Design and synthesis of novel scaffolds for drug discovery: hybrids of beta-D-glucose with 1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one, the corresponding 1-oxazepine, and 2- and 4-pyridyldiazepines.

Article abstract of DOI:10.1021/ol015698f

[structure: see text]. We describe the syntheses of novel tricyclic scaffolds that incorporate a fusion of a substituted pyranose ring with the seven-membered rings of 1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one and the corresponding oxazepine and pyrid

Full text of DOI:10.1021/ol015698f

ORGANIC
LETTERS
2001
Vol. 3, No. 7
1089-1092
Design and Synthesis of Novel
Scaffolds for Drug Discovery: Hybrids
of â-D-Glucose with
1,2,3,4-Tetrahydrobenzo[e][1,4]diazepin-5-one,
the Corresponding 1-Oxazepine, and 2-
and 4-Pyridyldiazepines
Le1ıla Abrous, John Hynes, Jr., Sarah R. Friedrich, Amos B. Smith, III,* and
Ralph Hirschmann*
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
rfh@sas.upenn.edu
Received February 12, 2001
ABSTRACT
We describe the syntheses of novel tricyclic scaffolds that incorporate a fusion of a substituted pyranose ring with the seven-membered rings
of 1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one and the corresponding oxazepine and pyridyldiazepine to generate the benzodiazepines, and
the related heterocycles. In each instance, the pyranose rings contain three protected hydroxyls, suitable for selective derivatization.
Privileged Scaffolds in Drug Discovery. The search for new
medicines continues to depend on the discovery of new leads,
uncovered either via rationally designed chemical entities
or the screening of sample collections, increasingly generated
by combinatorial or parallel syntheses. The design of such
libraries may involve novel scaffolds to which diverse side
chains are attached, the trajectories of which seek to explore
three-dimensional space. An important overlapping principle
is the concept of privileged (or promiscuous) structures,
recently updated by Patchett.1 The former term was intro-
duced by B. Evans et al.,2 as a descriptor that recognizes
the fact that seemingly minor changes in the structures of
(1) Patchett, A. A.; Nargund, R. P. Ann. Rep. Med. Chem. 2000, 35,
289.
10.1021/ol015698f CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/09/2001

