Amino anthracenediones-bis platinum complexes, useful as antitumoral agents

Compounds of the formula: ##STR1## are disclosed, such as 1,4-bis[2(3,6,9-trioxa)undecylamino-ethylamino]-5,8-dihydroxy anthraquinone 2HCl. These compounds exhibit antineoplastic activity and can be used to treat tumors.

This invention concerns new bis-platinum complexes, a method for their 
preparation and pharmaceutical compositions containing them. 
An object of this invention is bis-cis-platinum complexes of formula I: 
##STR2## 
wherein X, X', that can be the same or different, are ligands selected 
from the group consisting of Cl, Br, OH, CH.sub.3 SOCH.sub.3 .multidot.Cl, 
CH.sub.3 SOCH.sub.3 .multidot.Br, CH.sub.3 SOCH.sub.3 .multidot.OH or, 
taken together, from the anion of a linear or cyclic, optionally 
substituted, dicarboxylic acid; 
n is zero, 0.5 or an integer from 1 to 5; 
Solv is a solvent of crystallization selected from the group of water, 
C.sub.1 -C.sub.5 -alcohols, acetonitrile and ethylacetate; 
A is a disubstituted 1,4-anthracenedione of formula: 
##STR3## 
wherein each of Rc and Rd, that can be the same or different, are 
hydrogen or hydroxy; 
Rb is either a linear or branched C.sub.1 -C.sub.6 alkyl residue optionally 
substituted by hydroxy, C.sub.1 --C.sub.3 -alkoxy, C.sub.2 -C.sub.8 
-polyalkoxy or sulphonic groups, or it represents a residue of a 
mono-amino-sugar, in acetalic or linear form of formulae a and b 
respectively: 
##STR4## 
` wherein R.sub.1 is hydrogen, C.sub.1 -C.sub.3 -alkyl, hydroxymethyl or 
aminomethyl group, R.sub.2, R.sub.3 and R.sub.4 are amino, hydroxy or 
hydrogen with the proviso that at least one of them is hydrogen and only 
one of R.sub.1, R.sub.2 or R.sub.3 be an amino group, R.sub.5 is hydroxy, 
C.sub.1 -C.sub.3 -alkoxy or benzlyoxy; when R.sub.5 is hydroxy, the 
formulae a and b represent the same structure wherein the cyclic 
hemiacetalic form and the opened aldehydic form are in equilibrium, 
whereas when R.sub.5 is alkoxy or benzlyoxy, it may be either an .alpha. 
or a .beta.-oloside; 
Ra is hydrogen, C.sub.1 -C.sub.5 -alkyl, --(CH.sub.2 CH.sub.2 O).sub.p H, 
(CH.sub.2 CH.sub.2 O).sub.p OCH.sub.3, (CH.sub.2 CH.sub.2 O).sub.p 
CH.sub.2 H.sub.5 ; 
n is an integer from 2 to 3 and p is an integer from 1 to 6; 
and salts of said complexes with non-toxic and pharmaceutically acceptable 
acids. 
Pharmaceutically useful salts of compound I are those with inorganic acids, 
as hydrohalogenidric acids, e.g. hydrochloric, hydrobromic and hydroiodic 
acids; or with organic acids such as acetic, succinic, tartaric and 
fumaric acids. 
Examples of preferred aminosugars as ligands of the compounds of the 
invention are: 2-amino-desoxy-D-glucose(D-glucosamine), 
.alpha.-D-xylo-pyranosylamine, .alpha.-D-lyxo-piranoxylamine, 
.alpha.-D-manno-pyranosylamine, .alpha.-D-ribo-pyranosylamine, 
1-daunosamine, 1-acosamine, 1-ristosamine, 2-amino-2-desoxy-D-galactose 
(galactosamine, D-chondrosamine), .alpha.-D-arabino-pyranosylamine, 
6-amino-6-deoxy-.alpha.-D-glucopyranose, 2-amino-2,6-dideoxy-L-glucose, 
3-amino-3-deoxy-D-glucose, 2-amino-2,6-dideoxy-D-glucose, 
3-amino-3,6-dideo-D-mannose (mycosamine). 
The compounds of the invention are obtained by mixing the solution of an 
anthracenedione ligand II: 
##STR5## 
either as a free base or as a salt, wherein Ra, Rc, Rd and n have the 
above meanings, in a suitable solvent, with at least 2 molar equivalents 
of a platinum complex III 
EQU M.sup.(+) [PtX".sub.3 H.sub.2 N-Rb].sup.(-) (III) 
wherein M.sup.(+) is a cation, e.g. a cation of an alkaline metal or a 
quaternary phosphonium salt, X" is an univalent anion, preferably halogen 
(chlorine, bromine, iodine) and Rb is an alkyl residue of an amine or of 
an amino sugar as above described, dissolved in a suitable solvent, so 
giving rise to the formation of the compounds Ia: 
##STR6## 
wherein Solv, X", Ra, Rb, n, A have the above meanings. 
Compounds Ia may be optionally reacted with water in suitable medium to 
obtain compounds Ib: 
##STR7## 
wherein Solv, X", Ra, Rb, n, A are as above defined and X"' is hydroxy; 
finally, if desired, said compounds Ia, Ib are reacted with 
dimethylsulphoxide to give other compounds of the invention. 
Said compounds may also be treated with alkali, earth-alkali or silver 
salts of dicarboxylic acids such as malonic or succinic acids, optionally 
substituted, to give the compounds I wherein X and X', taken together, 
form the anion of dicarboxylic acid such as malonate, hydroxymalonate, 
1,2-cyclohexanedicarboxylate, etc. 
When the ligand is a salt, the compounds of the invention are also salts 
that, if desired, can be converted into neutral complexes by treatment 
with equimolar quantities of a base. 
If desired, neutral complexes of formula I can be converted into the 
corresponding slats by reaction with stoichiometric quantities of 
non-toxic pharmaceutically acceptable acids. 
