Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Reexamination Certificate
1999-12-29
2002-01-22
Nazario-Gonzalez, Porfirio (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C514S492000
Reexamination Certificate
active
06340770
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is related to a novel Pt(IV) complex used as an anti-cancer agent and preparing method thereof and more particularly a novel Pt(IV) complex having an octahedral structure and preparing method thereof.
2. Description of the Prior Art
Nowadays, many people suffer from cancer, and it is one of the most painful diseases. Since discovering a cancer, humans have constantly taken various efforts in researching in order to overcome the cancer, such as development of an anti-cancer agent, genetic treatment, operative treatment, radiotherapeutics and so on.
For example, platinum complexes, such as cis-Diaminedichloroplatinum(II) (hereinafter, referred to cisplatin) which is known as an effective anti-cancer agent, are widely used in a clinical field, and its various derivatives are under a clinical trial or under development. Among them, cisplatin
1-2)
, first disclosed in 1972, shows an excellent treatment effect in ovarian cancer, urinary bladder cancer and particularly prostatic cancer which is difficult to be treated using conventional anti-cancer agents.
3-10)
As shown in the following Chemical Formula I, cisplatin is a Pt(II) complex wherein Pt in center is stably combined with amines.
As same as conventional alkylating agent, anti-cancer mechanism of cisplatin is caused by position-exchanging between chlorine coordinate and DNA for forming a stable bonding state
66-67)
, and therefore DNA structure comes to be significantly changed.
68-69)
When dispensing cisplatin into especially where chlorine concentration is high (103 mM), such as blood, lymph and intestinal fluid, dissociation of chlorine ion from cisplatin is repressed because of high concentration of chlorine, and cisplatin comes to be permeated into cell by passive diffusion in the form of non-charged complex and subject to hydrolysis to be diaqua complex. It was reported that such phenomenon was because the chlorine concentration in cell was lower by thirty-folds than that of outside cell.
91)
Once permeated into cell, positively-ionized cisplatin in the form of aqua-complex, such as Pt(OH)
2
(NH
3
)
2
and Pt(OH)(OH
2
)(NH
3
)
2
, binds to DNA helix by electrical attraction.
92-93)
The rate of binding between cisplatin and DNA is same in both cancer cell and normal cell. However, comparing with normal cell, the growth rate of cancel cell is very fast and repairing rate is very slow when it is damaged. Therefore, hindrance caused by cisplatin is more significant in cancer cell than normal cell.
However, the clinical use of cisplatin has been frequently limited by the following drawbacks:
(1) Serious toxicity, such as nephrotoxicity, gastrointestinal toxicity, ototoxicity and neurotoxicity.
15-17)
Particularly, nephrotoxicity is very serious. Nephrotoxicity by cisplatin is mainly due to dose-limiting
22)
, that is, toxicity becomes serious as dose increases, which gives a rise to tubulorrhexis. Thereby, toxicity is directly manifested into renal cortex, and distal renal tubule, collecting tubule and particularly renal proximal tubule become damaged;
23-26)
(2) Low activity for certain kinds of cancers, such as breast and colon cancers;
18)
(3) Development of acquired resistance;
19-21)
and
(4) Poor solubility in water.
In an attempt to overcome these drawbacks of cisplatin, the 2
nd
-generation Pt complex, cis-diamine(1,1-cyclobutanedicarboxylato)platinum(II) (hereinafter, referred to carboplatin) was developed and is commercially available at present.
Carboplatin (Chemical Formula II), a compound where chlorine group of cisplatin is substituted with 1,1-cyclobutanedicarboxylato, is regarded as a good anti-cancer agent in that it shows lesser side effects such as nephrotoxicity and nausea if compared with cisplatin
31-32)
. Also, it has a sufficient solubility and shows similar effectiveness to cisplatin against ovarian cancer and small cell carcinoma in lung.
33-34)
However, Carboplatin also has a narrow anti-cancer spectrum
33),35)
and it is not effective in the treatment of cancer cells resistant to cisplatin, suggesting that cross-resistance between cisplatin and carboplatin.
36-37)
The resistance-existent mechanism against cisplatin is as follows:
First, when Pt complex attacks DNA, the repairing rate of a damaged DNA increases and a low-molecular weight of cell compound, such as glutathion having thiol group, increases. Thus, the agent is inactivated, and re-absorption of the agent into cell comes to be decreased.
Accordingly, anti-cancer agent in the future must be able to inhibit resistant cells. It is because that cancer cell comes to have resistance against cisplatin which has been used as anti-cancer agent during about 30 years. At present, even though various Pt(II) complexes is under development and experimentation, any one has limits and some problems. Thus, its substitutes are required.
In addition, in order to alleviate the pain of cancer patients, development of Pt complex capable of being used not only as injection but also as oral administration is required. As a compound capable of meeting such a requirement, at present, Pt(IV) complexes are considered.
Besides, there are many requirements which a new anti-cancer agent should meet, such as good water-solubility and lipophilicity, a low risk of nephrotoxicity and so on.
REFERENCES:
patent: 5288887 (1994-02-01), Khokhar et al.
patent: 5902826 (1999-05-01), Mogi et al.
Kim Won Kyu
Kwon Young-Ee
Whang Kyu Ja
Nazario-Gonzalez Porfirio
Sook Myung Women's University
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