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Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines XX44 В╨Ж4 В╤Ц-135-Benzene-tris-sydnone Imines.

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217
Anticoagulant Effects of Oligoamines
Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, XX I):
-
4,4’ ,4” (1,3,5)-Benzene-tris-sydnone Imines
Klaus Rehse* and Antje Martens
Institut fur Pharmazie der Freien Universitat Berlin, Konigin-Luise-Str. 2+4, D- 1000 Berlin 33
Received March 19, 1992
Antiaggregatorische und anticoagulante Eigenschaften von Oligoaminen, 20. Mitt.lh 4,4’,4”-(1,3,5)-Benzol-tris-sydnonimine
The synthesis of ten tris-sydnone imine derivatives, unknown up to now, is
described. All compounds are alkyl or arylalkyl substituted in 3-position of
the sydnone imine. The most powerful agent was the 3-propyl derivative
6c. It inhibits the aggregation of human platelets induced by collagen in a
concentration of 1 p o l / L half maximally. Its N-ethoxycarbonyl derivative
7c, which was designed as a prodrug, showed only small antithrombotic
effects in rats. The reason for this low degree of activity is discussed.
NaNOllHCI
n
1
R
H
H
9
3
1
no activity
6
1Cg
8
[pmol/Ll
2
3
H
I
H
H
H
H
H
P h P h
9
17
14
10
125
13
1
1
5
8
The starting material benzene- 1,3,5-tricarbaldehyde (2)
was obtained from technical 1,3-pentadiene (1) according
to Lonshch~kova~),
which proved to be the only economic
synthesis for this compound. Usually the first step of the
synthesis of sydnone imines is carried out in water and/or
methanol. As 2 is insoluble in these solvents, DMSO was
used instead. This meant removal of DMSO and replacement by CH30H/H20 before nitrosation of the intermediate
aminoacetonitriles 4. Normally this was achieved by dilution with water, precipitating compounds 4 as oils. Only 4a
had to be extracted with CHC13. - As oligoamines are poorly absorbed from the gastrointestinal tract4)a suitable prodrug was needed. Therefore 6c was acylated with ethyl chloroformate to give 7c. The oligoamines 8 are included in
Scheme 1 for comparison of the antiplatelet activity.
5
0
7
that the sydnone imine structure itself exhibited the anticoagulant effect.
Furthermore it was proven that the essential basic nitrogen functions in oligoamines could be replaced by heterocyclic imino groups. Because the
presence of three nitrogen functions could improve the desired activities2’,
we undertook the synthesis of trissydnone imines which have not yet been
reported in the chemical literature.
4
4
6
5
3
5
Die Synthese von zehn Vertretem aus der Reihe der bislang unbekannten
Trissydnonimine wird beschrieben. Alle Verbindungen sind in 3-Stellung
des Sydnonimins durch Alkyl- oder Arylalkylgruppen substituiert. Am
aktivsten war das 3-Ropylderivat 6c.Es hemmte die durch Collagen ausgeloste Thrombocytenaggregation an Humanthrombocyten schon in einer
Konzentration von 1 pmol/L halbmaximal. Als Prodrug wurde das N Ethoxycarbonyldenvat von 6c synthetisiert (7c). Es zeigte in Ratten jedoch
nur geringe antithrombotische Effekte. Der Grund hierfur wird diskutiert.
4
3
48
3
The structure of type 6 compounds is proven mainly by their NMR spectra. The ‘H-spectra show the characteristic signals for the methyl (6a: 4.36
ppm) or methylene groups (6b-k: 4.7 - 4.6 ppm) in the 3-position of the
sydnone imine, the imino protons at 10.2 ppm, and the singlet of the aromatic protons at 8. I ppm.
In the I3C-NMR spectrum the C-5 of the sydnone imines resonates at
167 ppm while the signal for the C-4 is seen at 111 ppm. The C-atoms in
1 , 3 , and 5-position of the benzene nucleus are observed at 136 ppm while
C2,4, and 6 give rise to a signal at 123 ppm.
