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Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines XXVIIIOligoamines with Fluorescent Properties. Part CFluorescent Oligoamines with Enhanced Hydrophilic Properties

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131
Oliogoamines and Seidel
Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, XXVIII:
Oligoamines with Fluorescent Properties
Part C: Fluorescent Oligoamines with Enhanced Hydrophilic Properties
Klaus Rehse* and Torsten Seidel
Institut f i r Pharmazie der Freien Universitat Berlin, Konigin-Luise-Str. 2 + 4, 14195 Berlin (Dahlem)
Received June 20, 1994
Antiaggregatorische und anticoagulante Eigenschaften von Oligoaminen, 28. Mitt.: Oligoamine mit fluoreszierenden Eigenschaften,
Teil C: Fluoreszierende Oligoamine mit verbesserten hydrophilen
Eigenschaften
Fifteen fluorescent oligoamines with one or two fluorescent groups and
two or three basic N-functions were prepared and tested for antiplatelet
activity (Born-test). Five compounds involving three different fluorophores, i.e. 2-fluorenyl, I-pyrenyl, and 9,phenanthryl, show an IC,, of
7-1 1 pmol/L. They are suitable to serve as probes in the field of oligoamine-biopolymere interactions.
Fluorescent molecules are a valuable tool for the investigation of absorption, distribution, metabolism, and excretion of a drug as well as for the elucidation of its mechanism as far as interactions with biologic macromolecules
are involved. This widespread applicability is due to the
rather specific detection, the low detection limits and hence
the possibility of a precise determination even in biological
systems. When using the fluorescent oligoamines so far
for the investigation of interactions with
albumine or phospholipids by the elegant continuous ultrafiltration method we had to recognize strong interactions
with the devices used, i.e. especially the ultrafiltration
chamber. The reason for this behaviour we supposed to be
the high lipophilicity of these molecules due to the presence
of several polycyclic aromates in one molecule. In order to
overcome these unwanted interactions we have synthesized
the compounds compiled in Tab. 1. The rationale was either
to have only one fluorescent system in the molecule or to
enhance the number of basic nitrogen functions which
become protonated at physiological pH-values. The synthesis of the desired compounds was performed according to
Scheme 1.
Starting from carboxylic acid chloride l a and an w-amino
acid l b the carboxamide carboxylic acids 2 are obtained.
Reaction with ethyl chloroformate gives the mixed anhydrides 3, which are not isolated but reacted with a suitable
amine to give the diamides 4 in good yields (- 60%). The
last step then is the reduction of 4 to the diamines 5b-e.
Reaction of the aldehydes 7a with the triamines 7b gave
intermediate triimines 6 which without further purification
were reduced by N a B b to 5f-g.
Arch. Pharm. (Weinheim)328,131-135(1995)
Fiinfzehn fluoreszierende Oligoamine mit ein oder zwei fluoreszierenden
Substituenten und zwei oder drei basischen Stickstoffunktionen wurden
dargestellt. Ihr EinfluB auf die Aggregation von Thrombocyten wurde
gepriift (Born-Test). Fiinf Substanzen mit drei verschiedenen Fluorophoren
zeigen eine halbmaximale Hemmung der Aggregation in Konzentrationen
von 7-1 1 pmolL. Sie sind geeignete Fluoreszenzmarker fur Untersuchungen von Wechselwirkungen zwischen Oligoaminen und Biopolymeren.
I
t
-HzO
Scheme 1: Synthesis of type 5 fluorescent oligoamines
The antiplatelet activities of 5b-p obtained in the Borntest are summarized in the last column of Tab. 1. Compound 5a which has been reported3)is included for comparison.
Compound 5d exhibits a similar activity as 5a showing
that R' = phenyl can be replaced by the fluorophore 1-pyrenyl with onry a slight loss in activity. Compound 5c was
synthesized to test a mere aliphatic substituent R2 instead of
an arylalkyl rest. It exhibits the same activity as 5d. In order
to compare the 2-fluorenyl with the 1-pyrenyl fluorophore
compounds 5b and 5c were prepared. They both were
slightly more active than 5d and 5e. Again an octyl substit-
0 VCH Verlagsgesellschaft mbH, D-6945 1 Weinheim, 1995
0366-6233/95/0202-0131 $5.00 + .25/0
132
Rehse and Seidel
Tab. 1: Antiplatelet activity of type 5 oligoamines with fluroescent
properties
Comp.
