New NO-Donors with Antithrombotic and Vasodilating Activities II3-Alkyl-N-nitroso-5-sydnone Imines.

79 1
NO-Donors
New NO-Donors with Antithrombotic and Vasodilating Activities, 11:
3-Alkyl-N-nitroso-5-sydnone
Imines
Klaus Rehsea)*,Klaus-Jurgen Schleifef')+),Thomas Ciborskia)+),and Helmut Bohnb)
a)
Institut fur Phannazie der Freien Universitat Berlin, Konigin-Luke-Str. 2 + 4,D-1000 Berlin 33
and
b, Cassella AG, Hanauer Landstr. 526, D-6000 Frankfurt am Main 60.
Received October 5 , 1992
Neue NO-Pharmaka mit antithrombotischen und gefallerweiternden
Eigenschaften, 2. Mitt.: 3-Alkyl-N-nitroso-5-sydnonimine
Fifteen 3-alkyl-, four 3-cycloalkyl-N-nitroso-5-sydnone
imines and five 3alkyl-N-nitro-5-sydnone imines were synthesized and their ability to inhibit platelet aggregation induced by collagen (Born-test) was studied in
vitro. Dependent on the chemical structure, the IC,,-values for the inhibition of platelet aggregation were in the range of 0.2-140 pnol/L. It is suggested that this scale reflects different binding properties of the nitrosimines with respect to the platelet membrane. Highest activities were
observed for the 3-hexyl (20 and the 3-cyclohexyl (2p) derivative. Three
nitrimines (3e, 3f, 3i) also showed IC5, values below 10 p n o l L . For the
nitrosimines 2a, 2f, and 2m antithrombotic activity was demonstrated in
vivo. They inhibited laser induced arterial thrombosis in anesthetized rats
up to 70% two h after oral administration. In conscious renal-hypertensive
dogs, the decrease in systolic blood pressure and left ventricular enddiastolic pressure suggests an antianginal activity of the compound 2a similar
to that of molsidomine (M). The smoother onset and the longer duration of
action of the new compound as compared to M could be a significant
advantage of 2a In the therapy of angina pectoris.
Funfzehn 3-Alkyl-, vier 3-Cycloalkyl-N-nitroso-5-sydnonimine
und funf
3-Alkyl-N-nitro-5-sydnonimine
wurden dargestellt und irn Born-Test auf
ihre Hemmwirkungen bezuglich der durch Collagen ausgelosten Aggregation von menschlichen Thrombocyten gepruft. Die beobachteten Effekte
waren stark strukturabhangig (ICs0 = 0,2-140pmol/L). Als Ursache kommt
unterschiedliches Bindungsvermogen an die Plattchenmembran in Frage.
Die geringsten Hemmkonzentrationen wurden fur das 3-Hexyl (20 und
das 3-Cyclohexylnitrosimin (Zp) gemessen. Drei N-Nitrosydnonimine (3e,
3f, 3i) zeigten ebenfalls IC,,-Werte unterhalb 10 pmol/L. Drei ausgewXh1te Nitrosimine (Za, Zf, Zm) hemmten bei Ratten die durch Laserstrahl
induzierte Thrombose in MesenterialgefaBen um bis zu 70%. Das 3Methylnitrosimin 2a senkte am wachen renal hypertensive Hund den
systolischen und den linksventrikuli3xen enddiastolischen Blutdruck. Diese
Eigenschaften machen auch antianginose Effekte vergleichbar mit Molsidomin wahrscheinlich. Der mildere Wirkungsbeginn und die langere Wirkungsdauer von 2a konnten im Vergleich zu Molsidomin von Vorteil bei
der Behandlung der angina pectoris sein.
Recently we reported on the antiplatelet and antithrombotic activities of 3-arylalkyl-N-nitroso-5-sydnone
imines').
The present study shows the results obtained with 3-alkyland 3-cycloalkyl derivatives of this new class of NO-compounds. The nitrosimines 2 were prepared as usual') from
the corresponding imines 1. Exact structures are given in
Table 1. To characterize the importance of the nitroso
group a small number of nitrimines 3, one sydnone (4a) and
one cyanoimine (5a) were synthesized. The nitrosation of 1
shifts the signal of the sydnone proton in 4-position from
8.11 ppm to 8.75 ppm (e.g. l a + 2a). The corresponding
nitrimine, however, shows a similar chemical shift (3a: 8.70
ppm). The differentiation between type 2 and type 3 compounds can be achieved by 13C-NMR spectroscopy: the signal for C-5 is found at 182.6 ppm for 2a while in 3a a
marked upfield shift to 172.8 ppm occurs.
the exocyclic NO. We could prove this by labeling Za with "N by reaction
of l a with Na"N0,. - The loss of molecular N, is solely a thermal reaction (at 100OC: Mf'-N2 = 33%). In the +FAB-mass spectrum at room temp.
no loss of N2 occurs. M+' forms the base peak. - For compound 2r frans
conformation could be ascertained by 'H-NMR spectroscopy (acetone):
the signal at 4.95 ppm (H-1') is a triplet of triplets (J = 12.2/4.0 Hz). This
proves that it is an axial proton. The proton adjacent to the methyl group of
the cyclohexane moiety (H-4') could be determined by a decoupling
experiment: when irradiating the methyl group at 0.98 ppm the signal at
1.62 ppm is simplified to a triplet of triplets (J = 12.2/3.4 Hz). The proton
undoubtedly has an axial position. The assignment of all other protons was
ascertained by 'H-correlation spectroscopy.
The nitrosirnines 2 show a remarkable solvatochromia (Fig. 1). We
interpret the results as an increasing contribution of the dipolar, quasiaromatic structure Za to the electron distribution in the molecule with
increasing polarity of the solvent. The fragility of the N-NO-bond becomes
evident in the electron impact mass spectra: in 2a the peak at m/z = 30
(NO+) is the base peak of the spectrum. This ion exclusively stems from
rn
Wfi
WCN
CHCl3:
+)
318
325
333
336
(4.29);
(4.29);
(4.26);
(4.20):
428
452
484
484
(2.07)
(1.88)
(1.89)
(1.90)
Part of the dissertations K.-J. Schleifer, FU Berlin 1992 and T. Ciborski.
FU Berlin 1991
Arch. P h r m . {Weinheirn)326,791-797 (1993)
Fig. 1: Solvatochromia of 2a (hhog E) in four solvents.
0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 19930365-6233/93/1010-0791
$5.00 + ,2510
792
Rehse and coworkers
Table 1: Structures and antiplatelet activities (Borri-test, collagen) of sydnone imine
derivatives. When DMSO had to be used to improve solubility in water (*) only ICso values below 85 wnol/L are due to the comDound tested.
vpditei
Icso
typeliten
R
JumoVLl
la
2a
z 500
2.4
Ic50
lumovLl
11
(CHJ)~-CH-CH~-
> 500
21
(CH~)~-CH-CHZ-
138
23
3a
25,
4a
2b
42'
2m (CHh-CH-(CH2)22n C ~ H ~ - O - ( C H ~ ) J -
62
20
(H3C)t-N-
10
2c
19
> 500
2d
2e
62
1P
2P
cyclohexyl
3-methyl-cycloheyl
13
cyclohexyl
3e
4.7.
