The combined organic layer was washed with water followed
by brine and then dried over MgSO4. Concentration of the
filtrate resulted in a semisolid which was crystallized from
CHCl3 to get additional 6c to yield: 785 mg, 65%; mp 207-8
°C dec (recrystallized from CHCl3); 1H NMR (CDCl3) δ 9.73
(d, J ) 7.3 Hz, 2H), 8.34 (s, 1H), 8.03 (d, J ) 8 Hz, 2H), 7.98
(s, 1H), 7.68 (m, containing a doublet at 7.66, J ) 8 Hz, 3H),
7.48 (m, 3H), 6.77 (dd, J 1 ) 12.8 and J 2 ) 7.3 Hz, 1H), 6.72
(dd, J 1 ) 12.8 and J 2 ) 7.3 Hz, 1H). Anal. (C19H14N2O2) C,
H, N.
1
2f: 62%; H NMR (DMSO-d6) δ 11.73 (s, 1H), 9.10 (s, 1H),
8.67 (s, 1H), 8.42 (s, 1H), 8.30 (d, 1H), 8.23 (s, 1H), 7.95 (d, J
) 7.5 Hz, 2H), 7.85 (d, J ) 9.3 Hz, 1H), 7.54 (t, J ) 7.2 Hz,
2H), 7.47 (t, J ) 8.4 Hz, 1H), 3.56 (br s, 4H), 1.89 (br s, 2H);
MS (CI) 319 (M + 1). Anal. (C18H18N6‚2HBr‚2H2O) C, H, N,
Br.
1
3e: 89%; H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.59 (s, 1H),
8.17 (s, 1H), 8.14 (s, 1H), 8.07 (d, J ) 9 Hz, 1H), 7.98 (d, J )
8.4 Hz, 2H), 7.88 (d, J ) 8.4 Hz, 2H), 7.73 (d, J ) 9 Hz, 1H),
3.70 (br s, 8H). Anal. (C21H22N10‚3HBr‚2H2O) C, H, N, Br.
3f: 81%; 1H NMR (DMSO-d6) δ 8.90 (s, 1H), 8.57 (s, 1H),
8.34 (br s, 1H), 8.30 (br s, 1H), 8.16 (s, 1H), 8.13 (s, 1H), 8.08
(d, J ) 9.3 Hz, 1H), 8.01 (d, J ) 8.1 Hz, 2H), 7.91 (d, J ) 8.1
Hz, 2H), 7.67 (d, J ) 9.3 Hz, 1H), 3.33 (br t, 8H), 1.87 (br t,
4H). Anal. (C23H26N10‚3HBr‚0.5H2O) C, H, N, Br.
1
3g: 87%; H NMR (DMSO-d6) δ 9.01 (s, 1H), 8.62 (s, 1H),
8.39 (s, 1H), 8.37 (s, 1H), 8.26 (d, J ) 9.6 Hz, 1H), 8.02 (d, J
) 8.7 Hz, 2H), 8.01 (d, J ) 8.7 Hz, 2H), 7.72 (d, J ) 9.6 Hz,
1H), 3.45 (br t, 8H), 1.93 (br t, 8H). Anal. (C25H50N10‚3HBr‚
1.5H2O) C, H, N, Br.
3j: 71%; 1H NMR (DMSO-d6) δ 11.35 (s, 1H), 11.22 (s, 1H),
9.01 (s, 1H), 8.66 (s, 1H), 8.22 (m, 2H), 7.99 (m, containing a
doublet at 8.00, J ) 8 Hz, 9H), 7.80 (m, 3H), 3.88 (sept, J )
7.3 Hz, 2H), 1.19 (d, J ) 6.8 Hz, 12H). Anal. (C23H33N10
3HBr). Quadruplicate analysis gave empirical formula C23
‚
-
H
33N10Br2.7O3.9
.
4e: 73%; 1H NMR (DMSO-d6) δ 9.23 (s, 1H), 8.76 (br s, 2H),
8.54 (s, 1H), 8.33 (s, 1H), 8.29 (d, J ) 9.3 Hz, 1H), 8.26 (s,
1H), 7.80 (d, J ) 9.3 Hz, 1H), 3.75 (s, 4H), 3.73 (s, 4H). Anal.
(C15H18N10‚3HBr‚2H2O).
4f: 80%; 1H NMR (DMSO-d6) δ 9.30 (s, 1H), 8.60 (s, 1H),
8.53 (br s, 1H), 8.50 (d, J ) 9.3 Hz, 1H), 8.46 (br s, 1H), 8.31
(s, 1H), 8.24 (s, 1H), 7.84 (d, J ) 9.3 Hz, 1H), 3.36 (br s, 8H),
1.88 (br s, 4H). Anal. (C17H22N10‚3HBr‚H2O) C, H, N, Br.