5
8
b
c
d
c
RI
I
m
a
R2
2-plle0y1
2-fluorcnyl
2-fluorenyl
I-pyrenyl
I-pyrenyl
4
4
4
4
4
I
5
5
5
5
5
2
3
3
3
3
3
2
knZY1
*Yl
CgHll
bnZY'
CgH,l
NH-CH2-9-anthryl
ICSI
~ltmoini
6
8
7
C ~ ~ H ~ J(351.4)
N O ~Calcd. C 75.2 H 7.17 N 4.0 Found C 75.5 H 7.30 N
3.9.- IR: 3303; 3044; 2936 1691; 1631; 1538; 1453; 1435; 1275; 1215;
733 Cm.'.- 'H-NMR ([D6]DMSO/CF$OOD): 6 (ppm) = 7.84 (d, J = 7.4
Hz, IH, 5-H), 7.79 (d, J = 7.7 Hz, 1H. 4-H), 7.57 (d, J = 7.2 Hz, IH, 8-H),
7.42 (s, IH, 1-H), 7.37 (dd, J = 7.317.3 Hz, lH, 6-H), 7.29 (dd, J = 7.4fl.2
Hz, lH, 7-H), 7.21 (d, J = 7.6 Hz, lH, 3-H), 3.89 ( s , 2H, 9-H), 3.06 (I, J =
7 Hz, 2H, NH-C&), 2.65 (I. J = 7.5 Hz, 2H, a-C&), 2.23 (t. J = 7 Hz, 2H,
CH,-CO-NH), 2.12 (t, J = 7.3 Hz, C&-COOH), 1.86 (tt, J = 7.6n.4 Hz,
2H, ar-CH,-CH,), 1.49 (tt, J = 7.6fl.4 Hz, 2H, NH-CHZ-Cb), 1.44 (tt, J =
7 3 7 . 2 Hz, 2H, CH2-CH2-COOH).-MS (80"): m/z = 351 (83%, M+'), 235
(12), 192 (100). 179 (45), 165 (l8), 159 (85). 100 (30).
'i
II
II
39
5-[[[3-(I -Py,enyl)-propyl]-carb(~nyl]-amino]-pentanoic
acid (2c)
65
uent (5c: n = 3, R2 = C5Hll) turned out to be as valuable as
an arylalkyl rest (5b: n = 3, R2 = phenyl). The concept to
enhance the number of basic functions but to retain two fluorescent groups in the molecule was not as successful. Only
the 9-phenanthryl derivative 50 exhibits an antiplatelet
activity in the desired range being as active as 5d or 5e.
Shorter (e.g. Sf, g, j, k, n, p) or longer (5i, m) distances
between the N-functions did not improve the results. The
anthryl(5h) or pyrenyl- (51) derivatives with the same interatomic distances as 50 both show decreased antiplatelet
activity. The introduction of a naphthyl rest (5p) as well did
not improve the situation
= 65 pmol/L). In summary
5b-e and 50 appear to be suitable tools for the fluorescence
measurements stated in the introduction.
Experimental Part
Devices and test systems are communicated'.2'.- IR spectra: in KBr.- 'HNMR spectra: [D,]DMSO at 300 MHz, unless otherwise stated.- Temp. in
"C.
For synthesis of type 2 carboxamido carboxylic acids the method of
Bayer was used4).
5-[[(2-Phenylethyl)-carbonyl]-aminoj-pentan~~ic
acid (2a)
From 10.1 g 3-phenylpropanoic acid chloride and 7.0 g 5-aminovaleric
acid. Crystals (ethanol), mp. 106". yield 70%.- C14H,9N03(249.3) Calcd.
C 67.4 H 7.68 N 5.6 Found C 67.1 H 7.87 N 5.5.- IR: 3297; 3052; 2942;
1691; 1636; 1535; 1434; 1273; 121 1; 698 cm-I. -lH-NMR/250 MHz: 6
(ppm) = 12.01 (bs, IH, COOH, D 2 0 exchange), 7.84 (m, lH, NH, D 2 0
exchange), 7.29-7.17 (m, 5H aromat.), 3.02 (dt, J = 716 Hz, 2H, NH-CH2),
2.80 (t, J = 7.6 Hz, 2H, C&-ph), 2.34 (1, J = 7.5 Hz, 2H, CH2-CO-NH),
2.18 (t, J = 7.4 Hz, 2H, CH,-COOH), 1.43-1.35 (m,4H, CH2-(Cli2),CH2).- MS ( 9 0 ' 0 m/z 249 (28%, M+9, 190 (12). 133 (14), 105 (58). 104
(100). 100(63),91 (87),77(12),65(13),55(11),44(13).
5-1[/3-(2-Fluorenyl)-propyl]-ca~bonyl]-amino]-pentanoic
acid (2b)
From 0.9 g 4-(2-fluorenyl)-butanoic acid chloride and 0.4 g 5aminovaleric acid. Light yellow crystals (ethanol), mp. 158'. yield 85%.-
From 4.1 g 4-(l-pyrenyl)-butanoic acid chloride and 1.6 g 5-aminovaleric acid. Light yellow crystals (ethanol), mp. 167". yield 75%.CzsHz5NO3(387.5) Calcd. C 77.5 H 6.50 N 3.6 Found C 77.3 H 6.49 N
3.6.- IR: 3305; 3032; 2941; 2870; 1691; 1638; 1537; 1414; 1272; 1204;
1180; 842 cm-'. -'H-NMR: 6 (ppm) = 12.04 (bs, IH, COOH, D 2 0
exchange), 8.40-7.93 (m, 9H aromat.), 7.86 (1, J = 6 Hz, lH, DzO
exchange), 3.31 (t. J = 7.6 Hz, 2H, ar-CH2), 3.09 (dt, J = 6.3/6 Hz, 2H,
NH-CH2), 2.23 (m,4H, CH2-CO-NH, CH2-COOH), 2.02 (tt, J = 7 3 7 . 5
Hz, 2H, ar-CH2-CH2), 1.52-1.42 (m,4H, CH2-(CI-J2)2-CH2).- MS (150"):
m/z = 387 (37%, M+'), 288 (16).229 (16), 228 (loo), 215 (57). 44 (10).
