Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-05
2002-02-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S184000, C514S186000, C514S187000, C514S188000, C514S492000, C544S225000, C546S002000, C546S010000, C556S137000, C548S101000, C548S108000
Reexamination Certificate
active
06350740
ABSTRACT:
DESCRIPTION
BACKGROUND OF THE INVENTION
FIELF OF THE INVENTION
The invention generally relates to a method for water-solubilization of cytotoxic trans-platinum compounds and to a method of killing tumor cells. In particular, the invention provides cytotoxic platinum compounds of the general formula SP-4-2-[PtX(L)(L′)(B)]+for the treatment of tumors.
BACKGROUND OF THE INVENTION
The use of cisplatin, cis-[PtCl
2
(NH
3
)
2
], and carboplatin, [Pt(CBDCA)(NH
3
)
2
] (CBDCA=1,1-cyclobutanedicarboxylate), in the treatment of certain cancers is well-established. Nevertheless, there is a continued interest in the design of structurally novel platinum compounds that show antitumor activity complementary to that of the clinical drugs. The fact that transplatin, trans-[PtCl
2
(NH
3
)
2
],
was found to be therapeutically inactive, has been considered a paradigm for the structure-activity relationships (SAR) of platinum(II) antitumor compounds; trans-Pt compounds have been dismissed as ineffective in vivo agents.
However, the presence of a planar ligand such as pyridine or quinoline, e.g., in trans-[PtCl
2
(NH
3
) (quinoline)],
dramatically enhances the in vitro cytotoxicity of the trans geometry [Farrell, N., Kelland, L. R., Roberts, J. D. and Van Beusichem, M.: Activation of the Trans Geometry in Platinum Antitumor Complexes. A Survey of the Cytotoxicity of Trans Complexes Containing Planar Ligands in Murine L1210 and Human Tumor Panels and Studies on Their Mechanism of Action. Cancer Res. 52:5065 (1992); Van Beusichem, M. and Farrell, N.: Activation of the Trans Geometry in Platinum Antitumor Complexes. Synthesis, Characterisation and Biological Activity of Complexes with Planar Ligands Pyridine, N-Methylimidazole, Thiazole and Quinoline. The Crystal and Molecular Structure of trans-dichlorobis(thiazole)platinum(II).
Inorg. Chem
. 31:634 (1992)] The cytotoxic activity of such “nonclassical” trans-platinum complexes has been discussed in terms of both an overall altered affinity toward biologically relevant (N and S) nucleophiles and unique DNA binding modes. Importantly, the newer trans-platinum compounds containing planar ligands display a different profile of cytotoxicity in comparison to cisplatin and retain their cytotoxic activity in cisplatin-resistant tumor cells. Thus, there is reason to believe that a trans-platinum compound in the clinic would have activity complementary to cisplatin, resulting in significant benefits to patients. However, such “nonclassical” trans-platinum species have been found to have limited bioavailability and, consequently, low in vivo activity. One possible explanation is lack of water solubility.
It would be highly desirable to have available additional platinum species for the treatment of cancer. It would be especially desirable if such compounds displayed high levels of cytotoxicity and were also water-soluble, thereby enhancing their bioavailability and potential in vivo usefulness for the treatment of tumors.
SUMMARY OF THE INVENTION
It is an object of this invention to provide a method for enhancing water-solubility and cytotoxicity of the trans-platinum geometry through production of cationic compounds.
It is a further object of this invention to provide a method for killing tumor cells and treating tumors in patients, comprising the step of administering to a patient in need thereof an effective amount of a platinum coordination compound of the general formula SP-4-2-[PtX(L)(L′)(B)]
+
where X is an anionic ligand; L and L′ represent ammines (NH
3
) or substituted or unsubstituted heterocyclic amines where the substituents are electrophilic or nucleophilic, and L and L′ may be the same or different, and B is a sulfoxide, usually dimethylsulfoxide R
2
R
3
SO (where R
2
=methyl and R
3
=methyl; however it should be understood that other alkyl substituted sulfoxides may be used in this invention and that R
2
and R
3
may be the same or different) or a heterocyclic nucleobase with a nitrogen in a ring which is connected to Pt.