Preferred solvents for the preparation of the reagent are water, mono- or 
polyhydroxylic C.sub.1 -C.sub.4 -alcohols particularly ethanol, ethylene 
glycols, polyglycols, acetonitrile, dimethylformamide, formamide, 
dimethylacetamide and mixtures thereof. Solutions of ligands and reagents 
are preferably mixed at temperatures ranging from -10.degree. C. to 
40.degree.-50.degree. C., preferably from -5.degree. C. to room 
temperature. 
Reaction times range from a few minutes to several days, but usually do not 
exceed 8 hours and periods lasting from a few minutes to 2-3 hours are 
often sufficient to complete the reaction. 
Aquo-complexes of formula Ib are obtained from complexes Ia, and their 
formation occurs by slow exchange of labile Cl with ligand OH, following 
to a prolonged treatment with water or aqueous solutions of compounds of 
formula Ia. 
Aquo-complexes are then obtained from aqueous solutions of compounds IB, by 
precipitation, preferably with low molecular weight alcohols. 
Whereas only some of the complexes Ia and Ib are provided with high 
solubility in water, all the complexes of Ia and Ib are characterized by a 
remarkable solubility in dimethylsulphoxide (DMSO). Immediate dilution 
with water of these solutions yields stable water solutions of the 
compounds of the invention. If the solutions of complexes Ia and Ib in 
DMSO are kept for a prolonged time, from 10 minutes to some days but 
preferably for same hours at room temperature, the introduction in the 
complex of a DMSO molecule coordinated to the platinum atom occurs. 
Complexes of formula I wherein at least one of X is CH.sub.3 SOCH.sub.3 
.multidot.Cl or CH.sub.3 SOCH.sub.3 .multidot.OH are isolated for instance 
by evaporation of DMSO or by precipitation with a suitable solvent and 
optional subsequent crystallization. 
Evaporation of DMSO is generally carried out under vacuum and all the above 
reactions are preferably carried out under inert gas atmosphere. The 
compounds of the invention wherein the labile ligand contains one and/or 
two DMSO moles per platinum atom are completely hydrosoluble and do not 
require dimethylsulphoxide and/or dimethylformamide as co-solvents for 
their solubilization in water. 
Preferred compounds of the invention are those wherein the anthracenedione 
ligand is salified at least by an equivalent of a monovalent acid, but 
more preferably by two equivalents of said acids. 
Particularly preferred compounds have the following formulae: 
##STR8## 
The amino anthracenediones of formula II used in the present invention are 
mostly known compounds and they are prepared using methods widely known in 
the literature, see for instance: R. K. Y. Zee-cheng et al., J. Med. 
Chem., 21, 291, 1978 and ibidem; 22, 501, 1979; K. C. Murdock et al. J. 
Med. Chem., 22, 1024, 1979; R. K. Hohnson et al., Cancer Chemotherap. Rep. 
63, 425 (1970); R. K. J. Zee-cheng et al., Drugs of the future 8, 229, 
1983 and cited references, U.S. Pat. No. 4,934,007. 
The anthracenedione compounds of formula II wherein Ra is (CH.sub.2 
CH.sub.2 O).sub.p H, (CH.sub.2 CH.sub.2 O).sub.p CH.sub.3 or (CH.sub.2 
CH.sub.2 O).sub.p C.sub.2 H.sub.5 (p is an integer form 2 to 6) are new 
and are prepared in the same way as known compounds having p.sub.2 =1, 
substituting the reagent H.sub.2 N--CH.sub.2 CH.sub.2 NH--(CH.sub.2 
CH.sub.2 O).sub.p2 Z wherein Z is H, CH.sub.3, C.sub.2 H.sub.5 with the 
corresponding reagent H.sub.2 N.multidot.CH.sub.2 CH.sub.2 -- 
NH--(CH.sub.2 CH.sub.2 O).sub.p1 Z, p.sub.1, p.sub.2 and Z being as above 
described. 
The platinum complexes of general formula III 
EQU M.sup.(+) [PtX".sub.3 H.sub.2 N-Rb].sup.(-) (III) 
are prepared according to methods usual for these kinds of 
mono-amino-platinum-II complexes. Detailed teachings are already described 
for the preparation of compounds III wherein M.sup.+ is K.sup.+ and 
Rb-NH.sub.2 is tertbutylamine (tba). For instance, the preparation of 
complex K[PtCl.sub.3 tba] is described by E. Bersanetti et al. in Inorg. 
Chim. Acta, 93, 167 (1984). 
More recently, other methods for the preparation of platinum aminotrichloro 
complexes have been described by F. D. Rochon et al, Inorg. Chem., 26, 
3065, 1987 and by S. Jaworski et al., Inorg. Chim. Acta, 153, 31, 1988. 
A detailed method for the preparation of aminotrichloroplatinum complexes, 
wherein the amino ligand is an aminosugar, is described hereinafter. 
Neutral dichloroplatinum complexes of formula [Ptcl.sub.2 (am)2] wherein 
(am) is an amino-sugar were disclosed by J. J. Hlavka et al., in U.S. Pat. 
No. 4,587,331 as compounds useful to induce regression and/or as 
palliatives in the treatment of tumors in mammals. 
Examples of transformations of aminotrichloro complexes to mixed 
diaminodichloro complexes of formula [PtCl.sub.2 (am)(am')] were reported 
by S. Jaworski (above cited) and by F. D. Ronchon et al., Can. J. Chem. 
64, 1894, 1986. Said references do not teach however the preparation of 
compounds wherein a ligand at least is an amino-sugar. 
The preparation of monoamino compounds wherein cation M.sup.+ is the 
triphenylphosphonium is described for instance by C. M. Abrams et al. 
Inorg. Chim. Acta 131, 3 (1987). A typical example of a compound prepared 
following this method is [(C.sub.6 H.sub.5).sub.4 P][PtCl.sub.3 
-(NH.sub.3)]. 
