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Tumor Inhibiting [12-Bisdifluorophenylethylenediamine]-dichloroplatinumII Complexes ISynthesis.

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115
[ 1,2-Bis(difluorophenyl)ethylenediamine]dichloro-Pt-complexes
Tumor Inhibiting [1,2-Bis(difluorophenyl)ethylenediamine]dichloroplatinum(I1) Complexes, I: Synthesis
Richard Miiller, Edith Schickaneder, Margaretha Jennerwein, Herta Reile, Thilo SpruR,Jiirgen Engel', and
Helmut Schonenberger
Institut fur Pharmazie, Lehrstuhl fur Pharmazeutische Chemie I1 der Universitat Regensburg, Sonderforschungsbereich 234. Universitatsstrak 3 I ,
D-8400 Regensburg, FRG
*
ASTA Pharma AG, Postfach 10 01 05, D-6000 F r a n k f u m a i n 1, FRG
Received December 22,1989
The synthesis of the diastereomeric 1,2-bis(2,3-, 2,4-, 2.5-, 2,6-,3,4-, 3,5-difluoropheny1)ethylenediamines (meso, D/L 8-13) from meso 1.2-bis(2-hydroxypheny1)ethylenediamine and the respective difluorobenzaldehyde by a
diaza-Cope-rearrangementand their conversion into the [ 1,2-bis(2,3-, 2,4-,
2.5-, 2,6-, 3,4-, 3,5difluorophenyl)ethylenediamine]dihaloplatinum(II)-complexes (meso, D/L 8-13PtC12; meso D/L 9-and 11-PtI2) with K2PtHalq (Hal
= CI, I) is described. From the diiodoplatinum(I1)-complexes (meso D/L 9and 11-PtI2) the beuer water soluble diaqua[l,2-bis(2.4- and 2.6-difluorophenyi)ethylenediamine]platinum(lI) sulfates (meso, D/L 9- and 11-PtSO4)
are obtained by reaction with Ag2S04.
Tumorhemmende [1,2-Bis(difluorphenyi)ethylendiamin]dichloroplatin(I1)-Komplexe,Teil I: Synthese
In a recent publication') we reported about 4-substituted (1,2-diphenylethylenediamine)platinum(II) complexes. Among a great number of synthesized platinum(I1) complexes the p-fluorosubstituted compounds
showed the best antitumor-activity on MDA-MB 231 (in vitro) mammary
carcinoma and on P-388 leukemia of the CDzF, mouse. In our further
the synthesis and antitumor activity of the diastereomeric [1.2bis(2-, 3-, and 4-fluorophenyl)-ethylenediamine]platinum(ll) complexes
was described. In several in vitro and in vivo tests the D/L compounds
proved to be equiactive with cisplatin, the meso compounds exhibited
lower activity. It was our aim to improve the antitumor-effect by disubstitution with fluorine in both phenyl rings.
schmitt4'. At a temp. below 120'C meso-l,2-bis(2-hydroxypheny1)ethylenediamine (meso 1) and the respective difluorobenzaldehyde reacted to the meso-N,N'-disalicylidene1,2-diphenyIethylenediamines 2-7 (Scheme I, Method A,
Table 1). Subsequent acidic hydrolysis yielded the mesoI ,2-diphenylethylenediaminesmeso 8 - meso 13 (Scheme I,
Method B, Table 3). In a reaction with the respective difluorobenzaldehyde the meso-N,N'-dibenzylidene-1.2-diphenyl-ethylenediamines 14-19 (Scheme I, Method C , Table 2)
were received. These diimines were identically substituted
in the four phenyl rings. At a temp. higher than 160°C a
meso-D/L stereoisomerisation took place. After sulfuric
acid hydrolysis a mixture of meso- and D L - 1,2-diphenylethylenediamines was obtained. The DL-compounds D/L 8,
9, and 11 (Scheme I, Method E/F, Table 3) could be extracted with ether or petrolether from the mixture. In certain
cases the more soluble D,L-diimines 20-22 (Scheme I,
Method D, Table 2) were separated from the meso-D/L pro-
This paper describes the synthesis of the [ 1,2-bis(difluorophenyl)ethylenediamine]platinum(II) compounds.
