Non-CNS acting opiates bearing guanidino substituents

Article abstract of DOI:10.1071/CH03199

A series of guanidino-substituted opiates based on morphine, diprenorphine, and buprenorphine have been synthesized. Guanidines with aryl and alkyl substituents as well as unsubstituted ones have been attached to the opiate nucleus with spacer units of varying length. The spacer groups have mainly been attached to the opiates via the opiate nitrogen atom. A few compounds involving attachment through opiate oxygen atoms have been prepared, but were found to be ineffective as analgesics. The activity of the compounds as analgesics has been evaluated using the phenylquinone (PQ) abdominal-constriction test and their ability to enter the CNS evaluated with the Straub tail response. The compounds most active in the PQ abdominal-constriction test and showing no Straub tail behaviour contained aryl-substituted guanidines.

Full text of DOI:10.1071/CH03199

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 427–438
Non-CNS Acting Opiates Bearing Guanidino Substituents
Kamani R. Subasinghe,A W. Roy Jackson,A,C Jacqui F. Young,A
Maria Papanastasiou,A and Bevyn JarrottB
A Centre for Green Chemistry, Monash University, Clayton VIC 3800, Australia.
B Department of Pharmacology, Monash University, Clayton VIC 3800, Australia.
C Author to whom correspondence should be addressed (e-mail: w.r.jackson@sci.monash.edu.au).
A series of guanidino-substituted opiates based on morphine, diprenorphine, and buprenorphine have been synthe-
sized. Guanidines with aryl and alkyl substituents as well as unsubstituted ones have been attached to the opiate
nucleus with spacer units of varying length. The spacer groups have mainly been attached to the opiates via the
opiate nitrogen atom. A few compounds involving attachment through opiate oxygen atoms have been prepared,
but were found to be ineffective as analgesics.
The activity of the compounds as analgesics has been evaluated using the phenylquinone (PQ) abdominal-
constriction test and their ability to enter the CNS evaluated with the Straub tail response.The compounds most active
in the PQ abdominal-constriction test and showing no Straub tail behaviour contained aryl-substituted guanidines.
Manuscript received: 30 July 2003.
Final version: 14 November 2003.
NR1
Introduction
Spacer
Opiate N
NHR2
The chemistry and pharmacology of opiates have been the
subject of extensive investigation.[1] A large number of struc-
turally modified natural opiates have been synthesized in an
effort to maintain good analgesic action while reducing abuse
potential and minimizing other undesirable side effects.[2]
Much recent effort has involved studies of selective opioid
receptor probes often involving dimeric opioid species.[3,4]
Another major debate in analgesia is on the importance
of activity on peripheral sensory nerves relative to actions
within the central nervous system (CNS). Opiates modi-
fied so as to restrict their transport through the blood–brain
barrier (bbb) have been synthesized by the inclusion of polar,
hydrophilic substituents. Thus, Portoghese and his collegues
incorporated zwitterionic amino acid residues into the opiates
naltrexamine and oxymorphamine[5] to achieve this. More
recent papers by the Portoghese group[6] describe the phar-
macology of guanidine-bearing opiates without mentioning
CNS access.
Scheme 1.
(Scheme 2), with the spacers having the general formula
–(CH2)n–(NH)0 or 1, where n = 0 and (NH)0 or n = 3 and
(NH)1, and the substituents R1 and R2 are H, alkyl, or aryl.
Two compounds in which the guanidino group was attached
via a three-carbon spacer to either the phenolic oxygen of
diprenorphine or to the secondary alcohol in morphine were
also synthesized. Pharmacological evaluation involved the
PQ abdominal-constriction test for analgesic action and the
Straubmousetailresponsetoindicatethepresenceorabsence
of CNS activity.
Results and Discussion
Synthesis of the Guanidino Compounds
Three different synthetic approaches were used.
In previous work, we developed peripherally acting anti-
histamine compounds whose access to the CNS was restricted
by the incorporation of strongly basic amidine or guanidine
groups which are protonated at physiological pH and are thus
too hydrophilic to cross the bbb.[7] In this paper, we report
the synthesis of modified opiates incorporating a guanidine
group as a strongly basic function and also report some pre-
liminary pharmacological results. The general structure of
the compounds is shown in Scheme 1.
Unsubstituted N-linked Guanidines
The unsubstituted N-linked morphine guanidine 5 was pre-
pared from di-TBDMS (tert-butyldimethylsilyl) protected
morphine 4 by treatment with cyanogen bromide, conver-
sion of the N-cyano normorphine derivative into a guanidine
with methylchloroaluminum amide,[8] and removal of the
protecting groups (Scheme 3).
Diprenorphine guanidines 7a–7c were prepared from
N-methyl diprenorphine analogues (6a–6c)[10] according to
the same procedure (Scheme 4).
In the present study, we chose opiates that were based
on morphine 1, diprenorphine 2, and buprenorphine 3
© CSIRO 2004
10.1071/CH03199
0004-9425/04/050427

428
K. R. Subasinghe et al.
HO
HO
HO
O
O
O
N
N
NCH3
MeO
MeO
HO
C
C
OH
OH
But
3
1
2
Scheme 2.
TBDMSO
HO
O
(a)
(b), (c), (d)
O
NH
1
N
NMe
NH2
TBDMSO
HO
4
5
Scheme 3. Reagents and conditions: (a) TBDMSCl, imidazole in dimethylformamide; (b) CNBr in
CH2Cl2; (c) Me3Al, NH4Cl in benzene; (d) HF in 10 : 1 CH3CN/tetrahydrofuran.
RO
RO
compound 11, OH groups were protected with TBDMS
groups, and the nitrile was reduced to the primary amine 13.
Reaction with 1H-pyrazole-1-carboxamidine[12] gave the O-
silyl protected guanidine 14 which was deprotected with HF
to give the guanidine 15 (Scheme 6).
A similar sequence of reactions was carried out from
nordiprenorphine 9 via the nitrile 16, the TBDMS-protected
nitrile 17, the protected amine 18, and the protected guanidine
19 to give the guanidine 20 (Scheme 7).
The buprenorphine derivative (21; R = H) was prepared
from norbuprenorphine 10 by a similar scheme but with-
out the use of protecting groups. The reaction of 10 with
reagents (a), (c), and (d) (Scheme 7) proceeded in good
yields (48% overall conversion) to the target guanidine (21;
R = H).A related phenolic methoxy derivative 22 (Scheme 8)
of the buprenorphine guanidine 21 was prepared by a similar
method.
O
O
NH
NMe
N
NH2
MeO
MeO
C
C
OH
OH
6
7
R
ꢀ or ꢁ
6a, 7a
6b, 7b
6c, 7c
Me
H
H
ꢁ
ꢁ
ꢀ
Scheme 4.
HO
HO
HO
A codeine analogue of 15 was prepared by reaction
of normorphine 8 with acrylonitrile followed by selective
O-methylation of the phenolic hydroxyl group using CH3I/
K2CO3 in acetone. The nitrile was then reduced with LiAlH4
and the resulting amine converted into the codeine-derived
guanidine 23 (Scheme 8) by reaction with 1H-pyrazole-1-
carboxamidine.
O
O
O
NH
NH
NH
MeO
MeO
HO
C
C
OH
But
OH
8
9
10
N-Substituted N-linked Guanidines
Scheme 5.
The morphine-related N-substituted guanidines 25a–25c
were prepared from the silyl-protected normorphine 24
by reaction with an appropriately substituted carbodiimide
(Scheme 9). Di-p-tolyl carbodiimide and 1,3-diisopropyl
carbodiimide were commercially available. The diphenyl
carbodiimide was prepared from the corresponding urea
by reaction with Burgess reagent[13] or triphenylphosphine
Unsubstituted Guanidines with a Spacer
Unsubstituted guanidines with a three-carbon spacer (n = 3)
were prepared from normorphine 8,[9] nordiprenorphine
9,[10] and norbuprenorphine 10[11] (Scheme 5). Normor-
phine 8 was reacted with acrylonitrile to give the cyano

Non-CNS Acting Opiates Bearing Guanidino Substituents
429
HO
HO
TBDMSO
(a)
(b)
O
O
O
CN
CN
N
NH
N
HO
HO
TBDMSO
8
11
12
TBDMSO
TBDMSO
(c)
(d)
O
NH
O
N
NH2
N
NH
NH2
TBDMSO
TBDMSO
13
14
(e)
HO
O
NH
N
NH
NH2
HO
15
Scheme 6. Reagents and conditions: (a) acrylonitrile, EtOH; (b) TBDMSCl, imidazole, 4-dimethylaminopyridine
in dimethylformamide; (c) LiAlH4, ether; (d) 1H-pyrazole-1-carboxamidine · HCl, di(isopropyl)ethylamine in
dimethylformamide; (e) HF in 10 : 1 CH3CN/tetrahydrofuran.
HO
TBDMSO
HO
(a)
(b)
O
O
O
CN
CN
NH
NH
NH
MeO
MeO
MeO
C
C
C
OH
OH
OH
9
16
17
TBDMSO
TBDMSO
(c)
(d)
NH
O
O
NH2
NH
N
N
NH2
MeO
MeO
C
C
OH
OH
(e)
18
19
HO
O
NH
NH
N
NH2
MeO
C
OH
20
Scheme 7. Reagents and conditions: (a) acrylonitrile, EtOH; (b) TBDMSCl, imidazole, DMAP in DMF; (c) LiAlH4,
ether; (d) 1H-pyrazole-1-carboxamidine · HCl, di(isopropyl)ethylamine in DMF; (e) NH4F in MeOH.

430
K. R. Subasinghe et al.
RO
H3CO
O
NH
N
NH
NH
O
NH2
N
NH
MeO
NH2
C
OH
But
HO
21 R ꢁ H
23
22 R ꢁ CH3
Scheme 8.
TBDMSO
HO
(b), (c)
(a)
O
Normorphine 6
O
NR
NH
N
NHR
TBDMSO
HO
25a R ꢁ Ph
24
25b R ꢁ p-MeOPh
25c R ꢁ p-Tol
Scheme 9. Reagents and conditions: (a) TBDMSCl, imidazole, 4-dimethylaminopyridine in dimethylfor-
mamide; (b) RN=C=NR in dimethylformamide; (c) NH4F in MeOH.
