Approaches to short-acting neuromuscular blocking agents: Nonsymmetrical bis-tetrahydroisoquinolinium mono- and diesters

Article abstract of DOI:10.1021/jm950477z

Nonsymmetrical bisquaternary mono- and diesters combining the potency- enhancing properties of the (1R)-laudanosinium group with a second unhindered quaternary ammonium moiety have been studied as a means of promoting short action with high-potency neuromuscular block. Atracurium-related nonsymmetrical diesters showed high potency, freedom from vagal blockade at neuromuscular blocking doses, and short action. Nonsymmetrical monoesters were short acting but showed varying degrees of vagal block.

Full text of DOI:10.1021/jm950477z

556
J . Med. Chem. 1996, 39, 556-561
Ap p r oa ch es to Sh or t-Actin g Neu r om u scu la r Block in g Agen ts: Non sym m etr ica l
Bis-tetr a h yd r oisoqu in olin iu m Mon o- a n d Diester s
Nirmal C. Dhar,† Robert B. Maehr,‡ Luke A. Masterson,† J ohn M. Midgley,*,† J ohn B. Stenlake,† and
William B. Wastila‡
Department of Pharmaceutical Sciences, University of Strathclyde, George Street, Glasgow G1 1XW, Scotland, and
The Wellcome Research Laboratories, Burroughs Wellcome Company, 3030 Cornwallis Road,
Research Triangle Park, North Carolina 27709
Received J une 29, 1995X
Nonsymmetrical bisquaternary mono- and diesters combining the potency-enhancing properties
of the (1R)-laudanosinium group with a second unhindered quaternary ammonium moiety have
been studied as a means of promoting short action with high-potency neuromuscular block.
Atracurium-related nonsymmetrical diesters showed high potency, freedom from vagal blockade
at neuromuscular blocking doses, and short action. Nonsymmetrical monoesters were short
acting but showed varying degrees of vagal block.
Ch a r t 1
In tr od u ction
Studies of the effects of structural, electronic, and
steric factors on the duration and potency of short-acting
neuromuscular blocking agents1-4 have shown that a
relatively short duration of action can be achieved in
such compounds as the symmetrical bisquaternary ester
1 but at the expense of inadequate potency and an
undesirable level of vagal blockade.
In the present study, the nonsymmetrical bisquater-
nary diesters 2 embody the advantages of the (1R)-
laudanosinium function with respect to potency and
freedom from vagal block.1 However, the 1-(3,4-
dimethoxybenzyl) group hinders attack at adjacent
â-CH and â-ester functions and could thereby increase
the duration of neuromuscular blockade. The nonsym-
metrical bisquaternary monoesters 3 and 4 attempt to
overcome this disadvantage. In these, the (1R)-laudano-
sinium unit is distanced from a single ester function and
linked through it to either an unhindered 1,2,3,4-
tetrahydroisoquinolinium function (3), typical of com-
pound 1, or a rigid 6-O-methylcodeinium group (4).
Accordingly, the countereffect on Hofmann elimina-
tion and hydrolysis (and hence duration) of the potency-
enhancing 1-(3,4-dimethoxybenzyl) group should be
removed. However, the single â-quaternary ester func-
tion retains the potential for facile Hofmann elimination
and unhindered rapid ester hydrolysis in vivo. The bis-
(1R)-laudanosinium monoester 5 provides a direct com-
parison with (1R,1′R)-atracurium (6a ).5
nonsymmetrical ditertiary bases 10 and 11, respectively,
followed by quaternization. The monoesters 3a -e
(Scheme 2, Table 1) were obtained from (1R)-tetrahy-
dropapaverine (12) (or its racemate 13) via the amino
alcohols 14-16, the acrylate esters 17-19, and the
nonsymmetrical diamino esters 20-23. 6-O-Methyl-
norcodeine (24) was prepared from 6-O-methylcodeine8
via 6-O-methylnorcodeine N-phenylcarbamate. Reac-
tion of the latter with hydrazine hydrate, as described
for the N-demethylation of codeine,9 yielded 24. Addi-
tion of 24 to 17 produced the diamino ester 25 (Scheme
3). Similar addition of 12 to 17 gave 26 (Scheme 4).