Useful instructions for the preparation of said phosphonium complexes are 
also described by F. D. Rochon et al. Inorg. Chem. 26, 3065(1987), 
allowing an easier isolation technique. The efficiency of platinum II and 
IV compounds as anti-tumor agents, and particularly that of amino-platinum 
II complexes have been described by Rosenberg (B. Rosenberg et al. Nature 
205, 965, 1965). 
The antineoplastic activity of said complexes has been proved in several 
tumor bearing animals. These compounds inhibit tumors such as ascitic 
leukaemia, Walker 256 carcinosarcoma, mammary tumors induced by 
dimethylbenzanthracene and ascitic melanoma B-16. Among these compounds 
cis-diaminodichloroplatinum II (CDDP) is the most studied and it has now 
entered in the clinical practice. Other platinum II complexes have also 
been successfully experimented in animals, see for example "Platinum, gold 
and other metal chemotherapeutic agents; chemistry and biochemistry"; S. 
J. Lippard Ed., A.C.S. Symp. Series, 209 Washington D.C. (1983). 
Cis platinum compounds currently used correspond to complexes of general 
formula: 
##STR9## 
wherein A is a carrier ligand, usually an aminic nitrogen residue. Said 
ligand can be monodentate (NH.sub.3, R-NH.sub.2, R-NH-R) or bidentate, 
e.g. 1,2-diaminoethane, while X is a leaving group which can also be 
monodentate (e.g. Cl--) or bidentate, 
##STR10## 
As shown in "Platinum complexes: a new class of antineoplastic agents" from 
F. R. M. Leh and W. Wolf, J. Pharmac. Sc. 65, 315, 1976, the function of 
the carrier ligand is of influencing the activity of the complex 
conferring to it particular steric and electronic characteristics and 
determining the basicity of the molecule, while on the leaving groups 
depends the use of hydrolysis of the complex, and then its survival in 
biological liquids. In other words, the leaving group should influence the 
possibility of the compound to reach the site of action, where selective 
release occurs. 
On the other hand, it is accepted that the carrier ligand is likely to be 
permanently bound to the platinum atom in the site of action (see 
Caradonna et al., "Platinum coordination complexes" page 914, M. P. Hacher 
et al., M. Nijhoff Publ., Boston, 1984). 
In the case of CDDP, its activity is displayed in the treatment of 
genito-urinary tumors, head and neck tumor and osteosarcoma. Clinical 
observation confirms the efficacy of the compound in a number of human 
tumors, and often in combination with other chemotherapeutic agents. Due 
to serious gastro-intestinal, renal side effects, hematologic and 
neurologic complications (ototoxicity) there is an increase in chemical 
work, with the aim of preparing new derivatives provided with better 
therapeutical index and a wider spectrum of action. 
With this purpose, cis platinum complexes have been described wherein the 
leaving group is formed by chelating systems for platinum atom, like those 
present in a polycyclic quinone, having an hydroxy group in peri position 
in a ring fused with the quinone ring 
##STR11## 
or by other hydroxyketonic chelating systems, such as for instance those 
disclosed in U.S. Pat. No. 4,283,342. 
Other examples of this kind of compounds are described in U.S. Pat. Nos. 
3,876,675 and 4,588,836. 
More particularly U.S. Pat. No. 4,296,030 describes the preparation of 
numerous 1,4-bis(amino-substituted)-5,8-dihydroxyanthracenediones of 
general formula V: 
##STR12## 
wherein R.sub.1 and R.sub.2 are hydrogen, C.sub.1 -C.sub.4 -alkyl or 
C.sub.2 -C.sub.4 -hydroxyalkyl groups and Q is a divalent alkyl residue 
(e.g. --(CH.sub.2).sub.n); and n is an integer from 2 to 4, and also the 
preparation of their chelates with metals are iron, platinum, copper, 
zinc, chromium, zirconium, cobalt, palladium. 
The preparation of these chelates is carried out by heating in a suitable 
solvent such as water, alcohols, dioxane or mixtures thereof to the reflux 
temperature for a period from 1 to 6 hours, a 
diamino-dihydroxyanthracenedione of formula V with an appropriate metal 
salt, which in case of platinum salts is platinum chloride or potassium 
tetrachloroplatinate to give compounds of formula VI: 
##STR13## 
wherein MX can be bis(platinum chloride chelate) or a tris(platinum 
chloride chelate). 
In EP A 109732 the preparation of particular cis-platinum complexes of 
formula VII is disclosed: 
##STR14## 
wherein Rc, Rd, p, XX', Solv have the above described meanings and R.sub.1 
', R.sub.2 ', R.sub.3 ', R.sub.4 ' that can be the same or different, are 
lower hydrogen alkyl, (CH.sub.2).sub.p --OH or taken together, form a 
nitrogen cyclic substituent such as morpholine, wherein platinum is not 
chelated to the quinone system but forms a cis-complex with the terminal N 
atom of the 1,4 chains. 
Said preparation comprises the reaction of a solution of 
1,4-diamino-dihydroxy anthracenedione with at least 1 molar equivalent of 
K.sub.2 PtCl.sub.4 at room temperature. 
The complexes of formula VII are characterized by surprisingly powerful 
cytotoxic effect, in comparison with other known cis-platinum complexes, 
this effect as shown by a long term survival of tumor bearing animals 
treated with the relatively higher dosages. 
The high activity of compounds VII and said unexpected long term survival 
have been ascribed to their particular vehiculating activity, i.e. 
capacity to act as a "carrier" for anthracenedione ligand independently on 
the relevant antineoplastic activity of the latter; the "in test" activity 
of the molecule was then a consequence of the particular characteristics 
of nitrogen vector as "carrier". 
In this specific case, it has been found out that the anthracenediones 
themselves can conveniently react with monoamino platinum complexes of 
formula III, that if taken alone have an almost irrelevant antineoplastic 
activity, to form new cis-diamino-platinum complexes, having a common 
anthracenedione carrier and that are able to improve long-term survival of 
tumor-affected animals, at very low dosages. 