For the synthesis of type 4 diamides the method of Okano" was used.
N-[4-(2-Fluor-enyl)-hu~[-5-[[(2-phenylethyl)-carbonyl]-amino]pentanoic acid amide (4a)
From 1.6 g 2a and 1.5 g 4-(2-fluorenyl)-butanamine.Light yellow
crystals (ethanol), mp. 187'. yield 50%.- C31H36N202(468.6) Calcd. C
79.4 H 7.74 N 6.0 Found C 79.1 H 7.79 N 5.9.- IR: 3305; 3052; 2928;
2858; 1638; 1536; 1453; 1268; 760; 736; 698 cm-l.- 'H-NMR
([D6]DMSO/CF3COOD):6 (ppm) = 7.83 (d, J = 7.5 Hz, IH, 5-H-fluoren.),
7.78 (d, J = 7.5 Hz, lH, 4-H-fluoren.), 7.55 (d, J = 7 Hz, IH, 8-H-fluoren.),
7.41 (s, IH, I-H-fluoren.), 7.35 (dd, J = 7.1/7.1 Hz, IH, 6-H-fluoren.),
7.30-7.19 (m, 7H aromat.), 3.88 (s, 2H, 9-H-fluoren.), 3.05 (m,4H, NHCH?), 2.80 (t, J = 7.5 Hz, 2H, CH2-ph). 2.65 (I. J = 7.5 Hz, 2H. CH2fluoren.), 2.34 (t. J = 7.6 Hz, 2H, CH2-CH2-ph),2.03 (t, J = 7.2 Hz, 2H,
(CH2)3-CH2-CO),1.61 (m, 2H, CH2-(CH2),-fluoren.), 1.44 (m,4H, CH2(CH2)2-CO-NH-(CH2)2-CHz),1.33 (m, 2H. (CH2)2-CH2-CH2-CO).-MS
(30"): m/z = 468 (84%, M+*),237 (14). 220 (20). 192 (14), 105 (22). 104
(16), 100 (loo), 91 (32). 69 (21).
5-([~3-(2-Fluorenyl)-propyl~-carhonyl]-amino]-N-ocryl-pentanoic
acid
aniide (4b)
From 0.7 g 2b and 0.3 g I-octanamine. Light yellow crystals (DMSO).
mp. 188", yield 65%.- C3&2N202 (462.7) Calcd. C 77.9 H 9.15 N 6.1
Found C 77.8 H 9.15 N 6.1.- 1R: 3301; 3059; 2918; 2851; 1634; 1538;
1454; 1422; 1277; 832; 759; 734 cm".- 'H-NMR ([D,]DMF): 6 (ppm) =
7.88 (d, J = 7.7 Hz, IH, 5-H), 7.85 (d, J = 7.5 Hz, IH, 4-H), 7.78 (m, 2H.
NH, D 2 0 exchange), 7.57 (d, J = 7 Hz, IH, 8-H), 7.44 (s, IH, 1-H), 7.38
(dd, J = 7 3 7 . 5 Hz, IH, 6-H), 7.30 (dd, J = 7.4/7.2 Hz, lH, 7-H), 7.26 (d, J
= 7.4 Hz, IH, 3-H), 3.91 (s, 2H, 9-H), 3.15 (m,4H, NH-CH2), 2.74 (m,
2H, CH2-ar), 2.18 (m, 4H, CH2-CO), 1.93 (m, 2H. CHZ-CH2-ar),1.60 (m.
2H, NH-CH2-C&-(CH2),-C0), 1.44 (m, 4H, CH2-CH2-CO-NH-CH2-CH2(CH&), 1.25 (m, 10 H, (CH,)j-CH& 0.86 (m, 3H, CH3).- MS (170'): m/z
= 462 (100%. M+'), 270 (74). 241 (12), 235 (28), 227 (35). 212 (26). 198
(45). 192 (52). 184 (31), 173 (64),172 (32). 165 (18), 156 (10). 143 (15),
128 (62). 114 (13). 100 (91). 71 (1 I), 57 (18), 43 (23).