The amino alcohol 28, which was obtained by reduc-
tion of ethyl 4-N-[(1R)-tetrahydropapaverin-2-yl]succi-
namide (27), was esterified with 5-bromovaleryl chloride
to form the bromo ester 29. Condensation of 29 with
potassium acrylate in HMPA in the presence of 18-
The nonsymmetrical bisquaternary nonsymmetrical
diester 7 combines the potency-enhancing laudanosin-
ium group in a mivacurium-type6 acylcholine ester
function (structurally favorable to butyrylcholinesterase
hydrolysis),7 with a second unhindered â-quaternary
ester intrinsically capable of both facile Hofmann elimi-
nation and rapid hydrolysis.
Ch em istr y
The nonsymmetrical diesters 2a ,b (Scheme 1, Table
1) were prepared by condensing 8, obtained in the same
manner as its 1S homologue,5 with 9a or 9b to give the
* Corresponding author.
† University of Strathclyde.
‡ Burroughs Wellcome Co.
X Abstract published in Advance ACS Abstracts, December 15, 1995.
0022-2623/96/1839-0556$12.00/0 © 1996 American Chemical Society

Short-Acting Neuromuscular Blocking Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2 557
Sch em e 1a
vagal block of compounds 1-5 and 7 relative to atra-
curium (6b) in anesthetized cats are given in Table 1.
The actions of the nonsymmetrical bisquaternary
diesters 2a (R1 ) H, R2 ) MeO) and 2b (R1 ) MeO, R2
) H) are spontaneously reversible. They are also
readily reversed by anticholinesterases. However, in
contrast to the corresponding symmetrical diester 1,
they are more potent and free from vagal block at
neuromuscular blocking doses.
All four methoquaternary monoesters 3a -d were less
potent neuromuscular blocking agents than the corre-
sponding diesters 2. Their actions were also spontane-
ously reversible and readily reversed by neostigmine,
but unlike the diesters, they showed vagal block at
neuromuscular blocking doses. Their durations of ac-
tion appeared to be shorter than those of atracurium
(6b) and 5.
The potency of the bis-methoquaternary monoester
4a was similar to those of 3a -d , but that of the bis-
allyl compound 4b was substantially lower. The action
of 4a was spontaneously reversible and reversed by
neostigmine, but it showed vagal block at neuromus-
cular blocking doses. The potency of 5 was comparable
to those of 2a ,b and atracurium. The pharmacological
profile of the nonsymmetrical bisquaternary nonsym-
metrical diester 7 was similar to those of compounds
3a -d , but it exhibited greater vagal block at neuro-
muscular blocking doses.
a
Reagents: (a) AcOH, C6H6; (b) MeI, CH3CN.
Ch a r t 2
Discu ssion
The atracurium analogue 5 is potent, is free from
vagal block, and, not unexpectedly, has a similar dura-
tion of action to that of atracurium. However, the
objective of attaining high potency and freedom from
vagal block at neuromuscular blocking doses with
shorter duration of action was met only in compounds
2a ,b. Although the differences are not capable of
statistical validation, compounds 3a -e, 4a , and 7
appeared to be less potent.
The differences between 2a ,b and the remaining
monoester compounds 3a -d , 4a , and 7 may well be a
consequence of their stereochemical composition. All
are mixtures of stereoisomers with either (1R,2R)- or
(1R,2S)-laudanosinium (cis or trans) configurations in
which the cis-isomers predominate (Table 1). This
preponderance of cis-isomers favors high potency in
compounds 2a ,b with atracurium-related â-ester con-
figurations.5,10 In contrast, the respective 9-, 11-, and
4-acyloxy functions of compounds 3, 4, and 7 are akin
to the 3-acyloxy function of mivacurium, in which the
1R,2R-isomers (cis) are some 10 times less potent than
the 1R,2S-isomers (trans).