HO
TBDMSO
(a)
(b)
NR
O
NR
O
13
N
NH
N
NH
NHR
NHR
HO
TBDMSO
26a R ꢁ Pri
26b R ꢁ Ph
27a R ꢁ Pri
27b R ꢁ Ph
26c R ꢁ p-Tol
27c R ꢁ p-Tol
Scheme 10. Reagents and conditions: (a) RN=C=NR in dimethylformamide; (b) NH4F in MeOH.
dibromide,[14] and the di-p-methoxyphenyl compound using
the triphenylphosphine dibromide.
thought that it was best to make sure that this dictum still
operated in the guanidino-substituted compounds. Accord-
ingly, the O-substituted guanidine 31 was prepared from
morphine 1. The phenolic OH of morphine 1 was protected
as an acetate. The secondary alcohol was treated with 3-
bromopropionitrile and the nitrile reduced to a primary
amine. This was converted into the guanidine 31 by reaction
with 1H-pyrazole-1-carboxamidine (Scheme 13).
Thediprenorphinederivative6cwastreatedwithNa/EtOH
followed by 3-bromopropionitrile to give the cyano com-
pound, which was reduced to the primary amine and then
converted into the guanidine 32 (Scheme 14).
N-Substituted Guanidines with a Spacer
The N-substituted guanidines (27a–27c) with a three-carbon
spacer were prepared in a similar manner from the silyl pro-
tected amine 13 (Scheme 10).
The silyl-protected amine 18 was converted into the
diphenyl-substituted guanidine 28 and deprotected to give
the N,Nꢀ-diphenyl-substituted guanidine 29 (Scheme 11).
A monosubstituted guanidine 30 (Scheme 12) was pre-
pared from the silyl-protected amine 13 by reaction with
N-phenylaminoiminomethanesulfonic acid[15] followed by
deprotection.
Pharmacology
O-Substituted Guanidines
Lack of CNS Activity
Although substitution of the 3-OH group in opioids has
been shown to lead to loss of activity in many cases,[16] we
All of the compounds were evaluated for CNS activity using
the Straub tail response of mice.[17] This response is regarded

Non-CNS Acting Opiates Bearing Guanidino Substituents
431
TBDMSO
HO
O
NPh
O
NPh
18
N
NH
N
NH
NHPh
NHPh
MeO
MeO
C
C
OH
OH
28
29
Scheme 11. Reagents and conditions: (a) PhN=C=NPh in dimethylformamide; (b) NH4F in MeOH.
HO
H
HN
N(CH2)4O
H2N
O
NPh
NH2
O
N
(a), (b), (c)
NH
6c
NCH3
HO
MeO
C
30
OH
Scheme 12.
32
Scheme
14. Reagents
and
conditions:
(a)
Na/EtOH,
HO
Br(CH2)3CN; (b) LiAlH4; (c) 1H-pyrazole-1-carboxamidine · HCl,
di(isopropyl)ethylamine in dimethylformamide.
(a), (b), (c), (d)
O
1
NMe
tests with detailed investigation of opiate receptor subtype
potencies.
HN
O
N(CH2)4
H2N
H
Analgesic Activity
31
The PQ abdominal-constriction test was used as a rapid
in vivo screening test for analgesic activity. This test has been
established as a reliable method of the estimation of activity
of peripherally acting analgesics.[20] The compounds were
evaluated using intraperitoneal injections and the results are
summarized in Table 1.
The dose of each opiate causing 50% of the maximum
response was compared with that of morphine, which was
in the 1–2 mg kg−1 range. The most potent compounds 25b,
25c, 27b, and 27c all contained diaryl-substituted guanidines
and the presence (in 27b and 27c) or absence (in 25b and
25c) of a three-carbon spacer did not have any significant
influence.
Perhaps surprisingly, the diphenyl-substituted compound
with no spacer group 25a showed diminished activity rel-
ative to the closely related compounds 25b and 25c which
contained p-OMe and p-Me substituted phenyl rings. The
dialkyl-substituted guanidine 27a showed only partial ago-
nist activity. A monoaryl guanidine 30 showed virtually no
analgesic activity.
The unsubstituted guanidine 15 was only tested orally and
not intraperitoneally and showed only limited activity. The
related diprenorphine-related 20 and buprenorphine related
21 unsubstituted guanidines showed activities that were only
slightly less than the diaryl-substituted morphine derivatives
Scheme 13. Reagents and conditions: (a) NaHCO3/Ac2O;
(b) Br(CH2)3CN/NaH; (c) LiAlH4; (d) 1H-pyrazole-1-
carboxamidine · HCl, di(isopropyl)ethylamine in dimethylformamide.
as a good indication of whether opioids are penetrating
the bbb into the CNS.[18] The results are summarized in
Table 1. All of the compounds showed less potency than
morphine, which showed activity at doses of ≥4 mg kg−1
.
The unsubstituted guanidine from buprenorphine 21 began
to show response at doses of ≥8 mg kg−1 and the unsubsti-
tuted guanidine from diprenorphine 20 showed very weak
response at high doses. The more lipophilic O-methylated
analogue 22 of the unsubstituted buprenorphine compound
21 showed Straub tail activity at 8 mg kg−1, a value com-
parable with morphine (see Table 1). The aryl-substituted
guanidines, e.g. 25 and 27, showed no response with doses
as high as 64 mg kg−1
.
The Straub tail test is associated with µ agonists but also is
active for compounds such as pethidine[19] which are selec-
tive κ agonists. As it was not possible to test for opiate
receptor selectivity, it is possible that the lack of Straub tail
activity for compounds 20 and 21 is due to them acting as
µ antagonists which is the main action of diprenorphine.
Future work is planned to supplement these initial screening

432
K. R. Subasinghe et al.
Table 1. Mouse phenylquinone-induced abdominal-constriction data (% inhibition)A and
Straub tail response data for the compounds
Compound
no.
PQ abdominal-constriction: IP dose [mg kg−1 B
]
Straub tail
response [mg kg−1 C
]
1
2
4
8
16
32
64
128
32
31
30
29
27a
27b
27c
25a
25b
25c
22
0
0
22
12
6
22
18
6
+
+
+
+
+
+
+
no
no
no
no
no
no
no
no
12
12
15
35
33
50
17
44
54
0
12
12
54
57
73
50
33
56
54
47
13
0
24
29
24
29
+
54
57
80
75
39
56
54
53
53
39
100
54
61
87
92
39
61
77
53
60
64
100
92
61
80
100
78
100
100
60
80
70
100
65
100
61
+
87
100
100
100
100
100
93
100
100
100
100
100
100
100
85
+
100
100
100
100
+
no
no
100
+
8 (3/3), 16 (3/3)
8 (1/3), 16 (1/3), 32 (3/3)
32 (weak), 64 (1/3)
4 (2/3), 8 (3/3)
21
20
Morphine
13
0
47
+
100
100
+
100
100
100
A
Each test was carried out on a group of three mice and the results were averaged.
Intraperitoneal (IP) dose and the symbol + indicates that the test animals died.
B
C Each test was carried out on a group of three mice and the number of mice which showed a positive
response/number of mice tested is shown in parenthesis.
25 and 27. Similarly, the phenol-O-methylated buprenor-
phine derivative 22 showed reasonable activity. The corre-
sponding codeine derivative 23 was only tested orally where
it showed limited activity.The unsubstituted guanidines with-
out a spacer based on morphine 5 and diprenorphine (7a–7c)
all acted as partial agonists with about one-tenth of the
activity of morphine 1.
Twocompounds 31and32werepreparedwheretheunsub-
stituted guanidino groups were attached by a three-carbon
spacer to the secondary hydroxyl group of the morphine 31
and to the phenolic hydroxy group of the diprenorphine 32.
Neither compound showed significant analgesic activity.
a Bruker BioApex 47 e− Fourier-transform mass spectrometer with
a 4.7 Tesla magnet and an Analytica electrospray source. Mass spectra
(EI) were recorded on a VG TRIO-1 Quadrupole mass spectrometer at
70 eV with a source temperature of 200◦C. Microanalyses were per-
formed by Chemical and Microanalytical Services, Belmont,
Australia, and the Campbell Microanalysis Laboratory, Otago, New
Zealand. Merck Silica Gel 60 (230–400 mesh, no. 9385) was used
for flash chromatography. Thin-layer chromatography (TLC) was per-
formed on Merck pre-coated silica gel 60 F254
.
Preparation of (5α,6α)-17-(2-Carboxamidino)-7,8-didehydro-
4,5-epoxymorphinan-3,6-diol 5
3,6-Bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-
17-methylmorphinan 4
Solid t-butyldimethylsilyl chloride (1.26 g, 8.4 mmol) was added to a
stirred solution of morphine 1 (1.00 g, 3.5 mmol) and imidazole (1.20 g,
17.6 mmol) in dimethylformamide (7 mL) under N2. The reaction mix-
ture was stirred at ambient temperature for 2 h and then heated at 90◦C
for4 h.Thereactionmixturewascooled, pouredintowater, andextracted
with dichloromethane. The dichloromethane layer was dried and
evaporated to give a yellow oil, which solidified. Recrystallization from
methanol gave 4 as colourless needles (1.13 g, 72%), mp 118–119◦C.
δH (200 MHz, CDCl3) 6.54 (1H, d, J 8.0), 6.38 (1H, d, J 8.0), 5.57
(1H, d, J 9.9), 5.21 (1H, dt, J 9.8, 2.7), 4.63 (1H, d, J 5.6), 4.19 (1H,
m), 3.33 (1H, m), 3.00 (1H, d, J 18.7), 2.60 (1H, s), 2.50 (1H, dd,
J 10.8, 4.0), 2.42 (3H, s), 2.42 (1H, m), 2.28 (1H, dd, J 18.6, 6.6),
2.00 (1H, td, J 12.0, 5.0), 1.80 (1H, m), 0.94 (9H, s), 0.90 (9H, s), 0.18
(3H, s), 0.11 (3H, s), 0.10 (3H, s), 0.07 (3H, s).
Summary
Guanidino derivatives of morphine, diprenorphine, and
buprenorphine have been synthesized. All the guanidines
showed less access than morphine to the CNS as deter-
mined by the Straub tail response. Substituted guani-
dines did not show a Straub tail response, even at high
doses (≤64 mg kg−1). The diprenorphine and buprenor-
phine derivatives with an unsubstituted guanidine attached
to the opiate ring nitrogen atom by a three-carbon spacer
showed moderate analgesic activity using the PQ abdominal-
constriction test with intraperitoneal injection. Diaryl-
substituted guanidines with both a three-carbon spacer and
with no spacer, i.e. with the opiate ring nitrogen atom incor-
porated into the guanidine group, showed highly promising
analgesic activity.