In preferred embodiments of the present invention, the platinum coordination compound is trans-[PtCl(Me
2
SO)(pyridine)
2
]
+
, or trans-[PtCl(9-ethylguanine)(NH
3
)
2
]
+
, or SP-4-2-[PtCl(9-ethylguanine)(NH
3
)(thiazole)]
+
, or SP-4-2-[PtCl(9-ethylguanine) (NH
3
)(benzothiazole)]
+
, or SP-4-2-[PtCl 9-ethylguanine)(NH
3
)(quinoline)]
+
, or SP-4-2-[PtCl(9-ethylguanine)(NH
3
)(isoquinoline)]
+
, or trans-[PtCl(9-ethylguanine) (4-picoline)
2
]
+
, or trans- [PtCl(1-methylcytosine)(NH
3
)
2
]
+
, or SP-4-2-[PtCl (1-methylcytosine)(NH
3
)(thiazole)],
+
or SP-4-2-[PtCl(1-methylcytosine)(NH
3
)(quinoline)]
+
, or SP-4-2-[PtCl(1-methylcytosine)(NH
3
)(isoquinoline)]
+
. Administration may be oral or parenteral.
It is a further object of the instant invention to provide new compositions of matter in the form of platinum coordination compounds: trans-[PtCl(Me
2
SO)(pyridine)
2
]
+
, SP-4-2-[PtCl(9-ethylguanine)(NH
3
)(thiazole)]
+
, SP-4-2-[PtCl(9-ethylguanine)(NH
3
) (benzothiazole)]
+
, SP-4-2-[PtCl(9-ethylguanine)(NH
3
)(isoquinoline)]
+
, trans-[PtCl (9-ethylguanine)(4-picoline)
2
]
+
, trans-[PtCl(1-methylcytosine)(NH
3
)
2
]
+
, SP-4-2-[PtCl(1-methylcytosine)(NH
3
)(thiazole)],
+
SP-4-2-[PtCl (1-methylcytosine) (quinoline)]
+
, and SP-4-2-[PtCl(1-methylcytosine)(NH
3
)(isoquinoline)]
+
.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION
Platinum compounds of the general formula [PtXA
m
B
3−m
], which show excellent solubility, have been previously described as anti-viral agents (U.S. Pat. No. 6,113,934, the complete contents of which is herein incorporated by reference). Surprisingly, some of these compounds also display cytotoxic properties. Therefore, the present invention provides novel forms of such compounds, a method for water-solubilization of cytotoxic trans-platinum compounds, a method for the use of such compounds as cytotoxic agents, and a method of use of such compounds to treat tumors. These compounds are prepared as salts, the cationic component of which is described by the formula SP-4-2[PtX(L)(L′)(B)]
+
.
It is an object of the present invention to provide a method of killing tumor cells and treating tumors by the administration of platinum complexes of the general formula:
SP-4-2[PtX(L)(L′)(B)]
+
In this formula:
a) X represents an anionic ligand such as halogens (e.g., Cl, Br, or I), alkoxides (e.g., OR where R═CH
3
, C
2
H
5
, or other lower alkyls), sulfhydryls (SR where R═CH
3
, C
2
H
5
, or other lower alkyls, where C
1-12
is preferred), and carboxylates (RCOO
−
where R═CH
3
, C
2
H
5
, etc.).Chloride is the preferred anionic ligand;
b) L and L′ represent ammines (NH
3
linked directly to the platinum metal), or substituted or unsubstituted heterocyclic amines, where the substituents are electrophilic or nucleophilic (e.g. C
1-12
alkyl, —NO
2
, —X (Cl, Br, I), -NR
2
where R is C
1-12
alkyl, -COOR where R is C
1-12
alkyl). Preferred heterocycles include but are not limited to thiazole, benzothiazole, imidazole, quinoline, isoquinoline, and picoline. Other useful heterocycles may include oxazole, indole, and acridine. L and L′ may be the same of different. Further, L and L′ are located “trans” to one another in the compounds. Note that, because four different substituents are present, “cis-trans” designations technically do not apply. The nomenclature “SP-4-2” follows the rules from Nomenclature of Inorganic Chemistry, Recommendations 1990, Blackwell Publicaitons, 1990. Edited by G. J. Leigh. [ISBN 0-632-02319-8; 0-6323-02494-1 ]. This nomenclature indic
Raymond Richard L.
Virginia Commonwealth University
Whitham Curtis & Christofferson, PC
LandOfFree
Transplatinum complexes as cytotoxic and anticancer agents does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Transplatinum complexes as cytotoxic and anticancer agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Transplatinum complexes as cytotoxic and anticancer agents will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2942620