The durations of action of compounds 1, 3, and 7 are
all similar (ca. 8 min) and shorter than that of atracu-
rium. This supports the hypothesis that absence of
steric effects due to bulky C-1 substituents in the
tetrahydroisoquinoline nucleus favors faster metabolic
degradation and hence shorter duration. Restraint of
the C-1 substituent in the methoquaternary (4a ) seems
to be ineffective.
crown-6 produced the unsaturated diester 30, which on
treatment with 9a yielded 31. Quaternization of 31
with methyl iodide gave 7 (Scheme 5). The comparator
symmetrical bisquaternary diester 1 was prepared as
shown in Scheme 6. The nonsymmetrical bisquaternary
esters 2, 3b-d , 4, 5, and 7 are mixtures of quaternary
ammonium stereoisomers generated in the final N-
alkylation step. The proportions of (1R,2R)-cis- and
(1R,2S)-trans-papaverinium isomers were determined
by both NMR and HPLC.
Exp er im en ta l Section
Melting points were recorded on either a Kofler Heizbank
or Gallenkamp melting point apparatus and are uncorrected.
IR spectra were obtained on either a Perkin-Elmer 710B or
Perkin-Elmer 781 spectrometer using liquid film or KBr disks
P h a r m a cologica l Resu lts
Neuromuscular blocking potencies, duration, sponta-
neous reversibility, reversibility with neostigmine, and

558 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2
Dhar et al.
for solid samples. 1H-NMR spectra were recorded on either a
Perkin-Elmer R32 or Bruker WM 250 (250 MHz) spectrometer
and 13C-NMR on a Bruker WM250 (250 MHz) spectrometer
in CDCl3, unless otherwise indicated, using either TMS or the
center of the CDCl3 peak as reference standard. IR, 1H-NMR,
and 13C-NMR spectra were in accord with the structures given.
Optical rotations were measured in CHCl3 on a Perkin-Elmer
241 polarimeter. Elemental analytical results are within
(0.4% of the calculated values, except where indicated.
Column chromatography was carried out on silica gel 60
(Merck; 70-230 mesh) and flash chromatography on silica gel
60 (Merck; 230-400 mesh). TLC was performed on Polygram
Sil G/UV254 250 µm plates in either dichloromethane/ethanol/
ammonia (DEA) or chloroform/methanol (CM), with visualiza-
tion by exposure to iodine vapor. Analytical HPLC was
performed on a Spectraphysics Spectraseries P100 instrument
using a 4.6 × 250 mm column packed with partisil silica (10
µm) and methanol/ethyl acetate/trifluoroacetic acid/98% H2-
SO4 (61.1/38.5/0.3/0.1) as mobile phase. Detection was at 280
nm.
1-[(1R)-Tetr a h yd r op a p a ver in -2-yl]-4,11-d ioxa -3,12-d i-
oxotetr a d ec-13-en e (8). (1R)-Tetrahydropapaverine (1.04 g,
3.028 mmol) in dry benzene (15 mL) was added dropwise over
1 h to hexamethylene diacrylate (3.43 g, 15.16 mmol) in dry
benzene (5 mL) containing glacial acetic acid (1 drop, ca. 20
mg) with constant stirring at 80 °C. The solution was refluxed
for 5 h. The solvent was removed, the viscous residue
dissolved in ether (200 mL), and the solution extracted with
dilute HCl. The aqueous solution was washed with ether (100
and 50 mL), made alkaline with NaOH solution, and extracted
with ether. The ethereal solution was dried (Na2SO4) and
evaporated to give 8 as a viscous oil (1.55 g, 93%), which
showed a single spot on TLC: TLC in CM (9/1), RF 0.88; [R]20
D
1
-40.8° (c 0.564); IR; H-NMR.
