Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-18
2002-07-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S307000, C514S314000, C514S336000, C514S359000, C514S383000, C514S396000, C514S397000, C546S148000, C546S176000, C546S280100, C546S282700, C546S350000, C548S255000, C548S262200, C548S267800, C548S311400, C548S346100, C548S343100
Reexamination Certificate
active
06420375
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a medicine, especially to novel fused ring compound having steroid C
17,20
-lyase inhibitory activity, or its production and pharmaceutical compositions containing the same.
BACKGROUND ART
Steroid C
17,20
-lyase converts 17-hydroxypregnenolone and 17-hydroxyprogesterone derived from cholesterol to androgen. Therefore, a medicine having steroid C
17,20
-lyase inhibitory activity suppresses the formation of androgen and estrogen which is produced from androgen, and is useful for the preventing and treating diseases whose exacerbation factor is androgen or estrogen. As the diseases whose exacerbation factor is androgen or estrogen, there may be mentioned, for example, prostate cancer, prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, breast cancer, uterine cancer, mastopathy, uterus myoma, endometriosis, etc.
It has been already known that some steroid type compounds and some non-steroid type compounds inhibit steroid C
17,20
-lyase. The steroid type compounds are disclosed in, for example, WO 92/15404, WO 93/20097, EP-A 288053, EP-A 413270, etc. As non-steroid type compounds, for example, (1H-imidazol-1-yl)methyl-substituted benzimidazole derivatives are shown in Japanese Published Unexamined Patent Application No.85975/1989, carbazole derivatives are shown in WO94/27989 and WO96/14090, azole derivatives are shown in WO95/09157, and 1H-benzimidazole derivatives are shown in U.S. Pat. No. 5,491,161.
Heretofore, steroid C
17,20
-lyase inhibitors which can actually be used as medicine have not been known. Thus, the early development of steroid C
17,20
-lyase inhibitors which are useful as medicine has been highly anticipated.
DISCLOSURE OF INVENTION
The present inventors have done extensive studies so as to find superior androgen synthetase inhibitors, especially steroid a C
17,20
-lyase inhibitors, and found that a compound having the formula (I)
has superior steroid C
17,20
-lyase inhibiting activity because of its specific structure and that the compound has less toxicity and has good properties as medicine. The present invention has been accomplished by these findings.
The present invention relates to:
(1) A compound of the formula:
[wherein A
1
is a 5 or 6-membered ring which may be substituted by a group not containing a cyclic group, A
2
is an aromatic ring which may be substituted, X is a divalent group, Y is a nitrogen atom or a methine group, Z is an ethenylene which may be substituted or ethynylene, R is a heterocyclic group which may be substituted, provided that 3,4-dihydro-6-[3-(1H-imidazol-1-yl)-1-propenyl]-2(1H)-quinolone and 2-[3-[5-ethyl-6-methyl-2-(benzyloxy)-3-pyridyl]-1-propenyl]benzoxazole are excluded.], or a salt thereof,
(2) A compound as shown in the above item (1), wherein R is a 5 or 6-membered nitrogen-containing heterocyclic group which may be substituted,
(3) A compound as shown in the above item (1), wherein R is an imidazolyl, a triazolyl or a pyridyl which may be substituted,
(4) A compound as shown in the above item (1), wherein R is an imidazolyl which may be substituted,
(5) A compound as shown in the above item (1), wherein the ring:
is naphthalene or tetraline,
(6) A compound as shown in the above item (1), wherein the ring:
is benzothiophene or benzofuran,
(7) A compound as shown in the above item (1), wherein the ring:
is benzothiophene,
(8) A compound as shown in the above item (1), wherein Z is an ethenylene which may be substituted,
(9) A compound as shown in the above item (1), wherein Z is an ethenylene which may be substituted by methyl or fluorine,
(10) A compound as shown in the above item (1), wherein Z is unsubstituted ethenylene,
(11) A compound as shown in the above item (1), wherein X is a divalent hydrocarbon group which may be substituted.