2f
0.2
Iq
2q
lr
3f
4.8,
2r
4-methyl-cyclohexyl
3-methyl-eyclohexyl
4-methyl-cyclohexyl
2.8
13'
> 500
5.5'
> 500
6*
2g
14,
2s
1-adsmantyl
3g
2h
2i
3i
42,
2t
2-(1-cyclohexeny1)-ethyl-
45'
9*
lu
2u
I-morpholinyl
1
t-morpholinyl
15
5a
isobutyl
85.
2j
2k
31
39.
9.5.
85.
38
The ability of the compounds 1-5 to inhibit the aggregation of human blood platelets induced by collagen is summarized in Table 1. All 3-alkyl-imines 1 (e.g. la, 11, l p ,
1s)are without effect. This is in contrast to the corresponding 3-N-substituted imine l u which is the active metabolite
of molsidomine, known as SIN 1. This difference shows the
stability of 1 against hydrolysis at physiological conditions.
In the series of nitrosimines 2, there are observed differences which do cover more than two orders of magnitude
(compare 2f and 21). The antiplatelet activities strongly
depend on the chain length of the 3-alkyl substituent. Optimum inhibition of platelet aggregating is found for the 3hexyl derivative 2f. A prolongation or shortening of only
one methylene group markedly decreases the antiplatelet
effect (2e, 2g). Further modifications with this respect do
not give favourable results as is pointed out either by 2b,
2c, 2d or 2h, 2i, and 2k. Branched hydrocarbon chains further decrease activity (compare the pairs: 2d/21 and 2e/2m).
The replacement of one methylene group by an 0-atom in
the hexyl compound 2f as well decreases activity but a considerable rest is retained (2n). The results obtained with a nhexyl rest stimulated us to prepare some cyclohexyl derivatives (2p, 2q, 2r): they are rather strong antiplatelet compounds, their ICso being in the range of some pmol/L.
The steric limitations of the cycloalkyl substituent are
pointed out by the adamantyl derivative 2s, the activity of
which is decreased by more than one order of magnitude as
compared with the cyclohexyl derivatives. The remarkable
activity found in the cyclohexylethyl compound 2t corresponds to the favorable results obtained with the corresponding phenylethyl product') (IC50= 0.7 pmol/L).
We have already shown that the activities in the Born-test
are due to the photolytical release of an active metabolite,
presumably NO. The electronic spectra of all compounds 2
(except 20 and 2u) are identical. Therefore, their ability to
absorb light and to be cleaved thereby should as well be the
same. The reason for the large differences in activity
should, therefore, not be related to the ease with which the
=N-NO bond is cleaved. A more plausible reason might be
an odd distribution of the test compounds in the probe. As
we know from our studies in the field of oligoamines')
hexyl or phenylethyl substituents are extremely capable to
bind to the platelet membrane by hydrophobic interactions.
This leads to an accumulation in the membrane and possibly enhanced passage through the membrane. This might
as well be the case with equally substituted nitrososydnone
imines. In this case a higher percentage of the compound
will release the active metabolite photolytically at or near
Arch. Pharm. (Weinheirn)326, 791.797 (1993)
793
NO-Donors
its site of action. Hereby a lower overall concentration i.e.
will be sufficient to develop the same effect as higher
concentrations of a more evenly distributed substance. The
two compounds of the moldsidomine type (20, 2u) join the
range of activities with other compounds of type 2. It is one
order of magnitude lower than l u , the active metabolite of
molsidomine. This suggests that the effects observed are as
well due to the photocleavage of the nitrosoimino group.
Since some 3-arylalkyl-N-nitro-sydnone-5
imines had
shown antiplatelet activities') we also prepared five nitrimines of type 3. Again we found a pronounced inhibition of
platelet aggregation (3e, 3f, 39, while the effect in 3a and
3g was small. However, no clear structure activity relationship could be established since some nitrimines were more
effective (3a, 3f, and 3g) and others were less effective (3e,
3i) than the corresponding nitrosimines.
The antithrombotic properties of three nitrosimines were
assayed in a thrombosis model3). These compounds were
selected according to their ICs0 in the Born-test. Three different orders of magnitude were chosen to get an idea
whether there is a correlation between the in vitro and in
vivo results. The thrombus formation represents the average
number of defined laser shots necessary to induce thrombus
formation in mesenterial arterioles or venoles in rats. The
percentage of inhibition was calculated with respect to the
maximal achievable effect in this model (TFI = 6, no
thrombus formation at all). The effects were observed 2 h
after oral administration of the drugs, as the vasodilating
effects of 2a had suggested this time interval (vide irzfra).
The data of Tab. 2 clearly show that there is a dose dependent inhibition of thrombus formation in arterioles and
venoles. According to our experience TFI 2 4 has to be
classified as a strong antithrombotic effect. As the data
show the effect of all three compounds is rather similar. It
does not reflect the large differences which are observed in
vitro. This is not so surprising when one takes into account
that in vivo no photolytic cleavage of the =N-NO-bond is
possible. This process has to occur biochemically. Presumably this is performed by a redox reaction in the liver. The
metabolite has then to be transported to its place of action
by the blood stream. Mere hydrolytic events are less probable as they should occur as well in (dark) platelet rich plasma which, however, is not the case. Beside their antiplatelet
activity, NO-donors such as organic nitrates and molsidomine are known to have a potent vasodilator effect which is
used in the therapy of angina pectoris5).Therefore, we also
tested the hemodynamic effects of the nitrosimine 2a in
conscious renal-hypertensive dogs. Oral administration of
the compound at a dose of 3 mg/kg resulted in a marked
decrease of the systolic blood pressure by 35 mm Hg (Fig.
2, right panel). The diastolic blood pressure was just slightly affected (-8 mm Hg) and LVEDP was moderately
Table 2: Antithrombotic properties of 2a, 2f, and 2m, 2 h after p . 0 . administration.
statistics: U-test, Wilcoxon et a1.4). TFI = thrombus formation index
0
-10
-20
-30
-40
-50
L
0
120
180
240
300
i-10
-50
1-10
60
0
360
60
min
4-
178 k 15
+BPd
llOf 10
120
180
240
300
360
min
-8- LVEOP
15f2
4-
cwtml
+ vlllues--
190f 18
+EPU
lOOf 13
-8- L M D P
16f4
Fig. 2: Effects of compound 2a (right panel, 3.0 m&g) and molsidomine (left panel, 0.2 m&g) on systolic blood pressure (BPs), diastolic blood pressure (BPd), and left ventricular enddiastolic pressure (LVEDP) in conscious renal-hypertensive dogs after oral administration.
Arch. Pharm. (Weinheim)326,791-797 (1993)
794
reduced. Heart rate and left ventricular contractility
remained almost unchanged. Thus, the hemodynamic profile of compound 2a was similar to that of molsidomine.
However, the time course of action was different (Fig. 2).