1
4g: 52%; H NMR (DMSO-d6) δ 9.32 (s, 1H), 8.68 (s, 1H),
Gen er a l P r oced u r e for th e P r ep a r a tion of (N-Alk yl-
gu a n yl)h yd r a zon es (F u n ction a l Gr ou p s e-j). A stirred
suspension of 1.8-2 equiv of substituted aminoguanidinium
iodide or bromide and the appropriate aldehyde (1 mmol) or 3
equiv of aminoguanidinium iodide or bromide with dialdehyde
(1 mmol) in absolute ethanol (3 mL) was slowly heated to
provide a clear solution. Stirring was continued under reflux
for 24 h. The product generally precipitated out from the
solution during reflux. The reaction mixture was then cooled,
acidified (pH < 2) with concentrated HBr, and stirred for 30
min. The solid product was filtered and purified by recrys-
tallization from aqueous ethanol containing HBr to provide
the desired guanylhydrazones in 80-90% yield.
1e: 90%; 1H NMR (DMSO-d6) δ 8.80 (s, 1H), 8.77 (d, J )
6.9 Hz, 1H), 8.21 (s, 1H), 8.02 (d, J ) 8.4 Hz, 2H), 8.00 (d, J
) 8.4 Hz, 2H), 7.84 (d, J ) 9 Hz, 1H), 7.76 (br t, 1H), 7.34 (t,
J ) 6.3 Hz, 1H), 3.72 (s, 4H). Anal. (C17H16N6‚2HBr) C, H,
N, Br.
8.58 (d, J ) 9.6 Hz, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.06 (br s,
4H), 7.85 (d, J ) 9.6 Hz, 1H), 3.48 (br s, 4H), 1.94 (br s, 4H).
Anal. (C19H26N10‚3HBr‚2H2O) C, H, N, Br.
5e: 80%; 1H NMR (20% D2O in DMSO-d6) δ 8.85 (s, 1H),
8.20 (m, containing a s at 8.19, 2H), 8.09 (s, 1H), 8.03 (s, 1H),
7.73 (m, containing a doublet at 7.74, J ) 8 Hz, 3H), 7.62 (d,
J ) 8 Hz, 2H), 7.30 (m, 2H), 3.67 (d, J ) 4.3 Hz, 8H). Anal.
(C23H24N10‚3HBr‚2H2O) C, H, N, Br.
5f: 85%; 1H NMR (DMSO-d6) δ 11.75 (s, 1H), 11.51 (s, 1H),
9.17 (s, 1H), 8.41 (m, containing a s at 8.42, 3H), 8.31 (s, 2H),
8.20 (s, 1H), 8.11 (s, 1H), 7.88 (d, J ) 8 Hz, 2H), 7.83 (d, J )
9 Hz, 1H), 7.68 (d, J ) 8 Hz, 2H), 7.53 (d, J ) 16.5 Hz, 1H),
7.46 (d, J ) 16.5 Hz, 1H), 3.34 (d, J ) 3.7 Hz, 8H), 1.87 (br s,
4H). Anal. (C25H28N10‚3HBr‚3H2O) C, H, N, Br.
5g: 1H NMR (DMSO-d6) δ 11.52 (s, 2H), 11.28 (s, 2H), 9.28
(s, 1H), 8.53 (d, J ) 9.8 Hz, 1H), 8.48 (s, 1H), 8.39 (s, 1H),
8.33 (s, 1H), 7.98 (m, containing a doublet at 7.93, J ) 8.5 Hz,
4H), 7.83 (d, J ) 9.7 Hz, 1H), 7.69 (d, J ) 8.5 Hz, 2H), 7.52
(m, 2H), 3.46 (s, 8H), 1.92 (s, 8H). Anal. (C27H32N10‚3HBr‚
2H2O) C, H, N, Br.
1f: 91%; 1H NMR (DMSO-d6) δ 8.84 (s, 1H), 8.80 (d, J ) 6.6
Hz, 1H), 8.35 (br s, 2H), 8.16 (s, 1H), 8.03 (d, J ) 8.4 Hz, 2H),
8.02 (d, J ) 8.4 Hz, 2H), 7.85 (m, 2H), 7.40 (t, J ) 6.6 Hz,
1H), 3.35 (br t, 4H), 1.89 (br t, 2H). Anal. (C18H18N6‚2HBr‚
H2O) C, H, N, Br.
6e: 1H NMR (30% D2O in DMSO-d6) δ 8.85 (s, 1H), 8.62 (s,
1H), 8.03 (d, J ) 9.3 Hz, 1H), 7.91 (m, 4H), 7.79 (d, J ) 9.3
Hz, 1H), 7.69 (d, J ) 8 Hz, 2H), 7.13 (dd, J 1 ) 15.6 and J 2
)

4324 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22
Sundberg et al.
8 Hz, 2H), 6.97 (m, 2H), 3.64 (s, 8H). Anal. (C25H26N10‚3HBr‚
1k . The crude residue was recrystallized from aqueous
acetone to provide a creamy solid which was converted to the
corresponding hydrochloride salt by bubbling HCl gas through
the methanolic solution followed by concentration to dryness
to provide amidine 1k as a light-greenish white solid: 73%;
1H NMR (DMSO-d6) δ 8.77 (s, 1H), 8.76 (d, 1H), 8.10 (d, J )
8.1 Hz, 2H), 7.85 (t, J ) 9 Hz, 1H), 7.80 (d, J ) 6.6 Hz, 1H),
7.76 (d, J ) 8.1 Hz, 2H), 7.36 (t, J ) 9 Hz, 1H), 3.51 (t, J ) 6.9
Hz, 2H), 3.39 (t, J ) 6.6 Hz, 2H), 2.02 (t, J ) 6.6 Hz, 2H), 1.83
(t, J ) 6.9 Hz, 2H); MS (CI) 291 (M + 1). Anal. (C18H18N4‚
2HCl‚2H2O) C, H, N, Cl.
