Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Reexamination Certificate
1998-12-30
2001-04-24
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
C546S006000
Reexamination Certificate
active
06221905
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new salts of anionic complexes of Ru(III) with ammonium cations which are particularly useful as antimetastatic and antineoplastic agents.
STATE-OF-THE-ART
The discovery of the antineoplastic properties of cisplatin (cis-diammino-dichloro-platinum (II)), so far widely used both in antitumor mono- and polychemotherapy, has fostered the interest in the study of the antitumor activity of the metallo-organic complexes. As for many antitumor agents, the specificity of action of the cisplatin, is directed towards neoplasms which affect specific compartments (testis, ovary, bladder, head-neck), while other kinds of tumors, such as those localised in the lungs and in the breast and the colon-rectal tumor, are almost insensitive to treatment with this drug (C. F. J. Barnard et al., Chemistry in Britain, 1001-1004, 1986).
Thus, research in the field of the coordination complexes is aimed at the development of new drugs containing Pt and/or other transition elements which can enable both the enlargement of the spectrum of use and the achievement of toxicity levels lower than those of the antitumor agents which are known in the state-of-the-art.
The potentiality of the use of ruthenium as antitumor agent as an alternative to platinum was studied for complexes of Ru (II) like, for example, cis-Ru(III)-tetrakis-dimethylsulfoxide (T. Giraldi et al.,
Cancer Res
., 37, 2662, 1977) and more recently for neutral complexes of Ru (III), such as fac-[RuCl
3
(NH
3
)
3
] (M. J. Clarke, Metal Ions in Biological Systems, 11(5), 231-281, 1980, Helmut Sigel Ed.). Moreover, several anionic complexes of Ru(III) with 5-membered heterocycles have been prepared, in particular imidazolium-bis-imidazole-tetrachloro-ruthenate (III) (B. K. Keppler et al.,
J. Cancer Res. Clin. Oncol
., 111: 166-168, 1986).
More recently, some Ru(III) complexes with DMSO have been developed; in particular, the WO 90/13553 international patent application describes some Ru(III) complexes having the formula (i):
[Ru(R
x
R
y
SO)(Cl
3
)AB] (i)
where R
x
R
y
SO is a sulfoxide, preferably dimethylsulphoxide, A is a sulphoxide or a chloride and B is a nitrogen ligand, selected from the group consisting of ammonia, primary, secondary and tertiary amines, and heterocycles containing nitrogen atoms.
These complexes, which can be used as antineoplastic agents, are neutral when A is a sulfoxide, while they possess a negative charge when A is a chloride; in this latter case, the anionic complexes are isolated in the form of the corresponding salts with alkaline and alkaline earth cations and preferably sodium.
Despite their antimetastatic activity, the above mentioned complexes exhibit some serious inconveniences which make the administration and formulation in adequate therapeutical compositions extremely difficult. As a matter of fact, these anionic complexes when isolated in the form of sodium salts, always contained two solvent molecules of crystallisation and cannot be isolated in a pure form, that is without these crystallisation molecules.
In particular, the [trans-RuCl
4
(DMSO)Im]Na 2DMSO, corresponding to formula (i) where R
x
=R
y
=methyl, A=Cl, B=imidazole and where the negative charge has been neutralized by Na+, is capable of exerting good antineoplastic and antimetastatic activities on tumor models in mice. Moreover, this salt has been characterised by good water solubility which allows for an easier administration.
However, this compound can be isolated only with two DMSO salvation molecules, as evidenced in the examples reported in the above mentioned international patent application (in particular, in the Examples 3, 4, 8 and 10) which reduce the compound stability.
Moreover, a qualitative variability of the crystallisation molecules, which can be DMSO, acetone and water, and more commonly two dimethylsulfoxide molecules (DMSO) (E. Alessio et al.
Inorganica Chimica Acta
, 203 (1993): 205-217) can be observed.