Chemistry
The meso-l,2-diphenylethylenediamines(meso 8 - meso 13)
were synthesized via [3.3] sigmatropic diaza-Cope-rearrange- ment reaction as described by Vogtle and Gold--
Die Synthese der diastereomeren 12-Bis (2.3-. 2.4-, 2.5-, 2.6-. 3.4, 3.5-difluorpheny1)ethylendiamine (meso, D/L 8-13) aus meso- I ,2-Bis(2-hydroxypheny1)ethylendiamin und dem entspr. Difluorbenzaldehyd durch eine DiazaCope-Umlagerung und ihre Uberfuhrung in die [1,2-Bis (2,3-, 2.4-, 2.5-,
2,6-, 3,4-. 3,5difluorphenyl)ethylendiamin]dihaloplatin(II)-Komplexe (meso, D/L 8-13 PtC12; meso, D/L 9- und 11-Ptlz) mit K2PtHal4 (Hal = CI, 1)
wird beschrieben. Aus den Diiodoplatin(l1)-Komplexen (meso. D L 9- und
11-PtI2) werden durch Reaktion mit Ag2SO4 die besser wasserloslichen
Diaqua[I,2-bis(2.4- und 2,6difluorphenyl)-ethylendiamin]platin(lI)sulfate
(meso, D/L 9- und 11-PtS04) erhalten.
Table 1: meso-N,N'-Disalicylidene-l,2-diphenyl-
compd.
substituent
m.p.
60
'H-NMI-Data.
ethylenediamines
hHz,
standard: W!SIm
solvent: C K l 3
OC
yield %
H-benzyl.
H-arom.
N=C-H
2
-
2,3-DiF
227-228
86
5.34
( m , 14H)
8.42 ( s , 2H)
.3
-
2,4-DiF
201-202
67
5.18 ( s , 2H)
6.55-7.52 ( m , 14H)
8.26 ( s , 2H)
4
2.5-DiF
236-238
74
5.26 ( s , 2H)
6.91-7.44 (m, 14H)
8.36 ( s , 2H)
5
2,6-DiF
237
45
5.72
(9,
2H)
6.68-7.22
8.15 ( s , 2H)
6
3,4-DiF
176-180
80
4.72
(5,
2H)
7
3,5-DiF
212-213
21
4.75 ( s , 2H)
(m, 14H)
6.76-7.42 (m. 14H)
6-77-7.44 (m, 14H)
Arch. Pharni. (Weinheini)324,115-120 11991)
(5,
2H)
6.74-7.52
OVCH Verlagsgesellschaft mbH. D-6940 Weinheim. 1991
8.24
( s , 2H)
8.26
(S,
2H)
0365-6233/91/0202-01l5 $3.50 + .25/0
116
Schonenberger and coworkers
Y
Y
I/
/I
1
1L-p
X
Y
CIL
a-12
Table 2: meso- and D/L-N,N'-Dibenzylidene-1,2diphenylethylenediarnines
'H-NMR-Data,
60
solvent: C K 1 3
cornpd.
H-benzyl
substituent
I
mesa
E-G
method
Scheme
m.p.
"C
yield %
.
MHz, standard: TMSINT
H-arorn.