1l. To a suspension of imidate intermediate from 1b (2.9
g, 13.3 mmol) in absolute EtOH (50 mL) was added freshly
distilled piperidine (2.63 mL, 26.6 mmol) at 0 °C. The mixture
was stirred at room temperature overnight. After removal of
solvent the residue was dissolved in minimum volume of 3 N
HCl. The solid was precipitated out by addition of acetone
and filtered. It was then purified by several recrystallizations
from aqueous acetone. The final product was recrystallized
from aqueous EtOH containing HCl to provide amidine 1l as
an off-white solid: 2.25 g, 45%; 1H NMR (DMSO-d6) δ 9.47
(br s, 1H), 9.36 (s, 1H), 8.91 (s, 1H), 8.85 (d, J ) 6.9 Hz, 1H),
8.27 (d, J ) 8.1 Hz, 2H), 7.93 (d, J ) 9.0 Hz, 1H), 7.87 (t, J )
7.5 Hz, 1H), 7.78 (d, J ) 8.4 Hz, 2H), 7.41 (t, J ) 6.6 Hz, 1H),
3.75 (m, 4H), 1.6 (m, 6H); MS (CI) 305 (M + 1). Anal.
(C19H20H4‚2HCl‚2H2O) C, H, N, Cl.
1m . Reaction of imidate ester hydrochloride from 1b with
morpholine as described above for 1l gave amidine 1m as an
off-white solid: 35%; 1H NMR (DMSO-d6) δ 9.71 (s, 1H), 9.64
(s, 1H), 8.89 (d, J ) 6.6 Hz, 1H), 8.30 (d, J ) 8.4 Hz, 2H), 7.98
(d, J ) 6.7 Hz, 1H), 7.90 (t, J ) 6.6 Hz, 1H), 7.80 (d, J ) 8.4
Hz, 2H), 7.46 (t, J ) 6.7 Hz, 1H), 3.82 (br s, 4H), 3.63 (br s,
2H), 3.54 (br s, 2H); MS (CI) 307 (M + 1). Anal. (C18H18N4O‚
2HCl‚H2O) C, H, N, Cl.
2k . Treatment of the imidate intermediate from 2b with
pyrrolidine following the procedure described for 1l gave
amidine 2k as an off-white solid: 44%; 1H NMR (DMSO-d6) δ
9.61 (s, 1H), 9.14 (s, 1H), 9.11 (d, 1H), 8.78 (s, 1H), 8.03 (d, J
) 7.2 Hz, 2H), 7.95 (d, J ) 9.3 Hz, 1H), 7.74 (d, J ) 9.3 Hz,
1H), 7.51 (t, J ) 6.9 Hz, 2H), 7.43 (t, J ) 7.5 Hz, 1H), 3.55 (t,
J ) 6.6 Hz, 2H), 3.49 (t, J ) 6.9 Hz, 2H), 2.06 (quintet, J )
6.6 Hz, 2H), 1.86 (quintet, J ) 6.6 Hz, 2H); MS (CI) 291 (M +
1). Anal. (C18H18H4‚2HCl‚1.5H2O) C, H, N, Cl.
2H2O) C, H, N, Br.
1
6f: H NMR (DMSO-d6) δ 11.49 (s, 1H), 11.44 (s, 1H), 8.95
(s, 1H), 8.78 (s, 1H), 8.22 (m, containing a doublet J ) 9.8 Hz,
4H), 7.93 (m, 6H), 7.73 (d, J ) 7.94 Hz, 2H), 7.20 (2d, J )
16.48 Hz, 2H), 6.96 (2d, J ) 16.48 Hz, 2H), 3.29 (s, 8H), 1.84
(br s, 4H). Anal. (C27H30N10‚3HBr‚3H2O) C, H, N, Br.
6g: 1H NMR (DMSO-d6) δ 11.24 (s, 1H), 11.20 (s, 1H), 8.98
(s, 1H), 8.79 (s, 1H), 8.25 (m, 2H), 8.05 (d, J ) 9 Hz, 1H), 7.99
(d, J ) 8 Hz, 2H), 7.87 (d, J ) 9 Hz, 1H), 7.79 (m, containing
a doublet at 7.74, J ) 8 Hz, 4H), 7.26 (d, J ) 15.87 Hz, 1H),
7.17 (d, J ) 15.87 Hz, 1H), 7.02 (m, 2H), 3.41 (s, 8H), 1.90 (s,
8H). Anal. (C29H34N10‚3HBr‚1.5H2O) C, H, N, Br.
Gen er a l P r oced u r e for th e P r ep a r a tion of Am id in es.
Meth od A: Dry HCl gas was bubbled through a solution of
nitrile (12.2 mmol) in nitrobenzene (50 mL) and absolute EtOH
(10 mL) at 0 °C for 1 h, and the resulting mixture was stirred
at room temperature for 16-20 h. The imino ether hydro-
chloride was precipitated by addition of dry Et2O and then
filtered. Excess nitrobenzene was removed by washing with
copious amounts of Et2O. The solid was dried under vacuum
and directly reacted with appropriate amine to make corre-
sponding amidines.
