Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-12
2003-11-18
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S341100, C548S338100, C548S341500, C548S110000, C548S336100, C548S342100, C548S315400, C548S315100, C548S255000, C548S250000, C548S252000, C548S312400, C548S235000, C548S311400, C548S314700, C548S195000, C548S237000, C548S311700, C514S063000, C514S365000, C514S374000, C514S381000, C514S359000, C514S397000
Reexamination Certificate
active
06649643
ABSTRACT:
This application is the National Phase filing of International Patent Application No. PCT/JP00/07283, filed Oct. 19, 2000.
TECHNICAL FIELD
The present invention relates to a medicine, especially to novel naphthalene derivatives having a steroid C
17,20
-lyase inhibitory activity, or its production and pharmaceutical compositions containing the same.
BACKGROUND ART
Androgen and estrogen, each of which is a sex hormone, are essential in a living body and have various physiological activities such as differentiation and proliferation of cell, etc. On the other hand, it has been found that each of androgen and estrogen works as a exacerbation factor in some diseases.
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 a steroid C
17,20
-lyase inhibitory activity suppresses 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, hirsutism, 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, 1H-benzimidazole derivatives are shown in U.S. Pat. No. 5,491,161, dihydronaphthalene derivatives are shown in WO99/18075.
Heretofore, steroid C
17,20
-lyase inhibitors which can actually be used as medicine have not been known. Thus, it has been expected the early development of steroid C
17,20
-lyase inhibitors which are useful as medicine.
DISCLOSURE OF INVENTION
The present invention provides:
(1) A compound of the formula:
wherein R is a hydrogen atom or a protecting group, R
1
is a lower alkyl group or a cyclic alkyl group, R
2
is a group represented by the formula:
(wherein a ring A
1
is a 5- or 6-membered ring containing an oxygen atom optionally having substituents, and a ring A
2
and a ring A
3
may have substituents), a group represented by the formula:
(wherein the ring B
1
is a 5- or 6-membered ring containing an oxygen atom optionally having substituents and a ring B
2
and a ring B
3
may have substituents) or a group of the formula:
(wherein each of R
3
, R
5
is a hydrogen atom, a lower alkyl group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, R
4
is an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents or a carbamoyl group optionally having substituents, R
6
is an optionally halogenated lower alkyl group and n is an integer of 0 to 3.), or a salt thereof,
(2) A compound as defined in (1), wherein R is (i) a hydrogen atom, (ii) a formyl group or (iii) a C
1-6
alkyl-carbonyl group, a phenyl-carbonyl group, a C
1-6
alkyl-oxycarbonyl group, an allyl-oxycarbonyl group, a phenyloxycarbonyl group, a C
7-10
aralkyl-oxy-carbonyl group, a trityl group, a N,N-dimethylaminosulfonyl group, a C
7-16
aralkyl-oxy-C
1-6
alkyl group each of which optionally has substituents selected from the group consisting of a halogen atom, a C
1-6
alkyl-carbonyl and nitro,
R
1
is a straight chain or branched C
1-6
alkyl group or a C
3-6
cycloalkyl group,
the ring A
1
is a 5- or 6-membered ring containing an oxygen atom together with carbon atoms as ring constituting atoms and the ring may further contain a nitrogen atom and a sulfur atom as the ring constituting atoms, optionally having 1 to 4 substituents selected from the group consisting of (i) a C
1-4
alkyl group optionally having substituents selected from the group consisting C
1-4