1-[(1R)-Tetr a h yd r op a p a ver in -2-yl]-14-(6,7,8-tr im eth ox-
yt et r a h yd r oisoq u in olin -2-yl)-4,11-d ioxa -3,12-d ioxot et -
r a d eca n e (10). Compound 8 (0.62 g, 1.09 mmol) and 6,7,8-
trimethoxytetrahydroisoquinoline (9a ) (0.26 g, 1.16 mmol)
were dissolved in dry benzene (15 mL) containing glacial acetic
acid (1 drop), and the mixture was heated at 80 °C for 20 h.
Evaporation of the solvent gave a viscous oil (0.9 g) which was
purified by column chromatography in CM (99/1) to yield 10
as a lightly colored viscous oil (0.71 g, 84%): [R]20 -32.3° (c
D
1
0.726); TLC in CM (98/2), RF 0.64; IR; H-NMR.
1-[(1R)-Tetr a h yd r op a p a ver in -2-yl]-14-(5,6,7-tr im eth ox-
yt et r a h yd r oisoq u in olin -2-yl)-4,11-d ioxa -3,12-d ioxot et -
r a d eca n e (11). Prepared from compound
8 and 5,6,7-
trimethoxytetrahydroisoquinoline (9b) as described for 10:
yield 90%; [R]20 -29.5° (c 0.604); TLC in CM (98/2), RF 0.68;
D
1
IR; H-NMR.
N-(9-Hyd r oxyn on yl)-(1R)-tetr a h yd r op a p a ver in e (14).
9-Bromononanol (1.03 g, 4.62 mmol) in acetonitrile (15 mL)
was added dropwise to (R)-tetrahydropapaverine (12) (1.57 g,
4.57 mmol) in acetonitrile (20 mL) with constant stirring at
82 °C and the solution refluxed for 70 h. The solution was
evaporated to give a yellow oil (2.58 g) and the crude product
purified by column chromatography in DEA (100/8/1) to yield
a viscous light brown oil. Crystallization from n-hexane gave
14 as colorless needles (0.83 g, 37%): mp 70 °C; [R]20 -61.0°
D
1
(c 0.50); TLC in DEA (100/8/1), RF 0.44; IR; H-NMR. Anal.
(C29H43NO5) C, H, N.
N-(11-H yd r oxyu n d eca n yl)-(1R)-t et r a h yd r op a p a ver -
in e (15): prepared as described for 14; yield 70%; mp 58-59
°C (from n-hexane); TLC in DEA (150/8/1), RF 0.35; IR; 1H-
NMR. Anal. (C31H47NO5) H, N, C: calcd, 72.48; found, 72.0.
N-(11-Hyd r oxyu n d eca n yl)-(1RS)-tetr a h yd r op a p a ver -
in e (16): prepared as described for 14; yield 85%; mp 82 °C
1
(from n-hexane); IR; H-NMR. Anal. (C31H47NO5) C, H, N.
1-[(1R)-Tetr ah ydr opapaver in -2-yl]-10-oxa-11-oxotr idec-
12-en e (17). Acryloyl chloride (0.146 g, 61 mmol) in dry
benzene was added dropwise to compound 14 (0.56 g, 1.15
mmol) in dry benzene containing a trace of pyrogallol and
maintained at 40 °C under nitrogen. After 1 h the solution
was filtered and the solvent removed under vacuum. The oily
residue was purified by flash chromatography in DEA (150/

Short-Acting Neuromuscular Blocking Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2 559
Sch em e 2a
a
Reagents: (a) Br(CH2)nOH, CH3CN; (b) CH2dCHCOCl, Et3N, C6H6; (c) AcOH, C6H6; (d) MeI, CH3CN; (e) CH2dCHCH2Br, CH3CN.
Sch em e 3a
a
Reagents: (a) AcOH, C6H6; (b) MeI, CH3CN; (c) CH2dCHCH2Br, CH3CN.
Sch em e 4a
prepared from 9b and 17 as described for 21; yield 85%; TLC
1
in DEA (150/8/1), RF 0.61; [R]20 -37.2° (c 0.25); H-NMR.