Arch. Pharm. (Weinheim) 328.131-135 (IYY5)
133
Oliogoamines and Seidel
N-(4-PhenylbutylJ-5-~[[3-(1
-pyrenyl)-propy1J-carbonylJ-amino]-pentanoic N-(4-Phenylbutyl)-N -[4-(1-pyrenyl)-butyll-pentane-15-diamine
dihydrochloride (5d)
acid aniide (4c)
From 3.9 g 2c and 1.5 g 4-phenylbutanamine. Light yellow crystals
(ethanol), mp. 174O, yield 65%.- C35H3*N202(518.7) Calcd. C 81.0 H 7.38
N 5.4 Found C 81.0 H 7.44 N 5.3.- IR: 3300; 3030; 2930; 2860 1639;
1541; 1459; 1274; 1208; 840; 698 cm-'.- 'H-NMR (CDCI3): 6 (ppm) =
8.30-7.83 (m, 9H, H-pyren.), 7.25-7.09 (m,5H phenyl), 5.71, 5.56 (2m,
2H, NH, D20 exchange), 3.36 (t, J = 7 Hz, 2H, CH2-pyren.), 3.24-3.15 (m,
4H, NH-CH2). 2.55 (t, J = 7.3 Hz, 2H, C&-ph), 2.25-2.18 (m,4H, CH2CO), 2.12 (t. J = 7.2 Hz, CH2-CH,-pyren.), 1.59 (m, 4H, NH-CH2-C&),
1.47 (m,4H, CH2-CH2-ph and CO-CH,-CH,-(CH2)2).- MS (160"): m/z =
518 (loo%, M*'), 290 (14), 228 (66). 215 (39). 148 ( I l ) , 100 (19), 91
(15).
Light yellow crystals (ethanol/H,O), mp. 266" (dec.), yield 60%.
C35H42N2 ' 2 HCI (563.6) Calcd. C 74.6 H 7.87 N 5.0 Found C 74.4 H 7.92
N 5.1.- IR: 3450; 2946; 2857; 2441; 1585; 1445; 1413; 1042; 846; 779;
702 cm-'.- 'H-NMR: 6 (ppm) = 8.99 (bs, 4H. NHz+,D 2 0 exchange), 8.347.98 (m, 9H,H-pyren.), 7.31-7.15 (m. 5H phenyl), 3.37 (m,2H, CH2pyren.), 2.93-2.83 (m, 8H, CH2-NH2+).2.59 (t. J = 7 Hz, 2H, CHZ-ph),
I .83 (m, 4H, (C&)2-CH2-pyren.), 1.62 (m,8H, CH2-CH2-CH2-CH2-CH2
and (CH2)2-CH2-ph).1.36 (m,2H, (CH2)2-CF12-(CH2)2.-MS (200"): m/z =
490 (loo%, M+'),371 (13). 342 (12). 340 (20). 286 (23). 273 (46), 257
(10). 247 (22), 228 (21), 218 (12), 215 (75), 202 (18), 162 (39), 112 (22).
98 (98). 91 (50),84 (63), 44 (50).
N-Octyl-N -[4-(1-pyrenyl)-butyll-pentane-1
J-diamine dihydrochloride
N-Octyl-S-[[[S-(l-pyrenyl)-propyll-carbonyl]-amino]-pentanoicacid
amide (4d)
From 3.1 g 2c and 1.0 g I-octanamine. Light yellow crystals (ethanol),
mp. 147". yield 40%.- C33H42N~02(498.7) Calcd. C 79.5 H 8.49 N 5.6
Found C 79.4 H 8.52 N 5.7.- IR: 3297; 3031; 2921; 2853; 1639; 1542;
1460; 1417; 1372; 1273; 1204; 1179; 839; 718 cm-'.- 'H-NMR (CDCI,): 6
(ppm) = 8.29-7.82 (m, 9H, H-pyren.), 5.95, 5.44 (2m, 2H, NH, D 2 0
exchange), 3.36 (t. J = 7 Hz, 2H, CY2-pyren.), 3.20-3.13 (m, 4H, NHCH2). 2.27-2.14 (m, 6H, C€J2-CH2-CO-NH-(CH2)3-CHz-CO),
I .42 (m, 4H,
NH-CH2-(CH2)2-CH2-CO),1.21 (m, 12 H, CH2)&H3), 0.83 (t, J = 7 Hz,
3H, CH3).- MS (130O): m/z = 498 (2%. M+'), 399 (64),228 (loo), 215
(56).
The type 4 amides were suspended in ether and reduced by excess
LiAIH4. The amines were purified by rotational chromatography and
recrystallized from the solvent stated.
N-[4-(2-Fluorenyl)-butyl]-N'
-(3-phenylpropyl)-pentane-I
,S-diamine
dihydrochloride (5b)
Light yellow crystals (ethan0uH20), mp. 297", yield 35%.- C 3 ' H d 2 ' 2
HCI (513.6) Calcd. C 72.5 H 8.24 N 5.5 Found C 72.5 H 8.29 N 5.4.- IR:
2945; 2855; 2806; 1578; 1451; 1398; 1346; 1043; IOOO, 825; 758; 7 4 0
698 cm-'.- 'H-NMR (CF,COOD): 6 (ppm) = 7.73 (m.2H, 4-H. 5-Hfluoren.), 7.53 (d, J = 7 Hz, lH, 8-H-fluoren.), 7.39-7.18 (m,9H aromat.),
3.86 (s, 2H, 9-H-fluoren.), 3.2-3.0 (m, 8H, C&-NH), 2.78 (m, 4H, C&ar), 2.13 (m,2H, CH2-CH2-ph), 1.85 (m,4H, (CH2)2-CH2-fluoren.),1.69
(m, 4H, CH2-C&-CH2-CH2-CH2), 1.37 (m, 2H, (CHz),-CH2-(CH2)2).- MS
(30'): rn/z = 440 (89%, M+'), 335 (15). 306 (19). 304 (38), 250 (29), 233
(19). 221 (12). 220 (31), 204 (19). 202 (86), 192 (39), 179 (65), 165 (19).
