Synthesis and application of [1,2,5]triazepane and [1,2,5]oxadiazepane as versatile structural units for drug discovery

Article abstract of DOI:10.1248/cpb.58.1001

Seven-membered heterocyclic [1,2,5]triazepane and [1,2,5]-oxadiazepane derivatives were synthesized as candidate structures for application in drug discovery in place of conventional piperazine or morpholine moieties, offering multiple sites for modification with functional groups. We first synthesized the Nprotected heterocycles, and then confirmed their utility by synthesizing analogues of the oxazolidinone antibacterial agent linezolid. The analogues exhibited potent in vitro and in vivo antibacterial activity. In particular, compound 10a exhibited good in vivo efficacy when administered intravenously in a murine model of systemic infection with methicillin-resistant Staphylococcus aureus SR3637. These seven-membered heterocycles are expected to be versatile structural units for drug discovery.

Full text of DOI:10.1248/cpb.58.1001

July 2010
Communication to the Editor
Chem. Pharm. Bull. 58(7) 1001—1002 (2010)
1001
Synthesis and Application of
[1,2,5]Triazepane and
[1,2,5]Oxadiazepane as Versatile
Structural Units for Drug Discovery
Fig. 2. Replacement of Six-Membered Heterocyclic Structures with
Seven-Membered Heterocyclic Structures
Hideyuki SUZUKI, Iwao UTSUNOMIYA, and
Koichi SHUDO*
Research Foundation Itsuu Laboratory; 2–28–10 Tamagawa,
Setagaya-ku, Tokyo 158–0094, Japan.
Received April 19, 2010; accepted April 23, 2010; published online
April 27, 2010
Reagents and conditions: (a) NaH, bis(2-chloroethyl)carbamic acid benzyl ester,
DMF, 60 °C; (b) 10% Pd/C, H2, EtOH; (c) 4-fluoronitrobenzene, i-Pr2NEt,
CH3CN.
Seven-membered heterocyclic [1,2,5]triazepane and [1,2,5]-
oxadiazepane derivatives were synthesized as candidate struc-
tures for application in drug discovery in place of conventional
piperazine or morpholine moieties, offering multiple sites for
modification with functional groups. We first synthesized the N-
protected heterocycles, and then confirmed their utility by syn-
thesizing analogues of the oxazolidinone antibacterial agent
linezolid. The analogues exhibited potent in vitro and in vivo an-
tibacterial activity. In particular, compound 10a exhibited good
in vivo efficacy when administered intravenously in a murine
model of systemic infection with methicillin-resistant Staphylo-
coccus aureus SR3637. These seven-membered heterocycles are
expected to be versatile structural units for drug discovery.
Chart 1. Synthesis of [1,2,5]Triazepane and [1,2,5]Oxadiazepane Bearing
a Boc Protecting Group at the 1-Position
ingly, we set out to synthesize several N-protected derivatives
and to examine whether they might be useful in medicinal
chemistry.