(12) A compound as shown in the above item (1), wherein X is a methylene which may be substituted,
(13) A compound as shown in the above item (1), wherein X is unsubstituted methylene,
(14) A compound as shown in the above item (1), which is 1-[(E)-3-(2-naphthyl)-2-propene-1-yl]-1H-imidazole or a salt thereof,
(15) A compound as shown in the above item (1), which is 1-[(E)-3-(2-naphthyl)-2-butene-1-yl]-1H-imidazole or a salt thereof,
(16) A compound as shown in the above item (1), which is 1-[(E)-3-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)-2-propene-1-yl]-1H-imidazole or a salt thereof,
(17) A compound as shown in the above item (1), which is 4-[(E)-3-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)-2-propene-1-yl]-1H-imidazole or a salt thereof,
(18) A compound as shown in the above item (1), which is 4-[-(E)-3-(5-methoxy-3-methylbenzo[b]thiophene-2-yl)-2-propene-1-yl]-1H-imidazole or a salt thereof,
(19) A pharmaceutical composition containing a compound as shown in the above item (1),
(20) A steroid C
17,20
-lyase inhibitory composition containing a compound of the formula:
[wherein A
1
is a 5 or 6-membered ring which may be substituted by a group not containing a cyclic group, A
2
is an aromatic ring which may be substituted, X is a divalent group, Y is a nitrogen atom or a methine group, Z is an ethenylene which may be substituted or ethynylene, R is a heterocyclic group which may be substituted.]or a salt thereof,
(21) An antitumor composition which contains a compound of the formula (I′) or salt thereof,
(22) An antitumor composition containing a compound of the formula (I′) or salt thereof as shown in the above item (21), wherein the antitumor composition is treating or preventing agent for breast cancer or prostate cancer,
(23) A method for treating mammal suffering from diseases whose exacerbation factor is androgen or estrogen, which comprises administering an effective amount of a compound of the formula (I) or a salt thereof;
(24) A method as shown in the above item (23) wherein the diseases whose exacerbation factor is androgen or estrogen is prostate cancer, prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, breast cancer, uterine cancer, mastopathy, uterus myoma, endometriosis;
(25) Use of a compound of the formula (I′) or salt thereof for the production of an antitumor composition for treating diseases whose exacerbation factor is androgen or estrogen;
(26) Use as shown in the above item (25) wherein the diseases whose exacerbation factor is androgen or estrogen is prostate cancer, prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, breast cancer, uterine cancer, mastopathy, uterus myoma, endometriosis; and
(27) A process for producing a compound of the above item (1), which comprises reacting a compound of the formula:
[wherein L is a leaving group, and each of the other symbols has the meanings as defined in the above item (1).] or a salt thereof with a compound of the formula:
M—R (III)
[wherein M is a hydrogen atom or a metal atom, and R has the meanings as defined in the above item (1).] or a salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
Examples of the “5 or 6-membered ring” in the “5 or 6-membered ring which may be substituted by a group not containing a cyclic group” represented by A
1
ring in the formula (I) include, for example, a 5 or 6-membered cyclic hydrocarbon, a 5 or 6-membered aromatic heterocyclic ring and a 5 or 6-membered non-aromatic heterocyclic ring, etc.
Examples of the 5 or 6-membered cyclic hydrocarbons include, for example, a C
5-6
cyclo alkane (cyclopentane, cyclohexane), a C
5-6
cycloalkene (cyclopentene, cyclohexene) and benzene, etc.,
The examples of the 5 or 6-membered aromatic heterocyclic groups include, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidi
Aono Tetsuya
Itoh Fumio
Kaku Tomohiro
Yamaoka Masuo
Chao Mark
McKenzie Thomas
Ramesh Elaine M.
Raymond Richard L.
Takeda Chemical Industries Ltd.
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