Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Reexamination Certificate
2002-08-12
2004-03-02
Nazario-Gonzalez, Porfirio (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
C556S137000
Reexamination Certificate
active
06699901
ABSTRACT:
The invention relates to novel kind of antitumor platin derivatives, more specifically to a derivative of double dicarboxylic acid diaminoplatin complex. The invention also relates to a process for preparation thereof, and to a pharmaceutical composition containing the same. Furthermore, the invention relates to application of the derivative in preparing antitumor pharmaceutics.
Since B. Rosenber found an antitumor effect of cis-dichlorodiaminoplatin in 1969, cisplatin has been used widely in clinical medicine as an antitumor drug of platin analogues. Though this kind of drug has obvious therapeutic effects to many cancers such as genitourinary cancer, nasopharyngeal cancer, cephalocircular cancer and lung cancer, it has high toxicity and severe side effects. Some undesirable effects such as nephrotoxicity, neurotoxcity, ototoxicity, nausea, vomitting are all constraints to its dosage and long term use. Carboplatin, one of the second-generation antitumor drugs of platin analogues, has a antitumor spectrum similar to cisplatin and has a cross drug-resistance. The therapeutical effect of carboplatin is a little inferior to that of cisplatin. Though the toxicity and side effects of carboplatin is significantly less than that of cisplatin, there still exists myelosuppression, and moreover it is not stable in aqueous solution. Therefore, active studies in search of antitumor pharmaceutics of platin analogues with high effect, low toxicity and broad-spectrum have had been made.
It is reported that many kinds of new antitumor drugs of platin analogues have entered into clinical trials in recent years, such as isoplatin, oxaliplatin, ormajplatin, lobaplatin, enloplatin, zeninplatin, L-NDOP, DWA-2114A and CI-973 etc. Though most of these new platin analogues have no cross drug-resistance with cisplatin, their antitumor strains are nearly identical to those of cisplatin, yet the antitumor spectrum is not broader and the stability in water is comparatively poor. As to toxicity, most of them are lower than that of cisplatin, some still display obvious nephrotoxicity, neurotoxicity and myelosuppression. For these reasons, none of them has been used clinically. As for the orally effective antitumor drugs of platin analogues, none has been reported up to now. It is desired that another kind of antitumor drugs of platin analogues with more effect, less toxicity and more stability in water.
After deep and thorough studying of platin analogous compounds, the inventor found surprisingly that derivatives of double dicarboxylic acid diaminoplatin complex could overcome the above-mentioned shortcomings, and have high effect, low toxicity and stability in water, thereby the present invention is effected.
The primary object of the invention is to provide a novel antitumor derivative of double dicarboxylic acid diaminoplatin complex that overcomes the shortcomings of the above-mentioned prior art.
Another object of the invention is to provide a process for preparing the derivative of double dicarboxylic acid diaminoplatin complex.
Still another object of the invention is to provide an antitumor pharmaceutical composition containing the derivative of double dicarboxylic acid diaminoplatin complex as active component.
A further object of the invention is to provide an application of the derivative of double dicarboxylic acid diaminoplatin complex in preparing antitumor pharmaceutics.
The invention relates to an antitumor derivative of double dicarboxylic acid diaminoplatin complex, characterized in that, it has following formula (I):
where
R
1
and R
2
are same or different, and independently represent hydrogen, a C
1
-C
12
-alkyl group, halogen, an amino group, a cyanide group, a hydroxyl group, an acyl group, a phosphoryl group or a phosphoamido group;
or represent a saturated or unsaturated 3-12-element carbocycle, which is formed by interlinking R
1
and R
2
together with the carbon atoms that R
1
and R
2
are attached to.
Preferably a saturated 3-6-element carbocycle is formed by interlinking R
1
, R
2
and the carbon atoms attached to them.
More preferably, the derivative of double dicarboxylic acid diaminoplatin complex is double 1,1-cyclopropane dicarboxylic acid diaminoplatin complex or double 1,1-cyclobutane dicarboxylic acid diaminoplatin complex.