benzodiazepines can produce a host of different biological
activities, which now include not only ligands for diverse
G-protein coupled receptors but also inhibitors of enzymes
such as reverse transcriptase,3 farnesyl transferase, κ-secre-
tase, and dihydrofolate reductase, as well as ligands for ion
channels. In the 1960s the so-called tricyclic scaffold,4 as
found in protriptyline, was similarly recognized to be
associated with diverse biological activities, depending on
the attached side chains and other modifications.5 Long ago,
Nature herself discovered privileged structures such as the
steroidal and the cyclic peptide scaffolds, as well as â-turns
and helices, etc. We have suggested6 that in addition to
incorporated heteroatoms, the side chain projections of
privileged ligand platforms, which include â- and γ-turns,
their components or their mimics, are recognized by common
structural motifs in G-protein coupled receptors, which make
these receptors complementary to the privileged platforms.
Although to our knowledge, no unifying three-dimensional
structural feature for privileged structures has been identified,
the lack of planarity present in the benzodiazepines suggested
itself as a possibility because it permits the exploration of
increased conformational space. Herein we describe the
design and synthesis of new scaffolds that are hybrids of
benzodiazepines, oxazepines and pyridyldiazepines with
sugars, wherein the latent hydroxyl groups of the pyranose
ring permit diverse, controlled derivatization at three sites.
The Chimeric Benzodiazepine-Sugar Scaffold.7 Our
initial approach8 toward the chimeric 1,4-benzodiazepin-5-
one-sugar system9 (Scheme 1) entailed acylation of (+)-1,
Scheme 1
(2) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger,
R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K.
A.; Springer, J. P.; Hirschfield, J. J. Med. Chem. 1988, 31, 2235.
(3) (a) Robl, J. A.; Cimarusti, M. P.; Simpkins, L. M.; Brown, B.; Ryono,
D. E.; Bird, E.; Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. J. Med.
Chem. 1996, 39, 494-502. (b) De Lombaert, S.; Beil, M.; Berry, C.;
Blanchard, L.; Bohacek, R.; Chatelin, R.; Gerlock, T.; Ghai, R. D.; Odorico,
L.; Sakane, Y.; Stamford, L. B.; Trapani, A. J. Abstracts of Papers, 212th
National Meeting of the American Chemical Society, Orlando, FL; American
Chemical Society: Washington, DC, 1996; MEDI 12. (c) Merluzzi, V. J.;
Hargrave, K. D.; Labadia, M.; Grozinger, K.; Skoog, M.; Wu, J. C.; Shih,
C.-K.; Eckner, K.; Hattox, S.; Adams, J.; Rosenthal, A. S.; Faanes, R.;
Eckner, R. J.; Koup, R. A.; Sullivvan, J. L. Science 1990, 250, 1411-
1413.
prepared from (-)-2,10 with acid 3 (X ) H), followed in
turn by azide reduction to afford the amine and ring closure
to produce the 1,4-benzodiazepin-5-one ring (Scheme 1).
Unactivated (X ) H) o-halide-substituted benzamides,11
however, failed to undergo ring closure under both thermal
and transition metal mediated conditions. We therefore
explored the synthesis of an activated precursor possessing
a para-nitro group obtained via coupling (+)-1 with 2-fluoro-
5-nitrobenzoic acid 3 (X ) NO2). Staudinger reduction12 of
the resulting azide yielded the amine, which upon heating
at 80 °C for 48 h in anhydrous acetonitrile furnished the
yellow, crystalline 1,4-benzodiazepin-5-one (+)-4 (mp 150-
152 °C) in 70% yield; the structure was confirmed by single-
crystal X-ray analysis. Dimer formation was observed when
the reaction was carried out at concentrations above 0.005
M. Importantly, (+)-4 possesses good cell permeability
properties with a log P ) 2.53, a high Papp value [17 × 10-6]
across Caco-2 cells13 and adequate solubility properties
[crystalline (+)-4: H2O 0.610 mg/mL; pH 7.4 buffer 0.54
mg/mL; 0.10 N HCl 5.073 mg/mL]. Reductive removal of
the nitro group utilizing the diazotization procedure of
Doyle14 afforded the parent congener (-)-5 in 42% yield
for the two steps.
(4) Arie¨ns, E. J.; Beld, A. J.; Rodrigues de Miranda, J. F.; Simonis, A.
M. In The Receptors: A ComprehensiVe Treatise; O’ Brien, R. D., Ed.;
Plenum: New York, 1979; pp 33-91.
(5) Davis, M. A. Ann. Rep. Med. Chem. 1968, 2, 13.
(6) Liu, J.; Underwood, D. J.; Cascieri, M. A.; Rohrer, S. P.; Cantin,
L.-D.; Chicchi, G.; Smith, A. B., III; Hirschmann, R. J. Med. Chem. 2000,
43, 3827 and references therein.
(7) Presented in part: Abrous, L.; Hynes, J., Jr.; Friedrich, S. R.; Smith,
A. B., III; Hirschmann, R. Abstracts of Papers, 220th National Meeting of
the American Chemical Society, Washington, DC; American Chemical
Society: Washington, DC, 2000; MEDI 254.
(8) Hynes, John, Jr., Ph.D. Dissertation, University of Pennsylvania,
Philadelphia, PA, 1996. See also: Woolard, F. X.; Paetsch, J.; Ellman, J.
A. J. Org. Chem. 1997, 62, 6102-6103.
(9) Bicyclic Diazepines; Fryer, R. Ian, Ed.; John Wiley and Sons: New
York, 1991; pp 183-946.
(10) Available from the known triol (-)-2 [Midoux, P.; Grivet, J. P.;
Delmotte, F.; Monsigny, M. Biochem. Biophys. Res. Comm. 1984, 119,
603] via dimethylacetal protection to afford (-)-10 (step 1) followed by
double inversion at C(3):
(11) Further investigation into transition metal mediated heteroaryl bond
formation methodologies may provide a possible alternative entry into the
tricyclic system. Using Pd: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (b) Yang, B. H.; Buchwald,
S. L. Org. Lett. 1999, 1, 35. (c) Rocca, P.; Marsais, F.; Godard, A.;
Quenguiner, G. Tetrahedron 1993, 49, 49. (d) Guram, A. S.; Rennels, R.
A.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1348. Using
Cu: (e) Lindley, J. Tetrahedron 1984, 40, 1433. Takei, T.; Matsuoka, M.;
Kitao, T. Bull. Chem. Soc. Jpn. 1981, 54, 2735. Matsuoka, M.; Makino,
Y.; Yoshida, K.; Kitao, T. Chem. Lett. 1979, 219.
(12) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635.
(13) An in vitro cell culture model of the intestinal mucosa. Apical to
basolateral flux of (+)-4 was measured. For a review see: Pauletti, G. M.;
Gangwar, S.; Siahaan, T. J.; Aube´, J.; Borchardt, R. T. AdV. Drug DeliVery
ReV. 1997, 27, 235.
(14) (a) Doyle, M. P.; Dellaria, J. F., Jr.; Siegfried, B.; Bishop, S. W. J.
Org. Chem. 1977, 42, 3494.
1090
Org. Lett., Vol. 3, No. 7, 2001