D
1-[(1R)-Tetr a h yd r op a p a ver in -2-yl]-13-(6-O-m eth yln or -
cod ein -17-yl)-10-oxa -11-oxotr id eca n e (25): prepared from
24 and 17 as described for 21; yield 82%; TLC in DEA (150/
1
8/1), RF 0.41; IR; H-NMR.
1,13-Bis[(1R)-tetr a h yd r op a p a ver in -2-yl]-10-oxa -11-ox-
otr id eca n e (26): prepared from 12 and 17 as described for
21; yield 15%; TLC in DEA (150/8/1), RF 0.51; IR; H-NMR.
a
1
Reagents: (a) AcOH, C6H6; (b) MeI, CH3CN.
6-O-Meth yln or cod ein e (24). 6-O-Methylcodeine8 (10.8 g,
34.5 mmol), phenyl chloroformate (12.6 g, 138 mmol), and
potassium carbonate (3.45 g, 34.5 mmol) were refluxed in dry
dichloromethane under nitrogen for 18 h. The reaction
mixture was filtered, and the solvent and excess phenyl
chloroformate were removed under vacuum to yield 6-O-
methylnorcodeine phenylcarbamate as a white solid (13.6 g,
94%): mp 134-135 °C (from n-hexane); 1H-NMR. Anal.
(C25H25NO5) C, H, N.
The phenylcarbamate (4.0 g, 9.52 mmol) was treated first
with 65% (10 mL) and then with 98% hydrazine hydrate (15
mL) with nitrogen bubbled through the mixture, which then
was heated at 150 °C for 5 h. Further 65% hydrazine hydrate
(10 mL) and 98% hydrazine hydrate (10 mL) were added, and
heating was continued for a further 19 h. The solution was
evaporated to dryness, the residue dissolved in chloroform, and
the solution extracted with KOH solution (30%, ×4). The
chloroform solution was dried (Na2SO4) and evaporated to give
a yellow oil. Flash chromatography in DEA (100/8/1) followed
by trituration with n-hexane gave 24 as a flaky white solid
(65%): mp 98-100 °C; TLC in DEA (100/8/1), RF 0.25; IR; 1H-
NMR; 13C-NMR. Anal. (C18H21NO3) C, H, N.
8/1) to yield 17 as a yellow oil (0.46 g, 74%): TLC in DEA (150/
1
8/1); RF 0.39; [R]20 -49.2° (c 0.81); IR; H-NMR.
D
1-[(1R)-Tetr a h yd r op a p a ver in -2-yl]-12-oxa -13-oxop en -
ta d ec-14-en e (18): prepared as described for 17 and used
without further purification; yield 99%; TLC in DEA (150/8/
1); RF 0.54; IR.
1-[(1RS)-Tetr a h yd r op a p a ver in -2-yl]-12-oxa -13-oxop en -
ta d ec-14-en e (19): prepared as described for 17 and used
without further purification; yield 40%; TLC in DEA (150/8/
1); RF 0.54; IR.
1-[(1R)-Tetr a h yd r op a p a ver in -2-yl]-15-(6,7,8-tr im eth ox-
yt e t r a h yd r oisoq u in olin -2-yl]-12-oxa -13-oxop e n t a d e c-
a n e (21). Compounds 9a (0.345 g, 1.55 mmol) and 18 (0.586
g, 1.03 mmol) were heated in dry benzene with a trace of
glacial acetic acid at 80 °C for 7 days. The solvent was
removed; the residue was azeotroped with dry benzene to
remove acetic acid and purified by flash chromatography in
DEA (300/8/1) to give 21 as a yellow oil (0.36 g, 45%): TLC in
1
DEA (150/8/1), RF 0.41; IR; H-NMR.
1-[(1R)-Tetr a h yd r op a p a ver in -2-yl]-15-(5,6,7-tr im eth ox-
yt e t r a h yd r oisoq u in olin -2-yl]-12-oxa -13-oxop e n t a d e c-
a n e (22): prepared from 9b and 18 as described for 21; yield
1
56%; TLC in DEA (150/8/1), RF 0.47; IR; H-NMR.