The fact that the crystallisation molecules vary in a way which is hardly controlled from one preparation to another causes problems of uncertainty in structural analysis, in the molecular weight determination and in the elemental analysis. Hence, problems related to the of the purity of the compound and its subsequent formulation may occur. As a matter of fact, the scarce structural reproducibility of these compounds implies that not always the same amount of ruthenium corresponds to the administered dose. Thus non-constant dosages and therapeutical activities that cannot easily be foreseen reduce the pharmacological interest of these compounds.
A further disadvantage of the above mentioned compound is due to pharmacological negative effects caused by DMSO, introduced in the organism in equimolar or double quantities with respect to the ruthenium complex and to its differentiating properties, as reported by Klaas Kramer et al. (Gen. Pharmac., vol. 26, n°6, pp. 1403-1497, 1995).
Finally, since the above mentioned salts contain salvation molecules, they rapidly degrade when exposed to open air at room temperature up to providing some brown semisolid substance.
SUMMARY
The Applicant has now surprisingly found new salts of Ru(III) anionic complexes with ammonium cations which exhibit a remarkable antimetastatic and antineoplastic activity. These salts correspond to formula (I):
where R
1
, R
2
and R
3
, equal or different from each other, are selected from the group consisting of H, C
1
-C
6
alkyl, linear or branched, saturated or unsaturated, C
3
-C
7
cycloalkyl, phenyl and aryl;
or NR
1
R
2
R
3
is a 5-7 membered nitrogen containing heterocycle, saturated or unsaturated, optionally containing one or more O, S and /or N atoms, said nitrogen atom being optionally substituted with a C
1
-C
4
alkyl, aryl or benzyl residue; said nitrogen containing heterocycle being optionally condensed with a benzo group and/or substituted with C
1
-C
4
alkyl, C
1
-C
4
alkoxyl, C
1
-C
4
alkylthio, aryl or benzyl groups;
where R
4
and R
5
, equal or different from each other, are selected from the group consisting of H, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, phenyl and aryl or R
4
and R
5
form, together with the S atom, a 4-7 membered heterocycle.
A further object of the present invention is a new process for the preparation of the above salts (I) which comprises the synthesis of [trans-RuCl
4
(R
4
R
5
SO)
2
][(R
4
R
5
SO)
2
H] (II), where R
4
and R
5
have the above meanings, which is obtained by treatment of RuCl
3
with R
4
-SO-R
5
in the presence of HCl, and the following reaction of the complex (II) with a nitrogen containing compound of formula NR
1
R
2
R
3
, in the presence of an organic solvent.
Moreover, the present invention relates to the pharmaceutical compositions containing therapeutically effective amount of at least one of the above salts of formula (I), in combination with the proper excipients and/or diluents and their use as antineoplastic and/or antimetastatic agents.
REFERENCES:
Alessio et al., Inorg. Chim Acta., 203 pp. 205-217, 1993.*
Sava et al. Chem. Biol. Interactions, 1995.*
Geremia et al., Inoorg. Chim Acta 253 pp. 87-90, 1996.*
Art Submitted in PCT is Reviewed WO98/00431.*
Canadian Journal of Chemistry, vol. 67, No. 3, Mar. 1989, Toronto, Press, (Canada), P.K.L. Chan et al.
Chemical Abstracts, vol. 110, 1989, (Columbus, Ohio, US), U.C. Sarma et al.
Chemical Abstracts, vol. 112, 1990, (Columbus, Ohio, US), G. Mestroni.
Journal of the Chemical Society, Dalton Transactions, 1973, I.P. Evans et al.
Chemical Abstracts, vol. 86, 1977, (Columbus, Ohio, US), T. Bora et al.
Alessio Enzo
Mestroni Giovanni
Sava Gianni
Hedman, Gibson & Costigan, P.C.
Shah Mukund J.
Sigea S.r.l.
Sripada Pavanaram K
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