We next envisioned ready access to the cis-fused sugar-
benzodiazepine 9 via a parallel sequence (Scheme 2). Toward
12 then effected removal of the Cbz group, which was
followed by cyclization and reduction of the resultant imine.
Preferential reduction from the pseudoequatorial face of the
strained intermediate cyclic imine afforded the cis-fused
benzodiazepine-sugar (-)-13 as the major product [4:1 cis/
trans], in an as yet unoptimized yield (20%), along with the
intermediate anilino-ketone, which could be recycled.
The Chimeric Oxazepine-Sugar Scaffold. Removal of
the protecting group in (-)-10, followed by coupling with 3
(X ) NO2) and cyclization using CsF as a base in DMF at
85 °C gave (-)-14 in 55% yield (Scheme 4).
Scheme 2
Scheme 4
this end, reaction of the C(3) axial azide (+)-615 afforded
(-)-7. Interestingly, reduction of (-)-7 with triphenylphos-
phine proved unsuccessful. The smaller, more reactive
trimethylphosphine did, however, furnish (-)-8. Unfortu-
nately, cyclization of (-)-8 to the cis-fused scaffold 9 proved
unsuccessful when the reaction was either heated or treated
with a variety of bases under varied temperature and solvent
conditions.
The Chimeric Pyridyldiazepine-Sugar Scaffolds. Simi-
larly, the isomeric 2- and 4-pyridyldiazepine-sugar scaffolds
(-)-19 and (-)-20 (Scheme 5) were obtained via cyclization
Our attention therefore turned toward a one-pot protocol,
involving first unmasking the aniline in (-)-12, followed
by intramolecular imine formation with concomitant reduc-
tion to furnish the cis- and trans-fused benzodiazepine-sugar
scaffolds. We began this sequence with removal of the
trifluoroacetamide group in (-)-109 (Scheme 3), followed
Scheme 5
Scheme 3
of the corresponding 2- and 4-chloro acyl pyridine interme-
diates (-)-17 and (-)-18. No reaction was observed in
absence of CsF; presumably the reaction pathway involves
a precedented in situ ipso-substitution16 of the acyl chloride
to give the more reactive acyl fluoride.
Having secured synthetic access to each of the chimeric
scaffolds, derivatives possessing a variety of side chains were
synthesized for broad screening; their biological evaluation
is underway at DuPont Pharmaceuticals Co. Optimization
of the one-pot cascade for the synthesis of the cis-fused
scaffold is also ongoing. Finally, we are exploring the
in turn by selective coupling with N-benzyloxycarbonyl
(Cbz)-protected anthranilic acid 11 and oxidation of the C(3)
hydroxyl to yield (-)-12. Catalytic hydrogenation of (-)-
(15) Available from alcohol (-)-10 by simple inversion (see ref 10, steps
4, 5, and 6).
(16) Finger, G. C.; Kruse, C. W. J. Am. Chem. Soc. 1956, 78, 6034.
Org. Lett., Vol. 3, No. 7, 2001
1091

potential inherent in the design of these scaffolds for
subsequent multisite functionalization via parallel synthesis
both in solution and on solid supports.
for helpful discussions, and C.P.D. and A.R. for cell
permeability data reported herein.
Supporting Information Available: Spectroscopic and
analytical data for intermediates leading to and including
(+)-4 from (-)-2, (-)-13, (-)-14, (-)-19, and (-)-20 and
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support was provided by the
National Institutes of Health (National Institute of General
Medical Sciences) through grant GM-41821. We thank Drs.
C. P. Decicco, A. Robichaud, D. Underwood, and J. Winkler
OL015698F
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Org. Lett., Vol. 3, No. 7, 2001