N=C-H
14
2,3 DiF
204-205
95
5.31
2H)
6.92-7.92 (rn, 12H)
8.51
( S ,
2H)
15
2,4 DiF
178-179
75
5.13 ( s , 2H)
6.51-8.38 (m, 12H)
8.41
(8,
2H)
16
2,5 DiF
-
86
17
2,6 DiF
225
6.93-7.40 (m, 12H)
8.60 ( s , 2H)
3,4 DiF
-
83
91
6.00 ( s , 2H)
LS
4.58 ( s , 2H)
6.87-7.81
( m , 12H)
7.83 ( s , 2s)
4 . 6 3 ( s , 2H)
6.45-7.38 (m, 12H)
7.91 ( s , 2H)
19
3,5 DiF
-
90
20
oil
80
21
2,5 DiF
3,4 DiF
oil
22
3,5 DiF
oil
58
58
duct. From the subsequent acidic hydrolysis the pure D/L1,2-diphenyIethylenediaminesD/L 10, 12, and 13, (Scheme
I, Method G, Table 3) were obtained. Except with D/L 10
all D/L- 1,Z-diphenylethylenediamineswere oils. They were
converted into the crystalline diammonium salts with a saturated solution of dry HC1 in diethylether: D/L 8., 9., 11. to
13.2 HC1 (Scheme I, Method H, Table 3).
The
( 1,2-diphenylethylenediamine)dihaloplatinurn(II)
complexes meso and D/L 8 to 13 PtC12; meso and D/L 9,
11-Pt12 (Scheme 11, Method I-M, Table 4 + 5) were synthesized by reacting K2PtCb or KzPt4 with the corresponding ligands in water or t-butanol/water solution at pH 5.56.5 and 50°C.
The diaqua ( 1,2-diphenylethylenediamine)platinum(II)
sulfates meso and D/L 9, 11-PtS04 (Scheme 11, Method N,
(5,
-
-
4.54
(9,
2H)
4.58 ( s , 2 H )
-
6.70-8.03 (m. 12H)
6.40-7.54
( r n , 12H)
8.11 ( s , 2H)
8.10
(S,
2H)
Table 6 ) were obtained by the reaction of the diiodoplatinum(I1) compounds with Ag2S04 in water.
'H-NMR-spectroscopy
The 'H-NMR spectra obtained for the (1,2-diphenyIethylenediamine)dihaloplatinum(II) comp1exe:s (Table 5) were
in accordance with the results of another publication5'.
Evaluable H-NMR-spectra of the diaquaplatinum(I1) complexes could not be obtained in available solvents like trifluoroacetic acid, DMF-d7 or CD30D because of insufficient
solubility or reactions with the solvent. The solubility of
these diaquaplatinum(I1) complexes in water was sufficient
to get clear solutions for the cell culture and animal
experiments but the solubility was too low for 'H-NMR
spectroscopy.
Arch. Pharni. IWeiirhrinri 324. IIS-120 (1991)
'
117
[ 1,2-Bis(difluorophenyl)ethylenediamine]dichloro-Pt-complexes
method I
K2PtC14
method K
KZPtIb
mesol- to mesa B-PtCL2, OIL lO-PtCI2
meso
HF -[,t@
i :
NH2
NH2
S c h e m e I1
9
a n d meso Q - P t 1 2
meso
sc'lene X I
O/L~-,1)-,l+ tolJ-PtC12
OIL? a n d Q I L l J - P t 1 2
conod.
SUbSt.
2 CI
2'
X
X
meso a n d OIL p - P t S O L
mcso a n d O I L U - P t S O ,
so;-
'H-NMR-Data, 60
solvent: CDC13
Table 3: 1,2-diphenylethylenediamines
cornpd.
substituents
rneso 4
m.p.
OC
yield %
N-H
H-benzyl
57
31
1.55 ( s , 4H)
1.72 (9, 4H)
4.52 ( s , 2H)
4.48 ( s , 2H)
6.88-7.30 ( m , 6 H )
6.88-7.39 (m, 6Ii)
211-214
113-114
oil
37
53
43
1.48 ( s , 4H)
1.77 ( s , 4H)
4.46 ( s . 2H)
4.53 ( s , 2H)
6.59-7.58 (m, 6It)
6.73-7.82 (m, 6H)
1.51 ( s , 4H)
4.49 ( s , 2H)
4.32 ( s , 2H)
6.84-7.32 (m, 6H)
6.62-7.29 (m. 6H)
D/L 9
D / L 10_
2.5 DiF
2.5 DiF
230-232
76-77
208-210
17
63
82
meso L
l
2,6 DiF
122-123
52
1.58 ( s , 4H)
1.66 ( s , 4H)
D / L A1
2.6 DiF
oil
47
2.15
2.6 DiF
n.d.
