Synthesis and antiviral activity evaluation of some new aminoadamantane derivatives. 2

Article abstract of DOI:10.1021/jm950891z

The synthesis of some new aminoadamantane derivatives is described. The new compounds were evaluated against a wide range of viruses [influenza A H1N1, influenza A H2N2, influenza A H3N2, influenza B, parainfluenza 3, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), thymidine kinase- deficient (TK^-) HSV-1, vaccinia, vesicular stomatitis, polio 1, Coxsackie B4, Sindbis, Semliki forest, Reo 1, varicella-zoster virus (VZV), TK^- VZV, human cytomegalovirus (HCMV), and human immunodeficiency virus type 1 (HIV- 1) and type 2 (HIV-2)]. Some of them proved markedly active against the influenza A H2N2 (compounds 4a,b, 5a, 6a, and 7a), H3N2 (compounds 5a, 6a, and 7a), and H1N1 (compounds 4b,c and 6d). Since compounds 5a, 6a, and 7a, amantadine, and rimantadine showed the same comparative pattern of potency against influenza strains H2N2, H3N2, and B, it may postulated that they act according to a similar mechanism, with regard to their 'amine' effect, on the M2 ion channel of influenza A (H1N1, H2N2, or H3N2). In general, no significant activity was noted with any of the new compounds against any of the other viruses tested, making their activity against influenza virus more specific and striking. Borderline activity was noted with some of the compounds (4b,c, 5a-c, and 8a) against HIV-1.

Full text of DOI:10.1021/jm950891z

J . Med. Chem. 1996, 39, 3307-3318
3307
Syn th esis a n d An tivir a l Activity Eva lu a tion of Som e New Am in oa d a m a n ta n e
Der iva tives. 2
Nicolas Kolocouris,*,† Antonios Kolocouris,† George B. Foscolos,† George Fytas,† J ohan Neyts,‡
Elisabeth Padalko,‡ J an Balzarini,‡ Robert Snoeck,‡ Graciela Andrei,‡ and Erik De Clercq‡
Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens,
Panepistimioupoli-Zografou GR-15771, Athens, Greece, and Rega Institute for Medical Research,
Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Received December 6, 1995X
The synthesis of some new aminoadamantane derivatives is described. The new compounds
were evaluated against a wide range of viruses [influenza A H1N1, influenza A H2N2, influenza
A H3N2, influenza B, parainfluenza 3, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-
2), thymidine kinase-deficient (TK-) HSV-1, vaccinia, vesicular stomatitis, polio 1, Coxsackie
B4, Sindbis, Semliki forest, Reo 1, varicella-zoster virus (VZV), TK- VZV, human cytomegalo-
virus (HCMV), and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)]. Some
of them proved markedly active against the influenza A H2N2 (compounds 4a ,b, 5a , 6a , and
7a ), H3N2 (compounds 5a , 6a , and 7a ), and H1N1 (compounds 4b,c and 6d ). Since compounds
5a , 6a , and 7a , amantadine, and rimantadine showed the same comparative pattern of potency
against influenza strains H2N2, H3N2, and B, it may postulated that they act according to a
similar mechanism, with regard to their “amine” effect, on the M2 ion channel of influenza A
(H1N1, H2N2, or H3N2). In general, no significant activity was noted with any of the new
compounds against any of the other viruses tested, making their activity against influenza
virus more specific and striking. Borderline activity was noted with some of the compounds
(4b,c, 5a -c, and 8a ) against HIV-1.
In tr od u ction
the N-methyl derivative 1 (R ) CH3) which inhibited
influenza A virus-induced cytopathicity at a concentra-
tion of 0.56 µg/mL while not being toxic to the host cells
at a concentration as high as 400 µg/mL. Furthermore,
some spiro[pyrrolidine-3,2′-adamantane]s 3 showed po-
tent activity against influenza A virus, parainfluenza
virus (Sendai), rhinovirus, and Coxsackie A21 vi-
ruses.16,17
In regard to the potency of the N-methyl analogs 1
and 3 (R ) CH3), derivative 1 with the pyrrolidine
nitrogen closer to the adamantane spiro system is 200
times more active in vitro than its counterpart 3.
Furthermore, compound 1 exhibits selectivity against
influenza A virus.
Amantadine (1-adamantanamine) has been estab-
lished as effective in the prophylaxis and treatment of
influenza A virus infections.1-4 Although initially li-
censed in 1966, the clinical use of amantadine has been
limited by central nervous system (CNS) side effects.5,6
On the other hand, the structural analog of amantadine,
rimantadine (R-methyl-1-adamantanemethanamine), has
been reported to be more active against influenza A
virus in vitro in laboratory experiments, in animals, and
also in human beings. Rimantadine has been consid-
ered to possess fewer side effects and appears to be the
drug of choice for the chemoprophylaxis and therapy of
influenza A.4,7,8
As a continuation of our efforts to explore the stereo-
electronic requirements for optimal antiviral activity of
spiro adamantane derivatives, we now report on the
synthesis and biological evaluation of several new spiro-
[piperidine-2,2′-adamantane]s 4 and spiro[morpholine-
3,2′-adamantane]s 5 bearing a 6-membered heterocyclic
ring. In contrast with analogs 1, 4, and 5, the two nuclei
of the new molecules 6 are allowed to rotate freely with
respect to each other. It is also noteworthy that the
latter contain the rimantadine skeleton which is also
present in the amines 7. In addition, following the
observation that 1-(1-adamantyl)pyrrolidine showed
antiviral action18 and aiming at investigating some new
structure-antiviral activity relationships of this skel-
eton, we have synthesized the pyrrolidines 8 and 9.
It has recently been demonstrated that the target of
this selective, strain-specific antiviral activity is the
hydrophobic, membrane-spanning domain of the small
M2 protein and that the adamantanamines inhibit virus
replication by blocking the M2 protein ion channel
function and subsequently its ability to modulate the
pH of the intracellular compartment in virus-infected
cells. This may account for the lack of activity of
amantadine and rimantadine against influenza B virus,
which does not possess this protein.9-14
We have recently reported the synthesis and antiviral
evaluation of some aminoadamantane derivatives:15
spiro[pyrrolidine-2,2′-adamantane]s 1 and spiro[cyclo-
propane-1,2′-adamantan]-2-amines and methanamines
2 (Figure 1). The antiviral activity assays revealed that
some of them exhibited potent antiviral activity against
influenza A virus accompanied by low cytotoxicity.
Particularly striking was the potency and selectivity of
Ch em istr y
The synthetic route followed for the synthesis of the
spiro[piperidine-2,2′-adamanantane]s 4 is presented in
Scheme 1. The Michael condensation of 2-nitroada-
mantane anion (10) with acrylic ethyl ester afforded the
corresponding ethyl ester as a crude oil.15 This was
† University of Athens.
‡ Katholieke Universiteit Leuven.
X Abstract published in Advance ACS Abstracts, J uly 1, 1996.
S0022-2623(95)00891-0 CCC: $12.00 © 1996 American Chemical Society

3308 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17
Kolocouris et al.
F igu r e 1.
Sch em e 1a
a
Reagents: (a) CH2dCHCO2Et, Triton B, t-BuOH, 55 °C; (b) NaOH, EtOH-H2O, reflux; (c) gas HCl, MeOH, room temperature; (d)
NaBH4, dioxane-H2O (1:1), room temperature; (e) SOCl2, toluene, 90 °C; (f) KCN, 18-crown-6, acetonitrile, reflux; (g) gas HCl, CH3OH,
reflux, then H2O, reflux; (h) i. H2/Ni, EtOH, 50 °C, ii. EtOH, reflux; (i) LiAlH4, DME, reflux; (j) R′COCl, Et3N, ether, room temperature;
(k) LiAlH4, THF, reflux.
purified by saponification, and the intermediate car-
boxylic acid was then esterified to the methyl ester 11.
Selective reduction of the methyl ester 11 with NaBH4
in dioxane-water19 gave the 2-nitro-2-adamantane-
propanol (12). Attempts at the direct conversion of
alcohol 12 to nitrile 14 via known procedures which
have been shown to proceed by activation of the alcohol
function as the trimethylsilyl derivative20 or via the
corresponding trifluoroacetate21 failed to succeed. Thus,
the above nitro alcohol 12 was converted to its chloride
13 upon treatment with SOCl2 at 90 °C. The nitrile 14
was obtained from the reaction of 13 with KCN in

New Aminoadamantane Derivatives
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3309
Sch em e 2a
a
Reagents: (a) CH2O, NaOH, dioxane, reflux; (b) H2/Ni, EtOH, 50 °C; (c) BrCH2COCl, KOH, H2O, dichloromethane; (d) KOH, H2O,
dioxane, reflux; (e) LiAlH4, THF, reflux; (f) R′COCl, Et3N, ether, room temperature.
Sch em e 3a
a
Reagents: (a) 1-AdCOCl, THF, reflux; (b) CaO, ∆; (c) NaBH4, MeOH-AcOH (3:1), -30 °C; (d) CH2O, NaCNBH3, acetonitrile, room
temperature; (e) R′COCl, Et3N, ether, room temperature; (f) LiALH4, THF, reflux.
acetonitrile in the presence of 18-crown-6.22 Meth-
anolysis of the nitrile 14 and hydrogenation of the
intermediate nitro ester 15 over Raney nickel catalyst
afforded the spiro[piperidine-2,2′-adamantan]-6-one
(16) after δ-lactamization in boiling ethanol. Reduction
of the δ-lactam 16 with LiAlH4 in DME led to the parent
spiro[piperidine-2,2′-adamantane] 4a . N-Acylation of
the latter followed by reduction of the intermediate
amides 17a ,b gave the N-methyl (4b) and N-ethyl (4c)
derivatives.
The synthesis of the spiro[morpholine-3,2′-adaman-
tane]s 5 is illustrated in Scheme 2. Hydroxymethyl-
ation of the 2-nitroadamantane (10) afforded the 2-nitro-
2-adamantanemethanol (18). Catalytic reduction of the
nitro alcohol 18 resulted in the 2-amino-2-adaman-
tanemethanol (19), which was treated with bromoacetyl
chloride to give the N-bromoacetamide 20 along with
traces of the N,O-bis(bromoacetylated) product. The
bromoacetamide 20 was then cyclized in alkaline me-
dium to afford the spiro[morpholine-3,2′-adamantan]-
5-one (21), which was converted to the parent morpho-
line 5a by means of LiAlH4 reduction. The amines 5b,c
were prepared by reduction of the intermediate amides
22a ,b, respectively. N-Methylation of the morpholine
5a according to Borch and Hassid23 (NaCNBH3, CH2O,
CH3CN) or Charles et al.24 (NaBH4, CH2O, CH3OH)
afforded a mixture of the N-methyl derivatives 5b,a in
a 9:1 ratio.
The synthesis of 2-(1-adamantyl)pyrrolidines is shown
in Scheme 3. 1-(1-Adamantylcarbonyl)-2-pyrrolidinone
(24) was obtained from the reaction of 1-adamantane-
carbonyl chloride with 1-(trimethylsilyl)-2-pyrrolidinone
(23).25 Dry distillation of the N-acylpyrrolidinone 24 in
the presence of CaO26-28 led to the 2-(1-adamantanyl)-
1-pyrroline (25). Reduction of pyrroline 25 with NaBH4
resulted in the 2-(1-adamantanyl)pyrrolidine (6a ), which
was converted to the desired N-substituted derivatives
6b-d via suitable alkylations.
2-Pyrrolidinemethanamine 8a was synthesized as
illustrated in Scheme 4. The reaction of methyl pyro-
glutamate (27) with 1-bromoadamantane in the pres-
18
ence of Ag2SO4 gave the methyl ester 28, which was
saponified to the 1-(1-adamantyl)pyroglutamic acid (29).
Acid 29 was converted into the amide 30, which was
then reduced with LiAlH4 to the amine 8a .

