Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-08
2001-06-26
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06251915
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a novel composition for treatment or prevention of prostate cancer, use of a compound for producing a pharmaceutical preparation for treatment or prevention of prostate cancer, and a method of treating or preventing prostate cancer by administering an effective amount of the compound to warm-blooded animals.
BACKGROUND INFORMATION
Testosterone 5&agr; reductase inhibitor is known as a therapeutic agent for benign prostatic hypertrophy that reduces prostate size by a mechanism of action that inhibits prostate cell growth caused by excessive male hormones (and mainly dihydrotestosterone) . In addition, testosterone 5&agr; reductase inhibitors such as Finasteride are sold as a therapeutic agent for benign prostatic hypertrophy in the United States of America and Europe. There are some testosterone 5&agr; reductase inhibitors on which clinical studies are being conducted in order to develop them as therapeutic agents for prostate cancer.
The reductive effects on the prostate correspond to the potency of testosterone 5&agr; reductase inhibitory activity. Different from benign prostatic hypertrophy, however, therapeutic effects on prostate cancer do not correspond to the potency of testosterone 5&agr; reductase inhibitory activity alone, since a greater number of factors are involved with respect to proliferation of prostate cancer.
N-[1-methyl-1-(4-methoxyphenyl)ethyl]-3-oxo-4-aza-5&agr;-androst-1-ene-17&bgr;-carboxamide is a compound disclosed in Japanese Patent Application (Kokai) No. Hei 8-73492 and Japanese Patent Publication (Kokoku) No. Hei 8-19151, and is a testosterone 5&agr; reductase inhibitor.
SUMMARY OF THE INVENTION
The inventors of the present invention conducted an earnest research on the synthesis of derivatives having testosterone 5&agr; reductase inhibitory activity and their pharmacological activity over many years. The inventors found that compounds like that mentioned above having a specific structure have an excellent prostate cancer therapeutic or preventive effect and accomplished the present invention.
The object of the present invention is to provide a composition for treatment or prevention of prostate cancer. In addition, another object of the present invention is to provide a use of the above-mentioned compound for the manufacture of a pharmaceutical for treatment or prevention of prostate cancer, and a therapeutic or preventive method for prostate cancer by administering an effective amount of the specified compounds) to warm-blooded animals.
The novel composition for treating or preventing prostate cancer of the present invention contains as its active ingredient a compound represented by the formula (I) below or pharmacologically acceptable salts thereof, preferably contains as its active ingredient N-[1-methyl-1-(4-methoxyphenyl)ethyl]-3-oxo-4-aza-5&agr;-androst-1-ene-17&bgr;-carboxamide, and more preferably is taken orally.
In addition, the novel use of a compound represented by the formula (I) below or pharmacologically acceptable salts thereof to produce a pharmaceutical for treatment or prevention of prostate cancer, preferably the use of N-[1-methyl-1-(4-methoxyphenyl)ethyl]-3-oxo-4-aza-5&agr;-androst-1-ene-17&bgr;-carboxamide for producing a pharmaceutical for treatment or prevention of prostate cancer, and more preferably it is taken orally.
The novel therapeutic or preventive method of the present invention is a therapeutic or preventive method for prostate cancer comprising the administration of an effective amount of a compound represented by the formula (I) below or pharmacologically acceptable salts thereof to warm-blooded animals, preferably a therapeutic or preventive method for prostate cancer comprising the administration of an effective amount of N-[1-methyl-1-(4-methoxyphenyl)ethyl]-3-oxo-4-aza-5&agr;-androst-1-ene-17&bgr;-carboxamide to warm-blooded animals, and more preferably by taking it orally.
wherein R
1
and R
2
may be the same or different and represent a hydrogen atom, a hydroxyl group, a protected hydroxyl group, or a lower alkoxy group.
In the formula (I),
the term “lower akoxy group” means a straight chain or branched chain alkoxy group having from 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy , n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy and 2,3-dimethylbutoxy, preferably a straight chain or branched chain alkoxy group having from 1 to 4 carbon atoms, more preferably a methoxy group.
The term “pharmacologically acceptable salts thereof” means the salts of the compound (I) of the present invention, which can be converted to salts thereof, examples of such salts preferably include alkali metal salts such as a sodium salt, a potassium salt and a lithium salt, alkaline earth metal salts such as a calcium salt and a magnesium salt , and metal salts such as an aluminum salt, an iron salt and a zinc salt.
Further, the compound (I) of the present invention, when it is allowed to stand in the atmosphere, may absorb some moisture, and it may, as a result, be a ssociated with absorption water or it may be converted to a corresponding hydrate. Such compounds are also included in the present invention.
The compound (I) of the present invention can be prepared according to the process shown below.
Process A
wherein R
1
and R
2
have the same meanings as defined above.
Process A is a method for preparing the desired compound (I) by condensing a carboxylic acid derivative (II) with an amine derivative (III).
Step A1 is to prepare the compound (I) by a reaction of compound (II) or a reactive derivative thereof with a compound (III). The reaction is carried out according to the conventional methods in peptide synthesis, for example an azide method, an active ester method, a mixed acid anhydride method or a condensation method.
In the above methods, the azide method is carried out as follows: the compound (II) or an ester thereof is reacted with hydrazine in an inert solvent (for example, dimethylformamide) at approximately room temperature to prepare an amino acid hydrazide. The amino acid hydrazide is reacted with a nitrous acid compound to afford an azide derivative, followed by the treatment of the azide derivative with an amine derivative (III).
The nitrous acid compound employable here may include, for example, alkali metal nitrites such as sodium nitrite or alkyl nitrites such as isoamyl nitrite.
The reaction is preferably carried out in an inert solvent, and the solvent employable here may include, for example, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide and pyrrolidones such as N-methylpyrrolidone. Two step reactions (preparation of azide and amide derivative (I)) are generally carried out in one reaction pot. The reaction temperature is −50° C. to 0° C. for the former reaction and −10° C. to 10° C. for the latter reaction, and the reaction time is 5 minutes to 1 hour for the former reaction and 10 hours to 5 days for the latter reaction.
The active ester method is carried out by a reaction of the compound (II) with an active esterification agent to give an active ester, followed by reaction of the active ester with an amine derivative (III).
Both reactions are preferably carried out in an inert solvent, and the solvent employable here may include, for example, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as diethylether and tetrahydrofuran, amides such as dimethylformamide and dimethylacetamide, and nitriles such as acetonitrile.
The active esterification agent employable here may include, for example, N-hydroxyl compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and N-hydroxy-5-norbornene-2,3- dicarboximide or disulfide compounds such as dipyridyldisulfide, and th
Kobayashi Tomowo
Kojima Koichi
Frishauf, Holtz Goodman, Langer & Chick, P.C.
Ramsuer Robert W.
Sankyo Company Limited
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