Comparative studies conducted on compounds of the invention, typical of 
which is compound (DHAQ) (PtCl.sub.2 tba).sub.2 .multidot.2HCl (coded BBR 
1939) of formula: 
##STR15## 
with a compound of EP109732, such as the compound coded BBR 1734, show the 
surprising results reached by the present invention. 
For instance, compounds BBR 1734 and BBR 1939 have been compared in 
leukaemia P.sub.388 in rats CD.sub.2 F.sub.1, with cis-platinum and 
mithoxanthrone (DHAQ.multidot.2HCl) as reference compounds. 10.sup.5 
leukaemic cells were injected at day 0 and the compounds were administered 
intraperitoneally the day after, defined as day 1 of the experiment. 
The data, shown in Table I clearly indicate the particular activity of BBR 
1939 in comparison with mithoxanthrone alone and cis-platinum. 
TABLE I 
______________________________________ 
Dosage MST LTS 
Compounds 
(mg/Kg, i.p.) 
(days) T/C % TOX (60 days) 
______________________________________ 
BBR 1734 -- 11-12 100 0 0 
37 TOXIC -- -- -- 
20 16 155 0/10 0/10 
15 26 252 0/10 3/10 
10 22 213 0/10 0/10 
7.5 26 252 0/10 1/10 
5.0 20 197 0/10 0/10 
BBR 1939 15 TOXIC -- -- -- 
10 36 300 1/10 2/10 
5 39 325 0/10 4/10 
2.5 26 216 0/10 1/10 
1.25 27 225 0/10 1/10 
cis-platinum 
14 11.5 99 2/7 0/7 
10 18.8 162 0/7 0/7 
6 22.5 198 0/7 0/7 
Mitoxan- 25.8 40.5 368 1/7 0/7 
throne 18.4 42.5 386 0/7 1/7 
11.1 36.5 331 0/7 1/7 
3.75 32.5 295 0/7 2/7 
______________________________________ 
Furthermore, it is immediately evident that low dosages such as 1.25 mg/kg 
of BBR 1939 allowed to obtain an higher survival of animals than the 
monoplatinum complex BBR 1734, whereas at four times higher dosages T/C % 
values of 325 were reached. 
The particular importance of the compounds of the invention is evidenced by 
results obtained in some forms of experimental leukaemic neoplasiae 
resistant to cis-platinum, e.g. L1210/CDDP leukaemia. 
Once again, dosages of about 5 mg/kg allowed to obtain T/C% values of 324. 
The data are reported in Table II. 
TABLE II 
______________________________________ 
Effect of BBR 1939 on leukaemia.sup.a) L1210/CDDP on rats CD.sub.2 Fl 
Comparison with CDDP 
Dosage MST LTS 
Compounds 
(mg/Kg, i.p.) 
(days) T/C % TOX (60 days) 
______________________________________ 
Controls 
-- 11.4 100 -- -- 
BBR 1939 
10 37 324 0/10 1/10 
5. 37 324 0/10 4/10 
2.5 18 157 0/10 3/10 
CDDP 12.5 9.3 103 1/10 0/10 
7.5 11.6 101 0/10 0/10 
5. 11.1 97 0/10 0/10 
______________________________________ 
.sup.a) 10.sup.5 cell/rat injected i.p. at day 
Compounds were administered at day "1 
The compounds of the invention are thus considered particularly useful for 
the treatment of neoplasiae that are resistant to treatment with 
cis-platinum complexes, and in particular to cis-diamino-dichloro-platinum 
(cDDP). In vitro comparative studies with cDDP further confirm the 
particular efficacy of the compounds of the invention. 
Table II shows some experimental data obtained "in vitro" with respect to 
other leukaemic forms such as human erythroleukosis K562, as a further 
proof of the wide spectrum of action of the compounds of the invention and 
of their high efficacy compared with cis-platinum. 
TABLE III 
______________________________________ 
Effect of BBR 1939 on in vitro growth.sup.b) of murine leukaemia.sup.a) 
L1210/CDDP and human erythroleukosis 
K562 b - Comparison with CDDP: 
Dose IC %.sup.c) 
After hours 
Cell line Drug ug/ml 24 48 72 
______________________________________ 
L1210/CDDP 
BBR 1939 0.1 65 90 98 
0.05 61 88 97 
0.01 48 78 94 
0.005 48 66 87 
0.001 23 17 53 
CDDP 50 80 99 100 
10 78 92 86 
5 54 87 84 
1 30 18 44 
0.5 20 8 37 
K562 BBR 1939 0.1 50 72 84 
0.5 37 66 78 
0.01 28 41 44 
0.005 10 23 26 
CDDP 100 56 85 91 
50 52 85 91 
10 35 76 87 
5 28 71 82 
1 22 52 54 
______________________________________ 
.sup.a) 10.sup.5 cells were plated in triplicate at time 
.sup.b) means used: RPMI 1640 + 10 Y FCS (inactivated in warm) + 
2mercaptoethanol 10.sup.-3 M 
.sup.c) IC %: inhibition percentage of cellular growth (treated animals 
against controls) 
The results of said experiments further confirm the activity of the 
compounds of this invention; moreover their efficacy seems to have no 
correlation with their toxicity. 
The compounds of the invention wherein Rb is the residue of an aminosugar 
exhibit an higher hydrophylic character which results in enhanced 
pharmacological properties. 
The compounds of the invention are deemed effective in man when 
administered at dosages ranging from about 0.05 mg to about 200 mg per 
m.sup.2 of body surface per day. The dosage of active principle for a 
patient weighing 70 kg ranges from 0.4 mg to about 420 mg, administered in 
a 24 hour period. 
This schedule can be established individually, in order to allow an optimal 
therapeutical result. 