The structure of 7c is characterized in the ’H-NMR spectrum by disappearance of the imine protons and appearance of the ethyl ester signals at
3.97 (4;J = 7 Hz) and 1.15 (t; J = 7 Hz) ppm. In addition the molecular ion
[M+H]+ = 670 is shown in the PI-FAB-mass spectrum.
Arch. Pharm. (Weinheim)326,217-219 ( I 993) 0VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1993
0365-6233/93/0404-0217 $5.00 + .25/0
218
The antiplatelet activities obtained for the trissydnone
imines 6 are compiled in Scheme 1. As compared to the
corresponding bissydnone imines, a nearly sevenfold
increase in activity can be stated. Interestingly, in type 8
compounds as well as in the bissydnone imines') the most
active compound has been an arylalkyl substituent in 3position of the sydnone moiety. The alkyl substituted compounds exhibited maximum activity with n = 6. In contrast
high activities of the title compounds are found in substances with n = 1-4. The peak activity is seen in 6c (n = 3),
which is the most active oligoamine detected so far. This
structure seems to be an optimum compromise between
binding forces and steric requirements in view of the attachment to the platelet membrane.
As it was the case with bissydnone imines in the trissydnone imines series no anticoagulant activities are observed.
In contrast 8f and 8k were the strongest inhibitors of the
fibrin formation (IC75< 50 pmol/L, Quick-test) found up to
now.
The trisethoxycarbonylsydnone imine 7c was tested in rats
for its antithrombotic activities. The results obtained in a
laser induced thrombosis model4) are shown in table 1.
Surprisingly only a small inhibition of thrombus formation
in venoles (5%) and arterioles (10%) is observed. As it is
well known that in such sydnone imines the ethoxycarbonyl-group is removed enzymatically6)the poor results
should have pharmacokinetic reasons. The very good
solubility of 6c in water suggests a good renal excretion, so
that the steady concentration of 6c might be too low to exert
stronger antithrombotic effects.
Table 1: Inhibition of laser induced thrombosis in rats. mTBI = medium
thrombus formation index, s = standard deviation, SEM = standard error of
the means, p = significance: Wiico,ron, Mann and Whirney's, U-test'); V =
venoles, A = arterioles
Experimental Part
The apparatus used') and the pharmacological7) tests were identical with
those of previous communications. - Temp. in "C.
I ..~,5-Betzieriet,-issydnoneimrnes
15 mmol of the m i n e hydrochloride 3 and 1.0 g KCN are dissolved in
8 ml H20. 0.81 g ( 5 mmol) 1,3,5-benezenetrialdehyde(2) in 13 ml DMSO
are dropped in while cooling the reaction flask with ice. The mixture is
stirred for 2 h at room temp. (rt.). A yellow brownish oil 4 precipitates.
The upper layer is discarded and the oil washed twice with H,O. Then it is
dissolved in 15-20 ml MeOH and 6 ml 4 N HCI added with cooling. A
solution of 10 g NaNO, in 8 ml H 2 0 is dropped in. The mixture is stirred
for 1 h at rt. Again an oil precipitates. The upper layer is discarded and the
Rehse and Martens
oil dissolved in ether or CH2C1, (5a-c). The solution is washed twice with
water, dried with Na,SO,, and the solvent is removed. With cooling 35 ml
of MeOH saturated with gaseous HCI are added. The mixture is kept for
12 h at 5". After removing the solvent the residue is washed with small
portions of ether (or CH,CI,) and recrystallized.
4,4' ,4' -(I ,3,5)-Benzene-tris-3-methylsydnoneimine hydrochloride (6a)
The aminoacetonitrile 4a does not separate and has to be extracted with
CHCI, and washed with water. The solvent is removed, the resulting oil
dissolved in MeOH and the reaction continued as usual.