The activity of 2a was slower and more prolonged. A
retarded intestinal absorption or a slower formation of the
active vasodilating metabolite could be responsible. The
active metabolite is probably NO since, in an other series of
experiments with isolated blood vessels, the relaxing activity of 2a was blocked by oxyhemoglobin, a known scavenger of NO6). Whereas the relatively high oral dose of 10
mg/kg of 2a had approximately the same moderate effect as
the lower dose, the administration of higher doses of molsidomine always resulted in an untolerable drop in BPs.
Thus, the new compound 2a with its smoother onset and
longer duration of action may have a substantial advantage
over molsidomine in the treatment of angina pectoris.
In summary 3-alkyl-nitroso-5-sydnoneimines exhibit
vasodilating and antithrombotic effects in vivo. As the former effect seems to be saturable these compounds not only
might be useful in the treatment of angina pectoris but as
well for simultaneous prophylaxis of thrombosis.
Experimental Part
The analytical apparatus7' and the test systemsx' were described.. The
method for the synthesis of the sydnone imines, the nitrosimines and the
sydnones (4) have been reported in detail". The nitrimines were prepared
from sydnone imine nitrates using the method of Brookes and Walker9).The implantation of chronic catheters for the hemodynamic measurement
in conscious dogs and the induction of renal hypertension were described"". Briefly, for continuous recording of the various hemodynamic parameters, the two catheters implanted in the aorta and the left ventricle of the
heart were connected to pressure transducers. When stable hemodynamic
conditions were achieved for at least 20 min, the test compound filled in a
gelatine capsule was adminictered orally and the effects were recorded for
6 h. Drug effects refer to control values obtained during the 20 min before
administration. Results are presented as mean (x) and standard error of the
mean (S.E.M.).
Rehse and coworkers
(C!&).MS (110OC): m/z = 141 (19%; M+*),84 (15), 68 (12), 57 (loo),
43 (39), 41 (97), 36 (57), 29 (57).
3-Cyclohexvl-S-sydnone imine hydrochloride (lp)
Powder (ethanol/ether), mp. 159°C (Lit."): 159-160°C). Yield 43%.C,H,,ClN,O (203.7) Calcd. C 47.2 H 6.93 N 20.6 Found C 47.0 H 7.20 N
20.5.- IR (KBr): 3084; 2977; 2945; 2921; 2856; 2660; 1666; 1577; 1468;
1459; 1440; 1400 1362; 1276; 1263; 1238; 1190 1161; 1145; 1085; 1053;
1009; 984; 937; 897; 817; 766; 695 cm~'.-UV (CH30H): h mdX (log E) =
204 (3.85), 292 nm (3.86): 'H-NMR/300 MHz ([D,jDMSO): 6 (ppm) =
9.78 (bs; 2H, =NH2+,D 2 0 exchange), 8.15 (s; lH, syd-H), 4.87 (m; IH, NCH), 2.21-1.22 (m; 10 H, cyclohexyl-H).- MS (+FAB/DMSO/glycerol):
m/z = 168 (64%; [M + HI+), 86 (33), 85 (loo), 82 (Sl), 80 (17), 78 (14),
77(10),66(19),62(11),60(15),55(11).
3-(3-Merhylcyclohe~yl)-S-s~dnone
iniine hydrochloride (1s)
Powder (isopropanol/ether), mp. 167°C (dec.). Yield 42%: C9H16ClN30
(217.7) Calcd. C 49.7 H 7.41 N 19.3 Found C 49.6 H 7.75 N 19.4.- IR
(KBr): 3157; 3065; 2926; 2862; 2841; 2611: 1702; 1673; 1566; 1477;
1456; 1373; 1343; 1291; 1250; 1169; 1076; 1039; 1005; 955; 934; 884;
860; 768; 729 cm-'.- UV (CHIOH): h max (log E) = 205 (3.81), 294 nm
(3.94).- 'H-NMR/300 MHz ([D,]DMSO): 6 (ppm) = 9.93 (bs; 2H, =NH2+,
D 2 0 exchange), 8.18 (s; IH, syd-H), 4.92 (m; lH, N-CH ax), 2.18-1.41
(m; 9H, cyclohexyl-H), 0.95 (d; J = 5.5 Hz, 3H, CHI).- MS
(+FAB/DMSO/glycerol): m/z = 182 (100%; [M + HI+), 149 (13), 97 (22),
86 (58), 73 (4).
3-(4-Merh?.l~~yclohexylJ-5-.~ydnone
imine hydrochloride ( l r )
Needles (isopropanol/ether), mp. 177OC (dec.). Yield 39%.C9H16ClN30(217.7) Calcd. C 49.7 H 7.41 N 19.3 Found C 49.5 H 7.51 N
19.5.- IR (KBr): 3105; 3023; 2950; 2929; 1681; 1560; 1475; 1449; 1372;
1274: 1238; 1159; 1074; 967; 930; 765; 648 cm-'.UV (CH,OH): h max
(log E) = 205 (3.79), 294 nm (3.91).- IH-NMR/300 MHz ([D,]DMSO): 6
(pprn) = 9.69 (s; 2H, =NH,+, DzO exchange), 8. I3 (s; 1 H, syd-H), 4.81 (m;
IH, H-1' ax), 2.20 (m; 2H, H-2'/H-6' eqj, 1.89 (m; 2H, H-2'/H-6' ax),
1.82 (m; 2H, H-3'm-5' eq), 1.46 (m; 1H, H-4' ax), 1.13 (m; 2H, H-3'/H5' ax), 0.90 (d; J = 6.5 Hz, 3H, CH,).- MS (100°C): m/z = 181 (10%;
M+'), 97 (75), 69 (1 I), 55 (loo), 41 (24), 39 (13).
3-Methyl-N-nirrosoJ-sydnone imine (2a)
Crqstals (ethanol/ether), mp. 151°C (Lit."': 155°C). Yield 63%:
C3H,CINI0 (135.5) Calcd. C 26.6 H 4.46 N 31.0 Found C 26.8 H 4.66 N
31.1.- 1R (KBr): 3333; 3159; 3007; 2981; 2959; 2892; 2753; 2662; 2620;
2580; 2269; 2141; 2096; 2057; 1678; 1576: 1522; 1476; 1448; 1431; 1321;
1172; 1127; 1090; 1049; 1003; 931; 761; 742; 690; 629; 605 cm-'.- UV
(CH?OH):h max (log E) = 205 (3.86), 292 nm (3.89).- 'H-NMR/300 MHz
(ID,jDMSO): 6 (ppm) = 10.03 (bs; 2H, =NH,+, D,O exchange), 8.1 1 (s;
IH, syd-H), 4.35 (s: 3H, N-CH,).- MS (140°C): m/z = 99 (43%; M+'), 67
(I(,),15(11),43(19),42(100),41(30),30(83).
