Syntheses and bioactivities of novel carbamates combining platelet activating factor (PAF) receptor antagonist with thromboxane synthase inhibitor (TxSI)

Article abstract of DOI:10.1016/S0960-894X(02)00186-5

Synthesis of carbamates 3b which possess dual-acting PAF antagonist/TxSI using unstable esters 1, diazepines 2, K₂CO₃ and 18-crown-6 is described.

Full text of DOI:10.1016/S0960-894X(02)00186-5

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1383–1386
Syntheses and Bioactivities of Novel Carbamates Combining
Platelet Activating Factor (PAF) Receptor Antagonist with
Thromboxane Synthase Inhibitor (TxSI)
Masakazu Fujita* and Taketsugu Seki
Omiya Research Laboratory, Nikken Chemicals Co., Ltd., 1-346, Kitabukuro-cho, Saitama-shi, Saitama 330-0835, Japan
Received 7 January 2002; accepted 5 March 2002
Abstract—Synthesis ofcarbamates 3b which possess dual-acting PAF antagonist/TxSI using unstable esters 1, diazepines 2, K2CO3
and 18-crown-6 is described. # 2002 Published by Elsevier Science Ltd.
Many alkanoic acid derivatives, such as compounds 1,
have been developed as Thromboxane A2 (TxA2) syn-
thase inhibitors or TxA2 receptor antagonists.1,2 We
have also generated a series ofcompounds represented
by 3,3 which possess dual-acting Platelet activating factor
Namely, to a solution ofesters 1 and diazepines 2 in
DMF was added K2CO3 followed by 18-crown-6 at
room temperature, and the mixture was stirred under the
same condition. Addition of0.6 equiv of18-crown-6
improved the yield ofcompound 3a (entry 1 vs 2). How-
ever, unexpectedly, it was found that compound 3b was
obtained in addition to the desired compound 3a (entries
2–5). Further, in the case ofaddition of1.0 equiv of18-
crown-6, it is noteworthy that compound 3b was
obtained as a major product (entry 6).
5
(PAF)4 antagonist and TxA2 synthase inhibitor.
2,3
In the course ofour works,
we have found that the
characteristic features of compounds 1 having a mesylate
group were unstable, and that, interestingly, the mesy-
late group can be readily converted to chlorine atom by
treatment with brine. In this publication, we would like
to report an efficient synthesis ofcarbamates 3b by uti-
lizing its character, K2CO3 and 18-crown-6, and their
bioactivities.
We considered that dialkyl carbonates should be formed
due to 18-crown-6, and reacted with amines to give
carbamates in the same way as generating trialkyl
phosphates from tripotassium phosphate by Fukui’s
group (Scheme 2).7 Therefore, it was expected that
reaction with diazepines 2 after converting more than
2.0 equivalents ofesters 1 into 1.0 equiv ofdialkyl car-
bonates should, at least, preferentially lead to com-
pound 3b. According to the above consideration, the
use of2.4 equivalents ofester 1b and 1.0 equivalent of
18-crown-6 afforded compound 3b in 87% isolated yield
(entry 7). Furthermore, although the dialkyl carbonates
could not be identified, compound 3b and the hydroxyl
substituted ester was obtained in 92% and recovered in
81% isolated yield, respectively, when using 1.2 equiv of
18-crown-6 (entry 8).8 From this result, we confirmed a
equation shown in Scheme 2.
In general, compound 3a was obtained as shown in
Scheme 1 by reaction ofethyl esters 12 and diazepines 26
in the presence ofa base. Experiments were carried out
to test the effect ofreagents on the yield ofcompounds
3a and 3b (Table 1).
In an initial experiment, we attempted the reaction using
only K2CO3. Reaction at 70 ꢀC afforded only compound
3a in 23% isolated yield. At more than 70 ꢀC, these
reactions gave lower yields ofcompound 3a along with
ready decomposition ofcompound 1a. Therefore, we
examined this reaction on addition of18-crown-6.
On the other hand, compound 3a was obtained in 81–
90% isolated yield by treatment with Et3N in refluxing
THF for 1 h, but in 38% isolated yield in refluxing
CHCl3 for 4 h (entries 9–11).
*Corresponding author. +81-048-641-2334; fax: +81-048-641-5749;
e-mail: mfujita-nikken@nifty.com
0960-894X/02/$ - see front matter # 2002 Published by Elsevier Science Ltd.
PII: S0960-894X(02)00186-5