3310 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17
Kolocouris et al.
Sch em e 4a
a
Reagents: (a) 1-BrAd, Ag2SO4, 100 °C; (b) NaOH, EtOH-H2O, room temperature; (c) i. SOCl2, 55 °C, ii. Me2NH, THF, room temperature;
(d) LiAlH4, THF, reflux.
Sch em e 5a
a
Reagents: (a) CH2dC(CO2H)CH2CO2H, 185 °C; (b) i. SOCl2, 65 °C, ii. Me2NH, THF, room temperature; (c) LiAlH4, THF, reflux.
Sch em e 6a
Sch em e 7a
a
Reagents: (a) 1-AdCOCl, Et3N, ether, room temperature; (b)
LiAlH4, THF, reflux.
Resu lts a n d Discu ssion
a
Reagents: (a) succinic anhydride, xylene, reflux; (b) i. SOCl2,
65 °C, ii. Me2NH, THF, room temperature; (c) LiAlH4, THF, reflux.
The aminoadamantane derivatives prepared were
evaluated according to previously reported methods34-39
against the following viruses: influenza A, influenza B,
parainfluenza 3, herpes simplex virus type 1 (HSV-1),
thymidine kinase-deficient (TK-) HSV-1, herpes simplex
virus type 2 (HSV-2), vaccinia, vesicular stomatitis, polio
1, Coxsackie B4, Sindbis, Semliki forest, Reo 1, varicella-
zoster virus (VZV), TK- VZV, human cytomegalovirus
(HCMV), and human immunodeficiency virus type 1
(HIV-1) and type 2 (HIV-2).
Michael condensation of 1-adamantanamine (31) with
itaconic acid29 gave the 1-(1-adamantyl)-5-oxo-3-pyrroli-
dinecarboxylic acid (32) (Scheme 5). The latter was
converted into the amide 33, which upon treatment with
LiAlH4 afforded the amine 8b.
The reaction of aldimine 34 with succinic anhydride30
in refluxing xylene gave a diastereomeric mixture of the
1
acids 35 and 36 (Scheme 6). Since the H NMR signals
The IC50 values obtained against influenza A for the
new compounds 4a -c, 5a , 6a ,d , and 7a were compa-
rable to and in some cases lower than those of the
reference compounds amantadine and rimantadine. In
general, these aminoadamantane derivatives did not
exhibit any significant activity against any of the other
viruses examined. This fact makes the activity of 4a -
c, 5a , 6a ,d , and 7a against influenza A virus even more
specific and striking.
Compounds 4b,c and 6d proved at least as active, if
not more active, than rimantadine and amantadine
against influenza A H1N1. In addition, compounds
4a ,b, 5a , 6a , and 7a were markedly active against
influenza A H2N2 virus, a strain with exquisite sensi-
tivity to amantadine and rimantadine. The same
compounds that were found active against influenza A
H2N2 virus, in particular compounds 5a , 6a , and 7a ,
were also active against influenza A H3N2 virus and
influenza B virus, albeit at higher concentrations. Also
of the methoxycarbonyl protons of this cis methyl ester
appear 0.5 ppm upfield with respect to the correspond-
ing protons of the trans isomer, it was possible to
estimate the relative yields of the diastereomeric acids
1
by integration of the H NMR spectra of the mixture of
the methyl esters which were obtained upon Me2SO4
treatment of the crude carboxylic acid product. The
ratio of the acids 35 to 36 was estimated to be 7(trans):
1(cis). Treatment of the diastereomeric mixture with
hot methanol led to the isolation of the acids 35 and 36
in pure form. Compounds 35 and 36 were in turn
converted into the amides 37 and 38 which were then
reduced with LiAlH4 to the pyrrolidines 8c,d .
The desired pyrrolidines 9a -d were prepared from
the corresponding carboxamides 43-46, upon reduction
with LiAlH4 (Scheme 7). The target compounds and
their intermediates were obtained in high yields, except
for pyrroline 25 which was afforded in 34% yield.

New Aminoadamantane Derivatives
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3311
Ta ble 1. Antiviral Activity and Cytotoxicity of Various Aminoadamantane Derivatives
virusa cellb MIC50c (µg/mL)
5c 6a
>10 15.8 >34
4a
4b
6.2
0.58
45
4c
4.4
31
5a
5b
6b
6c
6d
7a
7b
59
7c
influenza A, H1N1 MDCK
H2N2 MDCK
>35
29
1.7
22
4.3
>34
g14
58
4
>64
>80
19.7
0.24
43
60
>400
100
>200
>200
>200
>200
>400
>400
>400
>400
>400
>400
>400
>50
10.5
g57
g80
0.6
12.4
12
16.5
60
60
44.5
g100
g80
>100
>40
>40
>40
>40
>40
>100
>100
>100
>100
>100
>100
>100
>50
>20
>50
>40
>40
2.5
6
9
H3N2 MDCK
g65
g80
13
20
53
60
>60 >100
g80 >100
influenza B
parainfluenza 3
HSV-1
MDCK
Vero
HEF
HEF
HEF
HEF
HEF
HeLa
HeLa
HeLa
Vero
Vero
Vero
Vero
HEL
HEL
HEL
CEM
CEM
60
>400
>200
>200
>200
>200
>200
>400
>400
>400
>400
>400
>400
>400
>50
60
20
>400
>200
>200
>200
>200
>200
>400
>400
>400
>400
>400
>400
>400
>50
>400
>200
>200
>200
>200
>200
>400
>400
>400
>400
>400
>400
>400
>50
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>50
>400 >200
>400
>100
>100
>100
>100
>100
>400
>400
>400
>400
>400
>400
>400
>50
>400
>100
>100
>100
>100
>100
>400
>400
>400
>400
>400
>400
>400
>50
>10 >100 >400
>400
>400
>400
>400
>400
>400 >100
>400 >100
>400 >100
>400 >200
>400 >200
>400 >200
>400 >200
>40
>40
>40
>40
>40
>10
>10
>10
>10
>10
>40
>40
>40
>10
>10
>10
>10
>10
>40 >100
>40 >100
>40 >100
>40
>40
>40
>40
>40
TK- HSV-1
HSV-2
vaccinia
vesicular
stomatitis
polio 1
Coxsackie B4
>10 >100 >400
>10 >100 >400
>10 >100 >400
>10 >100 >400
>20
>20
>20
>8
Sindbis
Semliki forest
Reo 1
TK+ VZV
TK- VZV
HCMV
>50
>50
>50
>50
>50
>50
>40
>40
>20
>20
>20
>8
30
30
40
>40
>40
>50
>50
>40
>40
>50
>50
115
>200
>50
>50
>50
>50
>50
>50
>50
>50
>40
>40
>50
>50
>40
>40
HIV-1
HIV-2
200 158 ( 60 158 ( 60 158 ( 60
>200
>200
>200
>200
>8
>8
morphology
MDCK >250
>250
>400
100
>400
>50
>250
>400
100
>400
>50
>250
>400
>200
>400
>50
>250
>400
g400
>400
>50
>250
>400
>400
>400 g200
>50 >50
250
400
100
250
>400
200
>400
>50
250
>400
200
>400
>50
250
g200
100
200
>50
>250 >250 >250
>400 >400 >400
Vero
HEF
HeLa
HEL
>400
400
>400
>50
40
100 g100
>50 >50
40
100
200
>50
proliferation
viability
CEM 93 ( 5.7 >200
>200
>200
>200
>200 56 ( 12 120 115 ( 7.1 74 ( 9.2 18 ( 0.7
49 70 ( 8.5
8a
influenza A, H1N1 MDCK >70
8b
8c
8d
>34
9a
9b
9c
9d
amant rimant ribav
BVDU
ganciclovir
>36
16.1
>100
>100
>100
>10
>10
>10
>10
>10
>200
>200
>200
>100
>100
>100
>100
>20
>50
>20
g23
g40
>36
20.5 >100
g100
g60
>100
>10
>10
>10
>150
35
>150
>60
>47
>100
>100
>40
>40
>40
>40
>40
>100
>100
>100
>100
>100
>100
>100
32
>150
>100
>100
>100
>100
>40
>40
>40
>40
>40
>104
>100
>100
>100
>200
>100
>100
>100
>100
>100
>100
>100
>100
>200
>200
>200
>200
35
48
>28
19
-
-
-
-
-
-
-
-
H2N2 MDCK
H3N2 MDCK
MDCK
32.5
73
60
0.8 e0.14
48.7
5.6
2.4
>100
>100
>100
>10
>10
>10
g87
>100
>200
>40
>40
>40
>40
>40
100
>200
>200
>200
>200
>200
>200
>50
>50
>50
>40
>40
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
g12
g20
influenza B
parainfluenza 3
HSV-1
Vero
HEF
HEF
HEF
HEF
HEF
HeLa
HeLa
HeLa
Vero
Vero
Vero
Vero
HEL
HEL
HEL
CEM
CEM
>400
>200
>200
>200
>200
>200
>400
>400
>400
>400
>400
>400
>400
>50
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
150
>400
0.007
100
>200
0.7
>200
>400
>400
>400
>400
>400
>400
>400
-
>200
>200
>200
20
20
20
20
10
>400
>400
>400
70
>200
TK- HSV-1
HSV-2
0.02
0.002
>100
>100
vaccinia
>10
>10
>10
>10
vesicular
stomatitis
polio 1
>100
>100
>100
>100
>100
>100
>100
>20
>20
>5
>40
>40
>100
>100
>100
>100
>100
>100
>100
>20
>20
>20
>40
>40
100
-
-
-
-
-
-
-
-
>100
>100
>100
>100
>100
>100
30
20
>50
>20
>20
Coxsackie B4
Sindbis
Semliki forest
Reo 1
TK+ VZV
TK- VZV
HCMV
-
-
-
0.0037
15
-
>50
>50
115
>200
20
20
>50
>40
>40
-
>50
>40
>40
0.7
HIV-1
HIV-2
morphology
MDCK >250
250
>400
40
400
>50
250
>400
40
200
>50
250
400
40
200
>50
>250
>400
100
g400
>50
>250
>400
100
200
>50
>250
g200
100
200
>50
>250
400
200
200
>50
>250
250
>250
>400
400
g400
-
-
>400
400
>400
>200
-
-
-
Vero
HEF
HeLa
HEL
CEM
>400
g400
>400
>50
-
-
-
-
-
-
-
-
-
-
>100
-
-
-
proliferation
viability
>200
79 ( 8.5 79 ( 7.8 82 ( 26 99 ( 0.7 59 ( 3.5 33 ( 0.7 72 ( 4.2
-
a
Abbreviations and virus strains: amant, amantadine; rimant, rimantadine; ribav, ribavirin; influenza A H1N1 (A/Taiwan/1/86);
influenza A H2N2 (A2/J apan/305/57); influenza A H3N2 (X31); influenza B (Hong Kong/5/72); RSV, respiratory syncytial virus (Long);
HSV-1, herpes simplex virus type 1 (KOS); TK- HSV-1, thymidine kinase-deficient HSV-1 (B2006); HSV-2, herpes simplex virus type 2
(G); VZV, varicella-zoster virus; TK+ VZV, thymidine kinase-deficient VZV (YS); TK- VZV, thymidine kinase-deficient VZV (YS/R); HCMV,
human cytomegalovirus (AD-169); HIV-1, human immunodeficiency virus type 1 (IIIB/LAl); HIV-2, human immunodeficiency virus type
b
2 (ROD). Abbreviations: MDCK, Madin-Darby canine kidney; HEF, human embryonic fibroblasts [either embryonic lung (for cell
proliferation studies and antiviral studies) or embryonic skin-muscle (for cell morphology studies and antiviral studies)]. Vero, HeLa,
HEL, and MT-4 represent African green monkey kidney cells, human epithelial cells, human embryonic lung cells, and human
T-lymphocytes, respectively. c Minimum inhibitory concentration required to reduce virus-induced cytopathicity by 50%, to cause a
microscopically detectable alteration of normal cell morphology, or to reduce cell proliferation or cell viability by 50%. All data represent
average values for at least two separate experiments.
rimantadine was less active against influenza A H3N2
virus and influenza B virus than against influenza A
H2N2 virus. Based on their comparative pattern of
potency against the three influenza virus strains (H2N2,
H3N2, and B), it may be postulated that compounds 5a ,
6a , and 7a act according to a similar mechanism as
amantadine and rimantadine. Rimantadine, like aman-
tadine, is assumed to block influenza A virus replication

