Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-18
2004-02-10
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S256000, C546S280400, C546S283700, C546S284100, C514S337000, C514S338000
Reexamination Certificate
active
06689798
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel benzofuran derivatives. The present invention also relates to inhibitors of steroid 17&agr;-hydroxylase and/or steroid C17-20 lyase and pharmaceutical composition containing the novel benzofuran derivatives.
BACKGROUND OF THE INVENTION
In the formation of sex steroids in living bodies, 1)C21-steroids, such as a progesterone, are formed from cholesterol, 2)androgenic hormones, such as androstenedione and testosterone, which are C19-steroids, are synthesized from C21-steroids by steroid 17&agr;-hydroxylase and/or steroid C17-20 lyase, and 3)estrogens, such as estrone and estradiol, which are C18-steroids, are synthesized from these C19-steroids as a substrate by aromatase enzymes. All these sex steroids are known to exhibit various activities.
If the steroid 17&agr;-hydroxylase and/or steroid C 17-20 lyase or aromatase, which are enzymes synthesizing these sex steroids, are inhibited, in vivo formation of androgenic hormones and/or estrogens can be controlled. Thus, it is possible to prevent or treat various diseases, in which androgenic hormones or estrogens are involved as an exacerbation factor, such as prostate cancer, prostatic hypertrophy (prostatism), androgenic syndrome (masculinism), andromorphous baldness, breast cancer, mastopathy, uterine cancer, endometriosis, and ovarian cancer.
It is already revealed from numerous findings that these diseases relating to androgenic hormones, such as prostate cancer and prostatic hypertrophy, can be treated by reducing the amount of androgenic hormones in the blood. For example, conventionally decrease in the androgenic hormones was brought about by orchidectomy or adrenalectomy. A decrease in the androgenic hormones originating from the gonad gland by the administration of an LH-RH agonist, which is a kind of hypophysis hormone has been reported recently to exhibit treatment effects.
However, the above-mentioned evisceration is not only psychologically difficult to accept, but also may be accompanied by side effects caused by a decrease of mineral corticoid or glucocorticoid from the adrenal glands. The administration of an LH-RH agonist only inhibits synthesis of hormones of gonad gland origin and is not expected to decrease hormones originating from other organs such as the adrenal glands. In addition, a problem of “flare phenomenon” due to a temporary increase of hormones unique to the agonist has been indicated.
On the other hand, although anti-androgenic hormone agents antagonistic to androgenic hormone receptors have been developed, a recent report indicated a decrease in the effect of such an agent due to denaturing of the androgenic hormone receptors.
In view of this situation, development of a more effective agent for decreasing androgenic hormones is desired. It is possible to decrease greatly androgenic hormones by inhibiting steroid 17&agr;-hydroxylase and/or steroid C17-20 lyase. Therefore, inhibition of these steroids is expected to exhibit high effects in the treatment of various diseases in which the androgenic hormones are involved, such as prostate cancer, prostatic hypertrophy, and masculinization disease. In addition, inhibition of steroid 17&agr;-hydroxylase and/or steroid C17-20 lyase may result in interruption of estrogen synthesis.
Up to the present time, steroid compounds and non-steroid compounds have been known as inhibitors of steroid 17&agr;-hydroxylase and/or steroid C17-20 lyase. Examples include non-steroid compounds such as imidazole derivatives disclosed in Japanese Patent Laid-open Application No. 64-85975 and azole derivatives having a condensed three-ring structure disclosed in WO 95/09157. However, because these compounds are not necessarily satisfactory in their effects, development of compounds exhibiting higher activity has been desired.
SUMMARY OF THE INVENTION
In view of the above situation, the inventors of the present invention have carried out extensive studies to discover substances inhibiting steroid 17&agr;-hydroxylase and/or steroid C17-20 lyase. As a result, the inventors have found that a certain compound possessing a benzofuran skeleton exhibits potent inhibitory activity of steroid 17&agr;-hydroxylase and/or steroid C17-20 lyase, as well as aromatase. Therefore, an object of the present invention is to provide novel benzofuran derivatives, which inhibit steroid 17&agr;-hydroxylase and/or steroid C17-20 lyase.