23
3,4 DiF
92-93
8
meso 3
3.4 DiF
3.4 DiF
3.5 DiF
oil
256-258
181-182
50
86
34
13
3,5 DiF
oil
7
3,5 DiF
n.d.
S
* 2 HC1
9
D/L
meso
D/L
* 2 HC1
meso l_O
*
12
D/L l
&
meso
2 HC1
D/L 1
2
D/L
12 *
D/L
D / L 13
*
2 HC1
2 HC1
4.60 ( s , 2H)
6.71-7.49 ( m , 6H)
4.68 ( s , 2H)
6.77-7.52 (m, 6H)
1.45 ( s , 4H)
3.97 ( s , 2H)
6.98-7.39 (m, 6H)
1.61
2H)
3.99 ( s , 2H)
6.76-7.38 (m, 6H)
2.50 ( s , 4H)
4.00 ( s , 2H)
6.57-7.27 ( m , 6H)
1.59 ( s , 4H)
4.07 ( s , 2H)
6.51-7.08 (m, 6 H )
(5,
(9,
4H)
n.d.
IR-spectroscopy
The diaquaplatinum(II) sulfates (meso, D/L 9-PtS04;
meso, D/L- ll-PtSO4) show a strong absorption band at
1130 cm-' and a weaker one at 620 cm-I. These resonances
were indicative for an ionic sulfate residue. The water ligands showed a broad absorption band at 3440 cm". On the
basis of these results and of elemental analysis (table 6) we
supposed a structure in which two water molecules are
bound to the platinum atom with sulfate as counter ion. In
the case of a coordination of a sulfate residue the high Td
symmetry of the sulfate ion is lowered resulting in further
absorption bands6! In the IR-spectrum of meso-9-PtS04
weaker bands at 1190 cm-', 1000 cm", and 910 cm-' were
Arch. Pharm. (Weinheini) 324. 115-120 (1991)
H-arom.
134-135
oil
2.3 DiF
2.3 DiF
2.3 DiF
2.4 DiF
2,4 DiF
2.4 DiF
D/L
MHZ, standard: T M S ~ ~ ~
observed. We suspect that this compound is contaminated
with other types of coordination complexes. It should be
mentioned that no reactions between KBr and the platinum
compounds occur. The spectra remained unchanged when
recorded as a Nujol mull.
Experimental Part
Melting points (uncorrected): Biichi 510 melting points appararus or
Petri melting point apparatus if higher than 22WC - IR data: Perkin Elmer
Model 580 A. - 'H-NMR spectra: Varian EM 360 L 60 MHz spectrometer.
- 'H-NMR spectra of the platinum complexes: Bruker PFR-NMR spectrometer W M 250 MHz. - Elemental analysis: Microlaboratory of the
University of Regensburg
118
Schonenberger and coworkers
Table 4: (1,2-Diphenylethylenediamine)dihaloplatinum(II)
compd .
substituent
yield %
calcd.
found.
calcd.
found
calcd.