3312 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17
Kolocouris et al.
mmol) in EtOH/H2O (10 ml/3 mL). The mixture was heated
to 50 °C for 2 h. After removal of the solvent, water was added
and the mixture was extracted with ether. The organic phase
was washed with water and brine and dried (Na2SO4).
Concentration in vacuo afforded the nitro alcohol 12 (310 mg,
87%): mp 93 °C (Et2O-pentane); IR (Nujol) ν(NO2) 1536,
by blocking the ion channel of the small virus membrane
protein M2.9-14
It is also noteworthy that analogs 4b,c, 5a -c, and
8a exhibited borderline anti-HIV-1 activity. Further-
more, these compounds were not active against HIV-2.
It should also be pointed out that the anti-HIV-1 activity
is exhibited only by the spiro 6-membered analogs 4 and
5 but not by the spiro 5-membered analogs 1.15 These
aminoadamantane derivatives may merit further study
as potential leads for the development of new anti-HIV-1
agents.
In conclusion, it seems that the presence of 5- or
6-membered amino heterocycles and adamantane in one
frame greatly enhances the antiviral activity against
influenza A virus. This effect becomes more pronounced
when the nitrogen atom is closer to the adamantane
moiety.
Also the size of the amino heterocycle seems to be
critical for antiviral activity. In particular the antiviral
activity and specificity against influenza A virus is
enhanced in the 5-membered spiro analog 1 relative to
the 6-membered analogs 4 and 5. Furthermore, it
appears that the size of the N-alkyl group contributes
in a different manner to the activity of the compounds
against the different influenza A strains.
ν(OH) 3270 cm-1 1H NMR (CDCl3, 200 MHz) δ 1.20-2.10
;
(complex m, 17H, 4,5,6,7,8,9,10-H, CH2CH2CH2OH), 2.53 (s,
2H, 1,3-H), 3.60 (t, 2H, J ∼ 6 Hz, CH2CH2OH). Anal. (C13H21
-
NO3) C, H, N.
2-(3-Ch lor opr opyl)-2-n itr otr icyclo[3.3.1.13,7]decan e (13).
A mixture of the alcohol 12 (300 mg, 1.26 mmol), toluene (4
mL), and SOCl2 (930 mg, 8 mmol) was heated at 95 °C for 45
min. After removal of the solvent, ether was added and the
organic solution was washed with water, NaHCO3 (10%), and
then water. The ether extracts were dried (Na2SO4), and the
solvent was removed under reduced pressure. The residue was
chromatographed on neutral aluminum oxide (100-125 mesh)
with ether-hexane (1:1) as the eluent to give chloride 13 (310
mg, 96%): mp 58 °C (n-pentane); 1H NMR (CDCl3, 200 MHz)
δ 1.56-2.01 (complex m, 14H, 4,5,6,7,8,9,10-H, CH2CH2CH2-
Cl), 2.04-2.16 (complex m, 2H, CH2CH2CH2Cl), 2.53 (s, 2H,
1,3-H), 3.48 (t, 2H, J ∼ 6 Hz, CH2CH2Cl). Anal. (C13H20
-
ClNO2) C, H, N.
2-Nitr o-2-tr icyclo[3.3.1.13,7]d eca n ebu ta n en itr ile (14).
To a solution of the chloride 13 (240 mg, 0.93 mmol) and 18-
crown-6 (100 mg, 0.38 mmol) in dry acetonitrile (5 mL) was
added anhydrous KCN (182 mg, 2.79 mmol) at room temper-
ature. The mixture was then refluxed with vigorous stirring
for 2 h. After evaporation of the solvent, water was added
and the mixture was extracted with ether. The ether layer
was washed with water and brine and dried (Na2SO4).
Evaporation of the solvent afforded the nitrile 14 (228 mg,
99%): mp 117 °C (n-pentane); IR (Nujol) ν(NO2) 1527, ν(CN)
Exp er im en ta l Section
Melting points were determined using a Buchi capillary
apparatus and are uncorrected. IR spectra were recorded on
a Perkin-Elmer 833 spectrometer. 1H NMR spectra were
recorded on Bruker AC200 and AC300 spectrometers at 200
and 300 MHz, respectively, using CDCl3 as solvent and TMS
as internal standard. 13C NMR spectra were recorded on a
Brucker AC200 spectrometer at 50 MHz using CDCl3 as
solvent and TMS as internal standard. Carbon multiplicities
were established by DEPT experiments. The 2D NMR tech-
niques (XHCORR and COSY) were used for the elucidation of
the structures of some derivatives.
Microanalyses were carried out by the Service Central de
Microanalyse (CNRS), France, and the results obtained had a
maximum deviation of (0.4% from the theoretical value.
2-Nitroadamantane (10) was prepared from the oxime of
2-adamantanone.15 1-(Trimethylsilyl)-2-pyrrolidinone (23) was
prepared in 85.5% yield from the reaction of 2-pyrrolidinone
with Me3SiCl in the presence of Et3N in refluxing toluene:25
bp 102-104 °C (25 mmHg). The crystallization of hydrochlo-
rides 5b,c and 6d proved to be tedious and required totally
anhydrous conditions. Aldimine (34) and methyl pyro-
glutamate (27) were prepared using known procedures.18,25 The
pyrrolidines 39-41 were synthesized by reducing the corre-
sponding lactams with LiAlH4.31,32 The pyrrolidine 42 was
prepared upon reduction of 2-tert-butyl-1-pyrroline28 with
NaBH4. The synthesis of (1-adamantyl)-1-cyclopentanamines
7 has previously been reported.33
1
2244 cm-1; H NMR (CDCl3, 200 MHz) δ 1.45-1.63 (complex
m, 2H, CH2CH2CH2CN), 1.66-2.23 (m, 12H, 4,5,6,7,8,9,10-H),
2.01-2.23 (m, 2H, CH2CH2CH2CN), 2.33 (t, 2H, J ∼ 7 Hz,
CH2CH2CN), 2.53 (s, 2H, 1,3-H). Anal. (C14H20N2O2) C, H,
N.
Met h yl 2-Nit r o-2-t r icyclo[3.3.1.13,7]d eca n eb u t a n oa t e
(15). A solution of the nitrile 14 (220 mg, 0.89 mmol) in dry
MeOH (2.5 mL) was treated with a saturated methanolic
solution of gaseous HCl (5 mL). The resulting mixture was
refluxed for 90 min. A drop of water was added, and refluxing
was continued for 30 min. After evaporation of the solvent,
water was added, and the mixture was extracted with ether.
The ether layer was washed with NaHCO3 (10%), water, and
brine, dried (Na2SO4), and evaporated to give the methyl ester
15 (229 mg, 92%): mp 54 °C (n-pentane); IR (Nujol) ν(CdO)
1
1734, ν(NO2) 1533 cm-1; H NMR (CDCl3, 200 MHz) δ 1.38-
1.60 (complex m, 2H, CH2CH2CH2CO), 1.61-2.10 (m, 14H,
4,5,6,7,8,9,10-H, CH2CH2CH2CO), 2.26 (t, 2H, J ∼ 7 Hz,
CH2CH2CO), 2.53 (s, 2H, 1,3-H), 3.64 (s, 3H, CH3).
Spir o[piper idin e-2,2′-tr icyclo[3.3.1.13,7]decan ]-6-on e (16).
A solution of the nitro ester 15 (440 mg, 1.56 mmol) in ethanol
(20 mL) was hydrogenated in the presence of Raney nickel
catalyst under a pressure of 45 psi, at 50 °C, for 8 h. The
suspension was filtered to remove the catalyst, and the filtrate
was refluxed for 5 h. The solvent was evaporated, and the
residue was chromatographed on neutral alumina (100-125
mesh) with 1:1 chloroform-n-hexane as the eluent to afford
the δ-lactam 16 (334 mg, 97.4%): mp 165-166 °C (n-pentane);
Meth yl 2-Nitr o-2-tr icyclo[3.3.1.13,7]d eca n ep r op a n oa te
(11). 2-Nitro-2-adamantanepropanoic acid15 (8.1 g, 32 mmol)
was esterified in a methanolic solution of gaseous HCl to give
the methyl ester 11 as an oil which was crystallized on
cooling: yield 8.25 g (97%); mp 61 °C (n-pentane); IR (Nujol)
IR (Nujol) ν(NH) 3290, 3250, ν(CdO) 1653 cm-1 1H NMR
;
(CDCl3, 200 MHz) δ 1.49-2.13 (m, 18H, adamantane H, 3,4-
H), 2.28 (t, 2H, J ∼ 7 Hz, 5-H), 6.39 (br s, 1H, 1-H); 13C NMR
(CDCl3, 50 MHz) δ 16.2 (4-C), 26.6 (7′-C), 27.0 (5′-C), 30.4 (3-
C), 30.8 (5-C), 32.1 (4′-C, 9′-C), 33.6 (8′-C, 10′-C), 37.0 (1′-C,
3′-C), 38.4 (6′-C), 57.8 (2,2′-C), 172.1 (6-C). Anal. (C14H21NO)
C, H, N.
1
ν(CdO) 1735, ν(NO2) 1530 cm-1; H NMR (CDCl3, 200 MHz)
δ 1.56-2.05 (m, 12H, 4,5,6,7,8,9,10-H), 2.10-2.40 (m, 4H,
CH2CH2CO), 2.51 (s, 2H, 1,3-H), 3.63 (s, 3H, CH3).
2-Nitr o-2-tr icyclo[3.3.1.13,7]d eca n ep r op a n ol (12). To a
stirred suspension of the nitro ester 11 (410 mg, 1.54 mmol)
in dioxane-H2O (1:1, 10 mL) was added NaBH4 (580 mg, 15.4
mmol) in small portions, and stirring was continued for 22 h,
at room temperature. The mixture was acidified with HCl
(18%) under ice cooling and extracted with ether. The
combined ether extracts were washed with water and brine.
The solvent was removed under reduced pressure, and the
residue was treated with a solution of NaOH (62 mg, 1.54
Spir o[piper idin e-2,2′-tr icyclo[3.3.1.13,7]decan e] (4a). To
a stirred suspension of LiAlH4 (443 mg, 11.7 mmol) in dry
DME (20 mL) was added dropwise a solution of the lactam 16
(320 mg, 1.46 mmol) in dry DME (10 mL). The reaction
mixture was refluxed for 36 h and then hydrolyzed with water
and NaOH (10%) under ice cooling. The inorganic precipitate
was filtered off and washed with DME, and the filtrate was

