Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1996-10-04
1997-12-02
Prior, Kimberly J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
552610, A61K 3156, C07J 300
Patent
active
056936290
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/00642 filed Apr. 3, 1995.
TECHNICAL FIELD
The present invention relates to asteroid compound, and more particularly to a novel progesterone compound which has excellent neovascularization inhibitory action, and thus is useful as a remedy for malignant tumors, diabetic retinitis, rheumatism, etc. The invention also relates to neovascularization inhibitors containing the compound as the active ingredient.
BACKGROUND ART
Malignant tumors, diabetic retinitis, rheumatism, etc. are known as diseases in which neovascularization participates critically in the cause of disease or aggravation of pathology. Among such diseases, malignant tumors have widely been studied with respect to their relation to neovascularization, and it has come to be elucidated that neovascularization is crucial in the metastasis and prognosis of malignant tumors.
Recently, some substances exhibiting neovascularization activity have been reported. As such substances, there are known, for example, sulfated polysaccharides, platelet factor-4 (PF-4), pentosan polysulfates, TNP-470 (an analog of a mold product) tissue metalloproteinase inhibitors (TIMP), and minocycline. However, neovascularization inhibitory actions of these substances are not necessarily satisfactory, and there remains a need for development of neovascularization inhibitors with more excellent effects.
Estrogen is closely related to the genesis of endometrial carcinoma and mammary carcinoma, and therefore, anti-estrogen agents and high doses of progestogen have been used for their treatment. Specifically, medroxyprogesterone acetate, a progestogen, has been used as a remedy for mammary carcinoma and endometrial carcinoma. It has recently been reported that medroxyprogesterone acetate has neovascularization inhibitory action.
However, when the present inventors examined the neovascularization inhibitory action of medroxyprogesterone acetate, they found its action to be weak, and thus it is questionable was to whether medroxyprogesterone acetate manifests its effect at an ordinary clinical dose.
Accordingly, an object of the present invention is to provide a novel progesterone derivative having excellent neovascularization inhibitory action.
DISCLOSURE OF THE INVENTION
The present inventors synthesized a huge number of progesterone derivatives and screened them not only for their progestogen action but also for their neovascularization inhibitory action. As a result, they found that the 9.alpha.-fluoro-6.alpha.-methylprogesterone derivative represented by the following formula (1) exhibits neovascularization inhibitory activity not less than 20 times as potent as that of medroxyprogesterone acetate. The present invention was accomplished based on this finding.
Accordingly, the present invention provides a progesterone compound represented by the following formula (1): ##STR2##
The present invention also provides a neovascularization inhibitory agent containing the progesterone compound of formula (1) as an active component.
The present invention also provides a pharmaceutical composition containing the progesterone compound of formula (1) and a carrier for pharmaceuticals.
The present invention also provides use of the progesterone compound of formula (1) as a pharmaceutical.
The present invention also provides a method for the treatment of malignant tumors, diabetic retinopathy, and rheumatism, characterized by administering an effective amount of the progesterone compound of formula (1).
BEST MODE FOR CARRYING OUT THE INVENTION
In formula (1), which represents the progesterone compound of the present invention, examples of the hydrocarbon group R.sup.1 include C1-C23 linear or branched or cyclic alkyl or alkenyl groups, with C1-C17 alkyl groups being more preferred. Specific examples of particularly preferred R.sup.1 groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-tridecyl, n-tetradecyl, and n-pentadecyl. Of these, methyl and n-pentadecyl are part
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Chemical Abstracts, vol. 120, No. 21, May 23, 1994, AN-261586a, T. Yamamoto, et al., "Angiostatic Activities of Medroxyprogesterone Acetate and Its Analogs".
Chemical Abstracts, vol. 119, No. 7, Aug. 16, 1993, AN-063464a, F. Blei, et al., "Mechanism of Action of Angiostatic Steroids: Suppression of Plasminogen Activator Activity Via Stimulation of Plasminogen Activator Inhibitor Synthesis".
Chemical Abstracts, vol. 117, No. 11, Sep. 14, 1992, AN-104554j, H. Jikihara, et al., "Inhibitory Effect of Medroxyprogesterone Acetate on Angiogenesis Induced by Human Endometrial Cancer".
Journal of Organic Chemistry, vol. 28, No. 10, pp. 2633-2640, Oct. 1963, C. Bergstrom, et al., "9Alpha.-Fluoro-11-Deoxy Steroids".
Fujimori Shiho
Hibino Satoshi
Ichihara Yoshitatsu
Kohno Tetsuya
Nemoto Hideo
Meiji Milk Products Co. Ltd.
Prior Kimberly J.
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