First, we attempted to synthesize [1,2,5]triazepane and
[1,2,5]oxadiazepane frameworks bearing t-butoxycarbonyl
(Boc) protective groups. As shown in Chart 1, cyclization
precursors, di-protected hydrazine 1a14) and bis(2-
chloroethyl)carbamic acid benzyl ester,15) were treated with
NaH in N,N-dimethylformamide (DMF) to afford all N-pro-
tected [1,2,5]triazepane 2a in good yield, followed by cat-
alytic hydrogenation to obtain 3a protected with a Boc group
at the 1-position. The bulky Boc group at the 1-position is
Key words seven-membered heterocycle; piperazine; morpholine; oxa-
zolidinone; drug discovery; medicinal chemistry
Pharmacologically active low-molecular organic com- expected to decrease the basicity and nucleophilicity of the
pounds generally consist of a core structural unit, known 2-position relative to the 5-position. As expected, selective
as the pharmacophore, linked to appropriate functional arylation under basic conditions proceeded at the 5-position
group(s). Six-membered saturated heterocycles represented to afford nitrobenzene 4a, and catalytic hydrogenation of 4a
by piperazine or morpholine have been widely applied as provided aniline 5a without cleavage of the N–N bond of the
functional or linker units to develop antihistamines,1,2) an- [1,2,5]triazepane framework. Compound 5a should be a use-
tipsychotics,3,4) and antibacterial agents.5,6) Two examples are ful building block for N-aryl-type compounds. The
shown in Fig. 1.7,8)
[1,2,5]oxadiazepane derivative 5b were similarly synthesized
In particular, the piperazine ring is found in the structures from commercially available 1b.16)
of various pharmacologically active compounds as a linker or
The triazepane protected with Boc groups at the 1- and 5-
terminal structural unit. Piperazine has two N atoms that can positions (7) was also synthesized via a similar procedure
be readily functionalized and can be used to improve both starting from 1a and bis(2-chloroethyl)carbamic acid t-butyl
lipophilicity9) and hydrophilicity,10) which in turn can im- ester (Chart 2).17) This compound is also expected to be
prove bioavailability11) and pharmaceutical formulation prop- a versatile intermediate. For example, Pd-catalyzed N-aryla-
erties.12) We thought that the seven-membered heterocycles tion18,19) of compound 3a yielded a mixture of 2,5-diarylated
[1,2,5]triazepane and [1,2,5]oxadiazepane, which could be compound 8a, 5-arylated 8b, and 2-arylated 8c. However,
considered homologues of piperazine, might be similarly arylation of compound 7 under the same conditions afforded
useful (Fig. 2). Since [1,2,5]triazepane contains three N 2-arylated compound 9 in good yield (Chart 3).
atoms, a wide range of chemical modifications should be
We next examined the potential of the new compounds for
available. Only a few monocyclic [1,2,5]triazepane-type drug development. Oxazolidione antibacterial agents,20) rep-
compounds have been synthesized so far,13) and no resented by linezolid21) and eperezolid,22) are a new class of
[1,2,5]oxadiazepane derivatives have been reported. Accord- antibacterial reagents effective against methicillin-resistant
Staphylococcus aureus (MRSA)23) or vancomycin-resistant
Enterococcus faecium (VRE).24) Since these compounds con-
tain a six-membered saturated heterocycle (morpholine or
piperazine), we examined the effect of replacing these rings
with [1,2,5]triazepane and [1,2,5]oxadiazepane. The target
compounds were synthesized from 3a and 3b via similar
routes to those reported for the original compounds, respec-
tively.22,25) The new compounds 10a26) and 10b27) showed ex-
cellent in vitro antibacterial activity against MRSA or line-
Fig. 1. Two Examples of Drugs Bearing a Six-Membered Heterocycle,
Piperazine or Morpholine
∗ To whom correspondence should be addressed. e-mail: kshudo@itsuu.or.jp
© 2010 Pharmaceutical Society of Japan

1002
Vol. 58, No. 7
1452—1457 (1984).
2) Ranise A., Bondavalli F., Bruno O., Schenone S., D’Amico M., Par-
rillo C., Marrazzo R., Rossi F., Farmaco, 47, 1263—1283 (1992).
3) Bartl V., Svatek E., Dlabac A., Collect. Czech. Chem. Commun., 49,
1816—1826 (1984).
Reagents and conditions: (a) NaH, bis(2-chloroethyl)carbamic acid t-butyl ester,
4) Scott M. K., Reitz A. B., Villani F. J. Jr., Rasmussen C. R., U.S. Patent
5332732 (1994).
5) Ziegler C. B. Jr., Bitha P., Kuck N. A., Fenton T. J., Peterson P. J., Lin
Y., J. Med. Chem., 33, 142—146 (1990).
DMF, 60 °C; (b) 10% Pd/C, H2, EtOH.