3,6-Bis(t-butyldimethylsiloxy)-17-cyano-7,8-didehydro-
4,5-epoxymorphinan
A solution of 4 (0.40 g, 0.78 mmol) in dry benzene (5 mL) was added
dropwise to a stirred solution of cyanogen bromide (0.17 g, 1.53 mmol)
in dry benzene (5 mL) under N2. The reaction mixture was stirred
overnight at ambient temperature and then refluxed for 4 h. The mix-
ture was evaporated to dryness and the resulting solid was recrystallized
from methanol to give the product as colourless needles (0.33 g, 85%).
vmax/cm−1 2204 (m). δH (300 MHz, CDCl3) 6.59 (1H, d, J 8.1), 6.43
(1H, d, J 8.1), 5.66 (1H, d, J 9.7), 5.13 (1H, d, J 9.7), 4.64 (1H, d, J 5.6),
4.19 (1H, m), 3.99 (1H, m), 3.46 (1H, d, J 3.1), 3.25 (1H, m), 3.00 (1H,
d, J 18.8), 2.85 (1H, dd, J 18.8, 6.3), 2.70 (1H, s), 2.08 (1H, td, J 12.3,
Experimental
Syntheses
Melting points are uncorrected. Infrared spectra were recorded on a
Perkin–Elmer 1600 FT-IR spectrophotometer. 1H and 13C NMR spectra
were recorded using Bruker AC-200, DPX-300, and DRX-400 spectro-
meters. Electrospray (ES) ionization mass spectra were measured on

Non-CNS Acting Opiates Bearing Guanidino Substituents
433
6.1), 1.87 (1H, d, J 12.3), 0.94 (9H, s), 0.91 (9H, s), 0.18 (3H, s), 0.11
(6H, s), 0.09 (3H, s).
1.4), 4.19 (1H, m), 3.90 (1H, q, J 3.1), 2.85 (2H, m), 2.71 (1H, q,
J 6.3), 4.56 (1H, br s), 2.59 (1H, br d, J 4.1), 2.54 (1H, d, J 3.4),
2.49 (2H, t, J 6.5), 2.39 (1H, dd, J 18.5, 6.4), 2.0 (1H, m), 1.82 (1H,
m), 0.94 (9H, s), 0.91 (9H, s), 0.18 (3H, s), 0.11 (3H, s), 0.10 (3H, s),
0.07 (3H, s). δC (100 MHz, CDCl3) 150.03, 137.14, 133.83, 131.13,
128.17, 126.95, 121.31, 118.85, 118.47, 92.68, 69.35, 60.33, 57.81,
50.85, 44.36, 41.31, 35.99, 25.89, 25.79, 23.04, 18.31, 18.30, 18.24,
–4.41, –4.73, –4.81, –4.89.
3,6-Bis(t-butyldimethylsiloxy)-17-(2-carboxamidino)-
7,8-didehydro-4,5-epoxymorphinan
A solution of 3,6-bis(t-butyldimethylsiloxy)-17-cyano-7,8-didehydro-
4,5-epoxymorphinan (100 mg, 0.19 mmol) in dry benzene (2 mL) was
added to a solution of methylchloroaluminum amide[8] (0.28 mmol) in
benzene at ambient temperature and the reaction mixture was heated
at 80◦C under N2 for 20 h. This solution was cooled and the aluminum
complex was decomposed by carefully pouring the solution into a slurry
of silica gel (2.0 g) in chloroform. The mixture was stirred for 5 min and
filtered. The filter cake was washed with methanol (50 mL) and the
filtrate was evaporated to give a white solid (0.11 g), which was used in
the next step without further purification.
17-(3-Aminopropyl)-3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-
4,5-epoxymorphinan 13
A solution of 12 (0.20 g, 0.36 mmol) in dry ethyl ether (5 mL) was
added dropwise to a suspension of lithium aluminum hydride (0.13 g,
3.6 mmol) in dry ether (5 mL). After stirring for 3 h at ambient tem-
perature, wet ether was added to the reaction mixture followed by 10%
sodium hydroxide (1.5 mL). The solution was filtered and the white pre-
cipitate was washed with ether. The ether layer was evaporated under
reduced pressure to give the amine 13 as a clear liquid which solidi-
fied (0.20 g, 99%), mp 80◦C (Found: m/z 557.3565. [M + H]+ requires
557.3594). δH (400 MHz, CDCl3) 6.52 (1H, d, J 8.0), 6.36 (1H, d,
J 8.0), 5.54 (1H, dt, J 9.6, 1.4), 5.20 (1H, dt, J 9.6, 2.8), 4.62 (1H,
dd, J 5.5, 1.2), 4.19 (1H, m), 3.38 (1H, dd, J 6.3, 3.0), 2.92 (1H, d,
J 18.5), 2.77 (2H, br s), 2.55 (4H, m), 2.34 (1H, td, J 12.2, 3.5), 2.27
(1H, dd, J 18.5, 6.5), 1.94 (1H, td, J 12.5, 5.0), 1.80 (1H, d, J 11.2),
1.62 (2H, q, J 6.8), 1.5 (2H, br s), 0.94 (9H, s), 0.90 (9H, s), 0.18
(3H, s), 0.10 (3H, s), 0.09 (3H, s), 0.07 (3H, s). δC (100 MHz, CDCl3)
149.96, 136.93, 133.56, 131.36, 128.62, 127.58, 121.10, 118.37, 92.79,
69.45, 56.86, 52.95, 44.64, 44.62, 41.53, 40.87, 36.16, 31.30, 25.87,
25.78, 21.64, 18.29, 18.22, –4.42, –4.73, –4.82, –4.90.
(5α,6α)-17-(2-Carboxamidino)-7,8-didehydro-
4,5-epoxymorphinan-3,6-diol 5
A slurry of 3,6-bis(t-butyldimethylsiloxy)-17-(2-carboxamidino)-7,8-
didehydro-4,5-epoxymorphinan (106 mg, 19 mmol) in a 10 : 1 mixture
of acetonitrile and tetrahydrofuran was cooled in an ice bath, and 40%
aqueous HF (0.2 mL) was added dropwise. After stirring overnight
at ambient temperature, the reaction mixture was concentrated under
reduced pressure to give a light yellow solid, which was passed through
a short silica gel column using dichloromethane and methanol in 4 : 1
ratio as the eluent to give 5 as a white solid (64 mg, 98%), mp > 260◦C
(Found: m/z 314.1495. [M + H]+ requires 314.1504). δH (300 MHz,
(CD3)2SO) 7.42 (5H, br s), 6.52 (1H, d, J 8.0), 6.40 (1H, d, J 8.0), 5.63
(1H, d, J 9.9), 5.21 (1H, d, J 9.5), 4.74 (1H, d, J 5.7), 4.60 (1H, s), 4.15
(1H, d, J 2.6), 3.70 (1H, br s), 3.02 (1H, t, J 12.0), 2.85 (1H, m), 2.60
(2H, m), 2.02 (1H, td, J 12.0, 4.6), 1.78 (1H, d, J 12.7). δC (50 MHz,
(CD3)2SO) 155.77, 146.46, 139.08, 134.71, 129.65, 126.51, 123.11,
119.04, 117.05, 91.04, 66.07, 58.05, 52.16, 48.69, 43.11, 34.44, 28.86.
3,6-Bis(t-butyldimethylsiloxy)-17-[3-(2-carboxamidino)amino-
propyl]-7,8-didehydro-4,5-epoxymorphinan 14
Anhydrous dimethylformamide (2 mL) was added to a mixture of
compound 13 (0.20 g, 0.36 mmol), di(isopropyl)ethylamine (0.07 ml,
0.39 mmol), and 1H-pyrazole-1-carboxamidine hydrochloride (0.06 g,
0.39 mmol), and the reaction mixture was stirred at ambient tempera-
ture under N2 overnight. The mixture was evaporated to dryness under
reduced pressure and the residue was chromatographed on silica gel to
give 14 as a white solid (0.15 g, 72%) (Found: m/z 599.3790. [M + H]+
requires 599.3812). δH (200 MHz, CDCl3) 5.97 (1H, d, J 8.2), 5.86 (1H,
d, J 8.1), 5.03 (1H, d, J 9.6), 4.74 (1H, dt, J 9.6, 2.6), 4.13 (1H, dd, J 5.7,
1.2), 3.75(1H, m), 2.94(1H, m), 2.74(2H, m), 2.43(1H, d, J 18.8), 2.20–
1.75(6H, m), 1.49(1H, m), 1.25(3H, m), 0.40(9H, s), 0.38(9H, s), –0.37
(3H, s), –0.40 (3H, s), –0.42 (3H, s), –0.43 (3H, s). δC (50 MHz, CDCl3)
158.92, 150.89, 137.97, 134.72, 131.96, 129.20, 128.37, 122.31, 119.64,
93.61, 70.27, 57.33, 51.45, 49.00, 45.40, 41.69, 40.08, 36.42, 27.15,
26.41, 26.28, 22.47, 19.07, 18.99, –4.04, –4.39, –4.55.
Preparation of (5α,6α)-17-[3-(2-Carboxamidino)aminopropyl]-
7,8-didehydro-4,5-epoxymorphinan-3,6-diol 15
(5α,6α)-17-(2-Cyanoethyl)-7,8-didehydro-4,5-epoxymorphinan-
3,6-diol 11
Acrylonitrile (1.20 ml, 0.018 mol) was added to a suspension of normor-
phine 8 (1.00 g, 3.6 mmol) in absolute ethanol (20 mL), and the mixture
stirred for 2 days. The reaction mixture was evaporated under reduced
pressure and the solid residue was chromatographed on silica gel with
dichloromethane/methanol/25% ammonium hydroxide (9 : 2 : 0.2) to
give 11 as a white crystalline solid (0.49 g, 52%), mp 220◦C (Found:
m/z 325.1563. [M + H]+ requires 325.1552). δH (300 MHz, CDCl3)
6.12 (1H, d, J 8.1), 5.99 (1H, d, J 8.1), 5.18 (1H, dm, J 9.9), 4.84 (1H,
dt, J 9.8, 2.7), 4.37 (1H, dd, J 6.3, 1.3), 3.72 (1H, m), 3.02 (1H, dd,
J 6.2, 3.2), 2.87 (1H, q, J 1.6), 2.45 (2H, m), 2.34 (1H, t, J 6.0), 2.29
(1H, br d, J 5.8), 2.23 (2H, m), 2.17 (2H, t, J 6.4), 2.08 (1H, td, J 12.1,
3.4), 1.97 (1H, dd, J 18.6, 6.3), 1.62 (1H, td, J 12.4, 5.1), 1.41 (1H, m).
