Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-07-21
2001-07-03
Owens, Amelia (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S299000
Reexamination Certificate
active
06255339
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates to compounds having progesterone receptor binding inhibitory activity and pharmaceutical compositions containing the same.
2. Background Art
In recent years, also in Japan, there is a tendency for the number of patients suffering from breast cancer to increase, and it is foreseen that the number of patients suffering from breast cancer would become largest among the malignant tumors in women in the 21st century. Ovariectomy has for the first time been used as endocrinotherapy for breast cancer. Thereafter, adrenalectomy and hypophysectomy have been reported to be useful as therapy for breast cancer in progress, and, since then, surgical endocrinotherapy has been mainly used and made progress. In the surgical endocrinotherapy, an organ involved in the secretion of estrogen is removed to regress estrogen dependent breast cancer. This, however, results in loss of not only estrogen but also life-sustaining hormones, including steroid hormones, posing many problems associated with the quality of life.
Non-steroidal anti-estrogen agents typified by Tamoxifen Citrate which appeared in the latter half of 1970s, by virtue of high effect against breast cancer and much lower side effect than conventional androgen and estrogen, have become extensively applied in clinical investigations and replaced the surgical endocrinotherapy used as main therapy for breast cancer up to that point.
More recently, agents having a new mechanism of action, such as medroxyprogesterone acetate (MPA) (“NYUGAN NO RINSHO”, vol. 1, 201-213 (1986)), aromatase inhibitor, luteinizing hormone releasing hormone (LH-RH) agonist (“GAN TO KAGAKU RYOHO”, 16, 2729 (1994)) have been developed, resulting in diversified endocrinotherapy for breast cancer.
On the other hand, the treatment of breast cancer with an antiprogesterone agent based on progesterone receptor has been actively attempted particularly in recent years. For example, Mifepristone (RU38486) (FR2497807), Onapristone (ZK98299) (DE3321826) are under development.
Since, however, all of them have a steroidal skeleton, they have been pointed out to have side effect characteristic of steroid. Therefore, in order to overcome these problems, the appearance of an agent having progesterone receptor binding inhibitory activity without the steroid skeleton has been desired in the art.
The present inventors have previously succeeded in isolation of substance PF1092, having inhibitory activity against binding of progesterone to progesterone receptor, from a cultured mixture of a strain belonging to the genus Penicillium (Japanese Patent Application Nos. 20860/1995 and 17074/1996 and EP96100580.8, which are incorporated herein by reference).
SUMMARY OF THE INVENTION
The present inventors have now succeeded in synthesis of various derivatives of substance PF1092 and confirmed that these derivative still have progesterone receptor binding inhibitory activity. The present invention is based on such novel finding.
Thus, according to one aspect of the present invention, there is provided a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
wherein
R
1
represents
a hydroxyl group,
optionally substituted C
1
-C
10
alkyloxy,
optionally substituted C
2
-C
10
alkenyloxy,
optionally substituted C
2
-C
10
alkynyloxy,
C
3
-C
6
cycloalkyloxy,
C
2
-C
12
alkoxyalkyloxy,
five- or six-membered cycloalkyloxy containig one oxygen atom,
optionally substituted C
7
-C
15
aralkyloxy,
optionally substituted C
2
-C
11
alkylcarbonyloxy,
optionally substituted C
3
-C
11
alkenylcarbonyloxy,
optionally substituted C
3
-C
11
alkynylcarbonyloxy,
C
4
-C
15
cycloalkylcarbonyloxy,
C
2
-C
11
alkoxycarbonyloxy,
C
7
-C
15
aryloxy carbonyloxy,
optionally substituted C
8
-C
15
aralkylcarbonyloxy,
optionally substituted C
7
-C
15
aromatic acyloxy,
optionally substituted C
3
-C
15
heteroaromatic acyloxy having at least one hetero atom selected from the group consisting of nitrogen, oxygen, and sulfur atoms,