Most preferably, the derivative of present invention is double 1,1-cyclobutane dicarboxylic acid diaminoplatin complex ( ) of formula (II):
The invention also relates a process for preparing derivative of double dicarboxylic acid diaminoplatin complex, characterized in that, said derivative has following formula (I):
wherein
R
1
and R
2
are same or different, and independently represent hydrogen, a C
1
-C
12
-alkyl group, halogen, an amino group, a cyanide group, a hydroxyl group, an acyl group, a phosphoryl group or a phosphoamido group;
or represent a saturated or unsaturated 3-12-element carbocycle, which is formed by interlinking R
1
and R
2
together with the carbon atoms, that R
1
and R
2
are attached to;
said process comprises:
1) reacting substances of the genus of carboplatin or carboplatin with dicarboxylic acid ligand derivatives of formula (III)
2) wherein R
1
and R
2
have the meanings defined in formula (I), to produce the derivative of double dicarboxylic acid diaminoplatin complex of formula (I); or
reacting the dihalogen diaminoplatin having following formula (NH
3
)
2
PtX
2
wherein X is Cl or I,
with silver nitrate or silver sulfate in water, to produce hydrated diaminoplatin nitrate of the formula (NH
3
)
2
Pt(H
2
O)
2
(NO
3
)
2
or hydrated diaminoplatin sulfate of the formula (NH
3
)
2
Pt(H
2
O)
2
SO
4
; and then
reacting thus produced (NH
3
)
2
Pt(H
2
O)
2
(NO
3
)
2
or (NH
3
)
2
Pt(H
2
O)
2
SO
4
with dicarboxylic acid ligand derivatives of formula (III) or their sodium salts or barium salts,
wherein the R
1
and R
2
have the meanings defined in abovementioned formula (I), to produce double dicarboxylic acid diaminoplatin complex of formula (I).
According to the above processes of present invention for preparing double dicarboxylic acid diaminoplatin of formula (I), every preparation step can be proceed at temperatures within relatively wide range, usually from 0° C. to 100° C., preferably from 10° C. to 50° C. time of every step is generally 2 to 16 hours.
According to the aforementioned processes of the present invention for preparing double dicarboxylic acid diaminoplatin in formula (I), the reactions are usually carried out under normal pressure. However, the reactions are also can be proceeded under increased pressure or decreased pressure, that is the reactions are usually proceeded under pressure from 0.1 bar to 10 bars.
According to the above processes of the present invention for preparing dicarboxylic acid diaminoplatin of formula (I), isomolar of starting raw materials are often used. However, it is allowable that one of the raw materials is relatively excessive to other raw materials.
The raw materials, i.e. dihalogen diaminoplatin and dicarboxylic acid ligand derivatives, are all known substances and can be prepared by known processes.
Furthermore, present invention also relates to an antitumor pharmaceutical composition, characterized in that, this composition comprises at least one kind of derivatives of dicarboxylic acid diaminoplatin complex of formula (I) at concentration of 0.1-0.5 wt % as an active component and balance of pharmaceutical acceptable carriers.
According to the pharmaceutical composition of the invention, it is preferred that the derivatives of dicarboxylic acid diaminoplatin complex of formula (I) as active component are those derivatives, that have a saturated 3-6-element carbocycle formed in formula (I) by interlinking R
1
, R
2
and carbon atoms attached to them; more preferably it is double 1,1-cyclopropane dicarboxylic acid diaminoplatin complex or double 1,1-cyclobutane dicarboxylic acid diaminoplatin complex; most preferably it is double 1,1-cyclobutane dicarboxylic acid diaminoplatin complex.
The process for preparing the antitumor pharmaceutical composition of the in
Cui Weichuan
Yang Jinli
Yang Xuqing
Yang Zhenyun
Yin Yingwu
Fish & Richardson P.C.
Nazario-Gonzalez Porfirio
LandOfFree
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