E t h yl 4-[N-(1R)-Tet r a h yd r op a p a ver in -2-yl]su ccin a -
m id e (27). Ethyl succinoyl chloride (6.01 g, 17.5 mmol) in
dry THF was added dropwise (50 min) to compound 12 (6.01
g, 17.5 mmol) and triethylamine (5.3 g, 52.5 mmol) under
nitrogen in dry benzene, and the mixture was refluxed for 1.25
h. The cooled reaction mixture was filtered and evaporated,
the resulting oil was extracted with diethyl ether, and the
1-[(1RS)-Tetr a h yd r op a p a ver in -2-yl]-15-(6,7-d im eth ox-
yt e t r a h yd r oisoq u in olin -2-yl]-12-oxa -13-oxop e n t a d e c-
a n e (23): prepared from 9c and 19 as described for 21; yield
1
27%; TLC in DEA (150/8/1), RF 0.42; IR; H-NMR.
1-[(1R)-Tetr a h yd r op a p a ver in -2-yl]-13-(5,6,7-tr im eth ox-
ytetr a h yd oisoqu in olin -2-yl]-10-oxa -11-oxotr id eca n e (20):

560 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2
Dhar et al.
Sch em e 5a
a
Reagents: (a) EtOOC(CH2)2COCl, Et3N, C6H6; (b) LiAlH4, THF; (c) HCl, Br(CH2)4COCl, CH3CN; (d) CH2dCHCOOK, 18-crown-6,
HMPA; (e) AcOH, C6H6; (f) MeI, CH3CN.
Sch em e 6a
(0.26 g, 1.16 mmol) were refluxed in dry benzene (40 mL) and
glacial acetic acid (2 drops) for 23 h. The solvent was removed
and the residue azeotroped with dry benzene (×2) to remove
acetic acid to yield a brown oil. Purification by flash chroma-
tography in DEA (200/8/1) gave 31 as a viscous yellow oil (0.33
1
g, 56%): IR; H-NMR.
1,14-Bis[6,7,8-tr im eth oxytetr a h yd r op a p a ver in -2-yl]-4,-
11-d ioxa -3,12-d ioxotetr a d eca n e (33). 6,7,8-Trimethoxytet-
rahydroisoquinoline (9a ) (1.12 g, 5.0 mmol), hexamethylene
diacrylate (32) (0.55 g, 2.4 mmol), and glacial acetic acid (2
a
Reagents: (a) AcOH, C6H6; (b) MeI, CH3CN.
solution was cooled to yield 27 (7.34 g, 89%): mp 94 °C; [R]20
D
drops, ca. 40 mg) were heated together at 80 °C for 20 h. The
1
-73.3° (c 0.52); TLC in DEA (150/8/1), RF 0.42; IR; H-NMR.
reaction mixture was cooled, dissolved in dry toluene (15 mL),
stirred with Merck Kieselgel 60 (70-230 mesh, 200 mg) for 4
h, filtered, and evaporated to give a light viscous oil. Column
chromatography in chloroform on silica gel (70-230 mesh)
gave 33 as a viscous oil (1 g, 62%): TLC in CM (94/6), RF 0.76;
1H-NMR.
Qu a ter n a r y Sa lts. Ditertiary amino mono- and diesters
were treated with the appropriate alkyl halide by methods
previously described.1,2 Yields, stereoisomer ratios, physical
constants, and elemental analyses are reported in Table 1.
NMR data are available as supporting information.
Anal. (C21H33NO7) C, H, N.
N-(4-Hyd r oxybu tyl)-(1R)-tetr a h yd r op a p a ver in e (28).
Compound 27 (7.37 g, 15.62 mmol) in dry THF was added
dropwise to a refluxing suspension of LiAlH4 (2.96 g, 78.13
mmol) in dry THF under nitrogen, and the mixture was
refluxed for 2.5 h. The reaction mixture was cooled in ice, and
water (10 mL) was added cautiously followed in turn by 4 M
NaOH (10 mL) and then water (200 mL). The resulting
suspension was filtered through Kiesel gel and the THF
evaporated and extracted with CHCl3 (150 mL × 3). The
combined CHCl3 extracts were washed with saturated NaCl
solution, dried (Na2SO4), and concentrated to give a yellow oil.