Chart 2. Synthesis of [1,2,5]Triazepane Protected with Boc Groups at the
1- and 5-Positions
6) Dave C. G., Shah P. R., Pandya P. S., Shah G. K., J. Indian Chem. Soc.,
66, 810—812 (1989).
7) Schmutz J., Künzle F., Hunziker F., Gauch R., Helv. Chim. Acta, 50,
245—254 (1967).
8) Gibson K. H., U.S. Patent 5770599 (1998).
9) Valenta V., Prosek Z., Metysova J., Valchar M., Dlabac A., Protiva M.,
Collect. Czech. Chem. Commun., 50, 1070—1077 (1985).
10) Meanwell N. A., Hewawasam P., Thomas J. A., Wright J. J. K., Russell
J. W., Gamberdella M., Goldenberg H. J., Seiler H. M., Zavoico G. B.,
J. Med. Chem., 36, 3251—3264 (1993).
Reagents and conditions: (a) 2,5-dibromopyridine, Pd2(dba)3, 4,5-
11) Nonaka K., Ueno A., Arzeim. Forsh., 35, 1499—1502 (1985).
12) Selkirk A. B., Dey M. J., U.S. Patent 4973591 (1990).
13) Szotor K., Diss. Pharm. Pharmacol., 24, 385—388 (1972).
14) Dutta A. S., Morley J. S., J. Chem. Soc. Perkin Trans. 1, 1975, 1712—
1720 (1975).
bis(diphenylphosphino)-9,9-dimethylxanthene, t-BuONa, 1,4-dioxane, 80 °C.
Chart 3. Pd-Catalyzed N-Arylation of [1,2,5]Triazepanes 3a and 7
Table 1. Values of Minimum Inhibitory Concentration (MIC) of Oxazo-
15) Amble E., Dale J., Acta Chem. Scand. B, 33, 584—586 (1979).
16) Compounds 3a and 3b are available from Watanabe Chemical Indus-
tries, Ltd. as from April 5, 2010.
lidinone Derivatives 10a and 10b
17) Chambers M. S., Baker R., Billington D. C., Knight A. K., Middlemiss
D. N., Wong E. H., J. Med. Chem., 35, 2033—2039 (1992).
18) Yin J., Zhao M. M., Huffman M. A., McNamara J. M., Org. Lett., 4,
3481—3484 (2002).
19) Wolfe J. P., Buchwald S. L., Org. Synth. Coll. Vol., 10, 423 (2004).
20) Brickner S. J., Curr. Pharm. Des., 2, 175—194 (1996).
21) Clemett D., Markham A., Drugs, 59, 815—827 (2000).
22) Brickner S. J., Hutchinson D. K., Barbachyn M. R., Manninen P. R.,
Ulanowicz D. A., Garmon S. A., Grega K. C., Hendges S. K., Toops D.
S., Ford C. W., Zurenko G. E., J. Med. Chem., 39, 673—679 (1996).
23) Tomasz A. N., Engl. J. Med., 330, 1247—1251 (1994).
24) Dixson S., Brumfitt W., Hamilton-Miller J. M. T., Eur. J. Clin. Micro-
biol., 4, 19—23 (1985).
MIC (mg/ml)
Compound
S. aureus
SR3637
S. aureus
E. faecium S. pneumoniae
NRS271
SR27437
SR26180
linezolid
10a
10b
2
0.25
0.25
32
2
2
4
0.25
0.5
1
0.125
0.125
25) Tokuyama R., Takahashi Y., Tomita Y., Tsubouchi M., Iwasaki N.,
Kado N., Okezaki E., Nagata O., Chem. Pharm. Bull., 49, 361—367
(2001).
zolid-resistant S. aureus28) in comparison with linezolid
(Table 1). Furthermore, compound 10a exhibited good in
vivo efficacy when administered intravenously in a murine
model of systemic infection, with MRSA SR3637 as the in-
fectious organism.29) Thus, [1,2,5]triazepane and [1,2,5]oxa-
diazepane appear to have great potential as structural units
for drug development.