Ochre crystals (ethanol), mp. 133°C (Lit.12): 128'C). Yield 63%.C3H4N4O2(128.1) Calcd. C 28.1 H 3.14 N 43.7 Found C 27.9 H 3.1 1 N
43.5.- IR (KBr): 3417; 3052; 2953; 1646 1565: 1468; 1445; 1416; 1403;
1360; 1347; 1235: 1107; 1087: 1067; 1017; 960; 878; 830; 678; 640cm-I.UV (CH30H): h max (log E) = 333 (4.26), 484 nm (1.89).- 'H-NMR/250
MHz ([D,jDMSO): 6 (ppm) = 8.75 (s; IH, syd-H), 4.39 (s; 3H, N-CH,)."C-NMR/75.47 MHz ([DJDMSO): 6 (ppm) = 182.6 (s; syd-C-S), 106.5
(s; syd-C-4), 40.0 (s; N-CH3).- MS (100°C): m/z = 128 (9%; M+'), 100
(33), 99 (12), 98 (IS), 68 (25). 67 (47), 42 (48), 30 (loo), 28 (47).- MS
(+FAB/DMSO/glycerol): m/z = 129 (21%, [M + HI+), 99 (4), 93 (loo%,
[Gly + HI+), 55 (35).
.~-l.sohn!v1-.5-.s~dnoneimine hydt-ochloride (111
3-Etliyf-N-nitroso-5-sydnonek i n e (2b)
Needles (isopropanoliether), mp. 18 I O C . Yield 81%.- C,H12CIN10
(177.6) Calcd. C 40.6 H 6.81 N 23.7 Found C 40.4 H 6.94 N 23.7.- IR
(KBr): 3154: 3019; 2619; 1676; 1664; 1573; 1468; 1392; 1371; 1226;
1171; 1085; 100k 936; 891; 776; 617 cm-l.- UV (CH3OH): h mdX (log E)
= 205 (3.93), 293 nm (3.90): 'H-NMR/250 MHz ([D6]DMSO): 6 (pprn) =
9.96 (bs. 2H. =NH,+, D,O exchange), 8.15 (s; lH, syd-H), 4.51 (d;J = 7.2
Hz, 2H, N-CH2), 2.29 (m; lH, CH(CH3)2), 0.95 (d; J = 6.7 Hz, 6H,
Orange crystals (ethanol/ether), mp. 7 2 9 C (Lit.'? 63.5-65.5"C). Yield
50%: C4H6N,02 (142.1) Calcd. C 33.8 H 4.26 N 39.4 Found C 33.7 H
4.28 N 39.3.- IR (KBr): 3418; 3128; 2983; 1676; 1586 1565; 1417; 1380;
1307; 1262; 1219; 1111; 1016; 9 7 6 962; 944; 874; 795; 673; 637 cm-'.UV (CH3CN): h max (log E) = 333 (4.25), 484 nm ( I .Y I).- 'H-NMRI300
MHz ([D,]DMSO): 6 (ppm) = 8.84 (s; lH, syd-H), 4.72 (q: 2H, N-CH,),
1.62 (t; 3H, CH,).- MS (60"): m/z = 142 (8%; M+'), 114 (67), 112 (12), 82
3-Methyl-S-sydnonr iniine hydrochloride ( l a )
Arch. Pharm. (Weinheim) 326,791-797 (1993)
795
NO-Donors
(15), 67 (IOO), 56 (63), 55 (18), 54 (23), 53 (lo), 44 (13), 42 (11), 41 (19),
40 (20), 39 (lo).- MS (+FAB/DMSO/glycerol): m/z = 143 (100%; [M +
HI+), 142 (30), 114 (19), 113 (26), 112 (16), 82 (15), 68 ( I ] ) , 55 (12). 54
(16),43 (10).
3-Propyl-N-nitroso-5-sydnone
imine (212)
Orange crystals (isopropanoVether), mp. 95°C Yield 53%: C5H8N4O2
(156.1) Calcd. C 38.5 H 5.16 N 35.9 Found C 38.8 H 5.29 N 35.9.- IR
(KBr): 3429; 3133; 2969; 2877; 1589; 1567; 1458; 1413; 1374; 1301;
1250; 1128; 1017; 961; 906; 883; 788; 734; 643 cm-'.- UV (CH,CN): h
max (log E ) = 333 (4.25), 484 nm (1.91).- 'H-NMR/250 MHz
([DJDMSO): 6 (ppm) = 8.85 (s; 1H, syd-H), 4.67 (t; J = 7 Hz, 2H, NCH,), 2.04 (m; 2H, C&CH3), 0.96 (t; 3H, CH3).- MS (70"): m/z = 128
(25%, [M - N2]+'), 98 (17), 70 (lo), 68 (42), 67 (loo), 66 (1 I), 43 (27), 41
(20): MS (+FAB/DMSO/glycerol): m/z = 469 (2%, [3 M + HI+), 313
(22%, [2 M + HI+), 157 (loo%, [M + HI+), 156 (29), 128 (15), 127 (29),
127 (17), 97 (7).
3-Butyl-N-nitroso-5-sydnone
imine (2d)
Ochre crystals (isopropanol/ether), mp. 7 6 T . Yield 52%: C6H,f1402
(170.2) Calcd. C 42.4 H 5.92 N 32.9 Found C 42.5 H 6.08 N 32.9.- IR
(KBr): 3855; 3845; 3129; 2959; 2932; 2875; 2165; 1588; 1571; 1416;
1391; 1293; 1238; 1121; 1019; 965; 787; 643 cm-l.- UV (CH,CN): h max
(log E) = 333 (4.25), 484 nm (1.90): 'H-NMR/250 MHz ([D,]DMSO): 6
(ppm) = 8.84 (s; 1H, syd-H), 4.71 (t; J = 7.2 Hz, 2H, N-CH,), 2.01 (tt; J, =
7; J2 = 7 Hz, 2H, CH2-C2H5),1.38 (m;2H, CH2-CH3),0.93 (t; 3H, CH3).MS (+FAB/DMSO/glycerol): m/z = 171 (loo%, [M + HI+), 170 (40), 142
(27), 141 (37), 140 (27), 111 (lo), 84 (lo), 68 (24), 56 (38), 55 (17).
N-Nirroso-3-penryl-5-sydnone
imine (2e)
Ochre crystals (isopropanol/ether), mp. 74°C. Yield 70%.- C7H,,N40,
(184.2) Calcd. C 45.6 H 6.56 N 30.4 Found C 45.5 H 6.69 N 30.4.- IR
(KBr): 3302; 3056; 3006; 2942; 2921; 2868; 2856; 2166; 1565; 1465;
1448; 1417; 1383; 1368; 1338; 1269; 1236; 1173; 1080; 1062; 1021; 1010;
994; 951; 877; 821; 733; 672; 645 cm-'.- UV (CH,CN): h max (log E ) =
333 (4.25), 484 nm (l.89).- 'H-NMR/250 MHz ([D6]DMSO): 6 (ppm) =
8.84 (s; 1H, syd-H), 4.70 (t; J = 7.2 Hz, 2H, N-CH,), 2.04 (m; 2H, N-CH,CH,), 1.35 (m; 4H, (CH&-CH3), 0.89 (t; 3H, CH& MS (100'): m/z =
156 (3076, IM - NJ"), 123 (14). 109 (21). 98 (41), 96 (21), 82 (16). 71
(41), 69 (38), 68 (loo), 55 (16). 43 (27): MS (+FAB/DMSO/m-NO,-benzylalcohol): m/z = 185 (loo%, [M + HI+), 125 (lo), 98 (15). 79 (18), 69
(36).
