Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-01-04
2001-08-14
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S063000
Reexamination Certificate
active
06274561
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to an antitumor agent whose principal ingredient is a mixture of an organic compound which contains an amino group and a silyl group, and Adriamycin.
BACKGROUND OF THE INVENTION
The conventional antitumor agents in chemotherapy are mainly classified into a group of antibiotics (for instance Adriamycin) and a group of antimetabolites (for instance 5-fluorouracil). Each group relatively has a feature of a concentration dependence drug and a time dependence drug, and both groups have a problem of being toxic to normal cells. Recently, along with the progress of surgical treatment techniques, expectations for chemotherapy, especially for an antitumor agent whose side effects are minimized, are increasing.
Strong physiological activity of organic silicon compounds has been found by Voronkov et al of Russia (silatrane), and have been investigated in detail. However, sometimes some kinds of silatrane are strongly toxic in accordance with species of substitution group, and some of them have more strong toxicity than hydrocyanamic acid or strychnine. Recently, a group comprised of Shin-etsu Chemical Products Co., Ltd, and Keio University have investigated antineoplastic features of various kinds of organic silicon compounds, and have proceeded with development of relatively low toxicity and high activaty antitumor agents (Chemical Society of Japan, 1990, No.5, 566-574).
Inventors of this invention have already developed new antitumor agents of ring and chain compounds including silicon and nitrogen (hereafter; shortened to silamine compounds) by investigating thoroughly the antitumor features of silamine compounds (Japanese Patent Application 157518/94 and 157519/94).
However, although the toxicity of these silamine compounds are weaker than that of the antitumor agents such as Adriamycin, its antitumor activity is about {fraction (1/10)}, and said lower antitumor activity is pointed out as a problem.
The object of this invention is to solve the above mentioned problem of silamine compounds, and to provide a new antitumor agent of lower toxicity and high effectiveness.
DISCLOSURE OF THE INVENTION
The important point of this invention is an antitumor agent which comprises a mixture of a compound having the following chemical formula (A) and Adriamycin,
[wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
represent hydrogen atom, or alkyl group, allyl group or aralkyl group of carbon number 1 to 10; further, a pair of R
1
and R
2
, and a pair of R
5
and R
6
can be chemically bonded via alkylene, allylene or aralkylene group]
and an antitumor agent which comprises a mixture of a compound indicated by following chemical formula (B) and Adriamycin,
[wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
represent hydrogen atom, or alkyl group, allyl group or aralkyl group of carbon number 1 to 10; further, a pair of R
1
and R
3
, and a pair of R
6
and R
7
can be chemically bonded via alkylene, allylene or aralkylene group].
That is, in this invention, by combining Adriamycin which is an antitumor agent classified into conventional antibiotics with silamine compounds, those antitumor features act synergistically, and as the result, the toxicity which is a feature of Adriamycin can be relatively weakened. Adriamycin, as noted in The Merck Index, Eleventh Edition (1989), was formerly the generic name for Doxorubicin, and is (8S-cis)-10-[(3-amino-2,3,6-trideoxy)-&agr;-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione.
As the compound indicated by chemical formula (A) of this invention, following compounds can be mentioned. 4,7,13,16-tetraethyl-1,1,10,10-tetramethyl-4,7,13,16-tetraaza-1,10-disilacyclooctadecane, 1,1,4,7,10,10,13,16-octamethyl-4,7,13,16-tetraaza-1,10-disilacycloctadecane, 1,1,4,7,10,10,13,16-octaethyl-4,7,13,16-tetraaza-1,10-disilacycloctadecane and others.
Compound (A) can be obtained by the method disclosed in our previous document, Japanese Patent Application 157518/94.
That is, it can be synthesized using alkali metal compound, e.g. buthyllithium, as a catalyst, by a reaction of vinylsilane compound indicated by general formula (X) with N,N′ substituted ethylenediamine derivatives indicated by general formula (Y).
H
2
C═CH—SiR
1
R
2
CH═CH
2
(X)
[wherein R
1
and R
2
have the same meaning as given synonymus with the above].
