Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Reexamination Certificate
2000-04-18
2003-04-15
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
C556S137000, C556S136000
Reexamination Certificate
active
06548541
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the synthesis of a series of carboplatin analogs which can be reversibly activated and deactivated and the use of these carboplatin analogs to treat cancer.
Cisplatin (cis-diaminedichloroplatinum, cis-Pt(NH
3
)
2
Cl
2
) was the first anticancer platinum drug. It has been used as a chemotherapeutic agent for many years since the discovery of its anti-tumor activity by B. Rosenberg et. al. (
Nature
, 1965, 205: 698
; Nature
, 1972, 222: 385).
Chemical & Engineering News (Oct. 23, 1995) reported that “Cisplatin was first synthesized in the 1800s, but its anticancer activity was not discovered until the 1960s. In 1979, it was approved by the Food and Drug Administration for clinical treatment of testicular and ovarian tumors and cancers of the head and neck. Cisplatin and an analog, carboplatin, are now among the most widely used anticancer drugs.”
The Physician's Desk Reference (PDR) reports that cisplatin (the commercial name is Platinol®) can be used to treat testicular cancer, ovarian cancer, and bladder cancer. Rosenberg et al., U.S. Pat. No. 4,177,263, describes methods of treating cancer using cisplatin and cisplatin analogs. The compound was shown to be effective for treating leukemia and tumors induced in mice.
After so many years, cisplatin is still being widely used because of its efficacy. However, its critical drawback, the toxicity, is still a major concern.
Many people have attempted to change the ligand on platinum to make cisplatin analogs in order to reduce the toxicity or improve the efficacy. Examples are made by K. C. Tsou, et al. (
J Clin. Hemat. Oncol.
, 7: 322 (1977)); R. J. Speeder et al. (
J Clin. Hemat. Oncol
, 7: 210 (1977)); A. Mathew et al. (
Chem. Comm.
, 222 (1979)); D. Rose, et al. (
Cancer Treatment Reviews
, 12: 1 (1985)); and D. Alberts et al. (
Cancer Treatment Reviews
, 12, 83 (1985)).
In recent years, another platinum drug, carboplatin (Paraplatin®), has been widely prescribed. As a cisplatin analog, carboplatin is becoming more popular than cisplatin because it has a better therapeutic index. In other words, carboplatin has a better efficacy/toxicity ratio when used in the treatment of cancer. Nevertheless, carboplatin still has significant side effects and it has been used to treat only certain cancers. Therefore, there is a need to further improve carboplatin to make it less toxic or more versatile.
BRIEF SUMMARY OF THE INVENTION
This invention comprises the synthesis of a series of platinum(II) complexes as carboplatin analogs for the treatment of cancer. These platinum(II) complexes can be reversibly activated/deactivated in media with different pH values. These platinum(II) complexes can have a significantly reduced drug resistance. Because the ligands are abundant biologically, the drug resistance can be less than that of cisplatin or carboplatin. In addition, they can be used in treating cancers that are not treated by cisplatin or carboplatin because of the variety of the ligands.
Other objects, features, and advantages of the present invention will become apparent from the following detailed description. It should be understood that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of this invention is to significantly improve the performance of platinum drugs. Thus, a series of platinum(II) complexes are presented herein as carboplatin analogs. The platinum(II) complexes of this invention are similar to carboplatin in that each complex has two active sites individually protected by carboxylate groups. However, because each carboxylate group is part of the respective bidentate ligand, hydrolysis of the carboxylate only separates it from the Pt(II) ion, but not the molecule. Therefore, both carboxylate groups are able to reattach to Pt(II) under a higher pH condition, such as the normal biological condition. This behavior makes the complexes significantly different from carboplatin, in which carboxylate groups, when hydrolyzed, are permanently separated from the Pt(II) ion. As a result, these platinum(II) complexes can be much less toxic than other platinum drugs.
Another aspect of the present invention is to reduce the drug resistance after repeated treatment that is often seen with cisplatin or carboplatin treatment. Unlike carboplatin, the platinum(II) complexes of this invention utilize the carboxylate of phosphatidylserine, &agr;-amino acids, ,&bgr;-amino acids, or their derivatives as the ligands. Because the platinum(II) is camouflaged by these ligands, which are abundant in living organisms, these complexes are much less likely to incur drug resistance on repeated treatment. Therefore, the carboplatin analogs of this invention have advantages over cisplatin or carboplatin.
Yet another aspect of the present invention is to expand the number and the types of cancer in which the complexes can be effectively used. Cisplatin and carboplatin have been used only in some cancers, such as testicular and ovarian tumors, cancers of the head and neck, etc. It would be greatly beneficial to expand the use of platinum drugs to treat cancers that are not being treated by cisplatin and carboplatin.
The platinum(II) complexes of the present invention can have significantly different physical properties (such as solubility, affinity, permeability, stereo effect, etc.) from those of cisplatin or carboplatin because of the variety of ligands that can be used and because of the ability of amino acids to induce and stabilize some limited conformation themselves or when incorporated into small peptides. Therefore, these complexes can be useful in treating cancers that are not treated by cisplatin or carboplatin.
Therefore, the platinum(II) complexes of this invention have several distinct advantages over carboplatin including (1) they can be reversibly activated and deactivated, (2) they can have a significantly reduced drug resistance, and (3) they can be used to treat cancers that are not treated by cisplatin or carboplatin.
Platinum(II) Complexes Of The Present Invention
The complexes of the present invention can be represented by cis-Pt(II)L
1
L
2
, wherein each of L
1
and L
2
, independently is the carboxylate of phosphatidylserine, an &agr;-amino acid, a &bgr;-amino acid, or a derivative thereof, wherein each ligand is bidentate with −NH
2
and −COO
−
as the binding sites.
The following structure represents cis-Pt(valine)
2
:
Suitable acid, such as HCl, HBr, or HNO
3
, can be added to the complexes to make the free acid form, cis-Pt(II)Cl
2
L
1
L
2
, cis-Pt(II)Br
2
L
1
L
2
or cis-Pt(II)(NO
3
)
2
L
1
L
2
wherein each ligand is monodentate with −NH
2
as the binding site. The structure of PtCl
2
(Valine)
2
is shown as an example:
The &agr;- amino acid, &bgr;-amino acid, or derivative thereof, includes but is not limited to, alanine, aspartic acid, glutamic acid, glycine, isoleucine, leucine, phenylalanine, proline, serine, threonine, tyrosine, and valine.
Similar to carboplatin, the platinum(II) complexes of the present invention are more likely to be hydrolyzed in a cancerous area where the pH is lower than the normal biological pH. Thus, the two platinum(II) active sites are exposed to interact with DNA. In contrast to carboplatin, the active sites of the platinum(II) complex in this invention can be re-protected when they enter into a non-cancerous area because of the higher pH value. The activation/deactivation process for the platinum(II) complex is reversible. Therefore, potential side effects can be significantly reduced.
The reversible activation/deactivation reaction of the complexes of this invention may be illustrated by the example below:
Whereas for carboplatin, it is a one-way reaction as illustrated below:
Therefore, these platinu
Brinks Hofer Gilson & Lione
Carr Deborah D.
Unitech Pharmaceuticals, Inc.
Zayia Gregory H.
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