3-He~l-N-nitroso-5-sydnoneimine (2f)
Orange crystals (isopropanol/petrolether), mp. 7 I T . Yield 48%.C8Hl4N4o2(198.5) Calcd. C 48.4 H 7.12 N 28.3 Found C 48.3 H 7.11 N
28.4.- IR (KBr): 3051; 3003; 2940; 2910; 2867; 2852; 2114; 1566; 1466;
1451; 1421; 1384; 1353; 1344; 1313; 1296; 1253; 1234; 1175; 1079; 1063;
1022; 1015; 962; 944; 878; 826; 766; 726; 672; 645 cm-'.- UV (CH3CN):
h max (log E ) = 333 (4.26), 484 nm (1.89): 'H-NMR/250 MHz
([D6]DMSO): 6 (ppm) = 8.84 (s; 1H, syd-H), 4.70 (t; 2H, N-CH,), 2.03 (tt;
J, = 7, J2 = 7 Hz, 2H, N-CHz-CH,), 1.36 (m;6H, (C&),-CH3), 0.87 (t; 3H,
CH,).- MS (+FAB/DMSO/glycerol): m/z = 199 (100%. [M + HI+), 198
(35), 170 (38), 169 (45), 168 (31). 139 (lo), 112 (15), 85 (10).
3-Hepryl-N-nitroso-5-sydnone
imine (2g)
Orange crystals (acetonkther), mp. 83OC. Yield 76%.- C9HI6N4O2
(212.3) Calcd. C 50.9 H 7.59 N 26.4 Found C 50.9 H 7.73 N 26.5.- IR
Arch. Pharm. (Weinheim) 326, 791-797(1993)
(KBr): 3055; 3006; 2940; 2911; 2867; 2851; 2105; 1565; 1467; 1450;
1418; 1381; 1293; 1282; 1243; 1229; 1173; 1080; 1063; 1027; 1012; 969;
943; 876; 820; 721; 673; 646 cm-'.- UV (CH3CN): h max (log E ) = 333
(4.26), 484 nm (1.90).- 'H-NMR/250 MHz ([D,]DMSO): 6 (ppm) = 8.84
(s; 1H, Syd-H), 4.69 (ti J = 7.2 Hz, 2H, N-CH,), 2.05 (tt; J1 = 7, 52 = 7 Hz,
2H, N-CH,-CH,), 1.30 (m;8H, (C&)4-CH,), 0.86 (t; 3H, CH,).- MS
(+FAB/DMSO/glycerol): m/z = 213 (94%, [M + HI+), 212 (20), 184 (46),
183 (36). 182 (16), 126 (15), 86 (lo), 68 (20), 56 (100).
N-Nitroso9-ocryl-5-sydnone imine (2h)
Orange crystals (ethanol/ether), mp. 79OC. Yield 75%.- CiOHl8N4O2
(226.3) Calcd. C 53.1 H 8.02 N 24.8 Found C 53.1 H 8.32 N 24.8.- 1R
(KBr): 3139; 3006; 2945; 2919; 2851; 1708; 1565; 1465; 1418; 1381;
1370; 1341; 1316; 1282; 1273; 1251; 1235; 1160 1099; 1014; 977; 941;
909; 866; 793; 769; 721; 637 cm-l.- UV (CH3CN): h max (log E ) = 272
(3.65), 333 (4.28), 484 nm (1.90).- 'H-NMR/250 MHz ([D6]DMSO): 6
(ppm) = 8.84 (s; IH, syd-H), 4.69 (t; J = 7.2 Hz, 2H, N-CH2), 2.02 (tt; J, =
7, J2 = 7 Hz, 2H, N-CHz-CH2), 1.31 (m;10 H, (CE12)5-CH3),0.85 (t; 3H,
CH,).- MS (+FAB/DMSO/glycerol): m/z = 227 (93%, [M + HI+), 226
(29). 198 (41), 197 (32), 196 (37), 140 (37), 86 (14), 83 (14), 82 (13), 81
(lo), 78 (21). 77 (17), 70 (loo), 69 (18), 68 (60), 67 (14).
N-Nitroso-3-nonyl-5-sydnone
imine (2i)
Yellow needles (ethanol/ether), mp. 87OC. Yield 70%: C,,H20N,0,
(240.3) Calcd. C 55.0 H 8.39 N 23.3 Found C 55.0 H 8.60 N 23.3.- IR
(KBr): 3416; 3054; 2913; 2850; 1566; 1466; 1420; 1383; 1239; 1082;
1065; 1019; 982; 950; 820 cm-'.- UV (CH3CN): h max (log E ) = 333
(4.28), 483 nm (1.92).- 'H-NMR/250 MHz ([D6]DMSO): 6 (ppm) = 8.84
(s; 1H, syd-H), 4.68 (ti J = 7.2 Hz, 2H, N-CH,), 2.01 (tt; J1 = 7.2; 52 = 7
Hz, 2H, N-CH2-CHZ),1.28 (m; 12 H, (C&)6-CH3), 0.85 (t; 3H, CH,).- MS
(200°C): mlz = 212 (13%, [M - NJ"), 153 (18), 136 (18), 122 (28), 108
(88). 84 (64). 70 (79), 68 (86), 67 (loo), 56 (76), 54 (69), 42 (82): MS
(+FAB/DMSO/glycerol): m/z = 241 (loo%, [M + HI+),240 (38), 212 (48),
211 (24), 210 (46). 197 (14), 181 (lo), 167 (13), 82 (13), 154 (41), 140
(12), 115 (14), 86 (30). 85 (71), 83 (29), 79 (29).
3-Decyl-N-nitroso-5-sydnoneimine (2j)
Orange powder (methanol), mp. 84'C. Yield 62%: C,2H22N402(254.3)
Calcd. C 56.6 H 8.71 N 22.0 Found C 56.4 H 8.79 N 22.0.- IR (KBr):
3138; 3007; 2945; 2917; 2848; 1566; 1466; 1418; 1381; 1370; 1341; 1319;
1288; 1263; 1242; 1221; 1160; 1100 1017; 999; 953; 934; 886; 793; 741;
7 2 0 637 cm-l.- UV (CH,CN): h max (log E ) = 333 (4.24), 484 nm (1.90).'H-NMR/250 MHz ([D6]DMSO): 6 (ppm) = 8.84 (s; IH, syd-H), 4.69 (t; J
= 7.2 Hz, 2H, N-CH,), 2.05 (tt; Ji = 7.2; J, = 7 Hz, 2H, N-CHZ-CI&), 1.28
(m; 14 H, (CJIf&-CH3), 0.86 (t; 3H, CH& MS (+FAB/DMSO/glycerol):
m/z = 255 (18%, [M + HI'), 226 (43), 97 (16), 86 (21), 85 (24), 84 ( l l ) ,
83 (14), 81 (17), 79 ( I l ) , 71 (34), 69 (64). 57 (loo), 56 (22), 55 (91), 54
(11),53 (16).