Meth od B: A suspension of dinitrile 5b (0.45 g, 1.66 mmol)
in dry dioxane (10 mL) and absolute ethanol (5 mL) was cooled
in an ice-water bath, and dry HCl gas was bubbled through
it. A creamy solid precipitated from the reaction mixture
within 15 min, but the solid slowly went back in solution and
the reaction mixture was a clear red-colored thick solution
after 1 h. A yellow-colored solid slowly started to precipitate
from the solution, and HCl gas stream was continued for next
2 h. The cold reaction mixture was then stoppered, slowly
allowed to warm to room temperature, and left standing at
room temperature for 3 days with occasional shaking. The
reaction mixture was concentrated to dryness, keeping the
water bath temperature below 30 °C, and the resulting solid
residue was dried under vacuum overnight to provide the
imidate intermediate as a brown solid (763 mg).
Meth od C: Dry HCl gas was bubbled at 0 °C into a stirred
suspension of dinitrile 6a (0.51 g, 1.72 mmol) in dry dioxane
(6 mL) and absolute ethanol (3.6 mL). A yellow solid precipi-
tated from the reaction mixture within 15 min, and passage
of HCl gas was continued for 1 h. The reaction mixture turned
nearly clear and became thick. It was slowly allowed to warm
to room temperature with continuous stirring and left standing
at room temperature overnight. The reaction mixture was
concentrated to dryness, keeping the water bath temperature
below 30 °C, and the resulting solid residue was dried in a
vacuum for 2 h to provide the imidate intermediate (850 mg)
as a tan-colored solid.
Meth od D: To a stirred cold suspension of the correspond-
ing amine hydrochloride (30 mmol) in toluene (20 mL) was
slowly added trimethylaluminum (15 mL, 2 M in toluene, 30
mmol) through a dropping funnel at 0 °C. Stirring was
continued at this temperature for the next 15 min and at room
temperature for 1.5 h. The resulting clear colorless solution
of aluminum amide reagent was added to the suspension of
dinitrile (4.8 mmol) in toluene (20 mL) by cannulation at 0
°C. After addition was complete, the reaction mixture was
stirred at room temperature for 30 min and then heated to 80
°C for 24 h. During heating, the suspended reaction mixture
became clear and dark red in color. After being cooled, the
mixture was poured into a stirred slurry of silica gel (30 g) in
chloroform (80 mL), and the solid material was completely
transferred with methanol. The resulting mixture was stirred
at room temperature for 30 min. The silica gel was filtered
off and washed with hot methanol (3 × 50 mL). The filtrate
and washings were combined and concentrated under reduced
pressure to obtain crude amidine salts.
2m . Reaction of morpholine with the imidate intermediate
from 2b as described for 1l gave amidine 2m as an off-white
1
solid: 39%; H NMR (DMSO-d6) δ 9.89 (s, 1H), 9.72 (s, 1H),
9.11 (s, 1H), 8.78 (s, 1H), 8.02 (d, J ) 7.5 Hz, 2H), 7.93 (d, J
) 9.3 Hz, 1H), 7.65 (d, J ) 8.7 Hz, 1H), 7.51 (t, J ) 7.5 Hz,
2H), 7.43 (t, J ) 7.2 Hz, 1H), 3.81 (br s, 4H), 3.64 (br s, 2H),
3.45 (br s, 2H); MS (CI) 307 (M + 1). Anal. (C18H18N4O‚2HCl‚
H2O) C, H, N, Cl.
3k . The crude residue obtained from the reaction between
dinitrile 3b and pyrrolidine hydrochloride was recrystallized
from aqueous acetone and subsequently converted to the
corresponding hydrochloride salt following the procedure as
1
described for 1k to give amidine 3k : 62%; H NMR (DMSO-
d6) δ 9.60 (br s, 1H), 9.34 (br s, 1H), 9.10 (br s, 1H), 9.08 (s,
1H), 8.91 (br s, 1H), 8.82 (s, 1H), 8.20 (d, J ) 8.1 Hz, 2H), 7.82
(d, J ) 9.6 Hz, 1H), 7.71 (d, J ) 8.1 Hz, 2H), 7.55 (d, J ) 9.6
Hz, 1H), 3.52 (m, 3H), 3.43 (t, J ) 6.6 Hz, 1H), 2.04 (m, 2H),
1.86 (m, 2H). Anal. (C23H26N6‚3HCl‚2H2O) C, H, N, Cl.
5k . The residue from the reaction between dinitrile 5b and
pyrrolidine hydrochloride was dissolved in water, basified (pH
> 12), and then extracted with CHCl3 (4 × 25 mL). The CHCl3
solution was washed with water followed by brine and dried
over MgSO4. Removal of solvent afforded crude amidine as
free base. A methanolic solution was heated with MeOH/HCl
at 0 °C for 30 min and at room temperature for 1 h. After
concentrating to dryness, the resulting residue was dried
under vacuum and recrystallized from absolute EtOH/acetone
containing HCl to furnish amidine 5k as a creamy solid: 60%;
1H NMR (D2O) δ 9.01 (s, 1H), 8.24 (s, 1H), 7.93 (m, 2H), 7.77
(d, J ) 8.0 Hz, 2H), 7.58 (d, J ) 8.0 Hz, 2H), 7.46 (d, J ) 17.1
N-Su b st it u t ed Am id in es (F u n ct ion a l Gr ou p s k -o).
