Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-03-26
1998-09-15
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5483121, A61K 31415, C07D40306
Patent
active
058078800
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a novel azole derivative useful as a steroid 17-20 lyase inhibitor, a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof.
BACKGROUND ART
It is known that an enzyme, called steroid 17-20 lyase, is taking a role in the formation of androgen from cholesterol in the living body at the final step of its biosynthetic pathway. Steroid 17-20 lyase uses 17.alpha.--OH pregnenolone and 17.alpha.--OH progesterone as its substrates, which have a carbon substituent at the 17.beta. position and are formed from cholesterol, and cleaves a bonding between the 17 position carbon and the 20 position carbon of the carbon substituent, thereby effecting formation of various types of androgen. In consequence, inhibition of the enzyme activity of steroid 17-20 lyase renders possible repression of the formation of androgen and estrogen which is synthesized from androgen as its substrate and prevention and treatment of various diseases in which androgen and estrogen take parts as advancing factors. Examples of the diseases whose exacerbating factors are androgen and estrogen include prostatic cancer, prostatic hypertrophy, virilism, hypertrichosis, breast cancer, mastopathy, hysteromyoma and endometriosis.
On the other hand, it has been fully confirmed that reduction of the serum androgen level is useful in treatment of prostatic cancer and the like, and orchiectomy, LH-RH agonist or androgen antagonist is used in the clinical practice. However, orchiectomy is psychologically hardly acceptable, and the LH-RH agonist cannot block androgen except sex gland androgen and shows a transient flare phenomenon. With regard to the androgen antagonist, it has been known in recent years that its effects are reduced by mutation of androgen receptor. In consequence, it has been proposed to block effects of androgen on its receptor (total androgen block), and attempts have been made to use LH-RH agonist and androgen antagonist in combination.
A compound which inhibits steroid 17-20 lyase is considered to be a drug that can perform total androgen block by strongly blocking androgen due to its function and therefore is expected as a promising drug for the treatment of prostatic cancer and the like. In addition, being capable of reducing estrogen, a steroid 17-20 lyase inhibitor is expected as a more effective therapeutic agent for prostatic hypertrophy and as a drug having more smaller side effects in comparison with a therapeutic agent which blocks only androgen.
As steroid 17-20 lyase inhibitors, steroid type and non-steroid type compounds have been synthesized. As an example of the non-steroid type steroid 17-20 lyase inhibitor, a (1H-imidazol-1-yl)methyl-substituted imidazole derivative disclosed in an unexamined published Japanese patent application (Kokai) No. 64-85975 is known, which is a compound in which a substituted benzimidazolyl group as a condensed bicyclic group and a imidazolyl group are linked by a methine carbon or a methylene carbon.
However, the compound of the present invention has a condensed tricyclic group and therefore is structurally different from the above compound and is also a novel compound from the viewpoint of pharmacological effects because of its excellent steroid 17-20 lyase inhibiting activity and testosterone synthesis inhibiting activity as will be described later.
On the other hand, compounds having an imidazolyl group and a fluorenyl group as a condensed tricyclic group have been disclosed in an unexamined published Japanese patent application (Kokai) No. 47-1471 as a compound having an antifungal action and in U.S. Pat. No. 4,757,082 as a compound having an aromatase inhibiting function.
However, the structure of the compound of the present invention is different from those of the above compounds from a viewpoint that an azole ring is linked to a condensed benzene ring of the condensed tricyclic group via one carbon atom.
In addition, nothing is disclosed about steroid 17-20 lyase inhibiting activity of these known compounds.
As des
Ishihara Tsukasa
Kawaminami Eiji
Kudou Masafumi
Okada Minoru
Shimada Yoshiaki
Morris Patricia L.
Yamanouchi Pharmaceutical Co. Ltd.
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