δC (75 MHz, CDCl3) 145.28, 137.62, 131.84, 130.27, 127.82, 125.25,
118.75, 118.43, 115.94, 90.97, 65.97, 57.07, 49.87, 43.66, 42.92, 40.00,
34.77, 21.71, 16.01.
(5α,6α)-17-[3-(2-Carboxamidino)aminopropyl]-7,8-didehydro-
4,5-epoxymorphinan-3,6-diol 15
Compound 14 was deprotected using 40% HF in a 10 : 1 mixture of ace-
tonitrile and tetrahydrofuran. The precipitate was filtered and washed
with acetonitrile, dichloromethane, and methanol. Compound 15 was
obtained as a white solid (70 mg, 73%), mp > 260◦C (Found: m/z
371.2077. [M + H]+ requires m/z 371.2082). δH (200 MHz, D2O) 6.70
(2H, m), 5.70 (1H, br s), 5.35 (1H, br s), 5.05 (1H, br s), 4.30 (1H,
s), 3.60–2.75 (10H, m), 2.40–1.85 (4H, m). δC (50 MHz, D2O) 157.50,
146.00, 138.99, 134.07, 130.31, 126.63, 124.23, 121.35, 118.64, 91.29,
66.67, 59.65, 52.68, 47.28, 42.95, 39.17, 39.10, 33.35, 24.34, 21.93.
3,6-Bis(t-butyldimethylsiloxy)-17-(2-cyanoethyl)-7,8-didehydro-
4,5-epoxymorphinan 12
Solid t-butyldimethylsilyl chloride (0.50 g, 3.2 mmol) was added in
small portions to a stirred solution of 11 (0.47 g, 1.4 mmol), imidazole
(0.25 g, 3.6 mmol), and 4-dimethylaminopyridine (0.09 g) in anhydrous
dimethylformamide (1.5 mL) under N2. Stirring was continued for 17 h,
and the reaction mixture was poured into water (25 mL) and then
extracted with dichloromethane (100 mL). The organic layer was dried
(K2CO3) and concentrated. The residue was chromatographed on sil-
ica gel using ethyl acetate/hexane (1 : 1) to give 12 as a white solid
(0.69 g, 90%), mp 128–129◦C (Found: m/z 553.327. [M + H]+ requires
553.328). δH (400 MHz, CDCl3) 6.53 (1H, d, J 8.1), 6.37 (1H, d, J 8.1),
5.56 (1H, dm, J 9.7), 5.18 (1H, dt, J 9.7, 2.8), 4.64 (1H, dd, J 5.6,
Preparation of N-[3-(2-Carboxamidino)aminopropyl]-6,14-endo-
ethano-7α-(2-hydroxyprop-2-yl)-tetrahydronororipavine 20
Preparation of N-(2-cyanoethyl)-6,14-endo-ethano-7α-
(2-hydroxyprop-2-yl)-tetrahydronororipavine 16
Acrylonitrile (0.25 mL, 3.80 mmol) was added dropwise to a suspension
of nordiprenorphine 9 (400 mg, 1.08 mmol) in absolute ethanol (10 mL)
and stirred at ambient temperature overnight. The reaction mixture was

434
K. R. Subasinghe et al.
evaporated to dryness and the residue was chromatographed on silica
gel using 1 : 1 ethyl acetate/hexane to give 16 as a white crystalline
solid (280 mg, 62%), mp 236–238◦C (Found: m/z 425.2450. [M + H]+
requires 425.2440). δH (400 MHz, CDCl3/CD3OD) 6.61 (1H, d, J 8.0),
6.44 (1H, d, J 8.0), 4.31 (1H, s), 3.93 (2H, br s), 3.49 (3H, s), 2.92–
2.76 (2H, m), 2.75–2.65 (2H, m), 2.65–2.55 (1H, m), 2.55–2.34 (4H,
m), 2.33 (1H, dd, J 18.3, 6.3), 1.99 (1H, td, J 12.2, 5.0), 1.87–1.58
(4H, m), 1.32 (3H, s), 1.13 (3H, s), 1.08–0.95 (2H, m), 0.70 (1H, m).
δC (100 MHz, CDCl3/CD3OD) 145.61, 137.95, 131.69, 126.25, 119.12,
118.69, 116.53, 97.10, 96.28, 80.23, 74.63, 59.74, 52.24, 50.41, 46.42,
44.88, 43.01, 35.78, 35.18, 31.80, 29.29, 28.90, 24.28, 24.07, 17.05.
J 18.6), 2.60 (8H, m), 1.60 (8H, m), 1.26 (3H, s), 1.07 (3H, s), 0.86
(9H, s), 0.62 (2H, m), 0.07 (3H, s), 0.03 (3H, s). δC (50 MHz, CD3OD)
158.94, 150.16, 137.81, 133.71, 130.43, 122.52, 120.41, 97.05, 81.45,
75.96, 59.94, 52.97, 51.91, 49.33, 48.58, 48.46, 44.66, 40.09, 37.23,
36.74, 33.04, 30.60, 29.51, 27.38, 26.16, 24.05, 19.09, –4.11, –4.44.
N-[3-(2-Carboxamidino)aminopropyl]-6,14-endo-ethano-7α-
(2-hydroxyprop-2-yl)-tetrahydronororipavine 20
Ammonium fluoride (37 mg, 1.0 mmol) was added to compound 19
(57 mg, 0.09 mmol) in methanol (10 mL) and the reaction mixture
was stirred overnight at ambient temperature. The solvent was evap-
orated and the residue was chromatographed on silica gel using
dichloromethane/methanol/ammonium hydroxide (9 : 2 : 0.1) to give
20 as a white solid (44 mg, 96%), mp 186–188◦C (Found: m/z 471.2956.
[M + H]+ requires 471.2971). δH (300 MHz, CD3OD) 6.64 (1H, d,
J 8.0), 6.52 (1H, d, J 8.0), 4.61 (1H, s), 4.39 (1H, s), 3.54 (3H, s), 3.29
(2H, m), 3.13 (2H, d, J 19.3), 2.78 (4H, m), 2.40 (2H, m), 2.15 (1H, m),
1.80 (6H, m), 1.38 (3H, s), 1.31 (1H, m), 1.21 (3H, s), 0.72 (1H, br).
δC (75 MHz, CD3OD) 158.89, 147.38, 139.87, 132.82, 127.27, 120.68,
118.33, 96.95, 81.15, 75.91, 60.33, 52.97, 52.18, 48.25, 47.56, 45.49,
39.97, 37.32, 35.78, 32.78, 30.61, 29.53, 26.77, 26.14, 24.28, 18.83.
3-(t-Butyldimethylsilyl)-N-(2-cyanoethyl)-6,14-endo-ethano-
7α-(2-hydroxyprop-2-yl)-tetrahydronororipavine 17
Compound 16 (0.65 g, 1.53 mmol) was dissolved in dry dimethyl-
formamide (5 mL) and imidazole (0.12 g, 1.7 mmol), and 4-
dimethylaminopyridine (0.10 g, 1.7 mmol) was added. TBDMSCl
(0.28 g, 1.84 mmol) was then added at ambient temperature under N2.
After stirring the mixture for 2 h at ambient temperature, distilled water
was added and the reaction mixture was extracted with dichloromethane.
The dichloromethane layer was dried (K2CO3) and evaporated under
reduced pressure, and the residue was chromatographed on silica gel
using ethyl acetate/hexane, 2 : 1, to give 17 as a white crystalline solid
(0.74 mg, 89%), mp 139–142◦C (Found: m/z 539.3296. [M + H]+
requires 539.3304). δH (300 MHz, CDCl3) 6.61 (1H, d, J 8.0), 6.46
(1H, d, J 8.0), 4.93 (1H, d, J 0.9), 4.34 (1H, s), 3.49 (3H, s), 2.90
(1H, d, J 18.4), 2.57–2.85 (4H, m), 2.85–2.28 (5H, m), 2.00 (1H, td,
J 12.5, 6.0), 1.86 (1H, t, J 10.5), 1.80–1.70 (2H, m), 1.63 (1H, dd,
J 13.0, 2.0), 1.34 (3H, s), 1.15 (3H, s), 1.11–0.98 (2H, m), 0.95 (9H, s),
0.71 (1H, m), 0.17 (3H, s), 0.13 (3H, s). δC (75 MHz, CDCl3) 149.06,
136.80, 132.30, 128.20, 121.39, 119.10, 118.68, 96.12, 80.42, 74.27,
60.04, 52.57, 50.84, 47.78, 46.64, 43.36, 36.06, 35.52, 32.14, 29.69,
29.66, 25.60, 25.56, 24.84, 24.44, 18.17, 17.47, –4.44, –4.76.
Preparation of N-[3-(2-Carboxamidino)aminopropyl]-
6,14-endo-ethano-7α-(1-hydroxy-1,2,2-trimethylpropyl)-
tetrahydronororipavine 21
N-(2-Cyanoethyl)-6,14-endo-ethano-7α-(1-hydroxy-
1,2,2-trimethylpropyl)tetrahydronororipavine
6,14-Endo-ethano-7α-(1-hydroxy-1,2,2-trimethylpropyl)tetrahydronor-
oripavine 10[11] (0.20 g, 0.48 mmol) in absolute ethanol (7.5 mL) was
added to acrylonitrile (0.06 mL, 0.97 mmol) and stirred overnight at
ambient temperature. The reaction mixture was evaporated to dryness
and the residue was purified by column chromatography on silica gel
using dichloromethane/methanol/ammonium hydroxide (9 : 1 : 0.1) to
give a white crystalline solid (0.20 g, 89%), mp 254–256◦C (Found: m/z
467.2895. [M + H]+ requires 467.2909). δH (300 MHz, CDCl3) 6.69
(1H, d, J 8.0), 6.51 (1H, d, J 8.0), 5.78 (1H, s), 5.08 (1H, br s), 4.45 (1H,
s), 3.50 (3H, s), 3.05–2.30 (10H, m), 2.20–1.60 (6H, m), 1.40 (1H, m),
1.33 (3H, s), 1.02 (9H, s), 0.68 (1H, br s). δC (50 MHz, CDCl3/CD3OD)
145.48, 137.97, 131.85, 126.27, 119.20, 118.62, 116.53, 95.90, 80.54,
79.74, 59.86, 52.14, 50.33, 45.65, 43.26, 42.99, 39.89, 35.77, 35.22,
32.94, 29.12, 25.87, 24.20, 19.64, 17.68, 17.10.