New Aminoadamantane Derivatives
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3313
concentrated in vacuo. The residue was dissolved in ether and
extracted with HCl (5%). The aqueous layer was made
alkaline with solid Na2CO3 and extracted with ether. The
combined ether extracts were washed with water and brine
and dried (Na2SO4). After evaporation of the solvent, the
residue was chromatographed on neutral aluminum oxide
(100-125 mesh) with 1:1 ether-hexane as an eluent to give
the piperidine 4a (256 mg, 85.4%): mp 34 °C (n-pentane); IR
ethanol (10 mL). After refluxing for 4 h, the solvent was
removed and water was added. The mixture was extracted
with ether, and the ether layer was washed with water and
dried (Na2SO4). The solvent was evaporated almost to dryness,
petroleum ether was added, and the mixture was cooled to -15
°C for several hours until the product crystallized out. Filtra-
tion of the mixture afforded the nitro alcohol 15 as needles
which were washed with cold pentane. The filtrate was
chromatographed on silica gel (70-230 mesh) with ether-
hexane (2:1) as the eluent to give an additional amount of the
compound 18: yield 1.4 g (60%); mp 196 °C (Et2O-n-pentane);
1
(film) ν(NH) 3295 cm-1; H NMR (CDCl3, 300 MHz) δ 1.11-
2.02 (complex m, 21H, adamantane H, 1,3,4,5-H), 2.73 (t, 2H,
J ∼ 5 Hz, 6-H); 13C NMR (CDCl3, 50 MHz) δ 19.8 (4-C), 26.6
(5-C), 27.5 (7′-C), 28.0 (5′-C), 32.0 (4′-C, 9′-C), 33.2 (3-C), 33.3
(8′-C, 10′-C), 33.9 (1′-C, 3′-C), 38.9 (6′-C), 39.8 (6-C), 54.2 (2,2′-
C). Hydrochloride: mp >260 °C (EtOH-Et2O). Picrate: mp
>260 °C (MeOH-Et2O). Anal. (C20H26N4O7) C, H.
IR (Nujol) ν(OH) 3180, ν(NO2) 1536 cm-1 1H NMR (CDCl3,
;
200 MHz) δ 1.52-1.97 (m, 13H, 4,5,6,7,8,9,10-H, OH), 2.67
(s, 2H, 1,3-H), 3.98 (s, 2H, CH2O). Anal. (C11H17NO3) C, H,
N.
1-(E t h o x y c a r b o n y l)s p ir o [p ip e r id in e -2,2′-t r ic y c lo -
[3.3.1.13,7]d eca n e] (17a ). Ethyl chloroformate (390 mg, 3.61
mmol) in dry ether (10 mL) was added dropwise under ice
cooling to a stirred solution of the piperidine 4a (370 mg, 1.8
mmol) and triethylamine (640 mg, 6.30 mmol) in dry ether
(10 mL). The mixture was stirred at room temperature for
25 h. The precipitated triethylamine hydrochloride was
filtered off, and the filtrate was washed with water, cold HCl
(2%), water, and dried (Na2SO4). The solvent was evaporated,
and the residue was filtered through neutral alumina (100-
125 mesh) with ether as the eluent. After removal of the
solvent, the carbamate 17a (IR film ν(CdO) 1695 cm-1) was
obtained as an oil (320 mg, 64%) which was used without
further purification for the preparation of the derivative 4b.
1-Me t h y ls p ir o [p ip e r id in e -2,2′-t r ic y c lo [3.3.1.13 ,7 ]-
d eca n e] (4b). A solution of the carbamate 17a (320 mg, 1.22
mmol) in dry THF (10 mL) was added to a stirred suspension
of LiAlH4 (250 mg, 6.59 mmol) in dry THF (30 mL). The
reaction mixture was refluxed for 25 h and then hydrolyzed
with water and NaOH (10%) under ice cooling. The inorganic
precipitate was filtered off, and the filtrate was evaporated
under vacuum. The residue was chromatographed on neutral
aluminum oxide (100-125 mesh) with 1:4 AcOCH3-hexane
as the eluent to afford the piperidine 4b (200 mg, 80%): mp
55 °C; 1H NMR (CDCl3, 200 MHz) δ 0.98-2.02 (m, 15H,
3′,5′,6′,7′,8′,10′-H, 3,4,5-H), 1.38 (br d, 2H, J ∼ 12 Hz, 4′,9′-
H), 2.04-2.73, (br m, 4H, 1′-H 4′,9′-H, 6-H), 2.32 (s, 3H, CH3),
3.16 (∼t, 1H, J ∼ 12 Hz, 6-H); 13C NMR (CDCl3, 50 MHz) δ
18.4 (5-C), 19.7 (4-C), 22.4 (3-C), 27.3 (7′-C), 27.7 (5′-C), 29.1
(1′-C), 31.7 (4′-C), 32.0 (9′-C), 33.2 (8′-C, 10′-C), 34.0 (CH3),
35.1 (3′-C), 38.9 (6′-C), 47.6 (6-C), 57.9 (2,2′-C). Hydrochlo-
ride: mp 242 °C dec (EtOH-Et2O). Picrate: mp 236 °C
(MeOH-Et2O). Anal. (C21H28N4O7) C, H, N.
2-Am in o-2-tr icyclo[3.3.1.13,7]d eca n em eth a n ol (19). Ni-
tro alcohol 18 (3 g, 14.2 mmol) in ethanol (30 mL) was
hydrogenated in the presence of Raney nickel catalyst under
a pressure of 45 psi, at 50 °C, for 5 h. Filtration and removal
of the solvent under reduced pressure gave the amino alcohol
19 (2.52 g, 99%): mp 214 °C (Et2O-n-pentane); IR (Nujol)
ν(NH) 3376, 3317, ν(OH) 3100 cm-1 1H NMR (CDCl3, 200
;
MHz) δ 1.42-2.21 (m, 16H, adamantane H, NH2), 3.55 (s, 2H,
CH2O), 3.83 (br s, 1H, OH). Anal. (C11H19NO) C, H, N.
2 -B r o m a c e t a m i d o -2 -t r i c y c l o [3 .3 .1 .1 3 , 7 ]d e c a n e -
m eth a n ol (20). A solution of KOH (1.68 g, 30 mmol) in water
(50 mL) was added to a solution of the amino alcohol 19 (2.55
g, 14.1 mmol) in dichloromethane (150 mL). Bromacetyl
chloride (2.42 g, 15.4 mmol) in dichloromethane (50 mL) was
then added under ice cooling and vigorous stirring. Stirring
was continued for 2 h under cooling, and the aqueous layer
was decanted. The organic phase was washed with water, HCl
(3%), and water and dried (Na2SO4). The solvent was removed
under reduced pressure to afford 4.15 g (98%) of the brom-
acetamide 20. The IR spectrum of this derivative showed a
strong peak at 1660 cm-1 (CdO amide) and a very weak peak
at 1738 cm-1 (CdO ester). This compound was used without
further purification for the preparation of the morpholinone
21: mp 163 °C (Et2O); IR (Nujol) ν(NH), ν(OH) 3373, 3284,
ν(CdO) 1660 cm-1 1H NMR (CDCl3, 200 MHz) δ 1.49 (2H,
;
dd, J ∼ 12, 1.1 Hz, 4,9-H), 1.53-2.10 (m, 11H, 5,6,7,8,10-H,
4,9-H, OH), 2.23 (s, 2H, 1,3-H), 3.90 (s, 2H, CH2Br), 3.98 (s,
2H, CH2O), 6.66 (br s, 1H, NH).
Sp ir o[m or p h olin e-3,2′-t r icyclo[3.3.1.13,7]d eca n ]-5-on e
(21). A solution of KOH (6 g, 107 mmol) in water (8 mL) was
added to a solution of the bromacetamide 20 (3 g, 9.9 mmol)
in dioxane (50 mL). The resulting mixture was heated at
reflux for 2 h. After evaporation of the solvent, water was
added and the precipitated morpholinone 18 was filtered off,
washed with water, and dried: yield 3.08 g (98% from the
amino alcohol 19); mp 214-215 °C (MeOH-Et2O); IR (Nujol)
1-Ac e t y ls p i r o [p i p e r i d i n e -2,2′-t r i c y c lo [3.3.1.13 ,7 ]-
d eca n e] (17b). Compound 17b was prepared by the proce-
dure followed for 17a , by the reaction of acetyl chloride with
the piperidine 4a in the presence of triethylamine: yield
85.4%; mp 129 °C (Et2O-n-pentane); IR (Nujol) ν(CdO) 1645
1
ν(NH) 3458, 3262, ν(CdO) 1644 cm-1; H NMR (CDCl3, 300
MHz) δ 1.60-1.98 (m, 14H, adamantane H), 3.85 (s, 2H, 2-H),
4.13 (s, 2H, 6-H), 6.64 (br s, 1H, NH); 13C NMR (CDCl3, 50
MHz) δ 26.6 (7′-C), 27.0 (5′-C), 31.8 (4′,9′-C), 33.7 (8′,10′-C),
34.4 (1′,3′-C), 38.1 (6′-C), 57.7 (3,2′-C), 67.5 (2-C), 70.0 (6-C),
168.9 (5-C). Anal. (C13H19NO2) C, H, N.
cm-1 1H NMR (CDCl3, 200 MHz) δ 1.15-2.23 (m, 18H,
;
3′,4′,5′,6′,7′,8′,9′,10′-H, 3,4,5-H), 2.11 (s, 3H, CH3), 2.44 (br s,
1H, 1′-H), 3.27-3.53 (m, 2H, 6-H). Anal. (C16H25NO) C, H,
N.
1-E t h y ls p i r o [p i p e r i d i n e -2,2′-t r i c y c lo [3.3.1.13 ,7 ]-
d eca n e] (4c). Compound 4c was prepared upon reduction of
the amide 17b with LiAlH4 by the procedure followed for the
synthesis of 4b. The crude oily product was chromatographed
on neutral aluminum oxide (100-125 mesh) with AcOCH3-
hexane (1:10) as the eluent: yield 77%; 1H NMR (CDCl3, 200
MHz) δ 0.95-1.96 (m, 16H, 3′,5′,6′,7′,8′,10′-H, 3,4,5-H), 1.01
(t, 3H, A3X2, J AX ∼ 7 Hz, CH3CH2), 1.30 (br d, 2H, J ∼ 12 Hz,
4′,9′-H), 2.0-2.93 (br m, 5H, 1′-H 4′,9′-H, 6-H), 2.53 (q, 2H,
A3X2, J AX ∼ 7 Hz, CH3CH2); 13C NMR (CDCl3, 50 MHz) δ 14.3
(CH3), 17.5 (5-C), 19.5 (4-C), 24.5 (3-C), 27.4 (7′-C), 27.9 (5′-
C), 29.2 (1′-C), 31.6 (4′-C, 9′-C), 33.0 (10′-C), 33.5 (8′-C), 35.2
(CH2N, 3′-C), 38.8 (6′-C), 39.3 (6-C), 58.3 (2,2′-C). Hydrochlo-
ride: mp 209 °C dec (EtOH-Et2O). Picrate: mp 176 °C
(MeOH-Et2O). Anal. (C22H30N4O7) C, H.
Sp ir o[m or p h olin e-3,2′-tr icyclo[3.3.1.13,7]d eca n e (5a ). A
solution of the morpholinone 21 (1.21 g, 5.48 mmol) in dry THF
(30 mL) was added to a stirred suspension of LiAlH4 (1.8 g,
47.5 mmol) in dry THF (60 mL). The reaction mixture was
refluxed for 25 h and then hydrolyzed with water and NaOH
(10%) under ice cooling. The inorganic precipitate was filtered
off and washed with THF, and the filtrate was evaporated
under vacuum. The residue was dissolved in ether and
extracted with HCl (5%). The aqueous layer was washed with
ether, made alkaline with solid Na2CO3, and extracted with
ether. The ether phase was washed with water and brine,
dried (Na2CO3), and evaporated under vacuum to give 1.12 g
(98%) of the morpholine 5a as an oil: 1H NMR (CDCl3, 300
MHz) δ 1.51 (d, 2H, J ∼ 13 Hz, 4′,9′-H), 1.57-1.94 (m, 11H,
1′,3′,5′,6′,7′,8′,10′-H, NH), 2.0 (d, 2H, J ∼ 13 Hz, 4′,9′-H), 2.84
(t, 2H, A2X2, A part of the system, J AX ) 4.9 Hz, 5-H), 3.60 (t,
2H, X part of the system, A2X2, J AX ) 4.9 Hz, 6-H), 3.70 (s,
2H, 2-H); 13C NMR (CDCl3, 50 MHz) δ 27.5 (7′-C), 27.8 (5′-C),
31.7 (4′-C, 9′-C), 31.8 (1′-C, 3′-C), 33.2 (8′-C, 10′-C), 38.6 (6′-
2-Nitr o-2-tr icyclo[3.3.1.13,7]d eca n em eth a n ol (18). To a
solution of 2-nitroadamantane (10) (1.85 g, 10.3 mmol) in
dioxane (5 mL) were added an aqueous 37% formaldehyde
solution (1.85 mL) and NaOH (60 mg, 1.5 mmol) in 95%

