New NO-Donors with Antithrombotic and Vasodilating Activities II3-Alkyl-N-nitroso-5-sydnone Imines.
код для вставкиСкачать79 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) 2 3 4 5 6 7 8 9 10 11 12 13 K. Rehse, M. Kampfe, K.-J. Schleifer, Arch. Pharm. (Weinheim), 1993,326,483-487. K. Rehse, Drugs of the Future, 1988,13,941-950. K. Rehse, A. Kesselhut, V. Schein, M. Kampfe, B. Rose, E. Unsold, Arch. Pharm. (Weinheim), 1991,324,301-305. L. Sachs, Angewandte Statistik, Springer-Verlag. Berlin, 1984, p. 230238. W. Rudolph, J. Dirschinger, Eur. Heart. J . , 1991, 12 (Suppl. E ) , 3341. W. Martin, G.M. Villani, D. Jothianandan, R.F. Furchgott, J . Pharmacol. Exp. Ther., 1985,232,708-716. K. Rehse, T. Seidel, Arch. Pharm. (Weinheim), 1992,325,235-239. K. Rehse, U. Siemann, Arch. Pharm. (Weinheim), 1981,314,627-630. P. Brookes, J. Walker, J . Chem. Soc., 1957,4409-4419. H. Bohn, B. Rosenstein, J . Pharmacol. Merh., 1986,16,227-238. H.U. Daeniker, J. Druey, Helv. Chim. Acta, 1962,45,2426-2441. L.E. Kholodov, V.G. Yashunskii, J . Org. Chem. USSR, (Engl. Transl.) 1967.3, 1994-2000. K. Masuda, T. Kamiya, Y. Imashiro, T. Kaneko, Chem. 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