Journal of Medicinal Chemistry
Brief Article
primate. Current efforts are focused on a new optimization
program, driving the SAR on rat M5 to deliver an in vivo tool
for rodent addiction studies, and progress will be reported in
due course.
ABBREVIATIONS USED
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M5, muscarinic acetylcholine receptor subtype 5; CRC,
concentration−response curve; NAM, negative allosteric
modulator; MLPCN, Molecular Libraries Probe Production
Centers Network
EXPERIMENTAL SECTION
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Chemistry. The general chemistry, experimental information, and
syntheses of all other compounds are in the Supporting Information.
(S)-9b-(4-Chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihy-
dro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (8). To a mixture of 2-
(4-chlorobenzoyl)benzoic acid (5.21 g, 20.0 mmol, 1 equiv) and
ethylenediamine (2.67 mL, 40.0 mmol, 2 equiv) in toluene (30 mL,
0.67 M) was added p-toluenesulfonic acid monohydrate (∼0.1 g, 3
mol %). A Dean−Stark trap was used to remove water, while the
mixture was allowed to stir at reflux for 4 h. After cooling to ambient
temperature, the mixture was dissolved in dichloromethane. The
organic layer was washed with a saturated aqueous solution of sodium
bicarbonate and then with brine. Solvent was removed under reduced
pressure and the crude product was recrystallized from ethanol to give
2.86 g of pure 9b-(4-chlorophenyl)-2,3-dihydro-1H-imidazo[2,1-a]-
isoindol-5(9bH)-one (50.2% yield). To a solution of 9b-(4-
chlorophenyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one
(15 mg, 0.053 mmol, 1.0 equiv) and DIPEA (18 μL, 0.105 mmol, 2.0
equiv) in DCM (0.53 mL, 0.1 M) was added 3,4-difluorobenzoyl
chloride (9.9 μL, 0.079 mmol, 1.5 equiv). The mixture was allowed to
stir at ambient temperature for 2 h. The reaction was quenched with
methanol, and the organics were concentrated on a heated air-drying
block. Crude product was purified via Gilson preparative LC to obtain
12.0 mg of 5g (53.3% yield). The second eluting pure enantiomer of
5g was separated via CO2 supercritical fluid chromatography (Lux
cellulose-3, 10 mm × 250 mm column at 40 °C, back-pressure
regulated at 100 bar, MeOH cosolvent, 10% isocratic prep over 7 min
at 15 mL/min) and was determined to have >98% ee by chiral HPLC
analysis (Lux cellulose-3, 4.6 mm × 250 mm column at 40 °C, back-
pressure regulated at 100 bar, MeOH cosolvent, 5−50% over 7 min at
3.5 mL/min). 1H NMR (400.1 MHz, CDCl3) δ (ppm): 8.04−7.99 (m,
1H); 7.90−7.85 (m, 1H); 7.65−7.56 (m, 2H); 7.38−7.30 (m, 3H);
7.25−7.19 (m, 2H); 7.18−7.14 (m, 2H); 4.38−4.30 (m, 1H); 4.01−
3.93 (m, 1H); 3.82−3.75 (m, 1H); 3.34−3.25 (m, 1H). 13C NMR
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(100.6 MHz, CDCl3) δ (ppm): 172.07, 166.84, 151.81 (dd, JCF
=
254 Hz, 12.7 Hz), 150.33 (dd, JC−F = 252 Hz, 13 Hz) 145.77, 136.65,
134.94, 133.55, 132.91 (t, J = 4.8 Hz), 131.88, 130.61, 129.06, 128.97,
127.53, 124.03, 123.62 (dd, J = 6.8 Hz, 4 Hz), 117.94 (d, J = 17 Hz),
116.83 (d, J = 18 Hz), 87.37, 52.24, 39.70. SFC (214 nM) tR = 3.591
min (>98%). HRMS (TOF, ES+) C23H16N2O2F2Cl [M + H]+ calcd
mass 425.0868, found 425.0872. Specific rotation [α]23 −168.6° (c
D
0.75, CHCl3).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for selected
compounds, detailed pharmacology, and DMPK methods. This
material is available free of charge via the Internet at http://
AUTHOR INFORMATION
Corresponding Author
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*Phone: 615-322-8700. Fax: 615-343-3088. E-mail: craig.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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(15) Bridges, T. M.; Marlo, J. E.; Niswender, C. M.; Jones, J. K.;
Jadhav, S. B.; Gentry, P. R.; Weaver, C. D.; Conn, P. J.; Lindsley, C. W.
Discovery of the first highly M5-preferring muscarinic acetylcholine
receptor ligand, an M5 positive allosteric modulator derived from a
This work was generously supported by the NIH/MLPCN
Grant U54 MH084659 (C.W.L.) and Grant U54 MH084512
(Scripps).
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dx.doi.org/10.1021/jm4013246 | J. Med. Chem. XXXX, XXX, XXX−XXX