3314 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17
Kolocouris et al.
C), 39.9 (5-C), 53.7 (3,2′-C), 68.0 (6-C), 73.7 (2-C). Hydrochlo-
ride: mp >280 °C (EtOH-Et2O). Picrate: mp 273-274 °C
(MeOH). Anal. (C19H24N4O8) C, H, N.
H, 4-H), 2.53 (t, 2H, J ) 8.0 Hz, 3-H), 3.77 (t, 2H, J ) 7.6 Hz,
5-H). Anal. (C15H21NO2) C, H, N.
2-(1-Tr icyclo[3.3.1.13,7]d ecyl)-1-p yr r olin e (25). The N-
acyl lactam 24 (6 g, 24.3 mmol) was mixed thoroughly with
an equal weight of calcium oxide, and the mixture was placed
in a Pyrex tube fitted with a small vigreux column. The
mixture was gently heated with a flame until a melt was
formed and a vigorous reaction was observed. Reduced
pressure (25 mmHg) was then applied, and the heat was
continued until the crude product distilled off (above 150 °C).
The product was dissolved in ether and extracted with HCl
(5%). The aqueous phase was made alkaline with solid Na2-
CO3 and extracted with ether. The combined ether extracts
were washed with brine, dried (Na2SO4), and evaporated. The
residue was chromatographed on neutral aluminum oxide
(100-125 mesh) with ether-hexane (1:1) as the eluent to give
the oily pyrroline 25 (1.7 g, 34.5%): IR (film) ν(CdN) 1632
4-(E t h oxyca r b on yl)sp ir o[m or p h olin e -3,2′-t r icyclo-
[3.3.1.13,7]d eca n e] (22a ). The oily carbamate 22a was pre-
pared in 64% yield using the procedure for the preparation of
17a , by the reaction of ethyl chloroformate with the morpholine
5a in the presence of triethylamine, and used without further
purification for the preparation of compound 5b: IR (film)
ν(CdO) 1690 cm-1
.
4-Me t h y ls p ir o [m o r p h o lin e -3,2′-t r ic y c lo [3.3.1.13,7]-
d eca n e] (5b). Meth od A: Using morpholine 5a (300 mg,
1.45 mmol) as starting material and following the procedure
of Borch and Hassid23 or Charles et al.,24 ∼290 mg of an oily
product was afforded which was a mixture of the N-methyl
derivative 5b and the starting material 5a in a 9:1 ratio. The
nonmethylated morpholine 5a was removed by the following
procedure: To a stirred solution of the above mixture and
triethylamine (293 mg, 2.9 mmol) in dry ether (5 mL) was
added a solution of ethyl chloroformate (157 mg, 1.45 mmol)
in dry ether (10 mL), and the mixture was stirred at room
temperature for 24 h. Then water was added, and the mixture
was extracted with ether. The combined ether extracts were
washed with water and extracted with cold HCl (2%). The
aqueous layer was washed with ether, made alkaline with solid
Na2CO3 and extracted with ether. The ether layer was dried
over Na2SO4 and evaporated to give the morpholine 5b as an
oil (260 mg, 82%): 1H NMR (CDCl3, 200 MHz) δ 1.29-1.49
(br d, 2H, J ) 11 Hz, 4′,9′-H), 1.52-1.93 (m, 9H, 3′,5′,6′,7′,8′,10′-
H), 1.95-2.71 (br m, 4H, 1′-H, 4′,9′-H, 5-H), 2.40 (s, 3H, CH3),
3.20-4.30 (br m, 5H, 2,6-H, 5-H); 13C NMR (CDCl3, 50 MHz)
δ 27.2 (5′-C, 7′-C), 27.6 (1′-C, 3′-C), 31.7 (4′-C, 9′-C), 33.1 (8′-
C, 10′-C), 33.6 (CH3), 38.5 (6′-C), 47.9 (5-C), 57.5 (3,2′-C), 60.1
(6-C), 63.2 (2-C). Hydrochloride mp 231 °C dec (EtOH-Et2O).
Picrate: mp 239-241 °C (MeOH). Anal. (C20H26N4O8) C, H,
N.
1
cm-1; H NMR (CDCl3, 200 MHz) δ 1.57-1.88 (m, 2H, 4-H),
1.67 (br s, 4,6,10-adamantane H), 1.75 (br d, 6H, J ) 2.9 Hz,
2,8,9-adamantane H), 1.97 (s, 3H, 3,5,7-adamantane H), 2.44
(tt, 2H, J ) 7.9, 1.8 Hz, 3-H), 3.74 (tt, 2H, J ) 7.3, 1.8 Hz,
5-H); 13C NMR (CDCl3, 50 MHz) δ 22.3 (4-C), 28.2 (3,5,7-
adamantane C), 32.3 (3-C), 36.8 (4,6,10-adamantane C), 37.8
(2-C, 1-adamantane C), 40.2 (2,8,9-adamantane C), 60.5 (5-
C). Picrate: mp 200 °C (MeOH). Anal. (C20H24N4O7) C, H,
N.
2-(1-Tr icyclo[3.3.1.13,7]d ecyl)p yr r olid in e (6a ). Sodium
borohydride (440 mg, 11.5 mmol) was added portionwise to a
stirred solution of pyrrolidine 25 (1 g, 4.93 mmol) in 20 mL of
3:1 methanol-acetic acid cooled to ∼ -30 °C. The mixture was
stirred for 4 h at room temperature, and the solvent was
evaporated under reduced pressure. The residue was treated
with a 30% NaOH solution (30 mL), and the mixture was
extracted with dichloromethane. The combined organic ex-
tracts were washed with water and extracted with HCl (5%).
The aqueous phase was made alkaline with solid Na2CO3 and
extracted with dichloromethane, and the organic layer was
washed with water and brine and dried (Na2SO4). Removal
of the solvent under reduced pressure left the pyrrolidine 6a
(840 mg, 83%) as an oil: IR (film) ν(NH) 3313 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 1.32-1.80 (m, 17H, 2,4,6,8,9,10-adaman-
tane H, 3,4-H, NH), 1.89 (s, 3H, 3,5,7-adamantane H), 2.51 (t,
1H, J ∼ 8 Hz, 2-H), 2.73 (m, 1H, 5-H), 2.84 (m, 1H, 5-H); 13C
NMR (CDCl3, 50 MHz) δ 24.6 (3-C), 25.81 (4-C), 28.4 (3,5,7-
adamantane C), 34.9 (1-adamantane C), 37.3 (4,6,10-adaman-
tane C), 39.2 (2,8,9-adamantane C), 47.0 (5-C), 68.9 (2-C).
Meth od B: A solution of the carbamate 22a (260 mg, 0.93
mmol) in dry THF (10 mL) was added to a stirred suspension
of LiAlH4 (260 mg, 6.8 mmol) in dry THF (20 mL), and the
reaction mixture was refluxed for 25 h. The mixture was
worked up as for 5a to give the morpholine 5b (190 mg, 92%)
as an oil.
4-Ac e t y ls p ir o [m o r p h o lin e -3,2′-t r ic y c lo [3.3.1.13,7]-
d eca n e] (22b). Compound 22b was prepared by the proce-
dure used for 17a , by the reaction of acetyl chloride with the
morpholine 5a in the presence of triethylamine: yield 70%;
mp 170 °C (Et2O-n-pentane); IR (Nujol) ν(CdO) 1612 cm-1
;
Hydrochloride: mp 273 °C dec (EtOH-Et2O). Anal. (C14H24
-
ClN‚1/2C2H5OH) C, H, N.
1H NMR (CDCl3, 200 MHz) δ 1.58 (d, 2H, J ∼ 12 Hz, 4′,9′-H),
1.64-2.0 (m, 11H, 3′,5′,6′,7′,8′,10′-H, 4′,9′-H), 2.11 (3H, s, CH3),
2.66 (1H, s, 1′-H), 3.24-3.84 (br m, 4H, 2,5,6-H), 3.85 (d, 1H,
1-Acetyl-2-(1-tr icyclo[3.3.1.13,7)d ecyl]p yr r olid in e (26a ).
Compound 26a was prepared by the procedure used for 17a ,
by the reaction of acetyl chloride with the pyrrolidine 6a in
the presence of triethylamine. The product was purified by
filtration over neutral aluminum oxide (100-125 mesh) with
ether as the eluent: yield 99%; mp 129 °C (Et2O-n-pentane);
J ∼ 11 Hz, 6-H), 4.24 (d, 1H, J ∼ 11 Hz, 2-H). Anal. (C15H23
-
NO2) C, H, N.
4-E t h y ls p ir o [m o r p h o lin e -3,2′-t r ic y c lo [3.3.1.13 ,7 ]-
d eca n e] (5c). Compound 5c was obtained upon reduction of
the N-acetyl derivative 22b with LiAlH4, using the above-
mentioned procedure for the preparation of 5b (method B):
yield 70%; 1H NMR (CDCl3, 200 MHz) δ 1.02 (t, 3H, A3X2, J AX
∼ 7 Hz, CH3CH2), 1.28-1.43 (br d, 2H, J ∼ 12 Hz, 4′,9′-H),
1.52-1.99 (m, 9H, 3′,5′,6′,7′,8′,10′-H), 2.0-2.70 (m, 4H, 1′-H,
4′,9′-H, 5-H), 2.64 (q, 2H, A3X2, J AX ∼ 7 Hz, CH3CH2), 3.0-
4.10 (br m, 5H, 2,6-H, 5-H); 13C NMR (CDCl3, 50 MHz) δ 14.1
(CH3), 27.3 (5′-C, 7′-C), 27.9 (1′-C, 3′-C), 31.4 (4′-C, 9′-C), 33.2
(8′-C, 10′-C), 35.1 (CH2N), 38.5 (6′-C), 40.4 (5-C), 58.1 (3,2′-C),
59.8 (6-C), 65.4 (2-C). Hydrochloride: mp 260 °C dec (EtOH-
Et2O). Picrate: mp 155 °C (MeOH). Anal. (C21H28N4O8) C,
H, N.
1
IR (Nujol) ν(CdO) 1653 cm-1; H NMR (CDCl3, 200 MHz) δ
1.40-2.03 (m, 19H, adamantane H, 3,4-H), 2.07 (s, 3H, CH3),
3.25-3.40 (complex m, 1H, 5-H), 3.41-3.59 (complex m, 1H,
5-H), 3.98 (d, 1H, J ∼ 8.5 Hz, 2-H). Anal. (C16H25NO) C, H,
N.
1-Bu t a n oyl-2-(1-t r icyclo[3.3.1.13,7]d ecyl)p yr r olid in e
(26b). Compound 26b was prepared by the procedure used
for 17a , by the reaction of butanoyl chloride with the pyr-
rolidine 6a in the presence of triethylamine. The product was
purified by filtration over neutral aluminum oxide (100-125
mesh) with ether as the eluent: yield 98%; mp 75-77 °C (n-
pentane); IR (Nujol) ν(CdO) 1650 cm-1; 1H NMR (CDCl3, 200
MHz) δ 0.93 (t, 3H, J ∼ 7 Hz, CH3), 1.40-2.0 (m, 21H,
adamantane H, 3,4-H, COCH2CH2), 2.28 (t, 2H, J ∼ 7 Hz,
COCH2CH2), 3.21-3.40 (complex m, 1H, 5-H), 3.45-3.61
(complex m, 1H, 5-H), 4.30 (d, 1H, J ∼ 8.5 Hz, 2-H). Anal.
(C18H29NO) C, H, N.
1-(1-Tr icyclo[3.3.1.13,7]d e cylca r b on yl)-2-p yr r olid in -
on e (24). A solution of 1-adamantanecarbonyl chloride (13.2
g, 66.6 mmol) in dry THF (30 mL) was added dropwise at room
temperature to a solution of compound 23 (13.6 g, 87 mmol)
in dry THF (50 mL). The mixture was refluxed for 7 h, the
solvent was evaporated, and the residue was crystallized from
methanol at 0 °C to give the lactam 24 (15.4 g, 93.6%): mp
219 °C (MeOH); IR (film) ν(CdO) 1674 (amide), 1738 (lactam)
cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.57-1.76 (m, 6H, 4,6,10-
adamantane H), 1.81-2.29 (m, 11H, 2,3,5,7,8,9-adamantane
1-Meth yl-2-(1-tr icyclo[3.3.1.13,7]d ecyl)p yr r olid in e (6b).
Pyrrolidine 6a was methylated according to the procedure of
1
Borch and Hassid23 to give 6b as an oil: yield 83%; H NMR
(CDCl3, 200 MHz) δ 1.36-1.73 (m, 16H, 2,4,6,8,9,10-adaman-
tane H, 3,4-H), 1.84-2.02 (m, 4H, 3,5,7-adamantane H, 2-H),