Crystals (ethanol/aceton), mp. >300" (from 185" degr.). Yield 60 %.C,,H,,N,O, . 3 HC1 . I H,O (496.7) Calc. C 36.3 H 4.06 N 25.4 Found C
36.0 H 3.89 N 24.6.- IR (KBr): 3399; 3001; 1675; 1514; 1441; 1359;
1317; 1103; 1040; 947; 817: 792; 768; 697 cm-'.- UV (CH,OH): h max
(log E) = 206 (4.35),306 nm (4.29).- 'H-NMR / 300 MHz ([D&DMSO): 6
(ppm) = 10.17 (s, 6 H, NH2+,D 2 0 exchange), 8.16 (s, 3 H aromat.), 4.36
(s, 9 H, syd(3)-CH,).- I3C-NMR / 75 MHz (CD,OD): 6 (ppm) = 168.9
(syd-C-S), 137.2 (CH aromat.), 125.2 (C aromat), 39.9 (CH,).- MS (+
FABDMSO-glycerol): m/z = 369 (1 %, M+'), 333 ( I ) , 297 (I), 257 (I),
241 (6). 119 (7), 93 (100).
4,4' ,4"-(1,3,51-Benzene-tris-3-eth~lsydnone
imine hydrochloride (6b)
Crystals (ethanokther), mp. >300" (from 170" degr.). Yield S O %.CIxH21N90, . 3 HC1 .I H,O (538.8) Calc. C 40.1 H 4.86 N 23.4 Found C
49.3 H 4.93 N 22.9.- IR (KBr): 3420; 2978; 1669; 1505; 1462; 1373;
1259; I 1 19; 1095; 979; 935; 757; 698 cm-'.- UV (CH30H): h max (log e)
= 206 (4.44), 306 nm (4.64).- 'H-NMR / 300 MHz ([D&DMSO): 6 (ppm)
= 10.14 (s, 6 H, NH2+, D 2 0 exchange), 8.14 (s, 3 H aromat.), 4.71 (4. J = 7
Hz, 6 H, syd(3)-CH,), 1.48 (I, J = 7 Hz, 6 H, CH,).- MS (+ FABDMSOglycerol): m/z = 412 (9 8,
[M+H]+), 399 ( 3 ) , 372 (2), 326 ( I ) , 93 (100,
glycerol-H+).
4.4' ,4" -(I ,3,S)-Benzene-tris-3-propylsy~noneirnine hydrochloride (6c)
Crystals (isopropanol/aceton/ether), mp. >300" (from 1.53" degr.). Yield
40 %.- C21H27N901. 3 HCl . 1 H 2 0 (580.9) Calc. C 43.4 H 5.54 N 21.7
Found C 43.7 H 5.61 N 21.5.- IR (KBr): 3370; 3007; 2962; 2934; 1680;
1666; 1591; 1507; 1464; 1428; 1385; 1359; 1325; 1287; 1269; 1223; 1124;
1088; 950; 901; 812; 769; 702; 625 cm-'.- UV (CH,OH): h max (log E) =
206 (4.33, 302 nm (4.37): 'H-NMR / 300 MHz ([D,]-DMSO): 6 (ppm) =
10.20 (s, 6 H, NH,+, D,O exchange), 8.12 (s, 3 H aromat.), 4.64 (t. J = 7
H Z )(t,
,
Hz, 6 H, ~yd(3)-CHz),1.85 (tq, J = 7/7 Hz, 6 H, S Y ~ ( ~ ) - C H ~ - C0.92
J = 7 Hz, 9 H, CH,): "C-NMR / 75 MHz ([D,]-DMSO): 167.0 (syd-C-S),
136.3 (CH aromat.), 123.0 (C aromat.), 11 1.5 (s, syd-C4), 53.8 (t. syd(3)CHz), 21.2 (t. syd(3)-CH2-C&), 10.4 (q, CH,).- MS (+ FAB/DMSO-glycerol): m/z = 454 (43 %, [M+H]+), 441 ( S ) , 400 ( 3 ) ,93 (100, glycerol-H+).
