Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-18
2003-06-03
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S333500, C548S341500
Reexamination Certificate
active
06573289
ABSTRACT:
This application is a 371 of PCT/JP99/02143, filed on Apr. 22, 1999.
TECHNICAL FIELD
The present invention relates to a medicine, especially to novel naphthalene derivatives having steroid C
17,20
-lyase inhibitory activity, or its production and pharmaceutical compositions containing the same.
BACKGROUND ART
It is known that, in the biosynthesis of androgen in vivo, steroid C
17,20
-lyase acts at the final stage. That is, steroid C
17,20
-lyase converts 17-hydroxypregnenolone and 17-hydroxyprogesterone derived from cholesterol to dehydroepiandrosterone and androstenedione, respectively. Therefore, a medicine having steroid C
17,20
-lyase inhibitory activity suppress the formation of androgen and estrogen which is produced from androgen, and is useful for preventing and treating diseases whose exacerbation factor is androgen or estrogen. As the disease whose exacerbation factor is androgen or estrogen, there may be mentioned, for example, prostate cancer, prostatic hypertrophy, virilism, irsutism, male pattern alopecia, precocious puberty, breast cancer, uterine cancer, mastopathy, uterus myoma, endometriosis, adenomyosis of uterus, polycystic ovary syndrome, 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 expected.
DISCLOSURE OF INVENTION
The present inventors have done extensive studies so as to find superior steroid C
17,20
-lyase inhibitors, and found that a compound having the formula (I) which has a naphthalene ring structure having nitrogen-containing heterocyclic groups through substituted methylene chain at 2-position unexpectedly 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 a medicine. The present invention has been accomplished by these findings.
Thus the present invention relates to
(1) A compound of the formula:
wherein A
1
is an imidazolyl group, a thiazolyl group, an oxazolyl group or a pyridyl group, each of which may be substituted; R
11
is a hydrogen atom, a hydrocarbon group which may be substituted; or a monocyclic aromatic heterocyclic group which may be substituted; R
21
is a hydrogen atom or a lower alkyl group which may be substituted; R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, a thiol group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom, provided (1) that R
11
is a saturated hydrocarbon group which may be substituted when A
1
is an oxazolyl group which may be substituted or a thiazolyl group which may be substituted, (2) that R
7
is a hydroxy group which may be substituted or a lower alkyl group when A
1
is a pyridyl group and R
11
or R
21
is a hydrogen atom and (3) that R
21
is a lower alkyl group which may be substituted when R
11
is a hydrogen atom, a salt thereof;
(2) A compound as shown in the above item (1), wherein R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom;
(3) A compound as shown in the above item (1), wherein R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted or an acyl group;
(4) A compound as shown in the above item (1), wherein R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are independently a hydrogen atom, a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, or a halogen atom;
(5) A compound as shown in the above item (1), wherein A
1
is a 4- or 5-imidazolyl group which may be substituted or a 3- or 4-pyridyl group which may be substituted;
(6) A compound as shown in the above item (1), wherein A
1
is a 4- or 5-imidazolyl group which may be substituted with {circle around (1)} a C
1-4
alkyl group unsubstituted or substituted with a C
1-4
alkanoyl, carboxyl, or a C
1-4
alkoxy-carbonyl, {circle around (2)} a C
1-3
alkoxy group, {circle around (3)} a C
1-6
alkanoyl {circle around (4)} C
1-4
alkylsulfonyl, {circle around (5)} carbamoyl, a mono- or di-C
1-10
alkyl carbamoyl group, a mono- or di-C
6-14
arylcarbamoyl group or a mono- or di-C
7-16
aralkylcarbamoyl group, or {circle around (6)} sulfamoyl, a mono- or di-C
1-10
alkyl sulfamoyl group, a mono- or di-C
6-14
arylsulfamoyl group, or a mono- or di-C
7-16
aralkyl sulfamoyl group;
(7) A compound as shown in the above item (1), wherein A
1
is a 3- or 4-pyridyl group which may be substituted with {circle around (1)} a C
1-4
alkyl group unsubstituted or substituted with a C
1-4
alkanoyl, carboxyl, or a C
1-4
alkoxy-carbonyl, {circle around (2)} a C
1-3
alkoxy group, {circle around (3)} a C
1-6
alkanoyl {circle around (4)} C
1-4
alkylsulfonyl, {circle around (5)} carbamoyl, a mono- or di-C
1-10
alkyl carbamoyl group, a mono- or di-C
6-14
arylcarbamoyl group or a mono- or di-C
7-16
aralkylcarbamoyl group, or {circle around (6)} sulfamoyl, a mono- or di-C
1-10
alkyl sulfamoyl group, a mono- or di-C
6-14
arylsulfamoyl group, or a mono- or di-C
7-16
aralkyl sulfamoyl group;
(8) A compound as shown in the above item (1), wherein A
1
is a thiazolyl group which may be substituted;
(9) A compound as shown in the above item (1), wherein R
21
is a hydrogen atom or a lower alkyl group;
(10) A compound as shown in the above item (1), wherein R
21
is a hydrogen atom;
(11) A compound as shown in the above item (1), wherein one to three groups of R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are independently a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted, an acyl group or a halogen atom;
(12) A compound as shown in the above item (1), wherein one to three groups of R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are independently a C
1-6
alkyl group which may be substituted, a hydroxy group which may be substituted or a C
1-6
acyl group;
(13) A compound as shown in the above item (1), wherein R
11
is a hydrogen atom, a lower alkyl group which may be substituted, a phenyl group which may be substituted or a pyridyl group which may be substituted;
(14) A compound as shown in the above item (1), wherein R
11
is a hydrogen atom, a lower alkenyl group, a cyclic alkyl group, a phenyl group, a pyridyl group, or a lower alkyl group which may be substituted with halogen atom(s);
(15) A compound as shown in the above item (1), wherein R
11
is an C
1-6
alkyl group and R
21
is a hydrogen atom;
(16) A compound as shown in the above item (1), wherein R
11
is an isopropyl group and R
21
is a hydrogen atom;
(17) A compound as shown in the above item (1), wherein R
7
is a hydroxy group which may be substituted or a lower alkyl group;
(18) A compound as shown in the above item (1), wherein R
7
is (1) a hydroxy group which may be substituted with a lower alkanoyl group, a lower alkanoyloxy-lower alkyl group, a lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkyl group which may have one to 4 halogen atoms (e.g. fluorine atoms), or a benzyl group, (2) a halogen atom, (3) a lower alkyl group which may be substituted with a hydroxy grou
Kaku Tomohiro
Kusaka Masami
Ojida Akio
Tasaka Akihiro
Yamaoka Masuo
Chao Mark
McKane Joseph K.
Ramesh Elaine M.
Small Andrea D.
Takeda Chemical Industries Ltd.
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