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M. Fujita, T. Seki / Bioorg. Med. Chem. Lett. 12 (2002) 1383–1386
Scheme 1. Reagents and conditions: (a) Brine, CHCl3, rt, 77% quant.; (b) see Table 1.
Table 1. Coupling ofesters 1 with diazepines 2 to the target compounds 3
3a
Yield (%)c
3b
Yield (%)c
Entry
Estera+Diazepine
Reagentsb and conditions
Position
E/Zd
E/Zd
1
2
3
4
5
6
7
8g
9
10
11
1a (1.2 equiv)+2a
1a (1.2 equiv)+2a
1a (1.2 equiv)+2a
1c (1.2 equiv)+2a
1c (1.2 equiv)+2a
1a (1.2 equiv)+2a
1b (2.4 equiv)+2b
1a (2.4 equiv)+2a
1a (1.2 equiv)+2a
1a (1.2 equiv)+2a
1a (1.2 equiv)+2b
K2CO3, DMF, 70 ꢀC, 2 h
K2CO3, 18C6 (0.6 equiv), DMF, 70 ꢀC, 2 h
K2CO3, 18C6 (0.6 equiv), DMF, 70 ꢀC, 2 h
K2CO3, 18C6 (0.6 equiv), DMF, 70 ꢀC, 2 h
K2CO3, 18C6 (0.6 equiv), DMF, 70 ꢀC, 2 h
K2CO3, 18C6 (1.0 equiv), DMF, 70 ꢀC, 2 h
K2CO3, 18C6 (1.0 equiv), DMF, 70 ꢀC, 1 h
K2CO3, 18C6 (1.2 equiv), DMF, 70 ꢀC, 2 h
Et3N, THF, reflux, 1 h
3
3
4
3
4
3
3
3
3
3
3
(23)
43
(43)
63
52
18
2:3
1:2
2:3
1:1f
2:3
1:4f
16
trace
28
1:3
nde
21
26
1:3
(87)
(92)
1:6
1:9
(81)
(38)
(90)
1:2
1:2
1:2
Et3N, CHCl3, reflux, 4 h
Et3N, THF, reflux, 1 h
aEquivalents based on diazepines 2.
bEquivalents based on diazepines 2. 2.4 equivalents ofK CO3 was used.
2
cDetermined by 1H NMR spectra and HPLC analysis; isolated yields are given in parentheses.
dDetermined by 1H NMR spectra and HPLC analysis.
end, not determined.
fCombined 3a and 3b.
g(E/Z)-5-[[[3-(hydroxymethyl)phenyl-3-pyridyl]methylene]aminooxy]pentanoic acid ethyl ester was obtained in 81% isolated yield.
Scheme 2.