148 (17). 137 (24). 98 (loo), 91 (27). 84 (23), 69 (57). 44 (10).
N-[4-(2-Fluorenyl)-buiyl]-N
-octyl-pentane-1J-diamine dihydrochloride
(5c)
(5e)
Light yellow crystals (ethanol/H,O), mp. 224". yield 45%.- C 3 3 H a 2 . 2
HCI (543.6) Calcd. C 72.9 H 8.90 N 5.2 Found C 72.9 H 9.13 N 5.0.- IR:
3412; 2925; 2852; 2792; 1632; 1584; 1457; 1181; 1043; 845; 753; 722 cmI . - 'H-NMR: 6 (ppm) = 8.7 (bs, 4H, NH2+,D 2 0 exchange), 8.36-8.00 (m,
9H aromat.), 3.36 (m, 2H, CH2-pyren.), 2.93-2.81 (m, 8H, CH2-NH2+),
1.82 (m. 4H, (C&)2-CH2-pyren.), 1.59 (m, 4H, NH-CH2-CH2-CH2-CH2CH2-NH), 1.23 (m, 14 H, NH-(CH2)2-C&-(CH2)2-NHand (CH2),CH3),
0.85 (m,3H, CH,).- MS (270"): m/z = 470 (38%, M+'), 340 (19), 286 (15).
273 (35). 228 (35). 227 (27), 215 (loo), 202 (15). 198 (27), 142 (16). 112
(72). 98 (36), 84 (21), 44 (18).
Synthesis of 5f-p
18 mmol aldehyde, 9 mmol triamine, and a small amount of p-toluenesulfonic acid, dissolved in 70 ml of CHC13, are refluxed at a water
separator until no more water is formed. The mixture is washed with
water, dried with Na2S04 and the solvent removed in vacuo. The residue is
dissolved in 60 ml of absol. ethanol, 50 mmol NaBH, are slowly added
and the mixture is refluxed for 5 h. Water is added, the mixture is extracted
with CHCI,, the org. phase is dried with Na2S04 and the solvent is
removed. The residue is dissolved in ether and dry HC1 or oxalic acid in
ether are added. The precipitate is recrystallized from the solvent stated.
N-[(9-Anthryl)-methyl]-N' -[2-[(9-anthryl)-rnethylarnino]-ethyl]-ethane1.2-diamine trihydrochloride (Sf)
From 0.5 g N-(2-aminoethyl)-ethane-l,2-diamine and 2.1 g 9anthraldehyde. Yellow crystals (ethanol/H,O), mp. 283" (dec.), yield
SO%.- C34H,,N3 . 3 HCl .H20 (611.1) Calcd. C 66.8 H 6.26 N 6.9 Found
C 67.0 H 6.17 N 6.8.- IR: 3424; 2952, 2753; 1624; 1575; 1525; 1447;
1343; 1262; 1025; 959, 888; 784; 736 cm-'.- 'H-NMR/250 MHz
(CF,COOD): 6 (ppm) = 8.55 (s, 2H, 10-H), 8.14 (d, J = 8.8 Hz, 4H, I-H,
8-H), 8.08 (d, J = 8.4 Hz, 4H, 4-H, 5-H), 7.71 (dd, J = 8/7 Hz, 4H, 2-H, 7H), 7.60 (dd, J = 8/7 Hz, 4H, 3-H, 6-H), 5.41 ( s , 4H, ar-C&), 3.98, 3.77
(2m, 8H, CH2-CH2).- MS (200"): m/z = 483 (3%. M+'),191 (100).
Light yellow crystals (ethanol/H20), mp. > 300" (dec.), yield 25%.C3fi4JJ2 . 2 HCI(507.6) Calcd. C 71 .O H 9.53 N 5.5 Found C 70.8 H 9.43
N-[(9-Anthryl)-methyl]-N'-[2-[(9-anthrylJ-methylamino]-ethyl]-propaneN 5.4.- IR:3426,2925; 2852; 2797; 1617; 1455; 1045; 827; 761; 735 cm1 3-diarnine trihydrochloride (5g)
I.- 'H-NMR (CF3COOD): 6 (ppm) = 7.75 (m, 2H, 4-H, 5-H), 7.54 (d, J = 7
From 0.55 g N-(2-aminoethyl)-propane-1,3-diamineand 2.1 g 9Hz, IH, 8-H), 7.36 (m, 3H, I-H, 6-H, 7-H), 7.23 (d, J = 7.3 Hz, IH, 3-H),
anthraldehyde. Yellow crystals (ethanol/H20), mp. 276' (dec.), yield
3.86 (s, 2H, 9-H), 3.16 (m, 8H, C&-NH), 2.81 (m, 2H, C&-ar), 1.84 (m,
65%.- C35H35N3 . 3 HCI . H2O (625.1) Calcd. C 67.3 H 6.45 N 6.7 Found
10 H, (CH2)2-CH2-NH-CH2-CH2-CH2-CH2-CH2-NH-CH2-CY2-(CH2)5),
C 67.2 H 6.42 N 6.5.- IR: 3421; 2945; 2726; 1623; 1582; 1523; 1446;
1.34 (m, 12 H, C&-(CH2)2-NH-(CH,)2-(Cl12)5).MS (200'): m/z = 434
1343; 1262; 1053; 958; 885; 840; 784; 737 cm-'.- 'H-NMR/250 MHz
(47%. M+*),335 (15), 304 (16). 250 (26). 237 (11). 227 (17), 198 (17).