4,4' ,4" -(I ,3,5)-Benzene-tris-3-hutylsydnone imine hydrochloride (6d)
Crystals (ethanol/ether), mp. >300" (from 148" degr.). Yield 40 %.C24H33N903. 3 HC1 I H 2 0 (623.0) Calc. C 46.3 H 6.15 N 20.2 Found C
46.6 H 6.14 N 20.1.- IR (KBr): 3419; 3008; 2954; 2873; 1672; 1506;
1460; 1278; 1245; 1125; 959; 767; 700 cm-'.- UV (CH30H): h max (log E )
= 206 (4.33), 306 nm (4.28): 'H-NMR / 300 MHz ([D,]-DMSO): 6 (ppm)
= 10.20 (s, 6 H, NH,+, D,O exchange), 8.12 (s, 3 H aromat.), 4.66 (t, J = 7
Hz, 6 H, syd(3)-CH,), 1.75 (tt, J = 717 Hz, 6 H, ~yd(3)-CH2-C&), 1.34 (tq,
J = 7/7 Hz, 6 H, CH3-CH2), 0.84 (t, J = 7 Hz, 9 H, CH,).- MS (+
FAB/DMSO-glycerol): m/z = 496 (100 %, [M+H]+), 483 (12), 423 (24),
382 (15), 311 (19), 270 (23), 239 (21), 197 (29), 156 ( 4 3 , 129 (38), 102
(31).
Arch. Pharm. (Weinheimi 326,217-219 (I9931
219
Anticoagulant Effects of Oligoamines
4,4',4" -(I ,3,S)-Benzene-tris-3-penrylsydnone
imine hydrochloride (6e)
Crystals (ethanol/ether), mp. 134". Yield 35 %.- C27H3yNy01. 3 HC1 .
1.5 H 2 0 (674.1) Calc. C 48.1 H 6.73 N 18.7 Found C 48.4 H 6.63 N 18.7.IR (KBr): 3403; 3003; 2952; 2933; 2869; 1671; 1504; 1462; 1378; 1267;
1233; 1193; 1127; 1087; 953; 815; 699 cm-'.- UV (CH30H): h max (log E)
= 202 (4.38). 308 nm (4.30): 'H-NMR / 300 MHz ([D6]-DMSO): 6 (ppm)
= 10.24 (s, 6 H, NHz+,DzO exchange), 8.14 (s, 3 H aromat.), 4.67 (t, J = 7
Hz, 6 H, syd(3)-CH2),1.81 (tt, J = 7/7 Hz, 6 H, syd(3)-CH2-C&), 1.27 (m,
12 H, CH,-(-CH2-)2), 0.82 (t, J = 7 Hz, 9 H, CH,): MS (+ FABDMSOglycerol): m/z = 538 (96 %, [M+H]+), 525 (14), 507 (lo), 451 (22), 419
(15), 325 (16), 284 (20), 226 (24), 197 (33, 169 (40), 143 (34). 129 (38).
70 (97), 68 (100).
4,4' ,4"-(1,3,5)-Benzene-tris-3-hexylsydnonimine
hydrochloride (6f)
Crystals (ethanol/ether), mp. 137".Yield 35 %.- C30H45N903. 3 HCI . 2
H20 (725.1) Calc. C 49.7 H 7.22 N 17.4 Found C 49.8 H 7.14 N 17.2.- IR
(KBr): 3402; 2951; 2925; 2868; 1668; 1504; 1463; 1377; 1254; 1226;
1185; 1129; 1086; 949; 815; 770; 727; 699 cm-l.- UV (CH30H): h max
(log E) = 206 (4.38), 308 nm (4.29).- 'H-NMR / 250 MHz ([D6]-DMSO): 6
(ppm) = 10.19 (s, 6 H, NHz+, DzO exchange), 8.13 (s, 3 H aromat.), 4.67
(t, J = 7 Hz, 6 H, ~yd(3)-CHz),1.77 (tt, J = 7/7 Hz, 6 H, ~yd(3)-CHz-C&),
1.31-1.22 (m, 18 H, CH1-(-CH2-)& 0.83 (t, J = 7 Hz, 9 H, CH&- MS (+
FABDMSO-glycerol): m/z = 580 (100 % [M+H]+), 567 (23), 484 (22),
339 (21), 283 (22), 253 (24), 226 (23), 197 (41), 171 (45), 141 (41), 68
(57), 66 (45).