HN R
1
CH
2
CH
2
NHR
2
(Y)
[wherein R
1
and R
2
have the same meaning as given above].
As the reacting mechanism, it is considered that vinylsilane compound reacts with ethylenediamine derivative as a first step, then a cyclization reaction occurs, and this is considered to be so called two step cyclic addition reaction. Chemical reaction formula is indicated as follows.
As the compound indicated by chemical formula (B) of this invention, following compounds can be mentioned; 3,6,12,15-tetraethyl-9,9-dimethyl-3,6,12,15-tetraaza-9-silaheptadecane, 6,12-diethyl-9,9′-dimethyl-3,6,12,15-tetraaza-9-silaheptadecane, 4,7,7,10-tetramethyl-1,4,10,13-tetraaza-7-silatridecane, 4,10-diethyl-7,7-dimethyl-1,4,10,13-tetraaza-7-silatridecane, and others.
These compounds can be obtained by the above mentioned manufacturing method disclosed in Japanese Patent
That is, it can be synthesized by an addition reaction of bis(&agr;,&bgr;-unsaturated)silane derivatives and amine using alkali metal compound as a catalyst. This reaction is desirably carried out in the presence of alkali metal compound, and the preparing method of this alkali metal catalyst is strictly restricted. It can be obtained by a reaction between amine to be used and a specific organic alkali metal. As an organic alkali metal to be used, bulky lithiumamide, sodiumamide and potassiumamide represented by lithiumdiisopropylamide, alkyl and allyl lithium such as buthyllithium or diphenyllithium and aralkyllithium can be mentioned. Further, lithium hydride, sodium hydride and potassium hydride can be used.
Molar ratio of alkali metal compound to amine is possible to be from 1/100 to 100/1, and desirable region is from 1/10 to 3/1.
This reaction can be carried out in the presence of inert solvent. As a solvent, liquid which does not react with alkali metal amide catalyst under the reaction conditions can be used. Concretely, ethers such as diethylether, dioxane, tetrahydrofuran, dimethoxyethane or diglyme, aliphatic hydrocarbon such as pentane, hexane, cyclohexane or octane, dimethyl sulfoxide, aromatic hydrocarbon such as benzene or toluene, non-proton polar solvent such as N,N-dimethylformamide or hexamethylphosphorictriamide can be mentioned. In these solvents, ethers such as tetrahydrofuran, aromatic hydrocarbons such as benzene and aliphatic hydrocarbon such as hexane are preferably used.
Volume of solvent to be used in this invention is desirably to be from {fraction (1/10)} to 50 times to the volume of bis(&agr;,&bgr;-unsaturated)silane derivatives and more desirably from ½ to 20 times. In general, when quantity of solvent relatively increases, reaction velocity becomes slow.
Reaction temperature is not restricted, however, a desirable temperature region is from −78°C. to 150° C. and more desirable region is 0°C. to 80° C. And also reacting period is not restricted, however, a desirable reaction period is from 1 minute to 1000 hours, and more desirably from 10 minutes to 100 hours.
The ring or chain silamine compound (hereafter shortened to silamine compound) is mixed together with Adriamycin, and the mixture is evaluated as an antitumor agent. The mixing ratio of silamine compound is desirably from 0.01 to 500 parts to 1 part of Adriamycin by weight, and more desirably from 0.1 to 50 parts by weight.
At the mixing procedure of a silamine compound and Adriamycin, it is possible to use a solvent. As a solvent to be used, a buffer solution such as phosphoric acid buffer or HEPES buffer can be used as well as water. Further, for the improvement of dissolving feature of silami
Kataoka Kazunori
Kato Masao
Nagasaki Yukio
Takezawa Tsutomu
Goldberg Jerome D.
Japan Science & Technology Corp.
LandOfFree
Antitumor agents comprising as the principal compounds... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Antitumor agents comprising as the principal compounds..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antitumor agents comprising as the principal compounds... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2494072