New Aminoadamantane Derivatives
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3315
2.37 (s, 3H, CH3), 2.19-2.40 (complex m, 1H, 5-H), 2.83-3.02
(m, 1H, 5-H); 13C NMR (CDCl3, 50 MHz) δ 25.2 (3-C), 26.1 (4-
C), 28.4 (3,5,7-adamantane C), 37.0 (1-adamantane C), 37.2
(4,6,10-adamantane C), 39.2 (2,8,9-adamantane C), 46.5 (CH3),
58.8 (5-C), 75.6 (2-C). Hydrochloride: mp 244 °C dec (EtOH-
Et2O). Hyperchlorate: mp 168 °C (MeOH-Et2O). Anal.
(C15H26ClNO4) C, H, N.
saturated with dimethylamine under ice cooling and stirred
at room temperature for 5 h. The precipitate was filtered off
and washed with THF, and the filtrate was concentrated in
vacuo. The solid residue was treated with ether at 0 °C and
filtered to give the dimethylamide 30 (2.5 g, 76%), which was
used without further purification for the preparation of the
derivative 8a : mp 225-227 °C (THF-n-pentane); IR (Nujol)
ν(CdO) 1673 (lactam), 1645 (amide) cm-1
;
1H NMR (CDCl3,
1-Eth yl-2-(1-tr icyclo[3.3.1.13,7]d ecyl)p yr r olid in e (6c).
Compound 6c was prepared by the LiAlH4 reduction of the
N-acetyl derivative 26a , using the same procedure followed
for the preparation of 5c: yield 95%; 1H NMR (CDCl3, 200
MHz) δ 1.05 (t, 3H, J ∼ 7 Hz, CH3CH2), 1.38-1.78 (m, 16H,
2,4,6,8,9,10-adamantane H, 3,4-H), 1.92 (br s, 3H, 3,5,7-
adamantane H), 2.05-2.18 (m, 1H, 2-H), 2.19-2.50 (m, 2H,
200 MHz) δ 1.50-1.85 (m, 7H, 4,6,10-adamantane H, 4-H),
1.93-2.08 (m, 6H, 2,8,9-adamantane H), 2.10-2.29 (m, 2H,
3-H), 2.11 (s, 3H, 3,5,7-adamantane H), 2.42-2.70 (complex
m, 1H, 4-H), 2.96 (s, 3H, CH3), 3.02 (s, 3H, CH3), 4.69 (d, 1H,
J ) 8.35 Hz, 2-H). Anal. (C17H26N2O2) C, H, N.
N ,N -D im e t h y l-1-(1-t r ic y c lo [3.3.1.13,7]d e c y l)-2-p y r -
r olid in em eth a n a m in e (8a ). A solution of the amide 30 (2.16
g, 7.45 mmol) in dry THF (30 mL) was added to a stirred
suspension of LiAlH4 (2.26 g, 59.6 mmol) in dry THF (60 mL),
and the reaction mixture was refluxed for 20 h. Pyrro-
lidinemethanamine 8a was isolated following the procedure
used for compound 5a : yield almost quantitative; mp 68-70
CH3CH2), 2.60-2.83 (m, 1H, 5-H), 2.87-3.12 (m, 1H, 5-H); 13
C
NMR (CDCl3, 50 MHz) δ 14.3 (CH3), 25.5 (3,4-C), 28.5 (3,5,7-
adamantane C), 37.4 (1,4,6,10-adamantane C), 39.2 (2,8,9-
adamantane C), 53.3 (5-C), 54.9 (CH2N), 74.0 (2-C).
Hydrochloride: mp 273 °C dec (EtOH-Et2O). Anal. (C16H28
ClN) C, H, N.
-
1
1-Bu tyl-2-(1-tr icyclo[3.3.1.13,7]d ecyl)p yr r olid in e (6d ).
Compound 6d was prepared by the LiAlH4 reduction of the
N-butanoyl derivative 26b, using the procedure followed for
the preparation of 5c. The product was purified by column
chromatography on neutral aluminum oxide (100-125 mesh)
using a mixture of ether-hexane (1:14) as the eluent: yield
61%; 1H NMR (CDCl3, 200 MHz) δ 0.99 (t, 3H, J ∼ 7 Hz, CH3-
CH2), 1.13-1.72 (m, 20H, 2,4,6,8,9,10-adamantane H, 3,4-H,
CH3CH2CH2), 1.92 (br s, 3H, 3,5,7-adamantane H), 2.02-2.17
(m, 1H, 2-H), 2.19-2.49 (m, 2H, CH2N), 2.54-2.73 (m, 1H,
5-H), 2.84-3.02 (m, 1H, 5-H); 13C-NMR (CDCl3, 50 MHz) δ
14.3 (CH3), 20.7 (CH2CH3), 25.4 (3-C), 25.5 (4-C), 28.5 (3,5,7-
adamantane C), 31.8 (1-adamantane C), 37.4 (4,6,10-adaman-
tane C, CH2CH2CH3), 39.3 (2,8,9-adamantane C), 55.4 (5-C),
59.8 (CH2N), 74.3 (2-C). Hydrochloride: mp 191 °C (EtOH-
Et2O). Anal. (C18H32ClN) C, H, N.
°C (n-pentane); H NMR (CDCl3, 200 MHz) δ 1.37-1.85 (m,
16H, 2,4,6,8,9,10-adamantane H, 3,4-H), 1.87-2.06 (m, 1H,
CH2N), 2.03 (s, 3H, 3,5,7-adamantane H), 2.11-2.26 (m, 1H,
CH2N), 2.20 (s, 6H, 2 × CH3), 2.37-2.84 (m, 1H, 5-H), 2.72-
2.84 (m, 1H, 5-H), 3.01-3.17 (m, 1H, 2-H); 13C NMR (CDCl3,
50 MHz) δ 23.9 (4-C), 29.4 (3,5,7-adamantane C), 29.9 (3-C),
36.8 (4,6,10-adamantane C), 39.7 (2,8,9-adamantane C), 45.9
(5-C), 46.2 (2 × CH3), 53.0 (2-C), 54.0 (1-adamantane C), 67.9
(CH2N). Dihydrochloride: mp 235 °C dec (EtOH-Et2O).
Fumarate: mp 196 °C dec (EtOH-Et2O). Anal. (C21H34N2O4)
C, H, N.
5-Oxo-1-(1-t r icyclo[3.3.1.13,7]d ecyl)-3-p yr r olid in eca r -
boxylic Acid (32). A mixture of 1-adamantanamine (31) (6.98
g, 46.1 mmol), itaconic acid (6 g, 46.1 mmol), and water was
refluxed for 45 min. Water was removed under vacuum, and
the solid residue was heated at 185 °C for 40 min. The mixture
was cooled to room temperature, treated with ether, and
filtered to give the carboxylic acid 32 (9.6 g, 79%): mp 218-
219 °C (THF-n-pentane); IR (Nujol) ν(CdO) 1727 (acid), 1622
Met h yl 5-Oxo-1-(1-t r icyclo[3.3.1.13,7]d ecyl)-2-p yr r oli-
d in eca r boxyla te (28). A mixture of 1-bromoadamantane
(8.29 g, 38.5 mmol), Ag2SO4 (12 g, 38.5 mmol), and methyl
pyroglutamate (27) (19.3 g, 135 mmol) was stirred and heated
slowly to 80 °C when an exothermic reaction was observed.
Stirring was continued for 1 h at 100 °C. The mixture was
then cooled to room temperature and treated with dichloro-
methane. The inorganic precipitate was filtered off, and the
filtrate was washed several times with water, dried (Na2SO4),
and evaporated under reduced pressure to give an oily residue
which was crystallized by the addition of water. The precipi-
tated methyl ester 28 was filtered, washed exhaustively with
water, and dried: yield 9.54 g (89.5%); mp 154 °C (Et2O); IR
1
(lactam) cm-1; H NMR (DMSO, 200 MHz) δ 1.60 (br s, 6H,
4,6,10-adamantane H), 2.03 (m, 9H, 2,3,5,7,8,9-adamantane
H), 2.35 (dd, 1H, J ) 7.8, 16.6 Hz, 4-H), 2.45 (dd, 1H, J ) 9.0,
16.6 Hz, 4-H), 2.93-3.15 (m, 1H, 3-H), 3.35-3.70 (complex m,
2H, 2-H). Anal. (C15H21NO3) C, H, N.
N,N-Dim eth yl-5-oxo-1-(1-tr icyclo[3.3.1.13,7]decyl)-3-p yr -
r olid in eca r boxa m id e (33). Following the procedure used
for the preparation of 30, amide 33 was initially afforded as
an oil. This oily product was then worked up with 1:1 ether-
n-pentane, under ice cooling, to give the dimethylamide 33 as
a crystalline solid: yield 93%; mp 111-113 °C (Et2O); IR
(Nujol) ν(CdO) 1733 (ester), 1665 (lactam) cm-1 1H NMR
;
(CDCl3, 200 MHz) δ 1.50-1.68 (m, 6H, 4,6,10-adamantane H),
1.79-2.31 (complex m, 12H, 2,3,5,7,8,9-adamantane H, 3,4-
H), 2.38-2.67 (complex m, 1H, 4-H), 3.73 (s, 3H, CH3), 4.36
(d, 1H, J ) 8.4 Hz, 2-H). Anal. (C16H23NO3) C, H, N.
(Nujol) ν(CdO) 1674 (lactam), 1643 (amide) cm-1 1H NMR
;
(CDCl3, 200 MHz) δ 1.50-1.78 (m, 6H, 4,6,10-adamantane H),
1.87-2.26 (m, 9H, 2,3,5,7,8,9-adamantane H), 2.49 (dd, 1H, J
) 9.6, 16.5 Hz, 4-H), 2.60 (dd, 1H, J ) 8.8, 16.5 Hz, 4-H), 2.93
(s, 3H, CH3), 3.0 (s, 3H, CH3), 3.26 (quint, 1H, J ) 7.0 Hz,
3-H), 3.53 (t, 1H, J ∼ 9 Hz, 2-H), 3.75 (dd, 1H, J ) 7.5, 9.5 Hz,
2-H). Anal. (C17H26N2O2) C, H, N.
5-Oxo-1-(1-t r icyclo[3.3.1.13,7]d ecyl)-2-p yr r olid in eca r -
boxylic Acid (29). The methyl ester 28 (4.5 g, 16.2 mmol)
was saponified with KOH (1.38 g, 24.4 mmol) in an aqueous
ethanolic solution (25 mL of ethanol/5 mL of water) at room
temperature for 15 h. Most of the ethanol was removed under
vacuum, and the residue was diluted with water and extracted
with ether. The aqueous layer was acidified under ice cooling
with HCl (18%), and the precipitated acid 29 was filtered,
washed with water, and dried: yield 4.2 g (98.5%); mp >283
N ,N -D im e t h y l-1-(1-t r ic y c lo [3.3.1.13,7]d e c y l)-3-p y r -
r olid in em eth a n a m in e (8b). Compound 8b was prepared by
the LiAlH4 reduction of the amide 33, using the procedure
followed for the preparation of 8a : yield 90%; 1H NMR (CDCl3,
200 MHz) δ 1.10-1.41 (m, 2H, 3,4-H), 1.45-1.73 (m, 12H,
2,4,6,8,9,10-adamantane H), 1.82-2.02 (m, 1H, 4-H), 2.03 (br
s, 3H, 3,5,7-adamantane H), 2.12-2.35 (m, 3H, 2-H, CH2N),
2.18 (br s, 6H, 2 × CH3), 2.55-2.80 (m, 2H, 5-H), 2.88-3.07
(m, 1H, 2-H); 13C NMR (CDCl3, 50 MHz) δ 29.2 (4-C), 29.4
(3,5,7-adamantane C), 35.3 (3-C), 36.9 (4,6,10-adamantane C),
38.8 (2,8,9-adamantane C), 43.5 (5-C), 45.7 (2 × CH3), 49.3
(2-C), 52.6 (1-adamantane C), 65.0 (CH2N). Difumarate: mp
131 °C dec (EtOH-Et2O). Dipicrate: mp 234 °C dec (EtOH).
Anal. (C29H36N8O14) C, H, N.
°C (MeOH); IR (Nujol) ν(CdO) 1718 (acid), 1615 (lactam) cm-1
;
1H NMR (DMSO, 200 MHz) δ 1.58 (br s, 6H, 4,6,10-adaman-
tane H), 1.75-1.87 (m, 1H, 4-H), 1.88-2.03 (m, 6H, 2,8,9-
adamantane H), 2.04-2.22 (m, 2H, 3-H), 2.12 (br s, 3H, 3,5,7-
adamantane H), 2.23-2.37 (m, 1H, 4-H), 4.35 (∼d, 1H, J )
8.4 Hz, 2-H), 12.75 (br s, 1H, CO2H). Anal. (C15H21NO3) C,
H, N.
N,N-Dim eth yl-5-oxo-1-(1-tr icyclo[3.3.1.13,7]d ecyl)-2-pyr -
r olid in eca r boxa m id e (30). A mixture of the acid 29 (2.97
g, 11.3 mmol) and thionyl chloride (3.3 mL, 45.5 mmol) was
heated at 55 °C for 1 h. The excess thionyl chloride was
removed under vacuum, and the resulting solid chloride was
dissolved in dry THF (30 mL). The resulting solution was
tr a n s- a n d cis-5-Oxo-2-p h en yl-1-(1-tr icyclo[3.3.1.13,7]-
d ecyl)-3-p yr r olid in eca r boxylic Acid (35 a n d 36). A mix-
ture of N-benzylidene-1-adamantanamine (34) (4.39 g, 18.3
mmol), succinic anhydride (1.83 g, 18.3 mmol), and xylene (20
mL) was refluxed for 15 h. After removal of the solvent, the