alkanoyl, carboxyl and C
1-4
alkoxy-carbonyl, (ii) a C
1-3
alkoxy group, (iii) a C
1-4
alkanoyl group, (iv) a C
1-4
alkylsulfonyl group, (v) a carbamoyl group, (vi) a mono- or di-C
1-10
alkyl carbamoyl group, (vii) a mono- or di-C
6-14
arylcarbamoyl group, (viii) a mono- or di-C
7-16
aralkylcarbamoyl group, (ix) a sulfamoyl group, (x) a mono- or di-C
1-10
alkyl sulfamoyl group, (xi) a mono- or di-C
6-14
arylsulfamoyl group and (xii) a mono- or di-C
7-16
aralkyl sulfamoyl group,
the ring A
2
and the ring A
3
may have 1 to 3 substituents selected from the group consisting of (i) a C
1-4
alkyl group optionally having substituents selected from the group consisting C
1-4
alkanoyl, carboxyl and C
1-4
alkoxy-carbonyl, (ii) a C
1-3
alkoxy group, (iii) a C
1-4
alkanoyl group, (iv) a C
1-4
alkylsulfonyl group, (v) a carbamoyl group, (vi) a mono- or di-C
1-10
alkyl carbamoyl group, (vii) a mono- or di-C
6-14
arylcarbamoyl group, (viii) a mono- or di-C
7-16
aralkylcarbamoyl group, (ix) a sulfamoyl group, (x) a mono- or di-C
1-10
alkyl sulfamoyl group, (xi) a mono- or di-C
6-14
arylsulfamoyl group and (xii) a mono- or di-C
7-16
aralkyl sulfamoyl group at any substitutable position,
the ring B
1
is a 5- or 6-membered ring containing an oxygen atom together with carbon atoms as ring constituting atoms and the ring may further contain a nitrogen atom and a sulfur atom as the ring constituting atoms, optionally having 1 to 4 substituents selected from the group consisting of (i) a C
1-4
alkyl group optionally having substituents optionally having substituents selected from the group consisting C
1-4
alkanoyl, carboxyl and C
1-4
alkoxy-carbonyl, (ii) a C
1-3
alkoxy group, (iii) a C
1-4
alkanoyl group, (iv) a C
1-4
alkylsulfonyl group, (v) a carbamoyl group, (vi) a mono- or di-C
1-10
alkyl carbamoyl group, (vii) a mono- or di-C
6-14
arylcarbamoyl group, (viii) a mono- or di-C
7-16
aralkylcarbamoyl group, (ix) a sulfamoyl group, (x) a mono- or di-C
1-10
alkyl sulfamoyl group, (xi) a mono- or di-C
6-14
arylsulfamoyl group and (xii) a mono- or di-C
7-16
aralkyl sulfamoyl group,
the ring B
2
and the ring B
3
may have 1 to 3 substituents selected from the group consisting of (i) a C
1-4
alkyl group optionally having substituents selected from the group consisting C
1-4
alkanoyl, carboxyl and C
1-4
alkoxy-carbonyl, (ii) a C
1-3
alkoxy group, (iii) a C
1-4
alkanoyl group, (iv) a C
1-4
alkylsulfonyl group, (v) a carbamoyl group, (vi) a mono- or di-C
1-10
alkyl carbamoyl group, (vii) a mono- or di-C
6-14
arylcarbamoyl group, (viii) a mono- or di-C
7-16
aralkylcarbamoyl group, (ix) a sulfamoyl group, (x) a mono- or di-C
1-10
alkyl sulfamoyl group, (xi) a mono- or di-C
6-14
arylsulfamoyl group and (xii) a mono- or di-C
7-16
aralkyl sulfamoyl group at any substitutable position,
R
3
and R
5
is independently
(i) a hydrogen atom,
(ii) a C
1-4
alkyl group optionally having substituents selected from the group consisting of C
1-4
alkanoyl, carboxyl and C
1-4
alkoxy-carbonyl,
(iii) a group selected from the group consisting of a hydroxy group, a C
1-4
alkoxy group, a C
1-4
alkanoyloxy group, a carbamoyloxy group and a mono- or di-C
1-4
alkyl-carbamoyloxy group,
(iv) a group selected from the group consisting of a thiol group, a C
1-4
alkylthio group and a C
1-4
alkanoylthio group,
(v) a group selected from the group consisting of an amino group, a C
1-4
alkyl amino group, a di-C
1-4
alkylamino group and a C
1-4
alkanoylamino group,
(vi) an acyl gr
Kaku Tomohiro
Kusaka Masami
Ojida Akio
Tasaka Akihiro
Yamaoka Masuo
Chao Mark
Ramesh Elaine M.
Stockton Laura L.
Takeda Chemical Industries Ltd.
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