found
30.5
30.7
2.19
2.28
5.1
5.1
meso 8-PtCI2
2 . 3 DiF
94
D/L 8-PtC12
2 . 3 DiF
79
31.1
2.49
5.1
meso c)-PtC12
2 . 4 DiF
76
30.8
2.59
5.3
D / L 9-PtClZ
2 . 4 DiF
83
30.9
2.28
meso z-PtT2
2.4 DiF
8'7
D/L 2 - P t I 2
2 . 4 DiF
88
meso lo-PtC12
2 , 5 DiF
8'7
D/L lC-PtC12
2 . 5 DiF
9.1
23.0
22.9
1.65
30.7
5.0
3.8
2.31
2.19
3.6
3.9
1.68
23.0
30.6
1.84
5.1
5.1
5.2
meso z - P t C 1 2
2 . 6 DiF
8')
30.3
2.25
D/L g - P t C 1 2
2.6 DiF
68
30.8
2.30
meso l_1-Pt12
2,6 DiF
95
D/L G - P t I 2
2 , 6 DiF
95
meso 1_2-PtC12
3 , 4 DiF
8'1
D/L 1Z-PtC12
3 , 4 DiF
77
32.9
3.06
6.5
mew = - P t C l 2
3 . 5 DiF
94
30.7
2.33
5.0
D / L I_3=PtCl2
3 , 5 DiF
83
30.3
2.35
4.8
Table 5: 'H-NMR-Data
.
meso .8~-PtC12
30.6
30.9
D / L z-PtC12
D / L E-PtI2
meso I-.
0-PtCl2
2 . 3 DiF
m c x .11-PtC12
D / L J Y-PtCl,
meso l-1-Pt12
D / L __
llFPtI2
meso I 2 - - P t C l 2
D / L &?;-PtC12
3.8
3.8
5.1
5.1
2 , 3 DiF
2 . 4 DiF
2 . 4 DiF
2.4 Dip
2 . 4 DiF
2 . 5 DiF
2 , s DiF
2 . 6 DiF
2 . 6 DiF
2 , h DiF
2,6 DiF
3,4 DiF
3 , 4 DiF
6 (ppm)
NH
H benzyl
(m. br, 2H)
(m, br, 2H)
4.80
(m, br, 2H)
6.50
5.84
(m, br, 2H)
4.77
(m, br, 211)
6.55
(m, br, 2H)
7 . 0 7 ~ - 7 . 1 7 (m. 4H. 3 / 5 P o s . )
5.83
(m, br, 2H)
8.49--8.59 (m. 2H. 6 P o s . )
6.42
(m, br, 2H)
7 . 0 0 ~ ~ 7 . 2 6(m. 4H. 3/5 Pos.)
5.78
(m, br. 2 H )
4.78
(m, br. 2H)
(m,
7.07--7.15 (m.
8.43--8.52 (m,
7.00--7.18 (m.
8.07--8.13 (m,
6.47
5.70
( m , br, 2H)
( m , br, 2H)
4.67
(m, br. 2H)
6.32
(m, br, 2H)
4.71
(m, br, 2H)
4.74
( m , br, 2H)
7.21--7.48
7.26--7.36
(m,
4 / 5 Pos.)
4H.
(m, 4H, 4 / 5 P o s . )
(m, 2H. 6 Pos.1
7.12--7.30
8.38
D / L 1O-PtCl2
2.26
2.19
arom H
substituent
8.07--8.13
meso __
9-Pt12
4.9
3.8
s t a n d a r d : lNSIm
7.86
meso 1 - P t C 1 2
1.73
1.84
23.2
8.30 ( t , 2H, 6 P o s . )
D/L &PtC12
1.65
for (1,2-diphenylethylenediamine)dihaloplatinum(11) complexes 250 MHZ,
s o l v e n t : DMF-d7,
compd
23.3
22.9
(m,
2H, 6 P o s . )
4H.
3/5 Pos.)
2H. 6 P o s . )
5.88
4H. 3 / 5 P o s . )
5.56 (m, br, 2H)
2H, 6 POS.)
6.38 (m, br. 2H)
(m, 4 H , 4 / 5 P o s . )
2H. 6 Pos.)