3-Dodecyl-N-nitroso-5-sydnone
imine (2k)
Orange powder (methanol), mp. 89°C. Yield 82%.- CI4Hz6N4O2
(282.4)
Calcd. C 59.6 H 9.28 N 19.8 Found C 59.7 H 9.26 N 19.9.- IR (KBr):
3432; 3137; 2915; 2848; 1566 1465; 1420; 1382; 1340; 1271; 1251; 1235;
1101; 1012; 968; 941; 793; 719; 637 cm-'.- UV (CH,CN): h max (log E ) =
273 (3.77). 333 (4.27). 483 nm (1.89).- 'H-NMR/300 MHz ([D6]DMSO):
6 (ppm) = 8.83 (s; IH, syd-H), 4.68 (t; J = 7.2 Hz, 2H, N-CH,), 2.01 (tt; J,
= 7.2; J2 = 7 Hz, 2H, N-CH2-CH2), 1.27 (m; 18 H, (C€l2)&H3),
0.85 (t;
3H, CH3).- MS (+FAB/DMSO/glycerol): m/z = 283 (33%, [M + HI+), 255
(13), 254 (50). 229 (lo), 155 (10). 93 (loo%, [Gly + HI+), 86 (36), 75 (39).
70 (49).
796
3-Isohutyl-N-nitroso-S-sl.dnone
imine (21)
Orange needles (ethanol/ether), mp. 87°C. Yield 45%: C6HI0N4O2
(170.2) Calcd. C 42.4 H 5.92 N 32.9 Found C 42.6 H 6.11 N 33.0.- IR
(KBr): 3132; 2962; 2933; 2872; 1710; 1565; 1465; 1452; 1416; 1398;
1382; 1333; 1248; 1220; 1108; 1017; 957; 888; 827; 790; 742; 704; 644
c1n-I.- UV (CH3CN): h max (log E) = 333 (4.28), 484 nm (l.89).- 'HNMRi250 MHz ([D,]DMSO): 6 (ppm) = 8.82 (s; IH, syd-H), 4.56 (d; J =
7.2 Hz, 2H. N-CH2),2.38 (m;J = 6.8 Hz, IH, CH(CH,),), 0.99 (d; J = 6.7
Hz. 6H, (CH&).- MS (+FAB/DMSO/glycerol): m/z = 171 (100'36, [M +
HI+), 170 (161, 142 (26), 141 ( 2 9 , 140 (12). 68 (16).
Orange crystals (ethanol/ether), mp. 93°C. Yield 52%: C7Hl,N4O2
(184.2) Calcd. C 45.6 H 6.57 N 30.4 Found C 45.6 H 6.78 N 30.1.- IR
(KBr): 3103; 2956; 2871; 1669; 1561; 1471; 1410; 1396; 1382; 1365:
1325; 1299; 1241; 1149; 1117: 1016; 981; 959; 937; 880; 779; 726; 709;
647 cm-'.- UV (CHICN): h max (log E ) = 333 (4.28), 483 nm (1.90): 'HNMR/250 MHz ([D,]DMSO): 6 (ppm) = 8.85 (s; IH, syd-H), 4.72 (t; J =
7.4 Hz, 2H, N-CH2), 1.93 (dt; J , = 7.4; J2 = 6.6 Hz, 2H, N-CH,-CH,), 1.66
(m; IH, -CH(CH,)2), 0.95 ( d J = 6.6 Hz, 6H, (CH3)+ MS (100°C): m/z =
184 (296, M+'), 154 ( 2 ) , 71 (18), 68 (46), 55 (33), 43 (IOO), 41 (66), 30
Rehse and coworkers
(KBr): 3426; 3055; 2938; 2863; 2840; 1590; 1569; 1455; 1432; 1361;
1347; 1331; 1309; 1264; 1224; 1124; 1038; 1023; 964; 944,875; 847; 804
749; 665 cm-'.. UV (CH3CN):h max (log E ) = 333 (4.24), 483 nm (l.89),'H-NMR1300 MHz ([DJDMSO): 6 (ppm) = 8.90 (s; IH, syd-H), 4.92 (m;
IH, N-CH ax), 2.28-1.45 (m; 9H, cyclohexyl-H), 0.96 (d; J = 5.7 Hz, 3H,
CH+ MS (+FAB/DMSO/glycerol): m/z = 21 I (8%, [M + HI+), 186 (6).
149(44), 117 (13),97(12),78(16),73(11).
3-(4-Methylcyclohexyl)-N-nitroso-S-sydnone
imine (2r)
Yellow needles (methanol), mp. 1 3 5 T . Yield 64%.- C9H,,N,O2 (210.2)
Calcd. C 51.4 H 6.71 N 26.7 Found C 51.5 H 6.74 N 26.9.- IR (KBr):
3434; 3105: 2943; 2923; 2860; 1586; 1423; 1352; 1312; 1254; 1226; 1141;
1017; 977; 889; 778; 755; 664 cm-'.- UV (CH,CN): h max (log e) = 333
(4.27). 482 nm (1.91).- 'H-NMR/300 MHz ([DJDMSO): 6 (pprn) = 8.91
(s; IH, syd-H), 4.86 (m;IH, H-I' ax), 2.29 (m; 2H, H-2'/H-6' eq), 1.97
(m; 2H, H-2'/H-6' ax), 1.86 (m; 2H, H-3'm-5' eq), 1.49 (m; IH, H-4' ax),
1.17 (m; 2H, H-3'/H-S' ax), 0.92 (d; J = 6.5 Hz, 3H, CH,).- MS
(+FAB/DMSO/glycerol): m/z = 211 (2696, [M + HI+), 182 (12), 181 (IS),
98 (lo), 97 (loo), 95 (36), 85 (18), 80 (19), 78 (16), 74 ( I I ) , 70 ( I I ) , 68
(25),66 (23), 55 (24), 54 (IS).- MS (100'C): m/z = 182 (2% [M - N2]+'),
97 (48), 96 (31), 95 (18), 82 (14), 81 (21), 67 (12). 55 (loo), 41 (2% 39
(1 1).
(99).
3-Aduman~l-N-nitroso-S-sydnone
iniiize (2s)
3-i3-Etho.~~pro~py/)-N-nitr~)so-5-sydnone
imine (Zn)
Orange crystals (isopropanol/petrolether), mp. 40°C. Yield 39%:
C,H12N403(200.2) Calcd. C 42.0 H 6.04 N 28.0 Found C 42.2 H 6.30 N
27.7.- IR (KBr): 3430; 3105; 2968; 2866; 1569; 1420; 1383; 1288; 1230;
1 1 12; 1005; 959; 874; 769 cm-'.- UV (CH,CN): h max (log E ) = 333
(4.29), 484 nm (l.90).- 'H-NMR/300 MHz (CDCI,): 6 (ppm) = 8.17 (s;
IH, Syd-H), 4.85 (ti J = 6.8 Hz, 2H, N-CH,), 3.59 (ti J = 5.5 Hz, 2H, C&O-C2H,), 3.48 (q; 2H, 0-CHZ-CH,), 2.41 (tt; J l = 6.8; J2 = 5.5 Hz, 2H, NCH?-C&), 1.16 (t; 3H, CH&- MS (+FAB/DMSO/glycerol): m/z = 201
(78%,,[ M +HI+), 200 (6), 172 ( 1 I), 171 (22), 149 (20), 117 (8), 87 (17),
78 (32), 72 (7).