Treatment with hexane gave 28 as a white solid (5.8 g, 90%):
P h a r m a cology. Neuromuscular blocking properties and
vagal effects were measured in cats. The results are recorded
in Table 1.
1
mp 53-55 °C; TLC in DEA (150/8/1), RF 0.32; IR; H-NMR.
Anal. (C24H33NO5) C, H, N.
Mongrel cats weighing 2.0-5.0 kg were anesthetized with
a mixture of pentobarbitone sodium (17 mg/kg ip) and R-chlo-
ralose (80 mg/kg ip). Adequate levels of anesthesia were
maintained with supplemental doses of R-chloralose admin-
istered intravenously as needed. The trachea was cannulated,
and the animals were ventilated with room air (20 mL/kg) via
a Harvard Apparatus respiration pump adjusted to deliver 20
strokes/min. Arterial blood pressure was measured via a
cannula to the right femoral artery connected to a Statham
P23 transducer. Heart rate was determined from the ECG.
The right vagus was exposed, crushed ca. 2 cm distal to the
nodose ganglia, and placed on a shielded bipolar platinum
electrode. The vagus nerve was stimulated for 10 s every 5
min with a Grass S88 stimulator using the following param-
eters: 20 Hz, 0.5 ms duration, and supramaximal voltage of
10-15 V.
The left hind limb was rigidly secured, and the tibialis
tendon was isolated and attached to a Grass FT 03 force
displacement transducer. After sectioning the sciatic nerve
trunk, the peroneal nerve was placed on a shielded bipolar
platinum electrode. Stimuli of 0.2 ms duration and at a
supramaximal voltage were applied to the nerve at a rate of
0.15 Hz using a Grass S88 stimulator. Twitch tension in the
anterior tibialis was recorded during a resting tension of 50
N-(10-Br om o-5-oxa -6-oxod ecyl)-(1R)-tetr a h yd r op a p a -
ver in e (29). 5-Bromovaleryl chloride (2.44 g, 12.2 mmol) in
acetonitrile (20 mL) was added dropwise to 28 hydrochloride
(5.03 g, 11.1 mmol) in acetonitrile (40 mL) at 80 °C. The
mixture was heated at 80 °C for 5.25 h and left at room
temperature overnight and the solvent removed. Flash chro-
matography in DEA (200/8/1) gave 29 as a yellow oil (5.8 g,
1
90%): TLC in DEA (200/8/1), RF 0.45; IR; H-NMR.
N-(5,11-Dioxa-6,12-dioxotetr adec-13-en yl)-(1R)-tetr ah y-
d r op a p a ver in e (30). Potassium acrylate (0.133 g, 1.21 mmol)
and 18-crown-6 (17 mg, 0.067 mmol) were added to a solution
of 29 (0.588 g, 1.01 mmol) in HMPA (25 mL) under nitrogen,
and the suspension was stirred for 24 h at 40 °C. The reaction
mixture was filtered, the filtrate diluted with water (150 mL),
and the solution extracted with ether (100 mL × 4). The
combined ether extracts were washed with saturated NaCl
solution (100 mL × 2) and evaporated to yield 30 as a brown
oil (0.42 g, 73%): TLC in DEA (150/8/1), RF 0.50; IR; 1H-NMR.
1-[[(1R)-Tetr ah ydr opapaver in -2-yl]-14-(6,7,8-tr im eth ox-
yt et r a h yd r oisoq u in olin -2-yl]-5,11-d ioxa -6,12-d ioxot et -
r a d eca n e (31). Compounds 30 (0.42 g, 0.74 mmol) and 9a

Short-Acting Neuromuscular Blocking Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 2 561
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Ack n ow led gm en t . J .B.S., J .M.M., L.A.M., and
N.C.D. wish to thank Burroughs Wellcome Co. for
financial support for part of the chemical work.
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