N-(3-Aminopropyl)-3-(t-butyldimethylsilyl)-6,14-endo-ethano-
7α-(2-hydroxyprop-2-yl)-tetrahydronororipavine 18
Compound 17 (0.74 g, 1.36 mmol) in ether (30 mL) was added to a
suspension of lithium aluminium hydride (0.26 g, 6.80 mmol) in anhy-
drous ether (20 mL). After stirring for 4 h at ambient temperature, the
reaction mixture was cooled in an ice bath and excess ether (15 mL)
was added. The reaction was quenched by adding Na2SO4·10H2O cau-
tiously. The white precipitate was filtered off and the filter cake was
washed with ether. The filtrate was concentrated and chromatographed
with 9 : 2 : 0.2 dichloromethane/methanol/ammonium hydroxide to give
18 as a white solid (0.58 mg, 78%), mp 76–78◦C (Found: m/z 543.3612.
[M + H]+ requires 543.3617). δH (300 MHz, CDCl3/CD3OD) 6.48
(1H, d, J 8.0), 6.33 (1H, d, J 8.0), 4.18 (1H, s), 3.37 (3H, s), 2.87 (1H, d,
J 18.5), 2.68–2.53 (4H, m), 2.42–2.25 (3H, m), 2.25–2.05 (2H, m),
1.90–1.40 (8H, m), 1.21 (3H, s), 1.01 (3H, s), 0.90 (1H, br s), 0.82
(9H, s), 0.60 (1H, s), 0.04 (3H, s), 0.00 (3H, s). δC (75 MHz,
CDCl3/CD3OD) 148.66, 136.30, 132.15, 128.73, 121.02, 118.88, 95.97,
80.28, 74.58, 58.93, 52.30, 52.28, 47.39, 46.68, 43.22, 39.69, 35.65,
35.35, 31.82, 30.00, 29.45, 28.91, 25.23, 24.38, 22.65, 17.87, 17.23,
–4.79, –5.12.
N-(3-Aminopropyl)-6,14-endo-ethano-7α-(1-hydroxy-
1,2,2-trimethylpropyl)tetrahydronororipavine
N-(2-Cyanoethyl)-6,14-endo-ethano-7α-(1-hydroxy-1,2,2-trimethyl-
propyl)tetrahydronororipavine (154 mg, 0.32 mmol) in ether (5 mL) and
THF (5 mL) was added to a suspension of lithium aluminum hydride
(0.12 g, 3.2 mmol). After the usual workup, the residue was purified
by column chromatography on silica gel, using dichloromethane/
methanol/ammonium hydroxide (9 : 1 : 0.1) (92 mg, 61%), mp 132◦C
(Found: m/z 471.3218. [M + H]+ requires 471.3222). δH (300 MHz,
CD3OD) 6.60 (1H, d, J 8.0), 6.46 (1H, d, J 8.0), 4.36 (1H, d, J 1.5),
3.57 (3H, s), 3.02 (1H, d, J 18.3), 2.90–2.70 (4H, m), 2.57 (1H, dd,
J 12.0, 5.0), 2.52–2.45 (2H, m), 2.33 (1H, dd, J 12.2, 3.6), 2.25 (1H,
dd, J 18.5, 6.5), 2.17 (1H, t, J 10.0), 1.97 (1H, td, J 12.7, 5.6), 1.80 (2H,
br), 1.67–1.55 (3H, m), 1.37 (1H, m), 1.35 (3H, s), 1.10 (1H, m), 1.00
(9H, s), 0.71 (1H, br). δC (75 MHz, CD3OD) 147.30, 139.85, 133.68,
128.41, 120.51, 118.05, 97.37, 82.27, 81.36, 60.76, 53.62, 53.01, 47.47,
44.57, 44.54, 41.27, 40.85, 37.33, 36.97, 34.75, 30.79, 30.16, 26.85,
23.94, 20.68, 19.26.
3-(t-Butyldimethylsilyl)-N-[3-(2-carboxamidino)-
aminopropyl]-6,14-endo-ethano-7α-(2-hydroxyprop-2-yl)-
tetrahydronororipavine 19
Anhydrous dimethylformamide (0.5 ml) was added to a mixture of
compound 18 (70 mg, 0.13 mmol), di(isopropyl)ethylamine (0.02 mL,
0.13 mmol), and 1H-pyrazole-1-carboxamidine hydrochloride (19 mg,
0.13 mmol), and the reaction mixture was stirred overnight at ambient
temperatureunderN2.Thesolventswereevaporatedunderreducedpres-
sure and the residue was chromatographed on silica gel using 9 : 1 : 0.1
dichloromethane/methanol/ammonium hydroxide to give 19 as a white
solid (57 mg, 76%). δH (200 MHz, CD3OD) 6.50 (1H, d, J 8.1), 6.39
(1H, d, J 8.1), 4.23 (1H, s), 3.39 (3H, s), 3.10 (2H, m), 2.93 (1H, d,
N-[3-(2-Carboxamidino)aminopropyl]-6,14-endo-ethano-7α-
(1-hydroxy-1,2,2-trimethylpropyl)tetrahydronororipavine 21
N-(3-Aminopropyl)-6,14-endo-ethano-7α-(1-hydroxy-1,2,2-trimethyl-
propyl)tetrahydronororipavine (92 mg, 0.19 mmol) in dimethylforma-
mide (1 mL) was added 1H-pyrazole-1-carboxamidine hydrochloride
(31.5 mg, 0.21 mmol) and di(isopropyl)ethylamine (0.041 mL, 0.23

Non-CNS Acting Opiates Bearing Guanidino Substituents
435
mmol). The solvents were removed under reduced pressure and the
residue was purified by column chromatography on silica gel, using
dichloromethane/methanol/ammonium hydroxide (9 : 2 : 0.2) (82 mg,
85%), mp 166–168◦C (Found: C 60.3, H 8.5, N 9.7, Cl 9.0%, m/z
513.3431. C29H44O4N4·1.5HCl · 0.5H2O requires C 60.4, H 8.1, N 9.7,
Cl 9.2%, [M + H]+ 513.3440). δH (300 MHz, CD3OD) 6.68 (1H, d,
J 8.0), 6.55 (1H, d, J 8.0), 4.44 (1H, s), 3.62 (3H, s), 3.11 (1H, d,
J 18.5), 2.98 (1H, d, J 6.0), 2.82 (1H, t, J 10.5), 2.75–2.45 (4H, m),
2.40 (1H, dd, J 18.6, 6.0), 2.24 (1H, t, J 9.6), 2.06 (1H, td, J 12.7, 5.3),
1.92–1.60 (5H, m), 1.55–1.47 (2H, m), 1.41 (3H, s), 1.27–1.15 (2H, m),
1.06 (9H, s), 0.78 (1H, t, J 12.0). δC (75 MHz, CD3OD) 158.94, 147.13,
139.65, 133.35, 128.01, 120.62, 118.08, 97.06, 82.06, 81.36, 59.65,
53.02, 51.62, 47.15, 45.03, 44.14, 41.30, 41.27, 39.89, 36.42, 34.53,
30.38, 27.31, 26.87, 24.11, 20.77, 19.22.
δC (75 MHz, CDCl3) 150.24, 150.18, 137.40, 134.60, 130.63, 129.57,
128.04, 126.98, 122.51, 121.80, 119.03, 118.39, 92.87, 69.45, 52.42,
45.22, 40.12, 40.06, 35.77, 28.86, 26.14, 26.03, 18.55, 18.47, –4.16,
–4.43, –4.50, –4.64.
(5α,6α)-17-(Nꢀ,Nꢀꢀ-Bisphenyl-2-carboxamidino)-7,8-didehydro-
4,5-epoxymorphinan-3,6-diol 25a
17-(Nꢀ,Nꢀꢀ-Bisphenyl-2-carboxamidino)-3,6-bis(t-butyldimethylsiloxy)-
7,8-didehydro-4,5-epoxymorphinan was deprotected using 10 equiv-
alents of ammonium fluoride in methanol. The crude material was
chromatographed on silica gel using dichloromethane/methanol/ammo-
nium hydroxide (9 : 1 : 0.1) to give 25a as a fine white powde+r (148 mg,
73%), mp 182◦C (Found: C 72.1, H 5.9, N 9.0. C29H27N3O3 requires
C 72.1, H 5.6, N 8.7%). δH (300 MHz, CD3OD) 7.19 (4H, t, J 8.3),
6.98 (4H, d, J 8.6), 6.91 (2H, t, J 7.4), 6.60 (1H, d, J 8.1), 6.48 (1H,
d, J 8.1), 5.66 (1H, br d, J 9.9), 5.22 (1H, dt, J 9.9, 2.9), 4.84 (1H, dd,
J 6.3, 1.1), 4.64 (1H, t, J 3.3), 4.21 (1H, m), 3.76 (1H, dd, J 13.6, 4.8),
3.16 (1H, td, J 13.3, 3.7), 2.90 (1H, d, J 18.5), 2.79 (1H, dd, J 18.7,
6.2), 2.70 (1H, m), 2.11 (1H, td, J 12.8, 5.2), 1.84 (1H, br d, J 12.9).
δC (75 MHz, CD3OD) 154.07, 147.74, 147.30, 140.57, 134.58, 131.58,
130.15, 129.08, 126.36, 123.22, 121.81, 120.89, 118.40, 92.99, 67.96,
54.88, 45.61, 41.30, 40.87, 36.52, 29.73.