M. Fujita, T. Seki / Bioorg. Med. Chem. Lett. 12 (2002) 1383–1386
1385
Table 2. PAF antagonist and TxA2 synthase inhibitory activities ofcompounds 3a and 3b
Entrya
Product
R2
X
IC50 (mM)
ED50 (mg/kg, iv)
ED50 (mg/kg, po)
PAF antagonistb TxA2 synthasec PAF antagonistd TxA2 synthasee PAF antagonistd TxA2 synthasee
7
8
11
9
3b
3b
3a
H
NO
0.139
0.041
0.190
0.047
0.036
0.029
NT
0.062
0.069
0.067
0.060
>1.000
NT
0.7
0.2
0.8
0.2
0.02
0.1
NT
NT
0.1
0.1
0.1
0.1
NT
NT
0.02
0.01
>10.0
>10.0
>10.0
>10.0
>10.0
>10.0
>10.0
>10.0
NT
NT
0.1
0.05
Me NO
NO
Me NO
H
3a
(Æ)-E6123f
UK74505g
Ozagrel
Isbogrelh
0.025
1.55
NT
NT
0.024
0.0009
NT
aCorresponded to entry in Table 1.
bInhibition ofthe PAF-induced platelet aggregation in rabbit platelet rich plasma(PRP). This was performed according to the method ofTerashita
et al. with slight modification.9
cInhibition ofTxB production by incubating prostaglandin H2(PGH2) with human platelet microsomes. This was performed according to the
2
method ofTerashita et al. with slight modification. 10
dActivity in vivo was demonstrated by the ability to protect mice from the lethal effects ofan injection ofPAF. The ED 50 values represent the dose
reduced mortality by 50%. This was performed according to the method of Cooper et al. with slight modification.11
eInhibition ofserum TxB 2 production in the rats. This was performed according to the method of Terashita et al. with slight modification.10
fSee ref12.
gSee ref11.
hSee ref13.
Muller, T. H.; Weisenberger, H. J. Med. Chem. 1994, 37, 26.
(d) Ackerley, N.; Brewster, A. G.; Brown, G. R.; Clarke, D. S.;
Foubister, A. J.; Griffin, S. J.; Hudson, J. A.; Smithers, M. J.;
Whittamore, P. R. O. J. Med. Chem. 1995, 38, 1608.
2. Fujita, M.; Seki, T.; Inada, H.; Shimizu, K.; Takahama, A.;
Sano, T. Bioorg. Med. Chem. Lett. 2002, 12, 341.
Table 2 summarizes PAF antagonist and TxA2 synthase
inhibitory activities. Compounds 3a and 3b synthesized
by entries 7–9 and 11 in Table 1 were tested in vitro and
in/ex vivo. As the result, 3a and 3b showed little differ-
ence on activities. However, in a PAF-induced death
assay after intravenous administration in mice, the
action time ofcompounds 3b were quarter ofcom-
pounds 3a, respectively (data not shown). From the
result previously reported,3 these compounds appeared
to be not parted in the diazepine and the ester in vivo.
3. Fujita, M.; Seki, T.; Inada, H.; Shimizu, K.; Takahama, A.;
Sano, T. Bioorg. Med. Chem. Lett. 2002, 12, 771.
4. (a) Braquet, P.; Paubert-Braquet, M.; Koltai, M.; Bour-
gain, R.; Bussolino, F.; Hosford, D. Trends Pharm. Sci. 1989,
10, 23. (b) Sanchez-Crespo, M. Drug News Perspect. 1993, 6,
78. (c) Page, C. P. J. Allergy Clin. Immunol. 1988, 81, 144. (d)
Barnes, P. J. J. Allergy Clin. Immunol. 1988, 81, 152.
In conclusion, we have developed an efficient method
for the synthesis of carbamates 3b in good yield by uti-
lizing esters 1, 2.4 equiv ofK CO3 and 1.0 equiv of18-
2
5. (a) Hirsh, P. D.; Hillis, L. D.; Campbell, W. B.; Firth, B. G.;
Willerson, J. T. N. Engl. J. Med. 1981, 304, 684. (b) Oates, J.;
Fitzgerald, G.; Branch, R.; Jackson, E.; Knapp, H.; Roberts,
L. N. Engl. J. Med. 1988, 319, 689. (c) Fitzgerald, D. J.; Roy,
L.; Catella, F.; Fitzgerald, G. A. N. Engl. J. Med. 1986, 315,
983. (d) Fiddler, G.; Lumley, P. Circulation 1990, 81, 69.
6. For the preparation ofdiazepines 2, see: Miyazawa, S.;
Okano, K.; Shimomura, N.; Clark, R. S. J.; Kawahara, T.;
Asano, O.; Yoshimura, H.; Miyamoto, M.; Sakuma, Y.;
Muramoto, K.; Obaishi, H.; Harada, K.; Kajima, T.;
Yamada, K.; Tsunoda, H.; Katayama, S.; Abe, S.; Asakawa,
N.; Souda, S.; Horie, T.; Sato, T.; Machida, Y.; Katayama,
K.; Yamatsu, I. Chem. Pharm. Bull. 1991, 39, 3215.
crown-6. Moreover, the hydroxyl substituted ester was
recovered in good yield, and could be recycled. Hence,
this method would become one tool for bulk synthesis
ofthe compound or carbamates. Extension ofthis
methodology to other compounds is under investigation
in order to define the scope ofthis synthesis ofcarba-
mates. On the other hand, carbamates 3b indicated excel-
lent dual activity by intravenous administration. Further
synthetic studies and detailed biological investigations
including the study ofdiastereoisomers are currently in
progress and will be reported elsewhere.
7. Yoshida, Z.; Yoneda, S.; Nakamura, A.; Fukui, K. Kogyo
Kagaku Zasshi 1966, 69, 52.
8. Typical procedure for the synthesis of carbamates;
To a solution of 1a (543 mg, 1.25 mmol) in DMF (5 mL) was
added K2CO3 (173 mg, 1.25 mmol) followed by 18-crown-6
(165 mg, 0.62 mmol) at room temperature. After stirring for
30 min at room temperature, 2a (200 mg, 0.52 mol) was added
and the mixture was stirred at 70 ꢀC for 2 h. After cooling and
conventional work-up, the mixture was subjected to chroma-
tography to yield 3b with R2=Me as an orange foam (367 mg,
Acknowledgements
We thank Mr. Masashi Yano for HPLC and mass spectral
data, and Mr. Susumu Kanaya for biological data.
1
References and Notes
92%). 3b: H NMR (300 MHz, CDCl3): d (ppm) 1.16 (3H, t,
J=7.2 Hz), 1.50–1.81 (5H, m), 1.90–2.15 (1H, m), 2.04 (3H, d,
J=6.9 Hz), 2.24 (2H, t, J=6.9 Hz), 2.60 (3H, s), 3.14 (1H,
brs), 3.55–4.00 (1H, m), 4.03 (2H, q, J=7.2 Hz), 4.14 (2H, t,
J=6.0 Hz), 4.21 (1H, dd, J=6.6, 13.5 Hz), 4.39 (1H, brd,
J=16.8 Hz), 4.78 (1H, brd, J=16.8 Hz), 5.05 (2H, brs) 7.10–
7.50 (9H, m), 7.64, 7.78 (total 1H, each d, J=8.1 Hz), 8.51 (1H,
1. (a) Campbell, I. B.; Collington, E. W.; Finch, H.; Hayes, R.;
Lumley, P.; Mills, K.; Pike, N. B.; Robertson, G. M.; Watts, I. S.
Bioorg. Med. Chem. Lett. 1991, 1, 699. (b) Hoet, B.; Falcon, C.;
De Rey, S.; Arnout, J.; Deckmyn, H.; Vermylen, J. Blood
1990, 75, 646. (c) Soyka, R.; Heckel, A.; Nickl, J.; Eisert, W.;