4,4,',4"-(I ,3,5)-Benzene-tris-3-heptylsydnone
imine hydrochloride (6g)
Crystals (ethanol/ether). mp. 137",Yield. 35 %.- C13H5,N903.3 HCI . 1
H2O (749.2) Calc. C 46.2 H 4.70 N 19.0 Found C 46.3 H 4.54 N 18.7.- IR
(KBr): 3408; 2950; 2923; 2856; 1671; 1504; 1463; 1277; 1180; 1129; 959;
699 cm-l.- UV (CH30H): h max (log E) = 204 (4.41). 308 nm (4.34).- 'HNMR / 300 MHz ([D,]-DMSO): 6 (ppm) = 10.22 (s, 6 H, NH,', DzO
exchange), 8.14 (s, 3 H aromat.), 4.67 (t. J = 7 Hz, 6 H, syd(3)-CH2), 1.79
(tt, J = 7/7 Hz, 6 H, syd(3)-CHz-CH2),1.21 (m, 24 H, CH3-(-C&-)4), 0.83
(t, J = 7 Hz, 9 H, CH3).- MS (+ FABDMSO-glycerol): m/z = 622 (27 %,
[M+Hl+), 609 (13), 512 (I5), 253 (19), 226 (23), 212 (35), 197 (41), 169
(50), 143 (41), 114 (41), 78 (49). 68 (IOO), 66 (74).
1029; 956; 815; 751; 700 cm-I.- UV (CHIOH): h max (log E) = 204 (4.67),
308 nm (4.27): 'H-NMR / 300 MHz ([D6]-DMSO): 6 (ppm) = 10.26 (s, 6
H, NH2+,D 2 0 exchange), 8.09 (s, 3 H aromat.), 7.27-7.16 (m, 15 H aromat.), 4.67 (t, J = 7 Hz, 6 H, syd(3)-CHz), 2.68 (t, J = 7 Hz, 6 H, Ph-CH,),
2.10 (tt, J = 7/7 Hz, 6 H, syd(3)-CH2-C&).- MS (+ FABDMSO-glycerol):
m/z = 682 (2 %, [M+H]+), 156 (I), 128 (I), 119 (3), 117 (6), 115 (4), 91
(100). 76 (5).
4.4' ,4"-(1,3,5)-Benzene-tris-3-(4-phenylhu~l~-sydnone
imine hydrochloride (6k)
Crystals (ethanol/ether), mp. 132", Yield 30 %.- C42H4sN903. 3 HCI 1
H20 (851.3) Calc. C 59.3 H 5.92 N 14.8 Found C 59.2 H 5.74 N 14.5.- IR
(KBr): 3400; 3018; 2939; 1672; 1601; 1494; 1452; 1251; 1158; 1088;
1028; 954; 748; 699 cm-'.- UV (CH,OH): h max (log E) = 204 (4.64), 308
nm (4.27): 'H-NMR / 300 MHz ([D6]-DMSO): 6 (ppm) = 10.23 (s, 6 H,
NH2+. D2O exchange), 8.09 (s, 3 H aromat.), 7.26-7.15 (m. 15 H aromat.),
4.69 (t, J 7 Hz, 6 H, syd(3)-CHz), 2.53 (t, J = 7 Hz, 6 H, Ph-CHZ), 1.83
(tt, J = 7/7 Hz, 6 H, ~yd(3)-CH2-C&), 1.63 (tt, J = 7fl Hz, 6 H, Ph-CHIC&).- MS (+ FABDMSO-glycerol): m/z = 724 (1 %, [M+H]+), 131 (4),
115 (3,105 (9), 91 (loo), 77 (10).
4,4' ,4" -(I ,3,5)-Benzene-tris-N-ethoxycarhonyl-3-propyl.~ydn~ne
imine
17c)
0.9 g 6c are dissolved in 8 ml H 2 0 and 0.9 g ethyl chloroformate added.