( m , 4H, 4 / 5 P o s . )
5.95
(m, br, 2H)
6.52
( m , br, 2H)
5.11
(m, br, 2H)
8 . 3 9 (m, 2H. 6 P o s . )
6.52
( m , b r , 2H)
7.00--7.07 (m, 4 H . 3 / 5 P o s . )
5.45
( m , br, 2H)
7.39--7.52 (m, 2H. 4 P o s . )
6.69 (m. br, 2H)
7 . 0 1 - ~ 7 . 0 8 (m, 4H, 3 / 5 POS.)
5.45
7.2b7.48
6.70
7.05-7.29
( m , 2H. 4 P o s . )
(m,
(m,
7 . 0 1 - 7 . 0 8 (m,
7.36--7.48 (m,
7.30-7.39 (m,
4.75 (rn. br, 2H1
4.96
(m, br, 2H)
( m . br, 2H)
(m, br, 2H)
5.01
(m, br, 2 H )
4.93
(m. br, 2H)
5.07
(m, br. 2H)
7.00-7.08
4H. 3 / 5 P o s . )
5.35
(m, br. 2Hl
7.40--7.52
2H, 4 P o s . )
6.62
(m. br. 2H)
4H, 3 / 5 P o s . )
5.29
( m , br, 211)
2H. 4 POS.)
6.66 (m, br. 2H)
4H. 2 / 5 P o s . )
4.69 ( m , br, 2H)
5.87
(m, br, 2H)
7.82-7.91
(m, 2H, 6 Pos.)
6.33
(m, br, 2 H )
7.21-8.22
(m, 6H)
6.17
(m, br. 2H)
4 . 6 1 (m. br, 2H)
5.17
( m , br, 2H)
4.77
( m , br, 2H)
5.27
(m,
6.64 (m, br, 2H)
meso S - P t C l 2
3 . 5 DiF
7.12-7.21
7.41-7.49
D/L G - P t C 1 2
3 , 5 DiF
7.05-7.14
7.52-7.55
(m,
(m,
(m,
(m,
2H, 4 P o s . )
2H. 2/6 P o s . )
2H, 4 Pos.)
4H. 2 / 6 P o s . )
(m,
(m,
6.18 (m,
6.68 (m,
5.98
br. 2H)
6.38
br, 2Hl
br, 2H)
hr, 2H)
br, 2H)
Arch. Pharm. (Weinheini) 324. 11s-120 (1991)
119
[ 1,2-Bis(difluorophenyl)ethylenediamine]dichloro-Pt-complexes
Table 6: Diaqua-(1,2-diphenylethylenediarnine)platinum(II) sulfates
H
C
compd
.
substituents
~~~~
yield %
calcd.
found
N
calcd.
found
calcd.
2.64
2.53
2.65
2.71
2.70
4.6
4.2
"
4.3
"
4.5
''
4.3
found
~~~~~~
meso9-PtSO4
D/L9-PtSO4
2.4 DiF
2,4 DiF
72
76
27.5
meso Ll-PtS04
D/L Q-PtS04
2.6 DiF
2,6 DiF
74
21.9
27.5
27.7
64
27.4
nieso-NN -Disalicylidene- I .2-dipheriylethyleriediaaiir2es nieso-2 to
nieso-7 (niethod A)
meso-l,2-Bis-(2-hydroxyphenyl)ethylenediamine (meso 1: 0.1 mol) and
the respective isomeric difluorobenzaldehyde were heated under reflux in
100 ml of CH3CN for 3 h. The solution was stirred with a mechanical
stirrer. Then the mixture was concentrated to 50 ml. After standing in the
refrigerator for 1 h the precipitate was collected in a Biichner funnel,
washed with small amounts of ice-cold CH2CN and dried at the air.
distillation was performed until no salicylic aldehyde could be detected
with 2,4-dinitrobenzaldehyde.The hot solution was filtered. After cooling
the mixture was made alkaline with 20 % NaOH under ice cooling. The
diastereomeric bases were extracted with CH2Clp The org. layer was separated, washed with water and dried over MgS04. After removal of the
solvent the residue was treated with petrolether 40-60 (meso. D/L 9) or
with ether (meso, D/L 11). The diastereomeric compounds were separated
because the meso isomers were sparingly soluble but the D/L compounds
dissolved well.