Compounds 1l,m and 2k ,m were prepared following method
A. Compounds 1k , 3k , 5k , and 6k ,m ,n were prepared follow-
ing method D (compound 1k was also made by method A).
Compound 5o was prepared following method C.

Bis-Cationic Heteroaromatics as Macrofilaricides
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22 4325
Hz, 1H), 7.32 (d, J ) 17.1 Hz, 1H), 3.54 (m, 8H), 2.10 (m, 4H),
1.90 (m, 4H). Anal. (C25H28N6‚2.3HCl‚2.5H2O) C, H, N, Cl.
5o. The bis-imino ether HCl salt from 5b (450 mg, 1.66
mmol) was suspended in absolute EtOH (6 mL). Freshly
distilled isopropylamine (0.57 mL, 6.71 mmol) was added at 0
°C and stirred at room temperature for 24 h. After removal
of solvent, the residue was dried under vacuum. A methanolic
HCl (10 mL) solution of this residue was stirred at 0 °C for 30
min and at room temperature for 2 h. Removal of methanol
afforded a tan-colored solid which was recrystallized from
aqueous acetone in the presence of HCl to furnish amidine 5o
as a creamy solid: 500 mg, 58%; 1H NMR (D2O) δ 9.08 (s, 1H),
8.23 (s, 1H), 7.92 (m, 2H), 7.72 (d, J ) 8.5 Hz, 2H), 7.65 (d, J
) 8.5 Hz, 2H), 7.42 (d, J ) 16.48 Hz, 1H), 7.29 (d, J ) 16.48
Hz, 1H), 3.92 (sept, J ) 6.7 Hz, 2H), 1.28 (t, J ) 6.1 Hz, 12H).
Anal. (C23H28N6‚3HCl‚H2O) C, H, N, Cl.
6k . The crude solid isolated from the reaction of dinitrile
6a with pyrrolidine hydrochloride was recrystallized from
aqueous acetone to provide amidine (1.65 g) as a greenish solid
which was stirred with MeOH/HCl (30 mL) at 0 °C for 30 min
and at room temperature for 1 h. Evaporation of methanol
afforded a crude residue which was purified by recrystalliza-
tion from aqueous EtOH to give amidine 6k as a yellow solid:
1.4 g, 54%; 1H NMR (D2O) δ 8.41 (s, 1H), 8.11 (s, 1H), 7.77 (d,
J ) 9.3 Hz, 1H), 7.52 (m, 5H), 7.31 (d, J ) 16.1 Hz, 1H), 7.20
(d, 16.1 Hz, 1H), 6.63 (d, J ) 16 Hz, 1H), 6.50 (d, J ) 16.1 Hz,
1H), 3.60 (m, 4H), 3.32 (m, 4H), 1.97 (m, 8H). Anal. (C27H30N6‚
2.6HCl‚3.2H2O) C, H, N, Cl.
1r . To a suspension of imidate intermediate from 1d (3 g,
12.2 mmol) in absolute EtOH (20 mL) was added freshly
distilled ethylenediamine (1 mL, 15 mmol) at 0 °C. The
mixture was refluxed for 18 h. The residue obtained after
removing solvent was recrystallized from aqueous EtOH
containing HCl to give amidine 1r as a yellow solid: 2.8 g,
1
62%; H NMR (DMSO-d6) δ 8.51 (d, J ) 6.6 Hz, 1H), 8.20 (s,
1H), 7.77 (t, J ) 6.9 Hz, 1H), 7.67 (d, J ) 8.7 Hz, 1H), 7.46 (d,
J ) 8.4 Hz, 2H), 7.39 (d, J ) 8.4 Hz, 2H), 7.30 (t, J ) 6.9 Hz,
1H), 7.13 (d, J ) 16.8 Hz, 1H), 6.38 (d, J ) 16.8 Hz, 1H), 4.75
(s, 4H). Anal. (C18H16N4‚2HCl‚0.5H2O) C, H, N, Cl.
2p . The imidate ester hydrochloride from 2b (2.9 g, 13.3
mmol) was allowed to react with freshly distilled ethylenedi-
amine as described above for 1p to furnish amidine 2p as an
off-white solid: 2 g, 45%; 1H NMR (DMSO-d6) δ 11.19 (s, 1H),
9. 66 (s, 1H), 8.79 (s, 1H), 8.07 (d, J ) 7.2 Hz, 2H), 8.02 (s,
1H), 7.96 (d, J ) 8.7 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J ) 7.8 Hz,
2H), 7.42 (t, J ) 6.9 Hz, 1H), 3.99 (s, 4H); MS (CI) 263 (M +
1). Anal. (C16H14N4‚2HCl‚2H2O) C, H, N, Cl.
