Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-25
2003-05-06
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S396000, C546S343000, C548S335100
Reexamination Certificate
active
06559157
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel dihydronaphthalene compounds and processes for their preparation. The compounds of the present invention have excellent 17&agr;-hydroxylase and/or C
17-20
-lyase inhibiting activity, thromboxane A
2
synthesis inhibiting activity, and aromatase inhibiting activity, and are thereby useful as preventive and/or therapeutic agents for various male sex hormone- and female sex hormone-dependent diseases such as prostate cancer, prostatomegaly, masculinization, breast cancer, mastopathy, endometrial cancer, endometriosis, and ovarian cancer, as well as myocardial infarction, angina pectoris, and bronchial asthma.
BACKGROUND ART
As to the biosyntheses of sex steroids, which express various actions in the body, it is known that C
21
steroids, such as progesterone, are synthesized from cholesterol; further, male sex hormones such as androstenedione and testosterone, which are C
19
steroids, are synthesized by 17&agr;-hydroxylase and/or C
17-20
-lyase, and using these steroids as substrates, female sex hormones such as estrone and estradiol, which are C
18
steroids, are synthesized. Therefore, syntheses of male sex hormones and/or female sex hormones in the body can be suppressed by inhibiting these sex steroid synthesizing enzymes, i.e., 17&agr;-hydroxylase and/or C
17-20
-lyase or aromatases, which enables the prevention or treatment of diseases in which male sex hormones or female sex hormones act as exacerbating factors, such as prostate cancer, prostatomegaly, masculinization, breast cancer, mastopathy, endometrial cancer, endometriosis, and ovarian cancer.
Various findings have already shown that male sex hormone-dependent diseases such as prostate cancer and prostatomegaly can be treated by reducing male sex hormone levels in the blood. The therapeutic efficacy of reducing the level of male sex hormones by orchiectomy or adrenalectomy has been known for some times, and more recently, the efficacy of reducing the level of male sex hormones derived from gonads by the administration of an LH-RH (a pituitary hormone) agonist, has been recognized. However, the abovementioned surgical removal of organs is psychologically difficult to accept, and as well causes side effects and other disorders due to the reduction of mineral corticoids and glucocorticoids derived from the adrenal gland. Meanwhile, administration of the LH-RH agonist will inhibit syntheses of hormones derived from gonads only, but not from other organs such as adreahal gland, and even causes a temporary hormone increase known as a flare up phenomenon which is unique to agonists. On the other hand, an anti-male hormone agent to antagonize the male hormone receptor has been developed, but recently, its efficacy has been found to be diminished because of changes in the male sex hormone receptor. Against this background, a more effective male sex hormone reducing agent is desirable. In this connection, inhibition of 17&agr;-hydroxylase and/or C
17-20
-lyase is known to reduce the levels of male sex hormones to a high degree and can be expected to be highly effective in treating male sex hormone-related diseases such as prostate cancer, prostatomegaly, and masculinization. Furthermore, inhibition of 17&agr;-hydroxylase and/or C
17-20
-lyase also results in the suppression of female sex hormone syntheses.
To date, both steroid compounds and non-steroid compounds have been proposed as 17&agr;-hydroxylase/C
17-20
-lyase inhibitors. Examples of the non-steroid compounds include an imidazole derivative described in Japanese Patent Laid-open No. 64-85975 (1989), and a condensed tri-ring azole derivative described in Japanese Patent Application No. 07-510212 (1995). However, the efficacy of these compounds is not totally satisfactory and the development of compounds with higher activity has been desired.
DETAILED DESCRIPTION OF THE INVENTION
As a result of intensive study in view of the abovementioned state of affairs, the present inventors found that novel dihydronaphthalene compounds have excellent 17&agr;-hydroxylase and/or C
17-20
-lyase inhibiting activity, thromboxane A
2
synthesis inhibiting activity, and aromatase inhibiting activity. Namely, an objective of the present invention is to provide the novel dihydronaphthalene compounds and processes for producing the same.
The present invention relates to the novel dihydronaphthalene compounds and processes for producing the same. The compounds according to the present invention have excellent 17&agr;-hydroxylase and/or C
17-20
-lyase inhibiting activity, thromboxane A
2
synthesis inhibiting activity, and aromatase inhibiting activity, and are thus useful as preventive and/or therapeutic agents for various male sex hormone- and female sex hormone-dependent diseases, such as prostate cancer, prostatomegaly, masculinization, breast cancer, mastopathy, endometrial cancer, endometriosis, and ovarian cancer, as well as myocardial infarction, angina pectoris, and bronchial asthma.
The present invention relates to novel dihydronaphthalene compounds of the following general formula (1)
wherein R
1
represents hydrogen, hydroxyl, or alkyloxy, R
2
represents lower alkyl, aralkyl, or phenyl, and R
3
represents alkyl, phenyl, pyridyl, or imidazolyl.
More specifically, examples of the novel dihydronaphthalene compounds according to the present invention of general formula (1) include
(1) 3-[(1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(2) 3-[(5-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(3) 3-[(6-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(4) 3-[(7-methoxy-1-methyl-3 ,4-dihydro-2-naphthalenyl)methyl]pyridine,
(5) 5-methyl-6-(3-pyridylmethyl)-7,8-dihydro-1-naphthalenol,
(6) 5-methyl-6-(3-pyridylmethyl)-7,8-dihydro-2-naphthalenol,
(7) 8-methyl-7-(3-pyridylmethyl)-5,6-dihydro-2-naphthalenol,
(8) 4-[(1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(9) 4-[(5-methoxy-1-methyl-3 ,4-dihydro-2-naphthalenyl)methyl]pyridine,
(10) 4-[(6-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(11) 4-[(7-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(12) 5-methyl-6-(4-pyridylmethyl)-7,8-dihydro-1-naphthalenol,
(13) 5-methyl-6-(4-pyridylmethyl)-7,8-dihydro-2-naphthalenol,
(14) 8-methyl-7-(4-pyridylmethyl)-5,6-dihydro-2-naphthalenol,
(15) 4-[(1-ethyl-5-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(16) 4-[(1-ethyl-6-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(17) 4-[(1-ethyl-7-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(18) 4-[(6-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(19) 4-[(5-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(20) 4-[(6-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(21) 4-[(7-methoxy-3,4-dihydro-2-naphthalenyl)methyl]pyridine,
(22) 4-[(6-methoxy-1-propyl-3,4-dihydro-2-naphthalenyl)methyl]pyridine hydrochloride,
(23) 6-(4-pyridylmethyl)-7,8-dihydro-2-naphthalenol,
(24) 2-(1H-4-imidazolylmethyl)-6-methoxy-3,4-dihydronaphthalene hydrochloride,
(25) 4-[(7-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(26) 4-[(5-methoxy-1-methyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(27) 4-[(1-ethyl-6-methoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(28) 4-[(1-ethyl-7-methoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(29) 4-[(1-ethyl-5-methoxy-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole, hydrochloride,
(30) 4-[(6-methoxy-1-propyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(31) 4-[(5-methoxy-1-propyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(32) 4-[(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(33) 4-[(7-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(34) 4-[(5-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-1H-imidazole,
(35) 4-[(1-benzyl-6-methox
Hartmann Rolf Wolfgang
Ikeda Yoshikazu
Nakakoshi Masamichi
Nomoto Shin
Wachall Bertil
Daiichi Pharmaceutical Co. Ltd.
Fan Jane
Knobbe Martens Olson & Bear LLP
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