Preparation of N-[3-(2-Carboxamidino)aminopropyl)-6,14-endo-
ethano-7α-(1-hydroxy-1,2,2-trimethylpropyl)tetrahydronorthebaine 22
6,14-Endo-ethano-7α-(1-hydroxy-1,2,2-trimethylpropyl)tetrahydronor-
thebaine was obtained using a literature procedure[11] and converted
into 22 following the same reaction scheme as for the preparation of
21 described above, mp 148–149◦C (Found: C 63.4, H 8.5, Cl 6.5,
N 10.0. C30H46O4N4 · HCl requires C 64.0, H 8.4, Cl 6.3, N 10.0%). δH
(300 MHz, CD3OD) 6.75 (1H, d, J 8.1), 6.58 (1H, d, J 8.1), 4.40 (1H, d,
J 1.9), 3.84 (3H, s), 3.55 (3H, s), 3.27–3.15 (2H, m), 3.10 (1H, d, J 18.5),
2.85–2.71 (2H, m), 2.65–2.25 (5H, m), 2.19 (1H, t, J 9.5), 2.00 (1H, td,
J 12.7, 5.7), 1.90–1.55 (5H, m), 1.42 (1H, m), 1.36 (3H, s), 1.15 (1H,
td, J 12.5, 6.0), 1.00 (9H, s), 0.71 (1H, br s). δC (300 MHz, CD3OD)
159.11, 148.42, 143.22, 133.94, 130.20, 120.72, 116.38, 97.50, 82.23,
81.38, 59.83, 57.75, 53.02, 51.79, 47.26, 44.89, 44.49, 41.37, 40.13,
37.33, 36.83, 34.79, 30.54, 27.68, 26.95, 24.19, 20.79, 19.31.
Preparation of (5α,6α)-17-[Nꢀ,Nꢀꢀ-Bis(4-Methoxyphenyl)-2-
carboxamidino]-7,8-didehydro-4,5-epoxymorphinan-3,6-diol 25b
17-[Nꢀ,Nꢀꢀ-Bis(4-methoxyphenyl)-2-carboxamidino]-3,6-bis(t-
butyldimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan
Compound 24 (400 mg, 0.80 mmol) was reacted with bis(4-
methoxyphenyl)-carbodiimide (264 mg, 1.04 mmol) in anhydrous DMF
to give the protected guanidine as a light brown solid (586 mg, 97%),
mp 168–172◦C (Found: m/z 754.4072. [M + H]+ requires 754.4071).
δH (400 MHz, CD3OD) 7.11 (4H, d, J 9.0), 6.86 (4H, d, J 9.0), 6.59
(1H, d, J 8.1), 6.50 (1H, d, J 8.1), 5.64 (1H, d, J 9.8), 5.23 (1H, dt, J 9.7,
2.7), 4.74 (2H, dd, J 5.7, 1.2), 4.35 (1H, m, J 7.8), 3.82 (1H, m), 3.74
(6H, s), 3.35 (1H, dd, J 13.4, 3.2), 2.8–2.9 (2H, m), 2.72 (1H, m), 2.17
(1H, td, J 13.0, 5.2), 1.89 (1H, dd, J 13.8, 2.6), 0.98 (9H, s), 0.95 (9H,
s), 0.18 (3H, s), 0.17 (3H, s), 0.14 (6H, s). δC (75 MHz, CD3OD) 159.68,
155.91, 151.49, 138.95, 136.04, 131.53, 131.16, 127.80, 126.86, 125.82,
123.35, 120.32, 115.98, 93.61, 70.36, 57.26, 56.18, 48.51, 43.22, 40.99,
36.47, 30.82, 26.62, 26.45, 19.34, 19.29, –3.92, –4.26, –4.28, –4.47.
3,6-Bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan 24
t-Butyldimethylsilyl chloride (1.81 g, 12.0 mmol) was added in small
portions to a solution of normorphine 8 (1.50 g, 5.5 mol), imidazole
(1.00 g, 14.0 mol), and 4-(dimethylamino)pyridine (1.25 g, 10.0 mmol)
in anhydrous DMF (10 mL) under N2. After stirring for 4 h at ambi-
ent temperature, the reaction mixture was poured into water (25 mL)
and then extracted with dichloromethane. The organic layer was dried
(K2CO3) and concentrated. The residue was chromatographed on silica
gel using dichloromethane/methanol/ammonium hydroxide (9 : 2 : 0.2)
to give 24 as white crystalline solid (1.56 g, 57%), mp 105◦C (Found:
C 67.3, H 9.1, N 3.0, Si 11.3. C28H45NO3Si2 requires C 67.3, H 9.1,
N 2.8, Si 11.2%). δH (300 MHz, CDCl3) 6.54 (1H, d, J 8.0), 6.38
(1H, d, J 8.0), 5.58 (1H, d, J 9.8), 5.16 (1H, dt, J 9.6, 2.7), 4.61 (1H,
dd, J 5.6, 1.3), 4.19 (1H, m), 3.61 (1H, s), 3.00 (1H, m), 2.60–2.88 (5H,
m), 2.52 (1H, m), 1.87–1.50 (2H, m), 0.95 (9H, s), 0.91 (9H, s), 0.18
(3H, s), 0.11 (3H, s), 0.10 (3H, s), 0.08 (3H, s). δC (75 MHz, CDCl3)
149.03, 136.10, 133.03, 130.12, 127.14, 126.44, 120.32, 117.52, 92.17,
68.24, 50.82, 43.82, 40.64, 37.31, 35.65, 30.59, 24.91, 24.82, 17.32,
17.26, –4.47, –5.38, –5.67, –5.76.
(5α,6α)-17-[Nꢀ,Nꢀꢀ-Bis(4-methoxyphenyl)-2-carboxamidino]-
7,8-didehydro-4,5-epoxymorphinan-3,6-diol 25b
17-[Nꢀ,Nꢀꢀ-Bis(4-methoxyphenyl)-2-carboxamidino]-3,6-bis(t-butyl-
dimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan was deprotected
with ammonium fluoride and the crude material was chromatographed
on silica gel using dichloromethane/methanol/ammonium hydroxide
(9 : 2 : 0.2) to give 25b as a white solid. (390 mg, 95%), mp 158◦C
(Found: C 70.5, H 5.9, N 7.9%, m/z 526.2334. C31H31N3O5 requires
C 70.8, H 5.9, N 8.0%, [M + H]+526.2342). δH (400 MHz, CD3OD)
6.95–6.90 (4H, m), 6.82–6.77 (4H, m), 6.55 (1H, d, J 8.1), 6.44 (1H,
d, J 8.1), 5.62 (1H, dm, J 9.8), 5.16 (1H, dt, J 9.8, 2.7), 4.81 (1H, d,
J, 1.2), 4.56 (1H, t, J 4.6), 4.16 (1H, m), 3.71 (6H, s), 3.68 (1H, m), 3.11
(1H, td, J 13.2, 3.5), 2.83 (1H, d, J 18.4), 2.75 (1H, dd, J 18.7, 6.5),
2.58 (1H, m), 2.03 (1H, td, J 12.7, 5.1), 1.82 (1H, dd, J 13.0, 2.0). δH
(100 MHz, CD3OD) 157.24, 155.27, 147.61, 140.43, 138.96, 134.51,
131.37, 128.79, 126.07, 123.69, 120.74, 118.28, 115.55, 92.82, 67.83,
55.96, 55.08, 45.43, 41.36, 40.77, 36.35, 29.59.
Preparation of (5α,6α)-17-(Nꢀ,Nꢀꢀ-Bisphenyl-2-carboxamidino)-
7,8-didehydro-4,5-epoxymorphinan-3,6-diol 25a
17-(Nꢀ,Nꢀꢀ-Bisphenyl-2-carboxamidino)-3,6-bis-
(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan
Diphenylcarbodiimide (150 mg, 0.77 mmol) in anhydrous DMF (1 mL)
was added to 24 (250 mg, 0.52 mmol) in anhydrous DMF (2 mL) under
N2 and the solution was stirred at ambient temperature for 5 h. The
DMF was removed under reduced pressure and the resulting viscous oil
was chromatographed on silica gel using dichloromethane/methanol/
ammonium hydroxide (9 : 1 : 0.1) to give the protected guanidine as a
colourless oil (303 mg, 86%) (Found: m/z 694.3857. [M + H]+ requires
694.3860). δH (300 MHz, CDCl3) 7.37–7.22 (4H, m), 7.08–6.88 (6H,
m), 6.62 (1H, d, J 8.1), 6.46 (1H, d, J 8.1), 5.65 (2H, d, J 9.8), 5.52
(1H, br s), 5.22 (1H, dt, J 9.7, 2.8), 4.76 (1H, dd, J 6.2, 3.2), 4.70
(1H, dd, J 5.7, 1.2), 4.28 (1H, m), 3.67 (1H, dd, J 13.8, 4.5), 3.11 (1H,
td, J 13.4, 3.5), 3.00 (1H, d, J 18.7), 2.84 (1H, dd, J 18.8, 6.8), 2.69
(1H, m), 1.98 (1H, td, J 12.7, 5.0), 1.83 (1H, br d, J 12.6), 0.96 (9H,
s), 0.91 (9H, s), 0.24 (3H, s), 0.17 (3H, s), 0.17 (3H, s), 0.15 (3H, s).
Preparation of (5α,6α)-17-[Nꢀ,Nꢀꢀ-Bis(p-tolyl)-2-carboxamidino]-
7,8-didehydro-4,5-epoxymorphinan-3,6-diol 25c
17-[Nꢀ,Nꢀꢀ-Bis(p-tolyl)-2-carboxamidino]-3,6-bis
(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan
A suspension of 1,3-di-p-tolylcarbodiimide (122 mg, 0.55 mmol) in
anhydrous dimethylformamide was added to a solution of compound 24
(250 mg, 0.50 mmol) in anhydrous dimethylformamide (2 mL). After

436
K. R. Subasinghe et al.
stirring the mixture overnight at ambient temperature under N2, the
dimethylformamide was removed under reduced pressure. The residue
was chromatographed on silica gel using ethyl acetate/hexane (1 : 1) to
give the protected guanidine as a thick colourless liquid (356 mg, 98%)
(Found: m/z 722.4167. [M + H]+ requires 722.4172). δH (300 MHz,
CDCl3) 7.04 (4H, d, J 7.8), 6.83 (4H, br s), 6.58 (1H, d, J 8.1), 6.42
(1H, d, J 8.1), 5.62 (1H, d, J 9.7), 5.45 (1H, br s), 5.20 (1H, dt, J 9.5,
2.6), 4.73 (1H, m), 4.67 (1H, dd, J 5.7, 1.2), 4.23 (1H, m), 3.60 (1H, dd,
J 13.6, 4.2), 3.04 (1H, td, J 13.3, 3.0), 2.96 (1H, d, J 18.8), 2.79 (1H,
dd, J 18.8, 6.7), 2.64 (1H, t, J 2.4), 2.27 (6H, s), 1.94 (1H, td, J 12.0,
5.0), 1.78 (1H, d, J 12.0), 0.98 (9H, s), 0.95 (9H, s), 0.22 (3H, s), 0.15
(3H, s), 0.14 (3H, s), 0.12 (3H, s). δC (75 MHz, CDCl3) 160.72, 150.36,
149.89, 137.01, 134.16, 131.45, 130.37, 129.78, 127.86, 126.79, 121.43,
118.70, 92.57, 69.14, 51.96, 44.91, 39.81, 39.64, 35.47, 28.52, 25.82,
25.72, 20.59, 18.23, 18.15, –4.48, –4.74, –4.81, –4.96.