(CF3COOD):6 (ppm) = 8.52 (s, 2H, 10-H), 8.12-8.04 (m,8H, I-H, 4-H, 5179 ( 3 3 , 142 (28). 98 (loo), 84 (41). 72 (13). 44 (29).
Arch. Pharm. (Weinheim) 328,131-135 (1995)
134
H, 8-H), 7.68-7.57 (m, 8H, 2-H, 3-H, 6-H, 7-H), 5.39 (s, 2H, ar-CH2NH2+-(CH2)2-N),5.30 (s, 2H, ar-CH2-NH2+-(CH2),),3.94 (m, 2H, ar-CH2NH2+-CH2-CH2-N),3.70 (m, 2H, ar-CH2-NH2+-CH2-C&-N),3.60 (m,2H,
ar-CH2-NH2+-C&-(CH2)2), 3.34 (m, 2H, x-CH~-NH~+-(CH~)~C&),
2.43
(m, 2H, CHz-C&-CHz).- MS (200"): m/z = 497 (28%, M+'), 307 (20). 277
(33,221 (18), 207 (67), 191 (loo), 178 (73). 165 (20), 36 (45).
N-[(9-Anthryl)-meihyl]-N -[3-[(9-anthryl)-methylamino]-propyl]propane-13-diaminetrihydrochloride (5h)
Rehse and Seidel
N-[(I -Phenyl)-methyl]-N'
-[3-[(1-pyrenyl)-meihylaminol-propyll-propane13-diaminetrihydrochloride (51)
From 0.6 g N-(3-aminopropyl)-propane-1,3-diamine
and 2.1 g l-pyrenaldehyde. Yellow crystals (ethanol/H20), mp. 286" (dec.), yield 25%.C40H37N3. 3 HCI (669.1) Calcd. C 71.8 H 6.03 N 6.3 Found C 71.6 H 5.99
N 6.2.- IR:3385; 2946; 2760, 1587; 1452; 1242; 1185; 1052; 1OOO; 847;
753; 708 cm-'.- 'H-NMW250 MHz (CF3COOD): 6 (ppm) = 8.27-7.85 (m,
18 H aromat.), 4.93 (s, 4H, ar-CH2), 3.49 (m,4H, ar-CH2-NH2+-C&), 3.30
(m, 4H. ar-CH2-NH2+-(CH2)2-CH2),2.43 (m,4H,CH2-CH2-CH2).-MS
(190"): m/z = 559 (6%, M+'), 230 (15). 215 (loo), 36 (42).
From 0.65 g N-(3-aminopropyl)-propane-1,3-diamineand 2.1 g 9anthraldehyde. Yellow crystals (ethanol/H20), mp. 249". yield 65%.C3&137N3. 3 HCI (621.1) Calcd. C 69.6 H 6.49 N 6.8 Found C 69.5 H 6.40
N-[(I -Pyrenyl)-methyl]-N
-[3-[(1-pyrenyl)-methylaminol-propyll-butaneN 6.6.- IR: 3422; 2946; 2771; 1623; 1581; 1524; 1448; 1262; 1157; 1054;
1.4-diaminetrihydrochloride (5m)
959; 891; 842; 7 8 6 735 cm-'.- 'H-NMRL.250 MHz (CF3COOD):6 (ppm) =
From 0.7 g spermidine and 2.3 g 1-pyrenaldehyde.Light yellow crystals
8.59 (s, 2H, 10-H), 8.09 (m,8H, 1-H, 4-H, 5-H, 8-H), 7.72-7.56 (m,8H, 2(ethanol/H20),
mp. 288' (dec.), yield 30%.- C4'H3& . 3 HC1 . 'IzH20
H, 3-H, 6-H, 7-H), 5.40 (s, 4H, ar-CH2), 3.63 (m, 4H, ar-CH2-NH2+-C&),
(692.2) Calcd. C 71.1 H 6.26 N 6.1 Found C 71.2 H 6.16 N 6.0.- IR: 3416;
3.34 (m,4H, ar-CH2-NH2+-(CH2),)-C&).
2.50 (m, 4H, CH2-C&-CH3.MS (200'): m/z = 51 1 (638, M+'), 320 (67), 303 (30). 277 (54), 265 (44), 2938; 2771; 1582; 1433; 1243; 1184; 1057; 968; 845; 755; 709 cm-'.- 'HN W 2 5 0 MHz (CF,COOD): 6 (ppm) = 8.27-7.85 (m, 18 H aromat.), 4.94
245 (37), 219 (42), 206 (73), 191 (100). 178 (74), 165 (50), 152 (22).