Under cooling with ice, a solution of 0.9 g K2C03in 15 ml H 2 0 is dropped
in within 2 h. The mixture is stirred overnight. The precipitate is sucked
off and washed with H20. The residue is purified by rotational chromatography (Chromatotron, CHCI,/EtOH 9: 1). The oily product crystallizes
when stirred with ether. Colorless powder, mp. 152". Yield 70 %.C30H3yN90y(669.7) Calc. C 53.8 H 5.87 N 18.8 Found C 53.4 H 5.86 N
18.7.- IR (KBr): 2969 1669; 1616; 1493; 1462; 1390 1366; 1248; 1155;
1097; 1064; 981; 936; 887; 783; 695 cm-'.- UV (CH30H): h max (log E) =
224 (4.37). 296 (4.47), 334 nm (4.37).- 'H-NMR / 300 MHz ([D6]DMSO): 6 (ppm) = 8.08 (s, 3 H aromat.), 4.70 (t, J = 7 Hz, 6 H, syd(3)CHI), 3.97 (9, J = 7 Hz, 6 H, 0-CH,), 1.82 (tq, J = 7/7 Hz, 6 H, syd(3)CHZ-C&), 1.I5 (t, J = 7 Hz, 9 H, O-CHz-C&), 0.90 (t, J = 7 Hz, 9 H,
CH3).- MS (+ FABDMSO-glycerol): m/z = 670 (27 %, [M+H]+), 624
(29). 493 (33,424 (24), 169 (87), 116 (93), 87 (72), 74 (100).
4,J' ,4" -(I ,3,5)-Benzene-tris-3-octylsydnone
imine hydrochloride (6h)
Crystals (ethanol/ether), mp. 137'. Yield 30 %.- C&#y03
. 3 HCI .
1.5 H20 (800.3) Calc. C 54.0 H 7.93 N 15.8 Found C 54.1 H 7.73 N 15.7.IR (KBr): 3412; 2950; 2921; 2853; 1672; 1507; 1463; 1375; 1268; 1126;
1087; 959; 889; 816; 768; 723; 697 cm-'.- UV (CH30H): h max (log E) =
206 (4.41), 308 nm (4.33).- IH-NMR / 300 MHz ([D6]-DMSO): 6 (ppm) =
10.23 (s, 6 H, NH2+,D 2 0 exchange), 8.15 (s, 3 H aromat.), 4.68 (t, J = 7
Hz, 6 H, syd(3)-CH2), 1.78 (tt, J = 7/7 Hz, 6 H, syd(3)-CH2-CH2), 1.21 (m,
30 H, CH,-(-C&-),), 0.84 (t. J = 7 Hz, 9 H, CHI).- MS (+ FABDMSOglycerol): m/z = 664 (25 %, [M+H]+), 651 (6), 597 (7), 367 (7), 295 (7),
143 (18). 70 (100). 68 (86), 66 (31).
4,4' ,4" -(I ,3,S)-Benzene-tris-3-(3-phenylpropyl)-sydnone
imine hydrochloride (6i)
Crystals (ethanol/ether), mp. 132". Yield 20 %.- C,yH,9Ny03 . 3 HC1 .
l.SH~O(818.2)Calc.C57.3H5.54N15.4FoundC57.1 H5.30N 15.3.IR (KEr): 3407; 3018; 2944; 1669; 1601; 1495; 1453; 1267; 1166; 1088;
Arch. Pharm. (Weinheim)326,217-219 (1993)
References
1
2
3
4
5
6
7
Part XIX: K. Rehse, M. Kampfe, and A. Martens, Arch. Pharm.
(Weinheim),1993,326, 163-166.
K. Rehse, U. Lukens, G. Claus, Arch. Pharm. (Weinheim) 1987,320,
1233-1238.
T.I. Lonshchakova, B.I. Buzykin, G. Liakumovich, V.S. Tsivunin, J .
Org. Chem. USSR (Engl. Transl.) 1978, 14, 593; Chem. Abstr. 1978,
89, 108 397m.
K. Rehse, A. Kesselhut, V. Schein, M. Kampfe, B. Rose, E. Unsold,
Arch. Pharm. (Weinheim),1991,324,301-305.
L. Sachs, Angewandte Statist&, Springer-Verlag, Berlin, 1984, S. 230.
E. Schraven, Molsidornin, Urban & Schwarzenberg, Miinchen-WienBaltimore, 1979, S. 24.
K. Rehse, U. Siemann, Arch. Pharm. (Weinheim) 1981,314,627-630.
[Ph53]
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