3p . The bis-imino ether intermediate from 3b (3 g, 12.2
mmol) was treated with ethylenediamine (3.3 mL, 50 mmol)
as described above for 1r . After removal of EtOH, crude
residue was recrystallized from aqueous acetone containing
1
HCl to provide amidine 3p as a creamy solid: 2.3 g, 40%; H
NMR (DMSO-d6) δ 11.05 (br s, 1H), 10.78 (br s, 1H), 9.60 (s,
1H), 8.85 (s, 1H), 8.28 (d, J ) 8.4 Hz, 2H), 8.11 (d, J ) 8.4 Hz,
2H), 7.84 (s, 2H), 3.98 (br s, 8H). Anal. (C19H18N6‚3HCl‚2H2O)
C, H, N, Cl.
6m . The crude residue from the reaction between dinitrile
6a and morpholine hydrochloride was first purified and then
converted to the corresponding hydrochloride salt following the
procedure as described for 6k to give amidine 6m as a yellow
5p . To a stirred suspension of crude bis-imino ether HCl
salt from 5b (450 mg, 1.66 mmol) in absolute EtOH (5 mL)
was added ethylenediamine (0.35 mL, 4.04 mmol) at 0 °C. The
clear red-colored reaction mixture was stirred at room tem-
perature for 30 min and then refluxed overnight. The yellow
precipitate was filtered and dried. The yellow solid was
suspended in water (5 mL) and basified (pH > 9) with 10%
NaOH. The precipitate was filtered, washed with water, and
dried in air to give amidine as a free base (400 mg). To the
stirred suspension of free base in MeOH (10 mL) was added
methanolic HCl at 0 °C. The resulting clear solution was
stirred at 0 °C for 15 min and at room temperature for 2 h. A
gray solid was precipitated out. On warming to 60 °C the
reaction mixture became clear. Stirring was continued at 60
°C for 1 h. Evaporation of methanol resulted in a light-
greenish yellow solid which was recrystallized from aqueous
EtOH containing HCl to provide amidine 5p as a brown solid:
1
solid: 50%; H NMR (DMSO-d6) δ 9.59 (br s, 1H), 9.45 (br s,
1H), 9.14 (br s, 1H), 9.03 (s, 1H), 8.83 (s, 1H), 8.14 (d, J )
8.55 Hz, 3H), 7.86 (m, containing a doublet at 7.88, J ) 8.54
Hz, 3H), 7.66 (t, J ) 16.48 Hz, 2H), 7.26 (t, J ) 16.48 Hz, 2H),
3.71 (s, 16H). Anal. (C27H31N6O2‚3HCl‚H2O) C, H, N, Cl.
6n . The crude yellow solid obtained by reacting dinitrile
6a with 1-methylpiperazine hydrochloride was stirred with
MeOH/HCl (15 mL) at 0 °C for 30 min and at room temper-
ature for 1 h. It was then evaporated to dryness under reduced
pressure to give a creamy solid which was purified by recrys-
tallization from aqueous EtOH to provide amidine 6n as a
brown solid: 52%; 1H NMR (DMSO-d6) δ 8.89 (s, 1H), 8.58 (s,
1H), 8.05 (d, J ) 9.15 Hz, 1H), 7.93 (d, J ) 8.54 Hz, 2H), 7.79
(m, 3H), 7.50 (2d, J ) 15 Hz, 2H), 7.05 (t, J ) 15 Hz, 2H),
4.20 (s, 16H), 2.79 (s, 6H). Anal. (C29H36N8‚5HCl‚3H2O) C,
H, N, Cl.
1
390 mg, 50%; H NMR (DMSO-d6) δ 10.97 (s, 2H), 10.71 (s,
2H), 9.57 (s, 1H), 8.31 (s, 1H), 8.03 (d, J ) 8 Hz, 2H), 7.84 (m,
containing a doublet at 7.86, J ) 8 Hz, 4H), 7.60 (m, 2H), 3.97
(d, J ) 4.9 Hz, 8H). Anal. (C21H20N6‚2.3HCl‚2H2O) C, H, N,
Cl.
Cyclic N,N′-Dia lk yla m id in es (F u n ction a l Gr ou p s p-r ).
Compounds 1p -r , 2p , and 3p were prepared following method
A. Compounds 5p and 6p were prepared following methods
B and C, respectively.
6p . To a stirred clear solution of imino ether HCl salt from
6b (0.51 g, 1.72 mmol) in absolute EtOH (4 mL) was added
ethylenediamine (0.5 mL, 7.47 mmol) at 0 °C. The mixture
was stirred at room temperature for 15 min and then under
reflux overnight. The yellow precipitate was filtered. The
solid was suspended in water (8 mL) and basified (pH > 11)
with 10% NaOH. The undissolved solid was filtered, washed
with water, and dried in air to provide free base amidine (400
mg). Methanolic HCl (10 mL) was added to the stirred
suspended free base in MeOH (10 mL) at 0 °C. The resulting
mixture was stirred at room temperature for 30 min and then
refluxed for 1 h (not all solid went in solution). After removal
of methanol, the crude residue was purified by recrystallizaton
from aqueous EtOH containing HCl to furnish amidine 6p as
1p . To a suspension of imidate intermediate from 1b (2.9
g, 13.3 mmol) in absolute EtOH (50 mL) was added freshly
distilled ethylenediamine (2.13 mL, 32 mmol) at 0 °C. The
mixture was stirred under reflux overnight. After being cooled
to room temperature, the reaction mixture was concentrated
to 1/5 volume and diluted with ether. The solid precipitate
was purified by several recrystallizations from aqueous ac-
etone. The final product was recrystallized from aqueous
EtOH containing HCl to provide amidine 1p as a white solid:
1
1.8 g, 40%; H NMR (DMSO-d6) δ 10.74 (s, 1H), 8.82 (s, 1H),
8.75 (d, J ) 6.6 Hz, 1H), 8.27 (d, J ) 8.4 Hz, 2H), 8.13 (d, J )
8.7 Hz, 2H), 7.82 (d, J ) 9.0 Hz, 1H), 7.68 (t, J ) 7.5 Hz, 1H),
7.26 (t, J ) 6.6 Hz, 1H), 3.99 (s, 4H); MS (CI) 263 (M + 1).