(m, 4H, ar-CH2), 3.48 (m, 2H, ar-CH2-NH2+-CH2-(CH2)2-N),
3.37 (m,2H,
~ ~ - C H ~ - N H Z + - ( C H ~ ) ~ - C3.28
H ~ -(m,
N ) , 2H, ar-CH2-NH2+-CH2-(CH2)3),
N-[(9-Anihryl)-methyl]-N-[3-[(9-anthryl)-methylamino]-propyl]-buiane- 3.2 1 (m, 2H, ar-CH2-NHZ+-(CH2)&H2), 2.4 1 (m,2H, NH2+-CH2-CH2CH2-N), 1.90 (m. 4H, CHz-(CH2)2-CH2).-MS (180'): m/z = 573 (1%.
1.4-diamine irihydrochloride (5i)
M+'), 230 (13), 215 (100).
From 0.7 g spermidine and 2.1 g 9-anthraldehyde. Yellow crystals
(ethanol/H20), mp. 247' (dec.), yield 65%.- C37H42N3. 3 HCI (635.1)
Calcd. C 70.0 H 6.67 N 6.6 Found C 69.9 H 6.54 N 6.5.- IR: 3422; 2941;
N-[(9-Phenanihryl)-meihyl]-N
-[2-[(9-phenanihryl)-methylamino]-eihyl]2804, 1622; 1579; 1523; 1447; 1341; 1261; 1183; 1156; 1052; 958; 893;
propane-I,3-diamineirihydrochloride (5n)
781; 729 cm-'.- 'H-NMR/250 MHz (CF3COOD): 6 (ppm) = 8.49 (s, 2H,
From 0.55 g N-(2-aminoethyl)-propane-1,3-diamineand 2.1 g 9-phen10-H), 8.07 (m, 8H, I-H, 4-H, 5-H, 8-H), 7.81-7.47 (m,8H, 2-H, 3-H, 6-H,
anthraldehyde. Light yellow crystals (ethanol/H20),mp. 278". yield 45%.7-H), 5.27 (m, 4H, ar-CH2), 3.63 (m, 2H, ar-CH2-NH2+-C&-(CH2)2-N),
3.50 (m, 2H, ar-CH2-NH2+-(CH2)2-CH2-N),
3.29 (m, 2H, ar-CH2-NHz+- C35H35N3 . 3 HCI . H20 (625.1) Calcd. C 67.3 H 6.45 N 6.7 Found C 67.5
H 6.38 N 6.8.- IR:3423; 2949; 2746 1529; 1449; 1253; 1217; 1043; 1ooO;
CHZ-(CH~)~).
3.24 (m, 2H, ar-CH2-NH2+-(CH2)3-CYz).2.49 (m,2H,
895; 744; 725 cm-'.- 'H-NMR/250 MHz (CF3COOD): 6 (ppm) = 8.81,
NH2+-CH2-C&-CH2-N), 1.99 (m, 4H, CH2-(CH2),-CH2).-MS (180'): dz
8.70 (2d. J = 8 Hz, 4H, 4-H, 5-H), 7.98-7.69 (m,14 H aromat.), 4.90 (s,
= 525 (2%. M"), 207 (16). 191 (100), 178 (18), 84 (24).
2H, ar-C&-NH2+-(CH2)z-N),4.83 (s, 2H, ar-C&-NH2+-(CH&). 3.94 (m,
2H, ar-CHz-NH2+-C&-CH2-N),3.77 (m,2H, ar-CH2-NH2+-CH2-C&N),
3.57 (m, 2H, ar-CH2-NH2+-CfIz-(CH2)2),
3.39 (m, 2H, ar-CH2-NH2+N-[(I -Pyrenyl)-methyl]-N'-[2-[(1
-pyrenyl)-meihylaminol-ethyl]-eihane.
(CH2)2-CH2).2.51 (m, 2H, CH2-C&-CH2).- MS (240"): m/z = 497 (21%.
1.2-diaminetrihydrochloride (5j)
M+*),290 (20), 265 (27), 234 (36). 220 (26). 206 (43), 191 (100). 178
From 0.5 g N-(2-aminoethyl)-ethane-1,2-diamineand 2.3 g l-pyren( l l ) , 165 (34), 87 (32).
