5
12 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Iyengar et al.
Ta ble 1. Properties of New 2-Cyanoaziridine-1-carboxamidesa
solvent
impurity
no.
R
yield, %
94
mp, °C
98-100 2.47 (d, 1, J ) 3 Hz), 2.57 (d, 1, J ) 6 Hz), 2.8 (d, 3, J ) 5 Hz),
.05 (dd, 1, J ) 6, 3 Hz), 6.18 (br, s 1, NH)b
1H NMR signals, δ (ppm from TMS)
6
CH3i
3
7
8
9
C2H5j
63
92
81
64
25
50
71
54
91
89
50
58-62
1.1 (t, 3, 6 Hz), 2.4 (d, 1, J ) 3 Hz), 2.50 (d, 1, J ) 6 Hz), 2.97 (dd, 1,
J ) 6, 3 Hz), 3.3 (q, 2, J ) 6 Hz), 6.1 (br s, 1, NH)b
98-102 1.0 (t, 3), 1.4 (m, 2), 1.6 (m, 2), 2.5 (d, 1, J ) 3 Hz), 2.55 (d, 1, J ) 6 Hz),
n-C4H9
t-C4H9
c-C6H11
0.1H2O
3
.0 (dd, 1, J ) 6, 3 Hz), 3.2 (m, 2), 6.1 (br s, 1, NH)b
46-48
1.4 (s, 9), 2.84 (d, 1, J ) 3 Hz), 2.86 (d, 1, J ) 6 Hz), 3.0 (dd, 1,
J ) 6, 3 Hz), 5.8 (br s, 1, NH)c
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
98-102 1.2-1.5 (m, 5), 1.6-2.1 (m, 5), 2.45 (d, 1, J ) 3 HZ), 2.53 (d, 1, J ) 6 Hz),
3
.015 (dd, 1, J ) 6, 3 Hz), 3.6 (m, 1), 5.8 (br s, 1, NH)b
2.36 (d, 1, J ) 3 Hz), 2.46 (d, 1, J ) 6 Hz), 2.93 (dd, 1, J ) 6,
Hz), 4.4 (d, 2), 6.8 (br s, 1, NH), 7.4 (m, 5)b
C6H5CH2
42-44
oil
3
C2H5OCOCH2
C6H5k
0.75CH3OHd
1.22 (t, 3, J ) 7 Hz), 2.49 (d, 1, J ) 3 Hz), 2.56 (d, 1, J ) 6 Hz), 3.07 (dd,
b
J ) 6, 3 Hz), 3.91 (d, 2), 4.15 (q, 2, J ) 7 Hz), 6.74 (t, 1, NH)
88-90
2.65 (d, 1, J ) 3 Hz), 2.69 (d, 1, J ) 6 Hz), 3.57 (dd, 1, J ) 6, 3 Hz),
7
.05 (t, 1), 7.45 (d, 2), 7.60 (d, 2), 10.2 (br s, 1 NH)c
4-FC6H4
99-100 2.55 (d, 1, J ) 3 Hz), 2.68 (d, 1, J ) 6 Hz), 3.20 (dd, 1, J ) 6, 3 Hz), 7.0
d, 2, J ) 9 Hz), 7.5 (d, 2, J ) 9 Hz), 10.2 (br s, 1 NH)c
166-168 2.62 (d, 1, J ) 3 Hz), 2.74 (d, 1, J ) 6 Hz), 3.32 (dd, 1, J ) 6, 3 Hz), 7.54
d, 2, J ) 9 Hz), 7.74 (d, 2, J ) 9 Hz), 10.2 (br s, 1 NH)c
2.77 (d, 1, J ) 3 Hz), 2.81 (d, 1, J ) 6 Hz), 3.69 (dd, 1, J ) 6, 3 Hz), 7.8
d, 2, J ) 9 Hz), 8.2 (d, 2, J ) 9 Hz), 10.8 (br s, 1 NH)c
110-114 2.70 (d, 1, J ) 3 Hz), 2.71 (d, 1, J ) 6 Hz), 3.57 (dd, 1, J ) 6, 3 Hz), 7.44
d, 1, dd, J ) 3 Hz, J ) 6 Hz), 7.57 (d, 1, J ) 6 Hz), 7.68 (d, 3 Hz),
0.0 (br s, 1, NH)c
(
4-CF3C6H4
4-NO2C6H4
2,4-C12C6H3
(
0.1H2O
>230 dec
(
(
1
1
1
2
8
9
0
3,4-C12C6H3e
76
90
74
132-134 2.71 (d, 1, J ) 3 Hz), 2.73 (d, 1, J ) 6 Hz), 3.62 (dd, 1, J ) 6, 3 Hz), 7.5
(
(
dd, 1, J ) 9, 3 Hz), 7.6 (d, 1, J ) 9 Hz), 7.9 (d, 1, J ) 3 Hz), 10.6
br s, 1, NH)c
4-C2H5OCOC6H4
3-CH3COC6H5f
162-165 1.3 (t, 3, J ) 6 Hz), 2.72 (d, 1, J ) 3 Hz), 2.76 (d, 1, J ) 6 Hz), 3.64
(
(
dd, 1, J ) 6, 3 Hz), 4.3 (q, 2, J ) 6 Hz), 7.69 (d, 2, J ) 9 Hz), 7.73
d, 2, J ) 9 Hz), 10.63 (br s, 1 NH)c
110-112 2.6 (s, 3), 2.71 (d, 1, J ) 3 Hz), 2.74 (d, 1, J ) 6 Hz), 3.63 (dd, 1, J ) 6,
3
8
Hz), 7.5 (t, 1, J ) 9 Hz), 7.7 (d, 1, J ) 9 Hz), 7.85 (d, 1, J ) 9 Hz),
.1 (s, 1), 10.5 (br s, NH)b
2
2
2
2
1
2
3
4
2-CH3CO2C6H4
4-H2NSO2C6H4g
1-C10H7
10
39
56
10