methylene chloride. The methylene chloride layer was dried (Na2SO4)
and concentrated. Chromatography on silica gel using methylene chlo-
ride/methanol/ammonium hydroxide (9 : 2 : 0.2) gave the guanidine as
a white solid (104 mg, 48%). δH (300 MHz, CDCl3) 7.27 (4H, m), 7.06
(4H, d, J 7.4), 7.01 (2H, t, J 7.3), 6.60 (1H, d, J 8.1), 6.38 (1H, d,
J 8.1), 5.54 (1H, d, J 9.8), 5.16 (1H, dt, J 9.7, 2.6), 4.6 (3H, br),
4.51 (2H, dd, J 16.0, 1.0), 4.10 (1H, m), 3.55 (1H, m), 3.44 (1H, m),
3.30 (1H, m), 2.62 (3H, m), 2.27 (2H, m), 2.12 (1H, t, J 2.4), 1.75
(2H, m), 1.65 (1H, d, J 11.9), 1.45 (1H, td, J 12.5, 4.9), 0.96 (9H, s),
0.18 (3H, s), 0.16 (3H, s). δC (75 MHz, CDCl3) 154.30, 149.31, 146.15,
138.25, 132.92, 130.35, 129.28,128.28, 125.51, 122.79, 122.51, 118.81,
116.73, 92.14, 68.58, 57.57, 54.15, 44.13, 43.79, 42.12, 40.47, 35.02,
25.78, 25.50, 21.39, 18.29, –4.76, –4.82.
(5α,6α)-17-[3-(Nꢀ,Nꢀꢀ-Bisphenyl-2-carboxamidino)aminopropyl]-
7,8-didehydro-4,5-epoxymorphinan-3,6-diol 27b
(5α,6α)-17-[Nꢀ,Nꢀꢀ-Bis(p-tolyl)-2-carboxamidino]-
7,8-didehydro-4,5-epoxymorphinan-3,6-diol 25c
Compound 26b (220 mg, 0.34 mmol) in methanol (8 mL) was added
to ammonium fluoride (128 mg, 3.4 mmol) and the mixture was
stirred overnight. The reaction mixture was evaporated and the white
solid was chromatographed on silica gel using methylene chlo-
ride/methanol/ammonium hydroxide (9 : 2 : 0.2) to give 27b as a white
powder (109 mg, 61%), mp 126–128◦C (Found: C 71.2, H 6.6, N 10.4%,
m/z 523.270. C32H34N4O3 · H2O requires C 71.1, H 6.7, N 10.4%,
[M + H]+ requires 523.271). δH (400 MHz, CD3OD) 7.28 (4H, m),
7.12 (4H, m), 7.06 (2H, m), 6.49 (1H, d, J 8.1), 6.38 (1H, d, J 8.1),
5.55 (1H, dm, J 9.9), 5.19 (1H, dt, J 9.8, 3.0), 4.60 (1H, dd, J 6.3,
1.2), 4.05 (1H, m), 3.50–3.30 (3H, m), 2.85 (1H, d, J 18.7), 2.65 (3H,
m), 2.35–2.20 (2H, m), 2.19 (1H, m), 1.80 (2H, m), 1.60 (2H, m). δC
(100 MHz, CD3OD) 153.55, 147.40, 144.11, 140.20, 133.57, 132.11,
130.42, 129.76, 126.92, 124.77, 124.11, 120.46, 117.91, 92.77, 67.86,
58.81, 54.66, 45.52, 44.76, 43.08, 41.66, 36.27, 26.93, 22.41.
17-[Nꢀ,Nꢀꢀ-Bis(p-tolyl)-2-carboxamidino]-3,6-bis(t-butyldimethylsi-
loxy)-7,8-didehydro-4,5-epoxy-morphinan was deprotected using 10
equivalents of ammonium fluoride in methanol. The crude material was
chromatographed on silica gel using dichloromethane/methanol/ammo-
nium hydroxide (9 : 1 : 0.1) to give 25c as a white solid (247 mg,
93%), mp 156–158◦C (Found: C 74.9, H 6.4, N 8.3%, m/z 494.244.
C31H31N3O3 requires C 75.4, H 6.3, N 8.5%, [M + H]+ 494.244). δH
(300 MHz, CD3OD) 7.00 (4H, d, J 8.1), 6.85 (4H, d, J 8.3), 6.55 (1H,
d, J 8.1), 6.42 (1H, d, J 8.1), 5.60 (1H, d, J 9.8), 5.14 (1H, dt, J 9.5,
2.6), 4.79 (1H, dd, J 6.3, 1.1), 4.56 (1H, br), 4.15 (1H, m), 3.65 (1H,
br d, J 14.5), 3.07 (1H, td, J 13.0, 3.5), 2.83 (1H, d, J 18.4), 2.73 (1H,
dd, J 18.4, 6.0), 2.61 (1H, t, J 2.5), 2.21 (6H, s), 2.03 (1H, td, J 12.7,
5.1), 1.78 (1H, d, J 11.2). δC (75 MHz, CD3OD) 154.40, 147.56, 143.66,
140.33, 134.46, 133.15, 131.35, 130.64, 128.80, 126.08, 121.94, 120.73,
118.25, 92.77, 67.78, 54.88, 45.37, 41.29, 40.68, 36.28, 29.55, 20.78.
Preparation of (5α,6α)-17-[3-(Nꢀ,Nꢀꢀ-Bis(p-tolyl)-2-carboxamidino)-
aminopropyl]-7,8-didehydro-4,5-epoxymorphinan-3,6-diol 27c
Preparation of (5α,6α)-17-[3-(Nꢀ,Nꢀꢀ-Bisisopropyl-2-carboxamidino)-
aminopropyl]-7,8-didehydro-4,5-epoxymorphinan-3,6-diol 27a
17-[3-(Nꢀ,Nꢀꢀ-Bis(p-tolyl)-2-carboxamidino-aminopropyl]-3,6-
bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan 26c
17-(3-Aminopropyl)-3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-
epoxymorphinan 13 (193 mg, 0.35 mmol)in dimethylformamide (2 mL)
was added a solution of diisopropylcarbodiimide (66 mg, 0.52 mmol)
in dimethylformamide (2 mL) under N2, and the solution was
stirred overnight at ambient temperature. The dimethylformamide
was removed under reduced pressure and the residue was chro-
matographed on silica gel using dichloromethane/methanol (4 : 1)
to give 17-[3-(Nꢀ,Nꢀꢀ-bis-isopropyl-2-carboxamidino)aminopropyl]-
3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan26a
(120 mg, 91%). This compound was deprotected using NH4F (70 mg,
1.76 mmol) in methanol (3 mL) to give 27a as white solid (76 mg, 95%),
mp 170–172◦C (Found: m/z 455.3014. [M + H]+ requires 455.3021).
δH (300 MHz, CD3OD) 6.53 (1H, d, J 8.1), 6.42 (1H, d, J 8.1), 5.61
(1H, d, J 9.7), 5.27 (1H, d, J 9.7), 4.16 (1H, d, J 2.5), 3.83 (2H, m),
3.70 (1H, br s), 3.36 (2H, t, J 6.7), 3.26 (1H, m), 3.01 (1H, d, J 19.0),
2.82 (4H, m), 2.55 (2H, m), 2.17 (1H, m), 1.92–1.77 (3H, m), 1.24
(6H, s), 1.22 (6H, s). δC (75 MHz, CD3OD) 154.56, 147.43, 140.03,
134.39, 131.57, 128.64, 126.05, 120.68, 118.18, 92.71, 67.83, 58.77,
52.68, 46.38, 45.55, 44.63, 40.73, 35.49, 26.79, 22.95, 22.81.
1,3-Di-p-tolylcarbodiimide (109 mg, 0.49 mmol) was added to a solu-
tion of compound 13 (250 mg, 0.45 mmol) in anhydrous dimethyl-
formamide (5 mL), and the reaction mixture was stirred overnight
under N2. The dimethylformamide was removed under reduced pres-
sure and the residue was chromatographed on silica gel using 9 : 1 : 0.1
dichloromethane/methanol/ammonium hydroxide to give a thick liquid
(319 mg, 91%). δH (300 MHz, CDCl3) 7.02(4H, d, J 8.3), 6.76 (4H, d,
J 8.2), 6.50 (1H, d, J 8.0), 6.32 (1H, d, J 8.0), 5.76 (2H, br s), 5.52 (1H,
d, J 9.6), 5.10 (1H, dt, J 9.7, 2.5), 4.45 (1H, d, J 5.1), 4.05 (1H, m), 3.42
(2H, m), 2.26 (1H, m), 2.78 (1H, d, J 18.1), 2.58 (2H, t, J 5.8), 2.52
(1H, dd, J 12.3, 3.9), 2.24 (6H, s), 2.30–2.18 (2H, m), 2.14 (1H, m),
1.70 (2H, m), 1.59 (1H, d, J 11.5), 1.40 (1H, td, J 12.4, 4.7), 0.94 (9H,
s), 0.92 (9H, s), 0.17 (3H, s), 0.12 (3H, s), 0.10 (3H, s), 0.09 (3H, s).
δC (75 MHz, CDCl3) 150.03, 149.69, 140.97, 136.82, 133.40, 132.60,
130.92, 129.71, 128.22, 127.06, 122.85, 121.02, 118.27, 92.38, 69.11,
57.37, 53.75, 44.08, 43.98, 41.80, 40.71, 35.11, 25.67, 25.61, 25.44,
21.76, 20.64, 18.16, 18.08, –4.63, –4.77, –5.00.