aldehyde. Yellow crystals (ethanol/HzO), mp. 238". yield 65%.- C38H33N3
. 3 HC1 (641.1) Calcd. C 71.2 H 5.66 N 6.6 Found C 70.9 H 5.57 N 6.4.IR: 3432; 2919; 2846; 1602; 1453; 1245; 1184; 1137; 966; 846; 758; 710
N-[(9-Phenanihryl)-meihyl]-N
-[3-[(9-phenanihryl)-methylamino]cm-'.- 'H-NMR/250 MHz (CF,COOD): 6 (ppm) = 8.18-7.75 (m,18 H
propyl]-propane-l,3-diamine
trihydrochloride (50)
aromat.), 4.85 (s, 4H, ar-CH2), 3.79, 3.69 (21x1, 8H, CH2-CH2).- MS (160'):
From 0.65 g N-(3-aminopropyl)-propae-1,3-diamine
and 2.1 g 9-phenm/z531 (l%,M+'),215(100)
anthraldehyde. Crystals (ethanol/H20), mp. 277", yield a%.C36H37N3.3
HCI . H 2 0 (639.1) Calcd. C 67.7 H 6.63 N 6.6 Found 67.3 H 6.51 N 6.5.N-[(l -Pyrenyl)-methyl]-N
-12-[( I -pyrenyl)-methylamino]-ethyl]-propane- IR: 3421; 2947; 2752; 1584; 1449; 1252; 1218; 1060. 1ooO; 888; 742; 723
cm-'.- 'H-NMRL250 MHz (CF3COOD): 6 (ppm) = 8.78, 8.67 (2d, J = 8
13-diaminetrihydrochloride (5h)
Hz, 4H, 4-H, 5-H). 7.92-7.64 (m, 14 H aromat.), 4.80 (s, 4H, ar-CH2), 3.56
From 0.5 g N-(2-aminoethyl)-propane-1,3-diamineand 2.1 g 1(m, 4H, ar-CH2-NH2+-C&), 3.34 (m, 4H. ar-CH2-NH2+-(CH2)2-CHz),
2.48
pyrenaldehyde. Yellow crystals (DMSO), mp. 28 1' (dec.), yield 45%.(m, 4H, CHz-C!&-CH2).- MS (190'): m/z = 51 1 (3%. M+'), 207 (49). 191
C39H35N3 . 3 HCI . 1'/2 HzO (682.1) Calcd. C 68.7 H 6.06 N 6.2 Found C
(loo), 178 (20), 165 (lo), 101 (15).
68.7 H 6.14 N 6.2.- IR:3421; 2950; 2763; 1586; 1434; 1234; 1186; 1057;
845; 818; 757; 709 cm-'.- 'H-NMR/250 MHz (CF3COOD): 6 (ppm) =
8.16-7.76 (m, 18 H aromat.), 4.85 (s, 2H, U-CH~-NH~+-(CH~)~-N),
4.76
N-[(2-Naphthyl)-methyl]-N
-[2-[(2-naphthyl)-meihylamino]-eihyl](s,2H, ar-CH2-NH2+-(CH2)3), 3.80 (m, 2H, ar-CH2-NH2+-CH2-CH2-N), propane-1,3-diamineirihydrochloride (5Q)
3.66 (m, 2H, ar-CH2-NH2+-CH2-C&-N), 3.41 (m, 2H, ar-CH2-NH2+-CH2From 0.5 g N-(2-aminoethyl)-propane-1,3-diamine and 1.4 g 2(CH2)2), 3.27 (m, 2H, ar-CH2-NH2+-(CH2)2-C&),2.37 (m, 2H, CH2-CH2CH2).- MS (280'): m/z = 545 (53%. M"), 330 (60),301 (83). 230 (44), naphthaldehyde. Crystals (ethanoVH20), mp. > 300" (dec.), yield 50%.C Z ~ H .~3 ~
HCI
N (506.9)
~
Calcd. C 64.0 H 6.76 N 8.3 Found C 64.0 H 6.88
215 (loo),202 (20), 189 (13), 87 (40).
Arch. Pharm.(Weinheim)328,131-135(1995)
135
Oliogoamines and Seidel
N 8.3.- IR: 3430; 2937; 2765; 2710; 2596; 2416; 1599; 1449; 1271; 1019;
900; 856; 819; 745 an.'.-'H-NMR/250 MHz (CF3COOD): 6 (ppm) =
7.98-7.88 (m,8H aromat.), 7.61 (m,4H momat.), 7.45 (m, 2H aromat.),
4.61 ( s , 2H, ar-C&-NH2+-(CH2)2-N), 4.54 (s, 2H, ar-C&-NHz+-(CH2)3),
3.84 (m, 4H, NH2+-(CH&N), 3.47 (m,4H, C&-CH2-C&), 2.49 (m, 2H,
CH?-C&-CHz).- MS (120')
= 397 (11%. M+'), 227 (47). 184 (12),
170(16), 156(15), 141 (100).
References
1
2
3
4
5
Arch. Pharm. (Weinheim)328,131-135 (1995)
K. Rehse, T. Seidel, Arch. Phurm. (Weinheimj 1992,325,235-239.
K. Rehse, T. Seidel, Arch. Pharm. (Weinheimj 1994,327, 399-404.
K. Rehse, A. Carstensen, H.-J. Ernst, Arch. Pharm. (Weinheim) 1987,
320,724-729.
H.O. Bayer, H. Gotthardt, R. Huisgen, Chem. Ber. 1970, 103, 23562367.
A. Okano, M.Inaoka, S . Funabashi, M. Iwamoto, S. Isoda, R. Moroi,
Y. Abiko, M. Hirata, J. Med. Chem. 1972,15,247-255.
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properties, oligoamines, inhibition, xxviiioligoamines, effect, platelet, part, fluorescence, cfluorescent, enhance, anticoagulant, hydrophilic, aggregation
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