nieso-l.2-Diphe1iylethyle1iedianlbiesmeso-8 to nieso-13 (niethod B)
meso-N,N'-Disalicylidene-l,2-diphenylethylenediamine
(meso 2 to meso
7, 30 mmol) was hydrolyzed with 100 ml of 6 N H2S04 (meso 3: 3N
DIL-I .2-Bi.r(diflnorophenylLlh?.ied~aminesD L 1 0 DIL 12,13
(niethod G )
H2S04, meso 5 , 6 8N H2S04) and the salicylic aldehyde was removed by
steam distillation. The hot solution was filtered. After cooling the meso1,2-diphenylethylenediamine(meso 8 to meso 13) was precipitated with 20
% NaOH under ice cooling. The solution was stirred vigorously. The
diamine was extracted with CH2C12 and the org. layer was dried over
MgSO,. The solution was concentrated. The product crystallized upon addition of ether. The diamine was collected in a Biichner funnel, washed
with ether and dried over PzO5.
The D/L compounds D/L 10,12,13 could be obtained by an acidic steam
distillation from the D/L diimines 20-22 as described in method B.
meso-N," -Dihen:ylidene-I 2-diphen~lethytenedniines14 to 19
(method C)
Dichloro-l2-(dipheriylerhyleriediarine)pfatilrr~nr(//)meso 8 to nie.ro
13-PtCl~.DIL 1O-PrCl2(niethod I)
meso-1.2-Diphenylethylenediamine (meso 8 to meso 13, 0.1 mol) and
the respective difluorobenzaldehyde were heated under reflux in 100 ml of
CH$N for 5 h (meso 1 4 12 h). The mixture was concentrated until the
product began to precipitate. After standing in a refrigerator for 1 h the
product was collected in a Biichrier funnel, washed with small amounts of
ice-cold CH,CN and dried over P20j.
1,2-Diphenylethylenediamine is suspended in 10 ml of water. Under
warming (50°C) and stirring the ligand is dissolved by dropwise addition of
2N HCI. 10-20 ml tert.-butanol are added and the pH is adjusted to 6.5 with
0.5 N NaOH. After filtration 1 mmol KzPtC14 in 5 nil water is added
dropwise to the mixture. Under warming (50°C) the product precipitates
slowly from the solution. The pH must be adjusted several times to 6.5
with 2N NaOH. After 25-30 h stirring at 50'C in the dark, the reaction is
complete. The yellow product is collected by suction filtration using a no. 3
fritted glass filter, washed with N HCI, water and dried in vaccuo over
silica gel/CaClz at 80°C.
DL-N,N+-Dibenzylidene-l,2-diphenylethylenediamines
20-22 (method D)
meso-N,N'-Dibenzylidene-1,2-diphenylethylenedi~ines16, 18, 19
were molten. After 10 min. they were allowed to cool. The D/L compounds
could be isolated because of their better solubility in organic solvents ( 2 0
CHCI,; 21/22: CH2C12).
D L-I.Z-Bis-(23-diflnoropheriyl)efIe~iedianiirie(D,L 8) (niethod E)
meso 14 ( I 3 mmol) was dissolved in 50 rnl of anisole. The solution was
refluxed for 3 h (oil-bath temp. 160-18O'C). After cooling the solvent was
removed by steam distillation. The mixture of meso and D/L diimine was
hydrolyzed with 50 ml 6N HzSO4 and a further steam distillation was
carried out (5 h). The meso and D/L ethylenediamine 8 mixture was isolated as described in method B. The product was washed with ether. D/L 8
could be isolated from the filtrate. Meso 8 is not soluble in ether.