Anal. (C16H14N4‚2HCl‚2H2O) C, H, N, Cl.
1
a yellow solid: 425 mg, 50%; H NMR (DMSO-d6) δ 10.33 (s,
2H), 10.26 (s, 2H), 8.84 (s, 1H), 8.66 (s, 1H), 8.07 (d, J ) 8 Hz,
2H), 7.93 (d, J ) 16.48 Hz, 1H), 7.90 (d, J ) 16.48 Hz, 1H),
7.72 (m, 4H), 6.82 (d, J ) 16.48 Hz, 1H), 6.81 (d, J ) 16.48
Hz, 1H), 3.87 (s, 8H). Anal. (C23H22N6‚2.6HCl‚2H2O) C, H,
N, Cl.
1q. The imidate ester hydrochloride from 1b was treated
with freshly distilled 1,3-diaminopropane as outlined above
for 1p and provided amidine 1q as an off-white solid: 1.7 g,
1
37%; H NMR (DMSO-d6) δ 10.18 (s, 1H), 8.88 (s, 1H), 8.81
(d, J ) 6.6 Hz, 1H), 8.27 (d, J ) 8.4 Hz, 2H), 7.92 (d, J ) 8.4
Hz, 2H), 7.89 (d, J ) 8.7 Hz, 2H), 7.80 (t, J ) 7.2 Hz, 1H),
7.37 (t, J ) 6.3 Hz, 1H), 3.47 (br s, 4H), 1.95 (m, 2H); MS (CI)
277 (M + 1). Anal. (C17H16N4‚2HCl‚2H2O) C, H, N, Cl.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Su bsti-
tu ted Hyd r a zon es (F u n ction a l Gr ou p s s-w ). A stirred
mixture of the dialdehyde 3d (3.8 mmol) and hydrazine (8.17
mmol) in absolute ethanol (3 mL) was refluxed for 18 h.
A

4326 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22
Sundberg et al.
yellow solid precipitated from the solution during reflux. After
being cooled, the reaction mixture was acidified (pH < 2) with
concentrated HBr and stirred for 30 min. The undissolved
solid was filtered, dried, and recrystallized from aqueous
ethanol containing HBr to furnish hydrazones in 70-80%
yield.
3s: starting with 2-hydrazinopyrroline42 and following the
standard procedure; 83%; 1H NMR (DMSO-d6) δ 13.14 (s, 1H),
13.04 (s, 1H), 10.45 (s, 1H), 10.37 (s, 1H), 9.11 (s, 1H), 8.68 (s,
1H), 8.11 (m, containing a doublet at 8.10, J ) 8 Hz, 3H), 8.00
(d, J ) 8 Hz, 2H), 7.78 (d, J ) 8 Hz, 1H), 3.68 (m, 4H), 2.96
(m, 4H), 2.17 (m, 4H). Anal. (C23H24N8‚3HBr‚2H2O) C, H, N,
Br.
Ack n ow led gm en t. This research received financial
assistance from the WHO Onchocerciasis Control Pro-
gramme in West Africa and, at the University of
Georgia, from the UNFP World Band/WHO Special
Programme for Research and Training in Tropical
Disease (TDR) (ID 910332).
Refer en ces
(1) Sharma, S. Drugs for filariasis: Four decades of research. Adv.
Drug Res. 1993, 24, 119-260. Davies, J . B. Sixty years of
onchocerciasis vector control: A chronological summary with
comments on eradication, reinvasion and insecticide resistance.
Annu. Rev. Entomol. 1994, 39, 23-45.
(2) Abiose, A. O.; Awadzi, K.; Cupp, E. W.; Duke, B. O. L.; Gemade,
E. I. I.; Ottensen, E. A.; Petralanda, I.; Roungou, J . N.; Schulz-
key, M.; Weiss, N.; Baldry, D. A. T.; Dadzie, K. Y.; Ramachan-
dran, C. P.; Remme, J . M. F. WHO Report on Onchocerciasis
and Its Control; WHO: Geneva, Switzerland, 1995.
3t: 61%; 1H NMR (DMSO-d6) δ 9.15 (s, 1H), 8.75 (s, 1H),
8.39 (d, J ) 9.6 Hz, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.13 (m,
4H), 8.11 (s, 4H), 7.85 (d, J ) 9.6 Hz, 1H), 7.25 (t, J ) 7.8 Hz,
2H), 7.11 (m, 2H). Anal. (C25H20N6‚3HBr‚3H2O) C, H, N, Br.