Another object of the present invention is to provide novel steroid 17&agr;-hydroxylase and/or steroid C 17-20 lyase inhibitors and pharmaceutical compositions.
The present invention relates to novel benzofuran derivatives. The compounds of the present invention exhibit potent inhibitory activity of steroid 17&agr;-hydroxylase and/or steroid C17-20 lyase. They also inhibit aromatase. Due to its activity, the compounds of the present invention are useful as preventive and/or therapeutic agents for various diseases, in which androgenic hormones and estrogens are involved, such as prostate cancer, prostatic hypertrophy (prostatism), androgenic syndrome (masculinization), andromorphous baldness, breast cancer, mastopathy, uterine cancer, endometriosis, and ovarian cancer.
DETAILED DESCRIPTION OF THE INVENTION
Specifically, the present invention provides novel benzofuran derivatives represented by the following formula (I) or salts thereof:
wherein Py is a 2-, 3-, or 4-pyridyl group and R is a substituted or unsubstituted phenyl group or a substituted or unsubstituted aromatic heterocyclic group.
As examples of the aromatic heterocyclic group in the compound of the present invention, heterocyclic groups containing a nitrogen atom and/or sulfur atom as the heteroatom, such as a pyridyl group or thienyl group can be given.
As the substituent on the phenyl group or aromatic heterocyclic group in the compound of the present invention, a hydroxyl group, lower alkyl group, lower alkyloxy group, halogen atom, carboxyl group, lower alkyloxycarbonyl group, carbamoyl group, amino group, amino group which may be substituted with one or two substituents selected from a lower alkyl group and lower acyl group, nitro group, or cyano group can be given. The lower alkyl group is a linear, branched, or cyclic hydrocarbon group having 1-7 carbon atoms, wherein the hydrocarbon group may be substituted with a halogen atom, hydroxyl group, alkyloxy group, amino group, amino group which may be substituted with one or two substituents selected from a lower alkyl group and lower acyl group, nitro group, or cyano group. The number of the substituents may be 1-3, and two of them in combination may form a lower alkylenedioxy group. Preferable substituents are a hydroxyl group, lower alkyloxy group, halogen atom, amino group, and carboxyl group, and particularly preferable groups are hydroxyl, methoxyl, fluorine atom, amino group, and carboxyl.
The following compounds can be given as specific examples of novel benzofuran derivatives represented by the formula (I) of the present invention:
(1) 3-[6-(4-methoxyphenyl)benzo[b]furan-3-yl]pyridine,
(2) 4-[3-(3-pyridyl)benzo[b]furan-6-yl]phenol,
(3) 3-[6-(4-fluorophenyl)benzo[b]furan-3-yl]pyridine,
(4) 3-[6-(3-fluorophenyl)benzo[b]furan-3-yl]pyridine,
(5) 3-[6-(3-methoxyphenyl)benzo[b]furan-3-yl]pyridine,
(6) 3-[3-(3-pyridyl)benzo[b]furan-6-yl]phenylamine,
(7) 3-[6-(3-pyridyl)benzo[b]furan-3-yl]pyridine,
(8) 3-[6-(1,3-benzodioxole-5-yl)benzo[b]furan-3-yl]pyridine,
(9) 3-(6-phenylbenzo[b]furan-3-yl)pyridine,
(10) 3-[6-(3,4-dimethoxyphenyl)benzo[b]furan-3-yl]pyridine,
(11) 3-[3-(3-pyridyl)benzo[b]furan-6-yl]phenol,
(12) 4-[3-(3-pyridyl)benzo[b]furan-6-yl]- 1,2-benzenediol,
(13) 3-[6-(3-thienyl)benzo[b]furan-3-yl]pyridine.
In addition to the above-mentioned compounds, the derivatives of the present invention include salts formed from these compounds and an a
Ikeda Yoshikazu
Kimura Ken'ichi
Nakamura Junji
Nomoto Shin
Okue Masayuki
Aulakh Charanjit S.
Daiichi Pharmaceutical Co. Ltd.
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