101-102 2.38 (s, 3), 2.55 (br s, 1), 2.64 (br s, 1), 3.20 (br s, 1), 7.15 (br s, 2), 7.2-7.6
c,h
(
br s, 1), 7.68 (br s, 1), 7.96 (br s, 1, NH)
170-174 2.72 (d, 1, J ) 3 Hz), 2.74 (d, 1, J ) 6 Hz), 3.7 (dd, 1, J ) 6, 3 Hz), 7.26
s, 2, NH2), 7.69 (d, 2), 7.73 (d, 2), 10.6 (br s, 1, NH)c
98-100 2.6 (br s, 1), 2.7 (br s, 1), 3.2 (br s, 1), 7.4 (br s, 1), 7.5 (m, 3), 7.7 (br s, 1),
(
b,h
7
.8 (br s, 2), 8.1 (br s, NH)
3-C5H4N
0.2H2O
205 dec
2.72 (d, 1, J ) 3 Hz), 2.76 (d, 1, J ) 6 Hz), 3.65 (dd, 1, J ) 6, 3 Hz),
7
6
.36 (dd, J ) 3 Hz, 9 Hz, 1), 7.97 (dd, J ) 3, 6 Hz, 1), 8.28 (dd, J ) 3,
Hz), 8.71 (s, 1), 10.5 (br s, 1 NH)c
a
Analytical results were within (0.40% of theoretical values for all elements (C, H, N, C1, S, and F), except as shown in subsequent
footnotes. In some examples, water or the solvent impurities indicated in the table had to be added to reconcile the calculated and found
b
c
d
values for these elements. The solvent was CDC13. The solvent was DMSO-d6. The product was eluted from TLC plate scrapings by
CH3OH. N: calcd, 16.40; found, 15.68. f N: calcd, 18.32; found, 17.97. N: calcd, 21.04; found, 19.60. The expected doublets were not
e
g
h
resolved and appeared as broad singlets. MS (EI) 125 (M ). MS (EI) 139 (M+). k MS (EI) 187 (M ).
i
+
j
+
activity to imexon and more potent. These results
suggest that further studies on 13 as well as other
analogues described herein are desirable.
were recorded on a Varian-MAT311 spectrometer. Elemental
analyses were performed by Desert Analytics, Inc., Tucson,
AZ.
Concerning the possibility that N-substituted aziri-
dine-1-carboxamides are cytotoxic because they cyclize
to N-substituted imexon analogues, we have made no
in vivo studies; however, such cyclizations appear
unlikely because a strongly alkaline solution was re-
quired for the formation of imexon from 1.
P r epar ation of 2-Cyan oazir idin e-1-car boxam ides (Gen -
er a l Meth od ). To an ice-cooled mixture of 2-cyanoaziridine
(5) and toluene was added an ice-cold solution of an isocyanate
(1.05 equiv) in toluene at a rate to keep the temperature below
5
°C. The mixture was stirred for 1 h in an ice bath and then
placed in a refrigerator overnight. The resulting precipitate
was collected, washed with toluene, and dried under vacuum
to give the product. Table 1 gives the yields and properties of
the products (6-24).
Exp er im en ta l Section
Melting points were recorded on a Mel-Temp melting point
1
apparatus and are uncorrected. H NMR spectra were recorded
2-Cyanoaziridine-1-[N-[ethoxycarbonyl)methyl]carboxa-
mide] (12) was a colorless oil that did not crystallize on cooling.
It was dissolved in cold chloroform and diluted with cold
on a Bruker 250 WM spectrometer, and absorptions are
reported downfield from Me Si (δ values in ppm). Mass spectra
4