So, for instance, the dosage can be administered daily in subdivided parts, 
while the exact dosage depends obviously on age, weight and overall 
patient's conditions and the above dosages can be reduced as a consequence 
of the particular therapeutical situation. 
The active principle can also be administered by intravenous, 
intramuscular, subcutaneous or intraperitoneal route. 
A therapeutical dosage can also be administered at alternate days and/or at 
2 consecutive days followed by 2, 3 or more days without treatment. 
It is also possible to administer the compounds orally, at dosages at least 
3-10 times higher than that by parenteral route. 
The compounds of the invention can also be administered in experimental 
protocols of polychemotherapy in combination with other antineoplastic 
drugs, such as antracyclines, cyclophosphamide, bleomycine, vinblastine. 
They can also be used in combination with GSH in accordance with BE 904,717 
and Italian Patent Application No. 21925 A/86 of 7.10.1986. 
Pharmaceutical and veterinary compositions containing compounds of the 
invention must be prepared with the normal care used for the preparation 
of pharmaceutical compositions containing cis-platinum derivatives and 
include diluents and conventional supports. 
For instance, for intravenous administrations infusions, intramuscular and 
subcutaneous injections, isotonic aqueous solutions and respectively 
sterile solutions or suspensions in aqueous or non-aqueous vehicles are 
used, and they are preferably prepared immediately before use starting 
from lyophilized products prepared conventionally and containing the 
active principles of the invention. The invention is further illustrated 
but not limited by the following examples.

EXAMPLE 1 
A solution of 27 g of 2[(3,6,9-trioxa)undecyl)amino]-ethylamine in 50 ml of 
N, N,N', N'-tetramethylethylenediamine is deareated by argon-bubbling for 
20 minutes. 10.2 g of leuco-1,4,5,8-tetrahydroxyanthraquinone are added 
then under stirring. 
The solution is then heated under an inert gas atmosphere to 
50.degree.-52.degree. C. under constant stirring for 4 hours, then it is 
allowed to cool at room temperature. The separated crystalline solid, 
which is dark red, is filtered and washed with cold ethanol to give 17.5 g 
of 
leuco-1,4-bis[2(3,6,9-trioxa)-undecyl-amino-ethyl-amino]-5,6-dihydroxyanth 
raquinone. This compound is refluxed for 20 minutes in 200 ml nitrobenzene 
and the hot solution is filtered. The filtrate is heated to the boiling 
point and, after cooling, the precipitated solid is filtered and washed 
with ethanol to give 10.42 g of 
1,4-bis[2(3,6,9-trioxa)undecylamino-ethylamino]-5,6-dihydroxyanthraquinone 
A solution of compound (1.2 g) in 2-methoxyethanol is added with an excess 
of 8 N HCl in 2-methoxyethanol and, after cooling at 0.degree.-5.degree. 
C., the separated crystalline compound is filtered, to give 
1,4-bis[2(3,6,9-trioxa)-undecylamino-ethylamino]-5,6-dihydroxyanthraquinon 
e 2HCl. 
EXAMPLE 2 
Using in the procedure of Example 1 a leuco-1,4-dihydroxy-anthraquinone, 
1,4-bis[2(3,6,9-trioxa)-undecylamino-ethylamino]anthraquinone is prepared. 
EXAMPLE 3 
Using the following amines in the procedure of examples 1-2: 
2(11-hydroxy-3,6,9-trioxa-undecylamino)ethylamine and 
2(11-methoxy-3,6,9-trioxa-undecylamino)ethylamine, the following compounds 
were prepared: 
1,4-bis[2-(11-hydroxy-3,6,9-trioxa-undecylamino)ethylamino]-5,8dihydroxy 
anthraquinone.multidot.2HCl; 
1,4-bis[2-(11-hydroxy-3,6,9-trioxa-undecylamino)ethylamino]-anthraquinone. 
multidot.2HCl. 
EXAMPLE 4 
A solution of 
1,4-bis[2-(hydroxyethylamino)ethylamino]-5,8dihydroxy-anthraquinone.multid 
ot.2HCl (0.27 mmoles) in 20 ml water is added, with stirring and in the 
dark, to a solution of K[PtCl.sub.3 t-butylamine] 264 mg (0.64 mmoles) in 
20 ml deionized water. Addition is performed in 15 minutes. A crystalline 
precipitate begins to separate. 
Precipitation is completed in two hours. The crystalline precipitate is 
filtered, washed with ethanol, diethyl ether and dried under vacuum to 
give 160 mg of the bis-diamino-platinum complex: 
bis(cis-tert-butylamine-dichloro-platinum)-N,N-1,4-bis[2-(hydroxyethylamin 
o)ethylamino)]-5,8-dihydroxy-anthraquinone .multidot.2HCl.multidot.H.sub.2 
O, 
found % 29.95, H, 4.44; N, 6.90; Pt, 31.1; Cl, 16.9. 
calc. % 29.7, H, 4.45; N, 6.92; Pt, 32.1; Cl, 17.5. 
C.sub.30 H.sub.54 N.sub.6 O.sub.7 Pt.sub.2 Cl.sub.6 
IR 1609, 1561 cm.sup.-1 hydroxyquinone structure: 325, 307 cm.sup.-1 bond 
stretchings Pt-Cl typical for a cis-PtCl.sub.2 structure. 
EXAMPLE 5 
Using in the procedure of Example 4, 219.4 mg of complex K[Pt-Cl.sub.3 
-t-butylamine] and respectively 184 mg of 
1,4-bis[2-hydroxyethylamino)ethylamino]-anthraquinone, 140 mg of 
bis(cis-tert-butylamine-dichloro-platinum)-N,N-1,4-bis[2-hydroxyethylamino 
)-ethylamino]anthraquinone.multidot.2HCl.multidot.H.sub.2 O.: 
C.sub.30 H.sub.54 N.sub.6 O.sub.5 Pt.sub.2 Cl.sub.6 
found % C, 30.5; H, 4.57; N, 7.02; Pt, 32.2; Cl, 17.5. 
calc. % C, 30.46; H, 4.57; N, 7.11; Pt, 33.0; Cl, 18.0. 