optionally substituted C
4
-C
12
saturated heterocyclic carbonyloxy having at least one hetero atom selected from the group consisting of nitrogen, oxygen, and sulfur atoms,
C
1
-C
6
alkylsulfonyloxy,
optionally substituted C
6
-C
12
aromatic sulfonyloxy,
C
2
-C
7
alkylcarbamoyloxy
optionally substituted C
7
-C
12
aromatic carbamoyloxy,
optionally substituted C
2
-C
11
alkylcarbonylamino,
optionally substituted C
7
-C
15
aromatic acylamino,
a hydrogen atom,
optionally substituted C
1
-C
10
alkyl,
optionally substituted C
2
-C
10
alkenyl, or
optionally substituted C
2
-C
10
alkynyl;
R
2
represents
a hydroxyl group,
optionally substituted C
1
-C
10
alkyloxy,
optionally substituted C
2
-C
10
alkenyloxy,
optionally substituted C
2
-C
10
alkynyloxy,
C
3
-C
6
cycloalkyloxy,
C
2
-C
12
alkoxyalkyloxy,
five- or six-membered cycloalkyloxy containing one oxygen atom,
optionally substituted C
7
-C
15
aralkyloxy,
optionally substituted C
2
-C
11
alkylcarbonyloxy,
optionally substituted C
3
-C
11
alkenylcarbonyloxy,
optionally substituted C
3
-C
11
alkynylcarbonyloxy,
C
4
-C
15
cycloalkylcarbonyloxy,
C
2
-C
11
alkoxycarbonyloxy,
C
7
-C
15
aryloxy carbonyloxy,
optionally substituted C
8
-C
15
aralkylcarbonyloxy,
optionally substituted C
7
-C
15
aromatic acyloxy,
optionally substituted C
3
-C
15
heteroaromatic acyloxy having at least one hetero atom selected from the group consisting of nitrogen, oxygen, and sulfur atoms,
optionally substituted C
4
-C
12
saturated heterocyclic carbonyloxy having at least one hetero atom selected from the group consisting of nitrogen, oxygen, and sulfur atoms,
C
1
-C
6
alkylsulfonyloxy,
optionally substituted C
6
-C
12
aromatic sulfonyloxy,
C
2
-C
7
alkylcarbamoyloxy
optionally substituted C
7
-C
12
aromatic carbamoyloxy,
optionally substituted C
2
-C
11
alkylcarbonylamino,
optionally substituted C
7
-C
15
aromatic acylamino;
R
3
represents
a hydrogen atom
optionally substituted C
1
-C
10
alkyl, or
optionally substituted C
2
-C
10
alkenyl;
R
4
represents
a hydrogen atom
optionally substituted C
1
-C
10
alkyl, or
optionally substituted C
2
-C
10
alkenyl; and
R
5
represents
a hydrogen atom
optionally substituted C
1
-C
10
alkyl, or
optionally substituted C
2
-C
10
alkenyl,
provided that a compound wherein both R
1
and R
2
represent a hydroxyl group, R
3
and R
5
represent a hydrogen atom, and R
4
represents methyl, a compound wherein R
1
represents methylcarbonyloxy, and R
2
represents a hydroxyl group, R
3
and R
5
represent a hydrogen atom, and R
4
represents methyl, a compound wherein R
1
represents a hydroxyl group, R
2
represent methylcarbonyloxy, R
3
and R
5
represent a hydrogen atom, and R
4
represents methyl are excluded.
According to another aspect of the present invention, there is provided a process for producing a compound represented by the formula (I) according to claim
1
, wherein R
1
and R
2
represent a hydroxyl group, R
3
represents a hydrogen atom, R
4
represents a hydrogen atom, optionally substituted C
1
-C
10
alkyl, or C
2
-C
10
alkenyl and R
5
represents a hydrogen atom, said process comprising the steps of:
(a) oxidizing the following compound (11):
and then conducting acetal protection;
(b) reacting the resultant compound (12):
wherein W is a protective group of an acetal group, with benzenesulfonylmethyl in the presence of a base;
(c) protecting the resultant compound (13):
with a hydroxyl group and then conducting a ring-opening reaction in the presence of a base;
(d) subjecting the resultant compound (14):
to a ring-closing reaction with a Lewis acid;
(e) reducing the resultant compound (15):
(f) subjecting the resultant compound (16):
and 3-trimethylsilyl-3-buten-2-one to Michael addition and cyclocondensation in the presence of a base;
(g) condensing the resultant compound (17):
with &agr;-keto ester by aldol condensation in the presence of a base and optionally a catalytic amount of zinc chloride;
(h) heating the resultant
Ajito Keiichi
Kurihara Ken-ichi
Miyajima Kaori
Okonogi Tsuneo
Shinei Rie
Meiji Seika Kaisha Ltd.
Owens Amelia
Wenderoth , Lind & Ponack, L.L.P.
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