1
3u : 83%; H NMR (DMSO-d6) δ 9.08 (s, 1H), 8.82 (s, 1H),
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1996, 52, 861-869. Plaisier, A. P.; Alley, E. S.; Boatin, B. A.;
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8.20 (d, J ) 9.6 Hz, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 8.02 (d, J
) 8.4 Hz, 2H), 7.96 (d, J ) 9.6 Hz, 1H), 7.88 (d, J ) 8.4 Hz,
2H), 7.31 (d, J ) 3.9 Hz, 1H), 7.29 (d, J ) 3.6 Hz, 1H), 6.96 (d,
J ) 3.9 Hz, 1H), 6.94 (d, J ) 3.6 Hz, 1H). Anal. (C21H16H8S‚
3HBr‚3H2O) C, H, N, S, Br.
1
3v: 76%; H NMR (DMSO-d6) δ 9.15 (s, 1H), 8.82 (s, 1H),
8.52 (s, 1H), 8.45 (s, 1H), 8.27 (d, J ) 9 Hz, 1H), 7.96 (m, 5H),
7.77 (d, J ) 8.7 Hz, 2H), 7.75 (d, J ) 8.7 Hz, 2H), 6.90 (d, J )
8.7 Hz, 2H), 6.85 (d, J ) 8.7 Hz, 2H). Anal. (C29H26N6O4‚
3HBr‚3H2O) C, H, N, Br.
3w : 80%; 1H NMR (DMSO-d6) δ 11.77 (s, 1H), 11.57 (s, 1H),
8.94 (s, 1H), 8.68 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.90 (m,
2H), 7.73 (m, 8H), 7.36 (m, 4H), 2.31 (s, 6H). Anal. (C29H26N6-
O4S2‚HBr‚4H2O)
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P r ep a r a tion of Dieth yl 2-Th ia zolin ylm eth ylp h osp h o-
n a te. A mixture of 2-aminoethanethiol hydrochloride (9.62
g, 84.68 mmol), diethyl cyanomethylphosphonate (15 g, 84.68
mmol), and K2CO3 (11.71 g, 84.68 mmol) in absolute ethanol
(125 mL) was refluxed for 6 h. The reaction mixture was
filtered. After removal of ethanol, crude phosphonate was
distilled under high vacuum to furnish 11.4 g as an oil: 52%;
1H NMR (DMSO-d6) δ 4.09 (t, J ) 8.4 Hz, 2H), 3.98 (q, J )
7.2 Hz, 4H), 3.27 (t, J ) 8.4 Hz, 2H), 3.12 (d, J ) 21.3 Hz,
2H), 1.18 (t, J ) 7.2 Hz, 6H).
Gen er a l P r oced u r e for th e P r ep a r a tion of Vin ylth i-
a zolin es (F u n ction a l Gr ou p x). To a stirred solution of
diethyl 2-thiazolinylmethylphosphonate22 (2.2 mmol) in THF
(20 mL) was added n-BuLi (2.5 M in hexane, 2.2 mmol) at 0
°C. The reaction mixture was stirred at room temperature
for 30 min. A solution of aldehyde 1c (1.8 mmol) in THF (15
mL) was added to the reaction mixture or lithium enolate
solution was added to a suspension of dialdehyde 3d (0.8
mmol) in THF (15 mL) by a cannula and stirred at room
temperature for 2 h. Saturated NH4Cl was added to the
reaction mixture, and the aqueous layer was extracted from
CHCl3. The combined organic layers were washed with water
and brine, dried over MgSO4, and then concentrated. The
crude product was purified by recrystallization from absolute
EtOH.
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1x. This compound was prepared following the general
procedure from the phosphonate (2.1 g, 8.87 mmol) and
1
compound 1c (1.64 g, 7.39 mmol) as a white solid: 76%; H
NMR (CHCl3) δ 8.11 (d, J ) 7.5 Hz, 1H), 7.96 (d, J ) 8.1 Hz,
2H), 7.89 (s, 1H), 7.62 (d, J ) 8.7 Hz, 1H), 7.56 (d, J ) 8.1 Hz,
2H), 7.19 (dt, J 1 ) 9 and J 2 ) 0.9 Hz, 1H), 7.11 (d, J ) 16.2
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Hz, 1H), 7.04 (d, J ) 16.2 Hz, 1H), 6.79 (dt, J 1 ) 6.6 and J 2
)
0.9 Hz, 1H), 4.38 (t, J ) 8.1 Hz, 2H), 3.34 (t, J ) 8.1 Hz, 2H).
3x. This compound was prepared following the general
procedure from the phosphonate (4.74 g, 20 mmol) and
1
compound 3d (2 g, 8 mmol) as a white solid: 80%; H NMR
(CHCl3) δ 8.19 (s, 1H), 7.95 (d, J ) 8.1 Hz, 2H), 7.88 (s, 1H),
7.62 (d, J ) 9.3 Hz, 1H), 7.56 (d, J ) 8.1 Hz, 2H), 7.41 (d, J )
9.6 Hz, 1H), 7.12 (d, J ) 16.2 Hz, 2H), 7.03 (d, J ) 16.2 Hz,
2H), 4.40 (t, J ) 8.1 Hz, 2H), 4.39 (t, J ) 8.1 Hz, 2H), 3.37 (t,
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