Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Reexamination Certificate
2001-01-30
2001-12-25
Shaver, Paul F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C556S013000, C514S110000, C514S492000
Reexamination Certificate
active
06333422
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a thermosensitive cyclotriphosphazene-platinum complex conjugate which can be administered systemically or locally and has an excellent anticancer activity, its preparation method and an anticancer agent containing the same as an active ingredient. More particularly, the compound of the present invention is a biodegradable cyclotriphosphazene-platinum complex conjugate exhibiting thermosensitivity in the temperature range including the body temperature.
The present inventors have found that the derivatives obtained by nucleophilic substitution of chlorine atoms in hexachlorocyclotriphosphazene ((NPCl
2
)
3
) with a low or high molecular weight hydrophilic poly(alkoxyethylene glycol) and a hydrophobic amino acid ester exhibit thermosensitivity (Korean patent application No. 99-48800). The present inventors have succeeded in the preparation of their platinum complexes by introducing the (diamine)platinum(II) ion to the hydrolyzed amino acid groups of these trimeric derivatives. To our surprise, these novel trimeric platinum complex conjugates also exhibited thermosensitivity in a wide temperature range including the body temperature as well as high anticancer activity. These new thermosensitive platinum complex conjugate anticancer agents showing a controlled release property has never been reported. These compounds can be administered systemically or locally since the targeted drug delivery is possible using their thermosensitivity. We expect, therefore, these new compounds will provide a new and significantly improved therapeutic regimen in the treatment of solid tumors.
Thermosensitive polymers in the present invention refer to the polymers that can be solubilized in water at low temperatures but precipitates above a certain critical temperature due to the rapid decrease of their water-solubility. When such a phase transition is reversible, the phase transition temperature is called a lower critical solution temperature(LCST) or a cloud point. Below LCST, the hydrogen bonding between the polymer-water molecules is stronger than the hydrophobic interaction between the polymer-polymer molecules. As the temperature increases, however, the hydrogen bonding between the polymer-water molecules weakens whereas the hydrophobic interaction between the polymer-polymer molecules increases resulting in the precipitation of polymers in aqueous solution.
These thermosensitive polymers were widely studied in many fields is including mainly drug delivery systems, medical biomaterials, thin films, the separation process of biochemical reactions, cosmetics and optics. However, most of the conventional thermosensitive organic polymers are known to be hydrolytically non-degradable. In recent years, a few biodegradable polymers were reported (Jeong, B. et. al.,
Nature,
388, 860 (1997); Song, S.-C. et. al.,
Macromolecules,
32, 2188(1999); Lee, S. B. et. al.,
Macromolecules,
32, 7820 (1999)). Up to date, however, no thermosensitive anticancer drug has been reported. Cisplatin, a platinum complex, approved as an anticancer agent in 1979 by FDA in the United States has been used as one of the most effective chemotherapeutic agents to treat a variety of cancers such as testicular, ovarian, bladder, and head and neck cancers. Its use is limited, however, due to its high toxicity (LD
50
=13 mg/Kg, M. J. Cleare, Biochimie 60, 835(1978)). Even though the second-generation anticancer agent, carboplatin exhibits much lower toxicity than cisplatin (LD
50
=180 mg/Kg, M. J. Cleare, Biochimie 60, 835(1978)), it is not widely used since it is lower in anticancer activity and more expensive than cisplatin. Therefore, there is a great need for a third-generation anticancer agent that has higher and wider anticancer activity with lower toxicity than cisplatin.
SUMMARY OF THE INVENTION
Therefore, an object of the present invention is to develop a third-generation anticancer agent having a higher anticancer activity and lower toxicity than the conventionally used cisplatin.
To achieve this goal, the present inventors have discovered a novel class of the cyclotriphosphazene-platinum complex conjugate anticancer agents whose LCST can be designed variably for the desired purpose and controlled precisely, by introducing the solubilizing agent and the platinum complex into the biodegradable cyclotriphosphazene. These new cyclotriphosphazene-platinum complex conjugate anticancer agents of the present invention may be administered systemically or locally by using the thermosensitive properties of the drugs.
More particularly, an object of the present invention is to provide oligomeric thermosensitive cyclotriphosphazene-platinum complex conjugates having a stereo-specific chemical structure and LCST that can be designed for the desired purpose, by nucleophilic substitution of the chlorine atoms in hexachlorocyclotriphosphazene with a poly(alkoxyethylene glycol) and an amino acid ester, followed by hydrolysis of the substituted amino acid ester and subsequent reaction with a (diamine)platinum salt and the preparation method thereof.
Another object of the present invention is to provide an anticancer agent having the thermosensitive cyclotriphosphazene-platinum complex conjugate as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION
To achieve the above-mentioned goals, the present inventors have performed the following experiments. Hexachlorocyclotriphosphazene was reacted first with a hydrophilic poly(alkoxyethylene glycol) having different molecular weights, and then with a variety of hydrophobic amino acid esters to obtain a new class of cyclotriphosphazene derivatives with thermosensitive properties. The substituted amino acid eaters in the trimers were hydrolyzed with alkali, and then reacted with a (diamine)platinum(II) salt to obtain a cyclotriphosphazene-platinum complex conjugate formed by covalent bonding between the carboxylate groups of the amino acid and the platinum(II) cation. Surprisingly, we have found that these trimeric platinum conjugates exhibit thermosensitivity in a wide range of temperature depending on the kinds of substituents and the platinum derivatives. Furthermore, we have found that the LCST of the cyclotriphosphazene-platinum complex conjugates can be designed and controlled for the desired application purpose since the LCST of these cyclotriphosphazene-platinum complex can be varied easily by appropriate choice of different poly(alkoxyethylene glycol), amino acid and platinum derivatives.
The preparation method of the novel stereo-specific cyclotriphosphazene-platinum complex conjugates represented by Formula 1 of the present invention is described in detail as follows.
wherein, m is an integer selected from 2, 7 and 12; n is an integer selected from 0, 1, 2 and 3; x is an integer selected from 0, 1 and 2; and A
2
is a bidentate chelating diamine selected from the group consisting of 2,2-dimethyl-1,3-propanediamine (dmpda), trans(±)-1,2-diaminocyclohexane (dach) and 1,1-diaminomethylcyclohexane (dmach).
In the above, m selected from the integer of 2, 7, or 12 is a repeating unit of poly(alkoxyethylene glycol), n selected from the integer of 0 to 3 represents the length of the alkyl chain, x selected from the integer of 0 to 2 represents the length of the anionic amino acid residue.
The trimeric amino acid ester derivatives represented by Formula 2 was prepared by reacting hexachlorocyclotriphosphazene first with hydrophilic poly(alkoxyethylene glycol) and then with a variety of hydrophobic amino acid esters. By reacting the trimeric derivatives of Formula 2 with 3 moles of alkali earth metal hydroxide of Formula 3 or with 6 moles of alkali metal hydroxide of Formula 4 in methanol or ethanol for 3~5 hours, the intermediate cyclotriphosphazene-alkali earth metal salt of Formula 5 or the cyclotriphosphazene-alkali metal salt of Formula 6, respectively, were obtained. With this intermediate, 3 moles of (diamine)platinum sulfate or nitrate of Formula 7 was reacted in distilled water for 3~7 hours at
Lee Sang Beom
Sohn Youn Soo
Song Soo-Chang
Korea Institute of Science and Technology
Morrison & Foerster / LLP
Shaver Paul F.
LandOfFree
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