In summary, we synthesized seven-membered saturated
heterocyclic [1,2,5]triazepane and [1,2,5]oxadiazepane deriv-
atives as candidates for linker or terminal structural moieties
for drug development. Introduction of these structures into
oxazolidinone antibiotics in place of the original morpholine
or piperazine moieties yielded novel active compounds. We
consider that these heterocycles have great potential for
structural variation and functionalization in drug develop-
ment studies.
26) Data for 10a. Colorless powder; mp 127—128 °C (EtOH); 1H-NMR
(CDCl3) d: 3.10—3.18 (2H, m), 3.25—3.32 (2H, m), 3.35—3.41 (2H,
m), 3.74 (1H, t, Jϭ6.1 Hz), 3.82 (1H, dd, Jϭ7.1, 9.1 Hz), 3.85—3.91
(2H, m), 3.95—4.12 (2H, m), 4.01 (3H, s), 4.38 (2H, d, Jϭ4.5 Hz),
4.87—4.97 (1H, m), 6.71 (1H, t, Jϭ6.1 Hz), 7.11 (2H, d, Jϭ10.7 Hz).
13C-NMR (CD3OD/CDCl3ϭ1/9) d: 47.2, 47.3, 51.0, 51.6, 52.1, 55.4,
57.3, 60.3, 71.5, 102.5 (2C, d, Jϭ29 Hz), 124.7 (t, Jϭ15 Hz), 133.9 (t,
Jϭ13 Hz), 154.2, 158.2 (2C, dd, Jϭ9, 244 Hz), 174.0, 192.6. EI-LR-
MS m/z: 415 (MϩϪCO2), 355, 300, 169. Anal. Calcd for
C18H23F2N5O5S: C, 47.05; H, 5.05; N, 15.24. Found: C, 46.88; H, 5.00;
N, 15.18.
27) Data for 10b. Colorless powder; mp 176—177 °C (EtOH); 1H-NMR
(CDCl3) d: 3.41 (2H, t, Jϭ4.8 Hz), 3.47 (2H, t, Jϭ5.1 Hz), 3.82 (1H,
dd, Jϭ6.9, 9.0 Hz), 3.91—4.15 (5H, m), 4.01 (3H, s), 4.36 (2H, s),
4.88—4.98 (1H, m), 6.85 (1H, t, Jϭ6.3 Hz), 7.11 (2H, d, Jϭ10.5 Hz).
13C-NMR (CD3OD/CDCl3ϭ1/9) d: 47.2, 47.3, 50.3, 51.9, 54.5, 57.3,
57.4, 59.5, 71.5, 102.3 (2C, d, Jϭ30 Hz), 124.2 (t, Jϭ14 Hz), 133.9 (t,
Jϭ14 Hz), 154.2, 157.9 (2C, dd, Jϭ9, 244 Hz), 172.2, 192.7. EI-LR-
MS m/z: 416 (MϩϪCO2), 355, 213, 169. Anal. Calcd for
C18H22F2N4O6S: C, 46.95; H, 4.82; N, 12.17. Found: C, 46.93; H, 4.83;
N, 12.16.
28) Tsiodras S., Gold H., Sakoulas G., Eliopoulos G., Wennersten C.,
Venkataraman L., Moellering R., Ferraro M. Jr., Lancet, 358, 207—
208 (2001).
29) The ED50 value of compound 10a was 0.77 mg/kg/dose (linezolid:
2.13 mg/kg/dose) for intravenous administration.
Acknowledgements This work was supported by medicinal chemists
and biologists of Shionogi & Co., Ltd. Discovery Laboratory. We thank our
colleagues for fruitful discussions and for the evaluation of antibacterial ac-
tivity. Linezolid-resistant Strain NRS271 was kindly provided by the net-
work on antimicrobial resistance in Staphylococcus aureus (http://www.
narsa.net/content/default.jsp).
References and Notes
1) Buckle D. R., Outred D. R., Smith H., Spicer B. A., J. Med. Chem., 27,