DIL-1.2-Bis (difluoropheriy1)eth~Ieiiedianiiires
D L 9 , l l (method F)
meso-Diimine (25 mmol) was molten and then stirred for 10 min. (mechanical stirrer). After cooling 150 ml of 5N H2S04 were added. A steam
Arch. Pharni. (Weinhcini)314. 115-120 (1991)
DIL-I.2-DiphenylethylenediaminesDIL 8,9,11 ro 13 x 2 HCI (method H)
The free base is dissolved in a little bit of methanol. A saturated solution
of anhydrous HCI in ether is added. The crystalline precipitate is isolated
by suction filtration using a fritted glas filter. D/L 11 x 2 HCI doesn't
precipitate, but crystallizes after removing the solvent.
nieso-l,7-(Dipheri~leth~leriedianrine)diiodoplari~~~~t~i(ll)
nieso 9- and
nieso 11-Ptl2 (niethod K)
K2PtCI4 (1 mmol) and KI (20 mmol) were each dissolved in 10 ml of
water. The K1 solution was added to the KlPtCI4 solution. The mixture was
stirred for 30 min at 50°C. The color changed from red to black. This
indicated the formation of KzPtL. Furthermore the synthesis was carried
out as described in method 1. Instead of a K2PtC14 the K2Pt14solution was
used.
DIL-Dicliloro-I.2-(diphe~iyletiiyle~iedianiiiie)platiriimr(ll)
DIL 8. DIL 9
and DIL 11 to 13-PtC12(method L)
D.L-I ,2-Diphenylethylenediamine. 2 HCI CD/L 8 .: D/L 9 . and D/L 11
to 13 . 2 HCI: 1 mmol) was dissolved in 10 ml water and a solution of
KZPtC14 (1 mmol) in 8 ml water way added slowly. The pH is adjusted to
5.5 - 6.5 with N NaOH. The further reaction was carried out as described in
method I.
120
DIL-I,2-(Diphenylethylenediamine)diiodoplatin~(ll~
DIL 9-and DIL
11-Ptlz (method M)
The synthesis was carried out as described in method L. but instead of a
K2PtC14 solution the K2Ptla solution (see method H) was used.
Diaqua-l,2-(Diphenylethylenediamine)platinum(ll)
sulfates meso and DIL
9-, ll-PtSO4 (method N)
Diiodoplatinum(I1) complex (meso, DR. 9-, ll-Ptl2: 1 mmol) and
Ag2S04 (0.95 mmol) were suspended in 150 ml of water. The mixture was
stirred for 24 h at 50'C in the dark. The precipitated AgI was filtered off
using a no 4 fritted glas filter. The filtrate was freeze-dried. An excess of
water could be removed by drying in vaccuo over silica gelKaCl2.
Schonenbergerand coworkers
References
M. Jennerwein, B. Wappes, R. Gust, H. Schonenberger. J. Engel, S.
Seeber, and R. Osieka, J. Cancer Res. Clin. Oncol. 114,347 (1988).
R. Miiller, R. Gust, M. Jennerwein, H.Reile, R. Laske, W. Krischke,
G.Bernhardt. T. SpruB, J. Engel, and H. Schonenberger,Eur. J. Med.
Chem. 24,341 (1989).
H. Reile, T. Sp~l.3,G. Bernhardt, R. Muller, R. Gust, and H. Schonenberger, Arch. Pharm. (Weinheim), in press.
F. Vogtle and E.Goldschmitt, Chem. Ber. 109. 1 (1976).
J. Karl, R. Gust, T. SpruB, M.R. Schneider, H. Schonenberger,J. Engel, K.-H. Wrobel, F. Lux, and S. Trebert-Haeberlin, J. Med. Chem.
31.72 (1988).
K. Nakamoto in: Infrared spectra of inorganic and coordination compounds, 2nd edn., pp. 248-251, Wiley-Interscience,New York 1970.
[Ph767]
Arch. Pharm. (Weinheim) 324. 115-120 (1991)
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isynthesis, inhibition, complexes, bisdifluorophenylethylenediamine, tumors, dichloroplatinumii
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