N.N-l)in~ethyl-.5-izitrosoimino-s~dnone-3-an1ine
(20)
Yellow crystals (isopropanol), mp. 106°C (Lit.'?): 1 12-113°C). Yield
41%: C,H7NSO2 (157.1) Calcd. C 30.6 H 4.48 N 44.5 Found C 30.9 H
4.47 N 44.3.- IR (KBr): 3433; 3162, 3130; 3022; 2915; 1577; 1467; 1433;
1379; 1359; 1229; 1194; 1174: 1119; 1040; 1021; 978; 900; 871; 761; 730;
679: 652; 631 cm-'.- UV (CH,CN): h max (log E) = 257 (3.76). 330 (4.33),
477 nm (1.93); IH-NMR/300 MHz ([D,]DMSO): 6 (pprn) = 8.97 (s; IH,
syd-H), 3.34 (s; 6H, (CH&N).- MS (+FAB/DMSO/glycerol): m/z = 158
(91% (M + HI+). 157 (loo), 141 (17), 129 (19), 128 (18), 114 (12), 98
(41), 97 (62). 70 (10). 68 (15).
Yellow powder (methanol), mp. 148.5"C. Yield 72%: CI2HlhN4O2
(248.3) Calcd. C 58.0 H 6.50 N 22.5 Found C 57.8 H 6.56 N 22.5.- IR
(KBr): 3414; 3128; 2915, 2850; 2141; 1577; 1451; 1418; 1391; 1355;
1339; 1307; 1274; 1230; 1134; 1005; 973; 820; 792; 687 cm-'.- UV
(CH,CN): h max (log E) = 333 (4.29), 482 nm (l.90).- 'H-NMR/300 MHz
([DJDMSO): 6 (ppm) = 9.03 (s; IH, syd-H), 2.36 (s; 6H, a-H), 2.27 (s;
3H, P-H), 1.75 (s; 6H. y-H).- MS (+FAB/DMSO/glycerol): m/z = 249 (2%,
[M + HI+), 207 (12), 171 (8), 149 (9), 135 (33), 131 (12), 115 ( 1 0 0 98
(12), 78 (9).
3-[2-(Cyclohexenylethyl~]-N-nitr~~so-5-sydn~)ne
imine (2t)
Orange needles (ethanol), mp. 94OC. Yield 78%.- CI,,Hl,N4O2(222.2)
Calcd. C 54.0 H 6.35 N 25.2 Found C 54.1 H 6.50 N 25.0.- IR (KBr):
3412; 3125; 3097; 3054; 2926; 2855; 2831; 1673; 1580; 1564; 1433; 1410;
1383; 1345; 1336; 1279; 1238; 1189; 1135; 1103; 1085; 1069; 1015; 955;
919; 878; 795; 647 cm-'.- UV (CH3CN): h max (log E ) = 272 (3.48), 334
(4.21), 484 nm (l.90).- 'H-NMR/300 MHz ([D6]DMSO): 6 (ppm) = 8.80
(s; IH, syd-H), 5.43 (bs; IH, =CH-2"), 4.79 (1; J = 7 Hz, 2H, N-CH*), 2.66
(t; J = 7 Hz, 2H, N-CH,-CH,), 1.98-1.46 (m; 8H, cyclohexen-H).- MS
(+FAB/DMSO)glycerol): m/z = 223 (12%. [M+HI+), 162 (lo), 109 (lo),
107 ( I I), 91 (16), 79 (22). 66 (74).
N-Nirroso-3-(4-morpho/inyl)-sydnone
imine (2u)
.~-C?iL~tohc.~yl-N-nifro.~o-S-s~dnone
imine (Zp)
Orange needles (methanol). mp. 126°C (Lit."': 127.5-128°C). Yield
649.- C8H12N402
(196.2) Calcd. C 49.0 H 6.16 N 28.6 Found C 48.9 H
6.15 N 28.7.- IR (KBr): 3414,3130; 2932; 2853; 1570; 1446; 1415; 1364;
1351: 1294; 1270; 1249; 1222; 1112; 1023; 994; 958; 896; 877; 814; 790;
744; 663 cm-'.- UV (CH3CN): h max (log E ) = 333 (4.26), 482 nm (1.90):
'H-NMR/300 MHz (CDCI,): 6 (ppm) = 8.08 (s; IH, syd-H), 4.78 (m; IH,
N-CH ax), 2.41-1.45 (m;10 H, cyclohexyl-H).- MS (+FAB/DMSO/glycerol): m/z = 197 (4976, [M + HI+), I96 (18), 167 (2% 115 (17), 110 (10).
86 (45). 83 (100). 79 (21). 78 (3% 77 (10).
Yellow small crystals, mp. 126°C (dec.) (Lit.'": 130°C (dec.)). Yield
60%: IR (KBr): 3420; 3086; 2862; 2212; 1568; 1459; 1406; 1383; 1355;
1329; 1267; 1235; 1215; 1181; 1139; 1112; 1009; 985; 894; 875; 769; 722
cm-'.- UV (CH30H): h max (E) = 255 (3.79), 235 nm (4.31): 'HNMR/250 MHz ([D,]DMSO): 6 (ppm) = 9.09 (s; lH, syd-H), 3.88 (t; J = 5
Hz, 4H, 0-CHZ), 3.69 (t; J = 5 Hz, 4H, N-CH,).- MS (+FAB/DMSO/glycerol): m/z = 200 (100'36, [M + HI+), 199 (50), 171 (91), 141 (15), 140
(68), 139 (46), I15 (21).
N-Nifrnsydnone imines (3)
10 mmol 5-sydnone imine as its nitrate was added in portions to ice
cold, conc. H2S04 (10 ml). After 30 min at room temp. crushed ice is
Yellow small crystals (methanol), mp. 113'C. Yield 68%: C9HI4N4O2 added. The precipitate is sucked and recrystallized. The yield can he
improved when the remaining solution is extracted with CHCI,.
(210.2) Calcd. C 51.4 H 6.71 N 26.7 Found C 51.5 H 6.87 N 26.8.- IR
3-(3-Meth?/~~~ilrthexyl)-N-nifroso-S-sydnone
imine (2q)
Arch. Phurm. (Weinheim)326,791-797(1993)
797
NO-Donors
3-Methyl-N-nztro-5-sydnone
rmine (3a)
Crystals (isopropanol/acetone), mp. 170°C. Yield 39%.- C3H4N401
(144.1) Calcd. C 25.0 H 2.80 N 38.9 Found C 24.9 H 2.80 N 38.9.- IR
(KBr): 3138; 3033; 1587; 1554; 1463; 1448; 1432; 1399; 1379; 1326;
1281; 1260; 1232; 1175; 1098; 1029; 975; 968; 845; 775; 671; 641 cm I.UV (CH,CN): h max (log &) = 272 (4.39), 331 nm (4.09).- 'H-NMR/300
MHz ([D6]DMSO): 6 (ppm) = 8.70 (s; lH, syd-H), 4.37 (s; 3H, N-CH1).13C-NMR/75.47 MHz ([D6]DMSO): 6 (ppm) = 172 8 (s; syd-C-9, 110.6
(s; ~yd-C-4),40.0 (s; N-CH?).- MS (130°C): m/z = 144 (lZ%, M"), 98 (8),
68 (10). 67 (15), 46 (7), 42 (12), 41 (15), 30 (IOO), 28 (9).