3316 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17
Kolocouris et al.
solid residue was treated with NaHCO3 (6%) to alkaline pH.
The mixture was washed with ether, and the aqueous phase
was acidified under ice cooling with HCl (18%). The precipi-
tated mixture of acids 35 and 36 was filtered, washed with
water, and dried: yield 4.46 g (72%).
The above mixture was treated with 30 mL of hot methanol,
and the resulting solid residue was filtered to give 430 mg of
the cis acid 36: mp 283 °C (MeOH); IR (Nujol) ν(CdO) 1731
(acid), 1631 (lactam) cm-1; 1H NMR (DMSO, 200 MHz) δ 1.35-
1.58 (m, 6H, 4,6,10-adamantane H), 1.80-2.12 (m, 9H,
2,3,5,7,8,9-adamantane H), 2.23 (dd, 1H, J ) 8.7, 16.6 Hz, 4-H),
2.79 (dd, 1H, J ) 12.1, 16.6 Hz, 4-H), 3.43-3.63 (m, 1H, 3-H),
5.19 (d, 1H, J ) 8.7 Hz, 2-H), 7.10-7.39 (m, 5H, aromatic H).
Anal. (C21H25NO3) C, H, N.
5-H), 3.11 (t, 1H, J ) 7.4 Hz, 5-H), 4.23 (d, 1H, J ) 8.8 Hz,
2-H), 7.09-7.26 (m, 3H, aromatic H), 7.31-7.40 (m, 2H,
aromatic H); 13C NMR (CDCl3, 50 MHz) δ 28.8 (4-C), 29.4
(3,5,7-adamantane C), 36.9 (4,6,10-adamantane C), 39.8 (2,8,9-
adamantane C), 42.7 (3-C), 44.8 (5-C), 45.9 (2 × CH3), 53.5
(1-adamantane C), 60.7 (2-C), 61.3 (CH2N), 125.8, 127.1, 128.3
(5 tertiary aromatic C), 146.9 (quarernary aromatic C).
Difumarate: mp 126 °C (EtOH-acetone). Anal. (C31H42N2O8)
C, H, N.
Gen er al P r ocedu r e for th e P r epar ation of 1-(1-Tr icyclo-
[3.3.1.13,7]d ecylca r bon yl)p yr r olid in es 43-46. A solution
of 1-adamantanecarbonyl chloride (13.5 mmol) in dry THF (10
mL) was added dropwise under ice cooling to a stirred solution
of pyrrolidines 39-42 (11.1 mmol) and triethylamine (38.9
mmol) in dry THF (15 mL), and the mixture was stirred at
room temperature for 8 h. The precipitated triethylamine
hydrochloride was filtered off and washed with THF, and the
filtrate was washed with HCl (2%) and water, dried (Na2SO4),
and evaporated. The residue was filtered through neutral
aluminum oxide (100-125 mesh) with ether as the eluent.
2,2-Dim e t h yl-1-(1-t r icyclo[3.3.1.13,7]d e cylca r b on yl)-
p yr r olid in e (43): yield 57.3%; mp 107-109 °C (acetone-H2O);
The filtrate obtained above was evaporated to dryness, and
the solid residue was treated with hot methanol (15 mL). The
resulting solid was filtered off, and the remaining liquors were
evaporated to dryness to yield 3 g of the trans acid 35: mp
222 °C (MeOH); IR (Nujol) ν(CdO) 1731 (acid), 1637 (lactam)
cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.45-1.62 (m, 6H, 4,6,10-
adamantane H), 1.97 (s, 3H, 3,5,7-adamantane H), 1.98-2.11
(m, 6H, 2,8,9-adamantane H), 2.63-3.02 (m, 3H, 3,4-H), 5.37
1
(s, 1H, 2-H), 7.21-7.42 (m, 5H, aromatic H). Anal. (C21H25
NO3) C, H, N.
-
IR (Nujol) ν(CdO) 1616 cm-1; H NMR (CDCl3, 200 MHz) δ
1.57 (br s, 6H, 2 × CH3), 1.71-2.04 (m, 4H, 3,4-H), 1.85 (s,
6H, 4,6,10-adamantane H), 2.12 (br s, 9H, 2,3,5,7,8,9-adaman-
tane H), 3.87 (t, 2H, J ) 6.0 Hz, 5-H). Anal. (C17H27NO) C,
H, N.
P r oced u r e for th e Deter m in a tion of th e Ra tio of Acid s
35 a n d 36. A mixture of the crude acid (300 mg, 0.88 mmol),
anhydrous K2CO3 (122 mg, 0.88 mmol), dimethyl sulfate (223
mg, 1.77 mmol), and acetone (10 mL) was stirred for 16 h. The
inorganic precipitate was filtered off, and the filtrate was
evaporated to dryness. The ratio of the diastereomeric methyl
esters was then determined by NMR integration of the
corresponding methyl signals.
1-(1-Tr icyclo[3.3.1.13,7]d ecylca r bon yl)-1-a za sp ir o[4.4]-
n on a n e (44): yield 54.3%; mp 124-125 °C (acetone-H2O); IR
(Nujol) ν(CdO) 1611 cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.20-
1.33 (m, 2H, cyclopentane H), 1.35-1.55 (m, 2H, cyclopentane
H), 1.60-1.79 (m, 4H, 3,4-H), 1.67 (br s, 6H, 4,6,10-adaman-
tane H), 1.80-2.03 (m, 2H, cyclopentane H), 1.96 (br s, 9H,
2,3,5,7,8,9-adamantane H), 2.22-2.40 (m, 2H, cyclopentane H),
3.69 (t, 2H, J ) 6.2 Hz, 2-H). Anal. (C19H29NO) C, H, N.
1-(1-Tr icyclo[3.3.1.13,7]d ecylca r bon yl)-1-a za sp ir o[4.5]-
d eca n e (45): yield 54%; mp 140 °C (acetone-H2O); IR (Nujol)
t r a n s-N ,N -D im e t h y l-5-o x o -2-p h e n y l-1-(1-t r ic y c lo -
[3.3.1.13,7]d ecyl)-3-p yr r olid in eca r boxa m id e (37). Follow-
ing the procedure used for the preparation of 30, amide 37
was afforded with the following data: yield 91%; mp 215-
217 °C (THF-n-pentane); IR (Nujol) ν(CdO) 1682 (lactam),
1651 (amide) cm-1; H NMR (CDCl3, 200 MHz) δ 1.47-1.63
ν(CdO) 1605 cm-1; H NMR (CDCl3, 200 MHz) δ 1.05-1.38
1
1
(m, 6H, 4,6,10-adamantane H), 1.94 (br s, 3H, 3,5,7-adaman-
tane H), 2.0-2.13 (m, 6H, 2,8,9-adamantane H), 2.30 (dd, 1H,
J ) 15.9, 1.2 Hz, 4-H), 2.78-3.03 (m, 2H, 3,4-H), 2.83 (s, 3H,
CH3), 2.95 (s, 3H, CH3), 5.37 (s, 1H, 2-H), 7.18-7.39 (m, 5H,
aromatic H). Anal. (C23H30N2O2) C, H, N.
(m, 6H, cyclohexane H), 1.40-1.75 (m, 6H, cyclohexane H, 3,4-
H), 1.67 (br s, 6H, 4,6,10-adamantane H), 1.95 (s, 9H,
2,3,5,7,8,9-adamantane H), 2.62-2.83 (m, 2H, cyclohexane H),
3.69 (t, 2H, J ) 6.3 Hz, 2-H). Anal. (C20H31NO) C, H, N.
2-(1,1-Dim e t h yle t h yl)-1-(1-t r icyclo[3.3.1.13,7]d e cyl-
ca r bon yl)p yr r olid in e (46): yield 64.3%; mp 113-115 °C
(acetone-H2O); IR (Nujol) ν(CdO) 1626 cm-1; 1H NMR (CDCl3,
200 MHz) δ 0.81 (s, 9H, 3 × CH3), 1.44-2.10 (complex m, 4H,
3,4-H), 1.70 (br s, 6H, 4,6,10-adamantane H), 1.92-2.10 (m,
9H, 2,3,5,7,8,9-adamantane H), 3.10-3.29 (m, 1H, 5-H), 3.96-
4.14 (m, 1H, 5-H), 4.45 (dd, J ) 6.0, 8.9 Hz, 1H, 2-H). Anal.
(C19H31NO) C, H, N.
Gen er al P r ocedu r e for th e P r epar ation of 1-(1-Tr icyclo-
[3.3.1.13,7]d ecylm eth yl)p yr r olid in es 9a -d . A solution of
the amides 43-46 (4.6 mmol) in dry THF (15 mL) was added
to a stirred suspension of LiAlH4 (18.4 mmol) in dry THF (30
mL). The reaction mixture was refluxed for 25 h and then
hydrolyzed with water and NaOH (10%) under ice cooling. The
inorganic precipitate was filtered off and washed with THF,
and the filtrate was concentrated in vacuo. The residue was
dissolved in ether and extracted with HCl (5%). The aqueous
phase was made alkaline with solid Na2CO3, and the oil formed
was extracted with ether. The ether extracts were washed
with water and brine, dried (Na2SO4), and evaporated to give
the amines 9a -d as oily products.
tr a n s-N,N-Dim et h yl-2-p h en yl-1-(1-t r icyclo[3.3.1.13,7]-
d ecyl)-3-p yr r olid in em eth a n a m in e (8c). Compound 8c was
prepared by the LiAlH4 reduction of the amide 37, using the
procedure for the preparation of 8a : yield 90%; 1H NMR
(CDCl3, 200 MHz) δ 1.41-1.68 (m, 12H, 2,4,6,8,9,10-adaman-
tane H), 1.84-2.29 (m, 8H, 3,5,7-adamantane H, 3,4-H, CH2N),
2.21 (s, 6H, 2 × CH3), 2.87-3.13 (complex m, 2H, 5-H), 4.07
(s, 1H, 2-H), 7.08-7.31 (m, 3H, aromatic H), 7.39-7.49 (m,
2H, aromatic H); 13C NMR (CDCl3, 50 MHz) δ 27.3 (4-C), 29.8
(3,5,7-adamantane C), 37.2 (4,6,10-adamantane C), 40.4 (2,8,9-
adamantane C), 44.6 (5-C), 46.1 (2 × CH3), 47.1 (3-C), 53.5
(1-adamantane C), 63.0 (2-C), 63.3 (CH2N), 125.8, 126.7, 128.0
(5 tertiary aromatic C), 151.2 (quaternary aromatic C).
Difumarate: mp 177 °C dec (EtOH-acetone). Anal.
(C31H42N2O8) C, H, N.
cis-N,N-Dim eth yl-5-oxo-2-ph en yl-1-(1-tr icyclo[3.3.1.13,7]-
d ecyl)-3-p yr r olid in eca r boxa m id e (38). Following the pro-
cedure used for the preparation of 30, amide 38 was afforded
with the following data: yield 97%; mp 198-199 °C (THF-
n-pentane); IR (Nujol) ν(CdO) 1675 (amide), 1648 (lactam)
cm-1
;
1H NMR (CDCl3, 200 MHz) δ 1.53 (br s, 6H, 4,6,10-
2,2-D im e t h y l-1-(1-t r ic y c lo [3.3.1.13,7]d e c y lm e t h y l)-
p yr r olid in e (9a ): yield 84%; 1H NMR (CDCl3, 200 MHz) δ
0.88 (s, 6H, 2 × CH3), 1.35-1.77 (m, 10H, 4,6,10-adamantane
H, 3,4-H), 1.45 (d, 6H, J ) 2.3 Hz, 2,8,9-adamantane H), 1.91
(br s, 3H, 3,5,7-adamantane H), 1.96 (s, 2H, CH2N), 2.77 (t,
2H, J ∼ 7 Hz, 5-H); 13C NMR (CDCl3, 50 MHz) δ 20.9 (4-C),
23.1 (2 × CH3), 28.7 (3,5,7-adamantane C), 34.2 (1-adamantane
C), 37.3 (4,6,10-adamantane C), 39.6 (3-C), 41.7 (2,8,9-ada-
mantane C), 55.4 (5-C), 60.8 (2-C), 63.1 (CH2N). Hydrochlo-
ride: mp 285-287 °C dec (EtOH-Et2O). Anal. (C17H30ClN)
C, H, N.
adamantane H), 1.82-2.13 (m, 2,3,5,7,8,9-adamantane H),
2.28 (dd, 1H, J ) 8.4, 16.8 Hz, 4-H), 3.40 (dd, 1H, J ) 11.6,
16.8 Hz, 4-H), 3.59-3.71 (m, 1H, 3-H), 5.06 (d, 1H, J ) 8.8
Hz, 2-H), 7.02-7.14 (m, 2H, aromatic H), 7.22-7.34 (m, 3H,
aromatic H). Anal. (C23H30N2O2) C, H, N.
cis-N,N-Dim eth yl-2-ph en yl-1-(1-tr icyclo[3.3.1.13,7]decyl)-
3-p yr r olid in em eth a n a m in e (8d ). Compound 8d was pre-
pared by the reduction of the amide 38, using the same
1
procedure as for the preparation of 8a : yield 81%; H NMR
(CDCl3, 200 MHz) δ 1.38-1.90 (m, 15H, 2,4,6,8,9,10-adaman-
tane H, 3,4-H), 1.95 (br s, 3H, 3,5,7-adamantane H), 2.06 (s,
6H, 2 × CH3), 2.05-2.25 (m, 2H, CH2N), 2.80-2.95 (m, 1H,
1-(1-Tr icyclo[3.3.1.13,7]d ecylm et h yl)-1-a za sp ir o[4.4]-
n on a n e (9b): yield 96%; 1H NMR (CDCl3, 200 MHz) δ 1.17-

