+
+
Muscarinic Analgesics for Treatment Of IBS
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4 545
over NaCl/Na2SO4 then evaporated. The resulting oil was
purified by flash chromatography over silica gel (96.7% CHCl3,
3% EtOH, 0.3% NH4OH) to yield 32 (210 mg, 0.65 mmol).
Crystallization with oxalic acid in acetone gave a salt with mp
93-96 °C. Anal. (C14H18N3O4S2F3) C, H, N.
(+)-exo-6-[4-[4,4,4-Tr iflu or obu tyl)th io]-1,2,5-th ia d ia zol-
3-yl]-1-a za bicyclo[3.2.1]octa n e Oxa la te (33). The same
procedure as for compound 29 was used, but with 1-bromo-
4,4,4-trifluorobutane as the alkyl bromide: mp 101-105 °C.
Anal. as the oxalate salt (C15H20N3O4S2F3) C, H, N.
(5S,6S)-exo-6-[4-[(5,5,5-Tr iflu or op en tyl)th io]-1,2,5-th ia -
d ia zol-3-yl]-1-a za bicyclo[3.2.1]octa n e Oxa la te (34). The
same procedure as for compound 32 was used, but with
1-bromo-5,5,5-trifluoropentane as the alkyl halide: mp 125-
127 °C. Anal. as the oxalate salt (C16H22N3O4S2F3) C, H, N.
(5R,6R)-exo-6-[4-[(4,4,4-Tr iflu or obu tyl)th io]-1,2,5-th ia -
d ia zol-3-yl]-1-a za bicyclo[3.2.1]oct a n e Oxa la t e (35) a n d
(5R,6S)-en d o-6-[4-[(4,4,4-Tr iflu or ob u t yl)t h io]-1,2,5-t h ia -
d ia zol-3-yl]-1-a za bicyclo[3.2.1]octa n e Oxa la te (37). To a
solution of (+)-1-azabicyclo[3.2.1]octan-6-one29 (124 g, 1000
mmol) in EtOH (100 mL) was added a solution of (-)-
camphorsulfonic acid (232 g, 1000 mmol) in EtOH (200 mL).
The mixture was heated to 70 °C and slowly cooled over 2 h
to 5 °C. The precipitated crystals were collected by filtration
and washed with cold EtOH (3 × 40 mL). The crude compound
was crystallized from EtOH (150 mL) (57.3 g). The resolved
material was then converted to 35 and 37 by the same
procedure as for 29, using 1-bromo-4,4,4-trifluorobutane as the
alkyl halide. Crystallization with oxalic acid in acetone of the
exo and endo fractions gave [5R-(exo)]-6-[4-[(4,4,4-Trifluoro-
butyl)thio]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1]octane
oxalate (35) (mp 153-154 °C) and [5R-(endo)]-6-[4-[(4,4,4-
trifluorobutyl)thio]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1]-
octane oxalate (37) (mp 70 °C). Anal. for 35 (C15H20F3N3O4S2)
C, H, N. Anal. for 37 (C15H20F3N3O4S2) C, H, N.
intraluminal manometry catheters into the jejunum for motil-
ity measurements. Transmural potential difference was de-
termined using calomel half-cells connected by salt bridges;
one salt bridge was inserted into the lumenal fluid of the
jejunum and the other via a wick electrode into the serosal
cavity fluid. Each animal served as its own control for
assessment of drug effect.
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151 °C. Anal. (C15H20F3N3O4S2) C, H, N.
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camphorsulfonic acid (232 g, 1000 mmol) in EtOH (200 mL).
The mixture was heated to 70 °C and slowly cooled over 2 h
to 5 °C. The precipitated crystals wre collected by filtration
and washed with cold EtOH (3 × 40 mL). The crude compound
was crystallized from EtOH (150 mL) (57.3 g). The resolved
material was then converted to 38 by the same procedure as
for 29, using 1-bromo-4,4,4-trifluorobutane as the alkyl halide.
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6-[4-[(4,4,4-trifluorobutyl)thio]-1,2,5-thiadiazol-3-yl]-1-azabicyclo-
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-
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Mou se Wr ith in g An tin ociceptive Assay. Separate groups
of 5-10 mice (male Cr1: CF1, Charles River, Portage, MI) each
were administered vehicle or a dose of a test compound
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F er r et J eju n a l Motility a n d P oten tia l Differ en ce As-
sa y. Full details of this assay have been described else-
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