N-Nitro-3-pentyl-S-sydnone
imine (3e)
Crystals (isopropanol), nip. 93.5"C. Yield 80%.- C7HI2N4O3(200.2)
Calcd. C 42.0 H 6.04 N 28.0 Found C 42.0 H 6.21 N 28.0.- IR (KBr):
3421; 3147; 3010; 2952; 2924; 2869; 1601; 1570; 1451; 1430; 1327; 1260;
1169; 973: 773 cm-'.- UV (CH,CN): h max (log E ) = 239 (4.1 I ) , 332
(4.69).- IH-NMR/300 MHz ([D6]DMSO): 6 (ppm) = 8.78 (s; lH, syd-H),
4.70 (t; J = 7.2 Hz, 2H, N-CH2), 2.00 (m;2H, N-CH2-C&), 1.32 (m; 4H,
(C&)z-CH,), 0.88 (ti 3H, CHI).- MS (120'C): m/z = 200 (9%, M+'), 70
(16), 68 (67), 55 (19), 43 (53). 41 (70), 30 (100).
N-Nitro-S-hexyl-5-sydnone
imine (3f)
Crystals (isopropanol), mp. 103°C. Yield SO%.- CRHl4N40?(214.2)
Calcd. C 44.8 H 6.58 N 26.2 Found C 44.7 H 6.49 N 26.4.- IR (KBr):
3426; 3149; 2949; 2920; 2854; 1602; 1476; 1450; 1428; 1326; 1261; 1168;
973; 773 cm-'.- UV (CH3CN): h max (log E) = 267 (3.99), 332 nm (4.34).'H-NMR /300MHz ([DG]DMSO): 6 (ppm) = 8.79 (s; IH, syd-H), 4.71 (t;
J = 7.2 Hz, 2H, N-CH,), 2.00 (m; 2H, N-CH,-C&), 1.30 (m;6H, (C&),CH,), 0.87 (ti 3H, CH,).- MS (1 IOOC): m/z = 214 (5%, M"), 168 (3), 109
(7), 95 (5). 82 (7), 68 (52), 56 (1 I), 55 (21), 43 (51L 41 (38), 30 (100).
12 H, (C&)&CH,), 0.86 (t; 3H, CH3).- MS (145°C): m/z = 256 (0.196,
M+'), 210 (3). 137 (4), 123 (9), 109 (27), 95 (15), 83 (12), 68 (74), 57 (38),
55 (59). 43 (loo), 41 (98).
3-Methyl-sydnone (4a)
4a was prepared by a modification of Kholodov's method12): 10 mmol
2a were refluxed in 50 ml acetone until the red colour had disappeared (6
h). The solvent was evaporated and the residue purified by flash chromatography (CHCIgEtOH 4:1,0.25 bar, length of the column 30 cm). Brown
oil. Yield 58%.- C,H4N20, (100.1) Calcd. C 36.0 H 4.03 N 28.0 Found C
35.6 H 4.20 N 26.4.- IR (film): 3488; 3138; 3030 2953; 2096; 1852; 1726;
1418; 1388; 1198; 1156; 1088; 1062; 948; 870; 728; 616 cm-'.- UV
(CH,CN): h max (log E) = 277 nm (4.55): 'H-NMR/300 MHz
([DJDMSO): 6 (ppm) = 7.00 (s; IH, syd-H), 4.07 (s; 3H, N-CH,).- MS
(30°C): m/z = 100 (4%. M"), 42 (loo), 41 (15),40 (6), 30 (7), 28 (11).
N-Cyano-3-isohu~l-5-sydnone
imine (5a)
Beige powder (methanol), mp. 121OC. Yield 33%: C7H,$r140 (166.2)
Calcd. C 50.6 H 6.06 N 33.7 Found C 50.5 H 6.10 N 33.7.- IR (KBr):
3090 2965; 2877; 2183; 2150 1650; 1643; 1547; 1468; 1443; 1426; 1394;
1375; 1346; 1335; 1294; 1233; 1194; 1115; 1047; 963; 953; 940; 891; 765;
695 cm-'.- UV (CH30H): h max (log E) = 205 (4.14), 225 (4.20), 327 nm
( 3 . 9 9 - IH-NMR/300 MHz ([D6]DMSO): 6 (pprn) = 7.97 (s; lH, syd-H),
4.36 (d; J = 7.2 Hz, 2H, N-CH2), 2.27 (sept; J = 6.7 Hz, IH, CH(CH,)2).
0.94 (d; J = 6.7 Hz, 6H, CH(CFI,),).- MS (120°C): m/z = 166 (31%, M+'),
11 1 (3), 69 (13). 57 (IOO), 41 (90). 39 (13), 29 (83),27 (13).
References
1
N-Nitro-3-heptyl-5-sydnone imine (3g)
Crystals (isopropanol), mp. 108°C. Yield 50%.- C9Hr6N403(228.3)
Calcd. C 47.4 H 7.07 N 24.5 Found C 47.4 H 7.36 N 24.6.- IR (KBr):
3430; 3149; 2951; 2919; 2852; 1601; 1451; 1429; 1381; 1326; 1261; 1168;
973; 773; 724 cm-'.- UV (CH,CN): h max (log E) = 239 (3.65), 332 nm
(4.37).- 'H-NMR/300 MHz ([D6]DMSO): 6 (pprn) = 8.78 (s; lH, syd-H),
4.70 (t; J = 7.2 Hz, 2H, N-CH2), 1.99 (m;2H, N-CH2-C&). 1.30 (m; 8H,
(C&)4-CH3), 0.86 (t; 3H, CH,).- MS (125°C): m/z = 228 (2%, M+'), 182
(l), 109 (12), 98 (6), 95 (7), 70 (lo), 68 (67), 57 (74), 55 (46), 45 (12), 43
(89), 41 (loo), 31 (37).
N-Nitro-3-nonyl-5-sydnone
imine (3i)
Crystals (isopropanol), mp. 109°C. Yield 40%.- C1IHzoN403(256.3)
Calcd. C 51.5 H 7.86 N 21.9 Found C 51.3 H 8.18 N 21.9.- IR (KBr):
3435; 3150; 2950; 2917; 2850; 1601; 1570; 1450; 1429; 1381; 1328; 1262;
1169; 974; 773; 723 cm-'.- UV (CH,CN): h max (log E) = 241 (3.60), 332
nm (4.35).- 'H-NMR/300 MHz ([D6]DMSO): 6 (ppm) = 8.78 (s; lH, sydH), 4.68 (t: J = 7.2 Hz, 2H, N-CH,), 1.97 (m; 2H, N-CH,-C&), 1.27 (m;
Arch. Pharm. (Weinheim)326,791-797 (1993)
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[Ph95]