New Aminoadamantane Derivatives
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17 3317
action of adamantanamines against influenza A viruses: inhibi-
tion of the M2 ion channel protein. Semin. Virol. 1992, 3, 21-
30 and references cited therein. (c) Kiselev, O. I.; Blinov, V. M.;
Kozeletskaya, K. N.; Ilyenko, V. I.; Platonov, V. G.; Chupackin,
O. N. Molecular mechanism of action of antiviral adamantane
agents. Vestn. Ross. Akad. Med. Nauk 1993, 10-15.
(10) Grambas, S.; Hay, A. J . Maturation of influenza A virus
hemagglutinin-Estimates of the pH encountered during trans-
port and its regulation by the M2 protein. Virology 1992, 190,
11-18.
(11) (a) Pinto, L. H.; Holsinger, L. J .; Lamb, R. A. Influenza virus
M2 protein has ion channel activity. Cell 1992, 69, 517-528.
(b) Wang, C.; Lamb, R. A.; Pinto, L. H. Direct measurement of
the influenza A virus M2 protein ion channel activity in
mammalian cells. Virology 1994, 205, 133-140.
(12) (a) Ruigrok, R. W. H.; Hirst, E. M. A.; Hay, A. The specific
inhibition of influenza A virus maturation by amantadine: an
electron microscopic examination. J . Gen. Virol. 1991, 72, 191-
194. (b) Duff, K. C.; Gilchrist, P. J .; Saxena, A. M.; Bradshaw,
J . P. Neutron diffraction reveals the site of amantadine blockade
in the influenza A M2 ion channel. Virology 1994, 202, 287-
293.
(13) Ciampor, F.; Bayley, P. M.; Nermut, M. V.; Hirst, E. M. A.;
Sugrue, R. J .; Hay, A. J . Evidence that the amantadine-induced,
M2 mediated conversion of influenza A virus hemagglutinin to
the low pH conformation occurs in an acidic trans Golgi
compartment. Virology 1992, 188, 14-24.
(14) Grambas, S.; Bennett, M. S.; Hay, A. J . Influence of amantadine
resistance mutations on the pH regulatory function of the M2
protein of influenza A viruses. Virology 1992, 191, 541-549.
(15) Kolocouris, N.; Foscolos, G. B.; Kolocouris, A.; Marakos, P.; Pouli,
N.; Fytas, G.; Ikeda, S.; De Clercq, E. Synthesis and Antiviral
Activity Evaluation of some Aminoadamantane Derivatives. J .
Med. Chem. 1994, 37, 2896-2902.
(16) Lundahl, K.; Shut, J .; Schlatmann, J . L. M. A.; Paerels, G. B.;
Peters, A. Synthesis and antiviral activities of adamantane spiro
compounds 1. Adamantane and analogous spiro-3-pyrrolidines.
J . Med. Chem. 1972, 15, 129-132.
1.78 (m, 18H, 4,6,10-adamantane H, 3,4,6,7,8,9-H), 1.45 (d, 6H,
J
) 2.5 Hz, 2,8,9-adamantane H), 1.91 (br s, 3H, 3,5,7-
adamantane H), 1.99 (s, 2H, CH2N), 2.72 (t, 2H, J ∼ 7 Hz,
2-H); 13C NMR (CDCl3, 50 MHz) δ 21.2 (3-C), 24.0 (7,8-C), 28.7
(3,5,7-adamantane C), 32.1 (6,9-C), 34.4 (1-adamantane C),
37.3 (4,6,10-adamantane C), 39.0 (4-C), 41.7 (2,8,9-adamantane
C), 56.3 (2-C), 63.1 (CH2N), 73.2 (5-C). Hydrochloride: mp 269
°C dec (EtOH-Et2O). Anal. (C19H32ClN) C, H, N.
1-(1-Tr icyclo[3.3.1.13,7]d ecylm et h yl)-1-a za sp ir o[4.5]-
1
d eca n e (9c): yield 83%; H NMR (CDCl3, 200 MHz) δ 1.12-
1.37 (m, 6H, 6,10,7eq,9eq-H), 1.45 (d, 6H, J ) 2.2 Hz, 2,8,9-
adamantane H), 1.51-1.77 (m, 14H, 4,6,10-adamantane H,
3,4,7ax,8,9ax-H), 1.91 (br s, 3H, 3,5,7-adamantane H), 2.03 (s,
2H, CH2N), 2.80 (t, 2H, J ∼ 7 Hz, 2-H); 13C NMR (CDCl3, 50
MHz) δ 21.14 (3-C), 24.5 (7,9-C), 26.4 (8-C), 28.7 (3,5,7-
adamantane C), 32.2 (6,10-C), 33.7 (4-C), 34.4 (1-adamantane
C), 37.3 (4,6,10-adamantane C), 41.7 (2,8,9-adamantane C),
54.7 (2-C), 62.0 (CH2N), 63.8 (5-C). Hydrochloride: mp 282
°C dec (EtOH-Et2O). Anal. (C20H34ClN) C, H, N.
2-(1,1-Dim e t h yle t h yl)-1-(1-t r icyclo[3.3.1.13,7]d e cyl-
m eth yl)p yr r olid in e (9d ): yield 95%; 1H NMR (CDCl3, 200
MHz) δ 0.83 (s, 9H, 3 × CH3), 1.38-1.76 (m, 16H, 2,4,6,8,9,10-
adamantane H, 3,4-H), 1.93 (s, 3H, 3,5,7-adamantane H),
2.28-2.46 (m, 2H, 5-H), 2.2 (dd, 2H, AB, J AB ) 13.0 Hz, CH2N),
2.88-3.05 (m, 1H, 2-H); 13C NMR (CDCl3, 50 MHz) δ 25.5 (4-
C), 27.0 (3 × CH3), 28.7 (3,5,7-adamantane C), 35.3 (1-
adamantane C), 37.2 (4,6,10-adamantane C), 42.3 (3-C, 2,8,9-
adamantane C), 58.6 (5-C), 74.5 (CH2N), 76.9 (2-C).
Hydrochloride: mp 289-291 °C dec (EtOH-Et2O). Anal.
(C19H34ClN) C, H, N.
(17) (a) Van Hes, R.; Smit, A.; Kralt, T.; Peters, A. Synthesis and
antiviral activities of adamantane spiro compounds. J . Med.
Chem. 1972, 15, 132-136. (b) Mathur, A.; Beare, A. S.; Reed,
S. A. In vitro antiviral activity and preliminary clinical trials of
a new adamantane compound. Antimicrob. Agents Chemother.
1973, 4, 421-426.
Ack n ow led gm en t. These investigations were par-
tially supported by a research grant from the University
of Athens, the Biomedical Research Programme of the
European Commision, and grants from the Belgian
Nationaal Fonds voor Wetenschappelijk Onderzoek, the
Belgian Fonds voor Geneeskundig Wetenschappelijk
Onderzoek, and the Belgian Geconcerteede Onderzo-
eksacties. J . Neyts is a postdoctoral research assistant
from the Belgian National Fonds voor Wetenschappelijk
Onderzoek. We thank Anita Van Lierde, Frieda De
Meyer, Anita Camps, Ann Absillis, and Ria Van Ber-
waer for excellent technical assistance.
(18) Aldrich, P. E.; Hermann, E. C.; Meier, W. E.; Paulshock, M.;
Prichard, W. W.; Snyder, J . A.; Watts, J . A. Antiviral Agents.
2. Structure-Activity Relationships of Compounds Related to
1-Adamantanamine. J . Med. Chem. 1971, 14, 535-543.
(19) Bianco, A.; Passacantilli, P.; Righi, G. Improved procedure for
the reduction of esters to alcohols by sodium borohydride. Synth.
Commun. 1988, 18, 1765-1771.
(20) Davis, R.; Untch, K. G. Direct One-Step Conversion of Alcohols
into Nitriles. J . Org. Chem. 1981, 46, 2985-2987.
(21) Camps, F.; Gasol, V.; Guerrero, A. A simple one pot synthesis
of Nitriles from Alcohols. Synth. Commun. 1988, 18, 445-452.
(22) Cook, F. L.; Bowers, C. W.; Liotta, C. L. Chemistry of “Naked”
Anions. III. Reactions of the 18-crown-6 Complex of Potassium
Cyanide with Organic Substrates in Aprotic Organic Solvents.
J . Org. Chem. 1974, 39, 3416-3418.
Refer en ces
(23) Borch, R. F.; Hassid, A. I. A new method for the Methylation of
Amines. J . Org. Chem. 1972, 37, 1673-1674.
(1) Davies, W. L.; Grunert, R. R.; Haff, R. F.; McGahen, J . W.;
Neumayer, E. M.; Paulshock, M.; Watts, J . C.; Wood, T. R.;
Hermann, E. C.; Hoffmann, C. E Antiviral activity of 1-ada-
mantanamine (amantadine). Science 1964, 144, 862-863.
(2) Hoffmann, C. E. Amantadine HCl and Related Compounds. In
Selective Inhibitors of Viral Functions; Carter, W. A., Ed.; CRC
Press: Cleveland, 1973; p 199.
(3) Grunnert, R. R.; McGahen, J . W.; Davies, W. L. The in vivo
antiviral activity of 1-adamantanamine (amantadine). 1. Pro-
phylactic and therapeutic activity against influenza viruses.
Virology 1965, 26, 262-269.
(4) Dolin, R.; Reichman, R. C.; Madore, H. P.; Maynard, R.; Lindon,
P. M.; Webber-J ones, J . A controlled trial of amantadine and
rimandadine in the prophylaxis of influenza A infections. N.
Engl. J . Med. 1982, 307, 580-584.
(5) Couch, R. B.; J ackson, G. G. Antiviral agents in influenza-
Summary of influenza workshop VIII. J . Infect. Dis. 1976, 134,
516-527.
(6) Bryson, Y. J .; Monahan, C.; Pollack, M.; Shields, W. D. A
prospective double-blind study of side effects associated with the
administation of amantadine for influenza A virus prophylaxis.
J . Infect. Dis. 1980, 141, 543-547.
(7) Tsunoda, A.; Maasab, H. H.; Cochran, K. W.; Eveland, W. C.
Antiviral activity of R-methyl-1-adamantane methylamine hy-
drochloride. Antimicrob. Agents Chemother. 1966, 553.
(8) Tisdale, M.; Bauer, D. J . The relative potencies of anti-influenza
compounds. Ann. N. Y. Acad. Sci. 1977, 284, 254-263.
(9) (a) Hay, A. J .; Wolstenholme, A. J .; Skehel, J . J .; Smith, M. H.
The molecular basis of the specific anti-influenza action of
amantadine. EMBO J . 1985, 4, 3021-3024. (b) Hay, A. J . The
(24) (a) Sondengam, B. L.; Hentchoya Hemo, J .; Charles, G. Sur une
nouvelle me´thode de me´thylation des amines primaires et
secondaires. (New method of methylation of primary and
secondary [steroidal] amines.) Tetrahedron Lett. 1973, 261-
263. (b) Karnang, H.; Charles, G.; Sondengam, B. L.; Hentchoya
Hemo, J . Bis(alcoxyme´thyl)amines: pre´paration et re´duction;
N-dime´thylation se´lective d’amines primaires. (Bis(alkoxy-
methyl) amines: preparation and reduction; selective N-di-
methylation of primary amines.) Tetrahedron Lett. 1977, 3469-
3472.
(25) Rigo, B.; Lespagnol, C.; Pauly, M. Studies on Pyrrolidinones.
Synthesis of N-Acyl-pyroglutamic Esters with Bactericide and
Fungicide Properties. J . Heterocycl. Chem. 1988, 25, 49 and
references cited therein.
(26) Mundy, B. P.; Larsen, B. R.; Mckenzie, L. F.; Braden, G. A
convenient synthesis of Myosmine. J . Org. Chem. 1972, 37,
1635-1636.
(27) Mundy, B. P.; Larsen, B. R. A new approach to pyrrolidine and
piperidine alkaloids. Synth. Commun. 1972, 2, 197-200.
(28) Mundy, B. P.; Lipkowitz, K. B.; Lee, M.; Larsen, B. R. N-
Acyllactam Rearrangements. The Fate of the Carboxyl Carbon
and the Synthesis of 2-tert-Butyl-1-pyrroline. J . Org. Chem.
1974, 39, 1963-1965.
(29) Paytach, P. L.; Sparrow, E.; Gathe, J . C. The Reaction of Itaconic
Acid with Primary Amines. J . Am. Chem. Soc. 1950, 72, 1415.
(30) (a) Castagnoli, N., J r. The Condensation of Succinic Anhydride
with Benzylidinemethylamine. A Stereoselective Synthesis of
trans- and cis-1-Methyl-4-carboxy-5-phenyl-2-pyrrolidinone. J .
Org. Chem. 1969, 234, 3187-3189. (b) Castagnoli, N., J r.;

3318 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17
Kolocouris et al.
Cushman, M. The Condensation of Succinic Anhydrides with
Schiff Bases. Scope and Mechanism. J . Org. Chem. 1971, 36,
3404-3406. (c) Cushman, M.; Castagnoli, N., J r. The Synthesis
of trans-3′-Methylnicotine. J . Org. Chem. 1972, 37, 1268-1271.
(d) Cushman, M.; Madaj, E. J . A Study and Mechanistic
Interpretation of the Electronic and Steric Effects That Deter-
mine the Stereochemical Outcome of the Reaction of Schiff Bases
with Homopthalic Anhydride and 3-Phenylsuccinic Anhydride.
J . Org. Chem. 1987, 52, 907-915.
(35) De Clercq, E. Antiviral and antimetabolic activities of nep-
lanocins. Antimicrob. Agents Chemother. 1985, 28, 84-89.
(36) De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini,
J .; Maudgal, P. C. A novel selective broad-spectrum anti-DNA
virus agent. Nature 1986, 323, 464-467.
(37) Balzarini, J .; Karlsson, A.; Perez-Perez, M. J .; Vrang, L.;
Walbers, J .; Zhang, H.; Oberg, B.; Vandamme, A. M.; Camarasa,
M. J .; De Clercq, E. HIV-1-specific reverse transcriptase inhibi-
tors show differential activity against HIV-1 mutant strains
containing different amino acid substitutions in the reverse
transcriptase. Virology 1993, 192, 246-253.
(38) Kawana, F.; Shigeta, S.; Hosoya, M.; Suzuki, H.; De Clercq, E.
Inhibitory effects of antiviral compounds on respiratory cyncytial
virus replication in vitro. Antimicrob. Agents Chemother. 1987,
31, 1225-1230.
(39) Shigeta, S.; Konno, K.; Yokota, T.; Nakamura, K.; De Clercq, E.
Comparative activities of several nucleoside analogs against
influenza A, B, and C viruses in vitro. Antimicrob. Agents
Chemother. 1988, 32, 906-911.
(31) Moffatt, R. B. Antispasmodics. IX. 1-Azaspiro[4.5]decane and
Derivatives. J . Am. Chem. Soc. 1957, 79, 3186-3190.
(32) Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, pp
354, 357, 653.
(33) Fytas, G.; Kolocouris, N.; Foscolos, G. B.; Vamvakides, A.
Synthe`se et e´tude pharmacologique de quelques adamantyl-
cyclopentanamines. (Synthesis and pharmacological study of
some adamantylcyclopentanamines.) Eur. J . Med. Chem. 1991,
26, 563-566.
(34) De Clercq, E.; Descamps, J .; Verhelst, G.; Walker, R. T.; J ones,
A. S.; Torrence, P. F.; Shugar, D. Comparative efficacy of
antiherpes drugs against different strains of herpes simplex
virus. J . Infect. Dis. 1980, 141, 563-574.
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