IR 1595 cm.sup.-1 quinone; 325, 305 cm.sup.-1 Pt-Cl are obtained. 
EXAMPLE 6 
By substituting an anthraquinone prepared in accordance with examples 
1,2,3,4,5, the following bis-diaminoplatinum complexes were obtained: 
bis-(cis-tert-butylamine-dichloro-platinum)-N,N-{1,4-bis[2-(3,6,9-trioxa-un 
decylamino)-ethylamino]-5,8dihydroxyanthraquinone}.multidot.2HCl.multidot.H 
.sub.2 O.; 
bis-(cis-tert-butylamine-dichloro-platinum)-N,N-{1,4-bis[2-(3,6,9-trioxa-un 
decylamino)-ethylamino]-anthraquinone} 
bis-(cis-tert-butylamine-dichloro-platinum)-N,N-{1,4-bis[2-(11-hydroxy-3,6, 
9-undecylamino)-ethylamino]-anthraquinone}.multidot.2HCl.multidot.H.sub.2 
O.; 
bis-(cis-tert-butylamine-dichloro-platinum)-N,N-{1,4-bis[2-(11-methoxy-3,6- 
trioxa-undecylamino)-ethylamino]-5,8-dihydroxyanthraquinone}.multidot.2HCl. 
multidot.H.sub.2 O.; 
bis-(cis-tert-butylamine-dichloro-platinum)-N,N-{1,4-bis[2-(11-hydroxy-3,6, 
9-trioxa-undecylamino)-ethylamino]-5,8-dihydoxyanthraquinone}.multidot.2HCl 
.multidot.H.sub.2 O. 
EXAMPLE 7 
A bis-(aminediiopdoplatinum) [PtI.sub.2 NH.sub.2 R.sub.b ].sub.2, e.g. 
[PtI.sub.2 (H.sub.2 N--CH.sub.2 CH.sub.2 OH)].sub.2 (0.99 g) is suspended 
in a solution of 1.01 g of silver nitrate in 15 ml of deionized water and 
kept away from light. 
The mixture is stirred in the dark for two days at room temperature. It is 
then filtered on celite, and 0.6 g of potassium chloride are added to the 
clear solution of an aquo-nitrate platinum ethanolamine complex. 
The mixture is then stirred in the dark and at room temperature for 20 
hours and filtered. 
By adding to the solution an excess of tetraphenyl-phosphonium chloride, a 
crystalline precipitate of tetraphenylphosphonium 
[hydroxyethylaminetrichloroplatinum]-[(C.sub.6 H.sub.5).sub.3 P].sup.+ 
[PtCl.sub.3 --(H.sub.2 N--(CH.sub.2).sub.2 --OH)], C.sub.26 H.sub.27 
NCl.sub.3 OPPt, is obtained. 
found % C, 44.55; H, 3.75; N, 1.93; Cl, 15.38. 
calc. % C, 44.47; H, 3.85; N, 2.00; Cl, 15.18. 
EXAMPLE 8 
Using in the procedure of Example 7 a suitable bis-diamine-diiodo-platinum 
complex wherein the amino bond is selected in the group of 
3-hydroxypropylamine, 1,1-dimethyl-2-hydroxyethylamine and 
trihydroxy-methamine, the following platinum complexes were obtained: 
tetraphenylphosphonium[trichloro-3-hydroxymethyl-propylamine-platinate]; 
tetraphenylphosphonium[trichloro-1,1-dimethyl-2-hydroxyethylamine-platinate 
]; 
tetraphenylphosphonium[trichloro-trihydroxymethyl-methaneamine-platinate]. 
EXAMPLE 9 
A solution of 450 mg of 
tetraphenylphosphonium[trichloro-hydroxyethyl-amine-platinate] (0.64 
mmoles) in acetone is added slowly and under stirring to a solution of 
1,4-bis[2-(hydroxyethylamino)ethylamino]-5,8-dihydroxyantrhaquinone.multid 
ot.2HCl (150 mg; 0.27 mmoles) in 20 ml water. It is kept under stirring in 
the dark for 24 hours, then filtered and the solution is diluted with 
acetone for 1/3 of its volume. After 2 hours under stirring, it is 
filtered and the filtrate is then diluted with 6 volumes of acetone. 
It is left to rest for 12 hours at 5.degree.-0.degree. C. A crystalline 
precipitate (80 mg) of 
bis-(dichloro(2-hydroxyethyl-amine-platinum)]-N,N-1,4-bis[2-hydroxyethylam 
ino)-ethylamino]-5,8dihydroxyanthraquinone is obtained. 
Using in the same procedure the tetraphenylphosphonium salts prepared in 
accordance with Example 8, the following bis(diamino-dichloro-platinum 
complexes) were obtained: 
bis-(hydroxypropylamine-dichloro-platinum)-N,N-{1,4-bis[2-hydroxyethylamino 
)-ethylamino]-5,8dihydroxyanthraquinone}; 
bis-(1,1-dimethyl-2-hydroxyethylamine-dichloro-platinum)-N,N-{1,4-bis[2-hyd 
roxyethylamino)-ethylamino]-5,8dihydroxyanthraquinone}; 
bis-(trihydroxymethylmethamine-dichloro-platinum)-N,N-{1,4-bis[2-hydroxyeth 
ylamino)-ethylamino]-5,8dihydroxyanthraquinone}. 
EXAMPLE 10 
D(+)-glucosamine HCl (0.43 g 2 mmoles) and K.sub.2 CO.sub.3 (0.138 g, 1 
mmole) are added to a suspension of K.sub.2 PtCl.sub.4 (0.83 g, 2 mmoles) 
in dimethylformamide (60 ml) previously deareated, in an inert gas 
atmosphere and under stirring. The reaction mixture is heated for 7 hours 
at 60.degree.00 C. under inert atmosphere and then concentrated under 
reduced pressure up to a volume of 5 ml. The inorganic precipitate is 
centrifugated and filtered; the clear solution is diluted with an 
hexane-ethyl acetate mixture (3/1, v/v; 20 ml) to allow the separation of 
an oily mass. 