1386
M. Fujita, T. Seki / Bioorg. Med. Chem. Lett. 12 (2002) 1383–1386
s), 8.56 (1H, d, J=4.8Hz); 13C NMR (75 MHz, CDCl3): d (ppm)
11.9, 14.2, 17.6, 21.4, 28.4, 33.9, 42.8, 52.7, 60.2, 67.2, 74.4, 123.0,
127.2, 127.6, 128.7, 129.0, 129.3, 130.1, 131.1, 132.6, 134.3, 136.0,
136.5, 136.9, 137.2, 149.6, 149.7, 149.9, 153.1, 156.4, 173.3; IR
(KBr) 3420, 2936, 1731, 1705, 1592, 1538, 1416, 1378, 1304,
1231, 1113, 1038, 985 cmÀ1; HRMS (FAB+) m/z exact mass
calcd for C40H41ClN7O5S 766.2578, found 766.2579.
11. Cooper, K.; Fray, M. J.; Parry, M. J.; Richardson, K.;
Steele, J. J. Med. Chem. 1992, 35, 3115.
12. Miyazawa, S.; Okano, K.; Shimomura, N.; Clark, R. S. J.;
Kawahara, T.; Asano, O.; Yoshimura, H.; Miyamoto, M.;
Sakuma, Y.; Muramoto, K.; Obaishi, H.; Harada, K.;
Kajima, T.; Yamada, K.; Tsunoda, H.; Katayama, S.; Abe, S.;
Asakawa, N.; Souda, S.; Horie, T.; Sato, T.; Machida, Y.;
Katayama, K.; Yamatsu, I. Chem. Pharm. Bull. 1991, 39,
3215.
9. Terashita, Z.; Tsushima, S.; Yoshioka, Y.; Nomura, H.;
Inada, Y.; Nishikawa, K. Life Sci. 1983, 41, 1975.
10. Terashita, Z.; Imura, Y.; Tanabe, M.; Kawazoe, K.; Nishi-
kawa, K.; Kato, K.; Terao, S. Thromb. Res. 1986, 41, 223.
13. Kato, K.; Ohkawa, S.; Terao, S.; Terashita, Z.; Nishi-
kawa, K. J. Med. Chem. 1985, 28, 287.