(5α,6α)-17-[3-(Nꢀ,Nꢀꢀ-Bis(p-tolyl)-2-carboxamidino)-
aminopropyl]-7,8-didehydro-4,5-epoxymorphinan-3,6-diol 27c
Preparation of (5α,6α)-17-[3-(Nꢀ,Nꢀꢀ-Bisphenyl-2-carboxamidino)-
aminopropyl]-7,8-didehydro-4,5-epoxymorphinan-3,6-diol 27b
Ammonium fluoride (152 mg, 4.1 mmol) was added to a solution
of compound 26c (319 mg, 0.41 mmol) in methanol (10 mL), and the
reaction mixture was stirred overnight at ambient temperature. Solvent
evaporation followed by chromatography on silica gel using 9 : 2 : 0.2
dichloromethane/methanol/ammonium hydroxide gave 27c as a white
solid (224 mg, 99%), mp 128–129◦C (Found: C 73.0, H 6.8, N 9.8%,
m/z 551.3010. C34H38N4O3·0.5H2O requires C 73.0, H 7.0, N 10.0%,
[M + H]+ 551.3021). δH (300 MHz, CD3OD) 7.21 (4H, d, J 8.5), 7.15
(4H, d, J 8.5), 6.51 (1H, d, J 8.1), 6.38 (1H, d, J 8.1), 5.57 (1H, dm,
J 9.9), 5.19 (1H, dt, J 9.7, 2.6), 4.58 (1H, dd, J 6.3, 1.1), 3.98 (1H, m),
3.51 (2H, m), 3.39 (1H, m), 2.83 (1H, d, J 18.7), 2.75–2.61 (3H, m),
2.31 (6H, s), 2.37–2.30 (2H, m), 2.16 (1H, m), 1.82 (2H, m), 1.65–1.48
17-[3-(Nꢀ,Nꢀꢀ-Bisphenyl-2-carboxamidino)aminopropyl]-6-(t-
butyldimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan-3-ol 26b
Compound 13 (187 mg, 0.34 mmol) was added to a stirred suspension
of NaH (60% in oil, 16 mg, 0.40 mmol) in anhydrous dimethylfor-
mamide (2 mL) under N2. After stirring the mixture for 10 min,
a solution of diphenylcarbodiimide (97 mg, 0.50 mmol) in dimethyl-
formamide (2 mL) was added dropwise over 10 min. The carbodiimide
was prepared from 1,3-diphenylurea using the Burgess reagent.[14]
After stirring for 4 h at ambient temperature, the reaction mixture was
diluted with aqueous ammonium chloride (15 mL) and extracted with

Non-CNS Acting Opiates Bearing Guanidino Substituents
437
(2H, m). δC (75 MHz, CD3OD) 155.29, 147.36, 140.06, 137.43, 136.43,
133.63, 131.96, 131.41, 129.61, 126.84, 125.72, 120.49, 117.92, 92.80,
67.87, 58.40, 53.50, 45.38, 44.75, 42.96, 41.54, 36.06, 26.52, 22.65,
21.01.
Preparation of 3-[4-(2-Carboxamidino)aminobutyl]-6,14-endo-
ethano-7α-(2-hydroxyprop-2-yl)tetrahydrooripavine 32
The diprenorphine analogue 6c was prepared by a literature method[10]
and was converted into the guanidine 32 using the reaction sequence
outlined in Scheme 14. The guanidine was obtained as a thick liquid
(Found: m/z 499.3271. [M + H]+ requires 499.3284). δH (300 MHz,
CD3OD) 6.86 (1H, d, J 8.1), 6.70 (1H, d, J 8.2), 4.51 (1H, d, J 1.7),
4.14 (2H, dm, J 17.09), 3.52 (3H, s), 3.36 (1H, d, J 19.5), 3.26 (2H, t, J
6.6), 3.10 (1H, m), 2.92 (1H, m), 2.84 (3H, s), 2.78 (1H, m), 2.74 (1H,
m), 2.28 (1H, m), 1.98 (1H, t, J 9.5), 1.80 (7H, m), 1.47 (1H, m), 1.39
(3H, s), 1.33 (1H, m), 1.25 (3H, s), 0.78 (1H, m). δC (75 MHz, CD3OD)
159.40, 149.82, 143.62, 132.44, 127.48, 122.34, 119.93, 96.31, 81.03,
76.26, 71.76, 65.63, 53.79, 48.63, 47.98, 46.43, 44.16, 43.13, 38.10,
34.40, 32.63, 31.31, 30.36, 28.50, 27.83, 27.62, 26.48, 19.76.
Preparation of N-[3-(Nꢀ,Nꢀꢀ-Bisphenyl-2-carboxamidino)-
aminopropyl]-6,14-endo-ethano-7α-(2-hydroxyprop-2-yl)-
tetrahydronororipavine 29
A solution of diphenylcarbodiimide (134 mg, 0.69 mmol) in dimethyl-
formamide (2 mL) was added to a solution of compound 18 (250 mg,
0.46 mmol) in anhydrous dimethylformamide (2 mL), and the reac-
tion mixture was stirred overnight at room temperature. Evaporation
and chromatography on silica gel using dichloromethane/methanol/
ammonium hydroxide (9 : 1 : 0.1) gave the protected guanidine 26 as
a white solid (230 mg, 68%). This compound was deprotected with
10 equivalents of NH4F in methanol. Solvent evaporation followed
by chromatography on silica gel using dichloromethane/methanol/
ammonium hydroxide (9 : 1 : 0.1) gave 29 as a white solid (180 mg,
96%), mp 134–136◦C (Found: C 73.1, H 7.3, N 9.0%, m/z 623.359.
C38H46N4O4 requires C 73.3, H 7.4, N 9.0%, [M + H]+ 623.359). δH
(400 MHz, CD3OD) 7.29 (4H, m), 7.12 (4H, m), 7.06 (2H, m), 6.60
(1H, d, J 8.0), 6.46 (1H, d, J 8.0), 4.23 (1H, s), 3.51 (3H, s), 3.39 (1H,
m), 3.00 (1H, d, J 18.4), 2.73 (1H, d, J 6.3), 2.58 (1H, t, J 12.0), 2.5
(3H, m), 2.27 (2H, m), 1.71 (7H, m), 1.51 (1H, d, J 13.1), 1.29 (3H, s),
1.02 (3H, s), 1.02 (2H, m), 0.70 (1H, m). δC (100 MHz, CD3OD) 153.97,
147.33, 143.20, 139.71, 133.41, 130.45, 128.26, 125.14, 124.33, 120.40,
118.04, 97.50, 81.50, 75.96, 60.24, 52.96, 52.58, 49.85, 48.61, 47.96,
44.70, 41.24, 37.24, 36.64, 33.05, 30.60, 29.74, 27.67, 25.81, 23.78,
18.79.
Pharmacology
Pharmacology was carried out by MDS Pharma Services, Taiwan, a
laboratory that operates in general accordance with the International
Guiding Principles for Biomedical Research Involving Animals.
Phenylquinone (PQ) Writhing
The compounds were evaluated for possible analgesic activity in an ani-
mal model of peripheral pain—the PQ-induced abdominal-constriction
test in mice.[21] Groups of three male or female ICR mice (an outbred
strain of albino mice) weighing 22 2 g were employed. Various doses
(1, 2, 4, 8, 16, 32, 64, and 128 mg kg−1) of test substances were admin-
istered intraperitoneally. Vehicle consisting of 2% Tween 80 in 0.9%
NaCl was used for intraperitoneal injection. The control group received
vehicle alone. PQ at a dose of 2 mg kg−1 was injected intraperitoneally
30 min after the test substance and the number of constrictions exhibited
during the following 5–10 min period was recorded. Reduction in the
number of constrictions by 50% or more relative to the vehicle-treated
group indicated possible analgesic activity.
Preparation of (5α,6α)-7,8-Didehydro-4,5-epoxy-17-[3-(N-phenyl-
2-carboxamidino)aminopropyl)morphinan-3,6-diol 30
Compound 13 (137 mg, 0.24 mmol) in a mixture of acetonitrile (1 mL)
andtetrahydrofuran(2 mL)wasaddedtoN-phenylaminoiminomethane-
sulfonic acid[15] (50 mg, 0.24 mmol). After stirring the mixture
overnight at ambient temperature, the pH was adjusted to 12 with
1 M NaOH. The solvents were evaporated, water (10 mL) was added,
and the mixture extracted with dichloromethane. Solvent evapora-
tion followed by chromatography [on silica gel with dichloromethane/
methanol/ammonium hydroxide (9 : 2 : 0.2 and then 4 : 2 : 2)] gave 3,6-
bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-[3-(N-phenyl-
2-carboxamidino)aminopropyl]morphinan as a white solid (119 mg,
0.17 mmol, 77%). This compound was deprotected using 10 equiv-
alents of 48% HF in 4 : 1 acetonitrile/tetrahydrofuran (10 mL) and
purified by chromatography on silica gel using methylene chloride/
methanol/ammonium hydroxide (9 : 2 : 0.2) to give 30 as a white solid
(81 mg, 94%), mp 128◦C (Found: m/z 447.2399. [M + H]+ requires
447.2396). δH (300 MHz, CD3OD) 7.46 (2H, m), 7.30 (3H, m),
6.57 (1H, d, J 8.0), 6.47 (1H, d, J 8.0), 5.65 (1H, dm, J 9.7),
5.30 (1H, dt, J 9.7, 2.6), 4.19 (1H, m), 3.85 (1H, br s), 3.43 (2H,
t, J 6.5), 3.10–2.95 (4H, m), 2.77–2.55 (3H, m), 2.12 (1H, td,
J 13.0, 4.8), 1.99 (2H, m), 1.85 (1H, br s). δC (75 MHz, CD3OD)
157.20, 147.33, 140.10, 136.28, 134.51, 131.22, 131.12, 128.62, 128.07,
126.56, 125.43, 120.82, 118.30, 92.42, 67.61, 59.13, 52.19, 46.13,
44.26, 40.66, 40.06, 34.69, 26.08, 23.11.
Straub Tail Response
Straub tail is a typical reaction to the administration of morphine, in
which the tail becomes rigid and erect across the back of the animal.[17]
The mice were tested for the presence or absence of this reaction.
Acknowledgments
We thank Polychip Pharmaceuticals for financial support,
the Australian Research Council for supporting the Spe-
cial Research Centre for Green Chemistry, and Tasmanian
Alkaloids and Glaxo for the gifts of morphine and thebaine.
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Morphine 1 was converted into 31 using the reaction scheme outlined
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