After decantation of the surnatant, the oily mass is treated with 
3.times.20 ml of the hexane-ethylacetate mixture in order to remove 
dimethylformamide. The residual yellow oil is dried under vacuo and then 
crystallized from ethanol. 
0.89 g of potassium D(+) trichloro-glucosamine-platinate are obtained. 
Calc. for K[PtCl.sub.3 (glucosamine)]1/2 DMF 
(C.sub.7.5 H.sub.16.5 N.sub.1.5 O.sub.5.5 PtCl.sub.3 K) 
C.sub.16.2 H.sub.3.0 N.sub.3.8 
Found % C.sub.16.4 H.sub.3.2 N.sub.3.8 
Pt-Cl: 328, 325, 320 cm.sup.-1 (KBk) 
The compound is a uni-univalent electrolyte in aqueous solution. 
m=98 ohm.sup.-1 cm.sup.2 mole.sup.-1 for C=10.sup.-3 M/liter. 
EXAMPLE 11 
By substituting in the procedure of Example 10, the D(+)-glucosamine with 
an amino sugar selected in the group of 3-amino-3-deoxy-glucose, 
1-daunosamine, 1-acosamine, 1-ristosamine, 
6-amino-6-desoxy-.alpha.-D-glucopyranose, 
.alpha.-D-arabino-pyranosylamine, galactosamine, 
.alpha.-D-manno-pyranosylamine, 2-amino-2,6-dideoxy-D-glucose, mycosamine, 
.alpha.-D-ribopiranosyl-amine, .alpha.-D-xylo-pyranosylamine and of 
.alpha.-D-lixo-pyranosylamine, the following complexes are prepared: 
potassium-trichloro-N-(3-amino-3-deoxy-glucose)-platinate, 
potassium-trichloro-1-daunosamine-platinate, 
potassium-trichloro-1-acosamine-platinate, 
potassium-trichloro-1-ritosamine-platinate, 
potassium-trichloro-N-(6-amine-6-desoxy-.alpha.-D-glycopyranose)-platinate, 
potassium-trichloro-N-(.alpha.-D-arabino-pyranosylamine)-platinate, 
potassium-trichloro-N-(galactosamine)-platinate, 
potassium-trichloro-N-(.alpha.-D-manno-pyranosylamine)-platinate, 
potassium-trichloro-N-(2-amine-2,6-dideoxy-D-glucose)-platinate, or 
potassium-trichloro-N-(6-desoxy--glucosamine)-platinate, 
potassium-trichloro-N-(mycosamine)-platinate, 
potassium-trichloro-N-(.alpha.-D-ribo-pyranosylamine)-platinate, 
potassium-trichloro-N-(.alpha.-D-xilo-pyranosylamine)-platinate, 
potassium-trichloro-N-(.alpha.-lixo-pyranosylamine)-platinate. 
EXAMPLE 12 
A solution of 
1,4-bis-[2-(hydroxyethylamino)ethylamino]-anthracene-9,10-dione.multidot.2 
HCl (0.24 g, 0.5 mmoli) in water (20 ml) is slowly added to a solution of 
potassium trichloro-D(+)-glucosamine-platinate. 1/2 DMF (0.56 g, 1 mmole) 
in 20 ml of water in inert gas atmosphere and under stirring. The mixture, 
after being kept for 18 hours at room temperature in inert gas atmosphere, 
is evaporated to dryness under reduced pressure. The residual mass is then 
extracted with a methanol/chloroform mixture (4/1 vv, 30 ml), filtered and 
diluted with an excess of diethyl ether. 
A crystalline solid precipitate which is filtered and dried under vacuo to 
obtain 0.62 g of 
bis-[cis-dichloro-D(+)-glucosamine-platinum]-N,N-1,4-bis[2(hydroxyethylami 
no)ethylamino]anthracene-9,10dione.multidot.2HCl H.sub.2 O. 
Pt-Cl 320-315 cm.sup.-1 
found % C, 29.8; H, 4.3; N, 5.9; Cl, 15.1. calc. for C.sub.34 H.sub.56 
N.sub.6 O.sub.14 Pt.sub.2 Cl.sub.6 : 
C, 29.7; H, 4.1; N, 16.1; Cl, 15.5. 
EXAMPLE 13 
A solution of 0.256 g of 
1,4-bis[2-(hydroxyethylamino)ethylamino]-5,8dihydroxy-anthracene-9,10-dion 
e in water (20 ml) is added to a solution of potassium 
trichloro-1-daunosamine-platinate (0.49 g) in water (18 ml), in inert gas 
atmosphere and under stirring. The solution is allowed to stand for 24 
hours, then it is evaporated under vacuo. 
The residue is suspended in 10 ml of dimethylformamide and, after 
filtration of KCl, the solution is diluted with ethanol (40 ml). 
A crystalline precipitate is obtained which is filtered to give 0.41 g of 
bis-[(cis-dichloro-(1)daunosamine-platinum]-N,N-1,4-bis[2-(hydroxyethylami 
no)ethylamino]-5,8-dihydroxy-anthracene-9,10-dione, as a non-hydrochloride 
species whose structure is confirmed by the IR spectrum. 
I.R.: .nu.(Pt-Cl) 320 e 310 cm.sup.-1 (KBr). 
EXAMPLE 14 
According to the procedures of Examples 12 and 13, by reacting a potassium 
amino-sugar-trichloro-platinate prepared as in Examples 10 and 11 and a 
suitable anthracenedione, the following complexes are prepared: 
bis-[cis-D(+)-glucosamine-dichloro-platinum]-N,N-1,4-bis[2-(hydroxyethylami 
no)ethylamino]-5,8-dihydroxy-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-1-daunosamine-dichloro-platinum]-N,N-1,4-bis[2-(hydroxyethylamino) 
ethylamino]-5,8-dihydroxy-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(6-amino-6deoxy-.alpha.-glucosamine-dichloro-platinum]-N,N-1,4-bis 
[2-(hydroxyethylamino)ethylamino]-5,8-dihydroxy-anthracene-9,10-dione.multi 
dot.2HCl; 
bis-[cis-(6-amino-6deoxy-.alpha.-glucopyranose)dichloro-platinum]-N,N-1,4-b 
is[2-(hydroxyethylamino)ethylamino]anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(3-amino-3deoxy-glucose)dichloro-platinum]-N,N-1,4-bis[2-(hydroxye 
thylamino)ethylamino]-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(3-amino-3deoxy-glucose)dichloro-platinum]-N,N-1,4-bis[2-(hydroxye 
thylamino)ethylamino]-5,8-dihydroxy-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(.alpha.-D-arabino-pyranosylamine)dichloro-platinum]-N,N-1,4-bis[2 
-(hydroxyethylamino)ethylamino]-5,8-dihydroxy-anthracene-9,10-dione.multido 
t.2HCl; 
bis-[cis-(.alpha.-D-arabino-pyranosylamine)dichloro-platinum]-N,N-1,4-bis[2 
-(hydroxyethylamino)ethylamino]-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(galactosamine)dichloro-platinum]-N,N-1,4-bis[2-(hydroxyethylamino 
)ethylamino]-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(1-acosamine)dichloro-platinum]-N,N-1,4-bis[2-(hydroxyethylamino)e 
thylamino]-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(1-acosamine)dichloro-platinum]-N,N-1,4-bis[2-(hydroxyethylamino)e 
thylamino]-5,8-dihydroxy-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(1-ristosamine)dichloro-platinum]-N,N-1,4-bis[2-(hydroxyethylamino 
)ethylamino]-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(1-ristosamine)dichloro-platinum]-N,N-1,4-bis[2-(hydroxyethylamino 
)ethylamino]-5,8-dihydroxy-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(.alpha.-D-manno-pyranosylamine)dichloro-platinum]-N,N-1,4-bis[2-( 
hydroxyethylamino)ethylamino]-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(.alpha.-D-manno-pyranosylamine)dichloro-platinum]-N,N-1,4-bis[2-( 
hydroxyethylamino)ethylamino]-5,8-dihydroxy-anthracene-9,10-dione.multidot. 
2HCl; 
bis-[cis-(mycosamine)dichloro-platinum]-N,N-1,4-bis[2-(hydroxyethylamino)et 
hylamino]-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(mycosamine)dichloro-platinum]-N,N-1,4-bis[2-(hydroxyethylamino)et 
hylamino]-5,8-dihydroxy-anthracene-9,10-dione.multidot.2HCl, and their 
non-hydrochloride species. 
EXAMPLE 15 
According to each one of the previous examples, the following compounds 
were prepared: 
bis-[cis-(6-deoxy-glucosamine)dichloro-platinum]-N,N-1,4-bis[2-amino-ethyla 
mino]-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(6-deoxy-glucosamine)-dichloro-platinum]-N,N-1,4-bis[2-(hydroxyeth 
ylamino)ethylamino]-5,8-dihydroxy-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(.alpha.-D-lixo-pyranosylamine)-dichloro-platinum]-N,N-1,4-bis[2-e 
thylamino)ethylamino]-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(.alpha.-D-xylo-pyranosylamine)dichloro-platinum]-N,N-1,4-bis[2-(h 
ydroxyethylamino)ethylamino]-5,8-dihydroxy-anthracene-9,10-dione.multidot.2 
HCl; 
bis-[cis-(.alpha.-D-ribo-pyranosylamine)-dichloro-platinum]-N,N-1,4-bis[2-i 
sopropylaminoethylamino]-anthracene-9,10-dione.multidot.2HCl; 
bis-[cis-(.alpha.-D-ribo-pyranosylamine)-dichloro-platinum]-N,N-1,4-bis[2-( 
hydroxyethylamino)ethylamino]-5,8-dihydroxy-anthracene-9,10-dione.multidot. 
2HCl, and their non-hydrochloride species. 
EXAMPLE 16 
0.044 g of disodium malonate (0.30 ml) dissolved in the minimum amount of 
water, are added to a solution of 0.20 g of 
bis-[cis-glucosamine-dichloroplatinum]-N,N-1,4-bis[2-(hydroxyethylamino)et 
hylamino]-anthracene-9,10-dione (0.15 mmol) in 40 ml of DMF. The mixture is 
heated to 40.degree. C. for 4 hours in inert atmosphere, concentrated 
under vacuo and filtered. After addition of ether, 0.17 g of 
bis-[glucosaminemalonate-platinum]-N,N-1,4-bis[2-(hydroxyethylamino)ethyla 
mino]-anthracene-9,10-dione are obtained. 
Analysis: C, 34.9; H, 2.2; N, 6.4; Pt, 28.1. 
Calc. for C.sub.40 H.sub.58 N.sub.6 O.sub.22 Pt.sub.2 : C, 35.2; H, 2.1; N, 
6.2; Pt 28.6. 
EXAMPLE 17 
According to the procedure of the previous example, by treating 
bis-[cis-tert-butylamine-dichloro-platinum]-N,N-1,4-bis[2-(hydroxyethylami 
no)ethylamino]-5,8-dihydroxy-anthraquinone, with sodium bicarbonate and 
then, after filtration and re-dissolution in DMF, with the disodium salt 
of succinic acid, 
bis-[tertbutylaminosuccinate-platinum]-N,N-bis[2-(hydroxyethylamino)ethyla 
mino]-5,8-dihydroxy-anthraquinone is obtained.