Benzothiophenes and related compounds as estrogen agonists

Details Benzothiophenes and related compounds as estrogen agonists Benzothiophenes and related compounds as estrogen agonists

1996-07-01

2004-06-29

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S202000

Reexamination Certificate

active

06756388

ABSTRACT:

BACKGROUND OF THE INVENTION
The value of naturally occurring estrogens and synthetic compositions demonstrating “estrogenic” activity has been in their medical and therapeutic uses. A traditional listing of the therapeutic applications for estrogens alone or in combination with other active agents includes: oral contraception; relief for the symptoms of menopause; prevention of threatened or habitual abortion; relief of dysmenorrhea; relief of dysfunctional uterine bleeding; an aid in ovarian development; treatment of acne; diminution of excessive growth of body hair in women (hirsutism); the prevention of cardiovascular disease; treatment of osteoporosis; treatment of prostatic carcinoma; and suppression of post-partum lactation [Goodman and Gilman, The Pharmacological Basis Of Therapeutics (Seventh Edition) Macmillan Publishing Company, 1985, pages 1421-1423]. Accordingly, there has been increasing interest in finding newly synthesized compositions and new uses for previously known compounds which are demonstrably estrogenic, this is, able to mimic the action of estrogen in estrogen responsive tissue.
From the viewpoint of pharmacologists interested in developing new drugs useful for the treatment of human diseases and specific pathological conditions, it is most important to procure compounds with some demonstrable estrogen-like function but which are devoid of proliferative side-effects. Exemplifying this latter view, osteoporosis, a disease in which bone becomes increasingly more fragile, is greatly ameliorated by the use of fully active estrogens; however, due to the recognized increased risk of uterine cancer in patients chronically treated with active estrogens, it is not clinically advisable to treat osteoporosis in intact women with fully active estrogens for prolonged periods. Accordingly estrogen agonists are the primary interest and focus.
Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more that 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. These cost the nation over $10 billion. Hip fractures are the most serious, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecast to increase three-fold over the next 60 years, and one study estimates that there will be 4.5 million hip fractures worldwide in 2050. Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
Estrogen is the agent of choice in preventing osteoporosis or post menopausal bone loss in women; it is the only treatment which unequivocally reduces fractures. However, estrogen stimulates the uterus and is associated with an increased risk of endometrial cancer. Although the risk of endometrial cancer is thought to be reduced by a concurrent use of a progestogen, there is still concern about possible increased risk of breast cancer with the use of estrogen.
There is a need for improved estrogen agonists which exert selective effects on different tissues in the body. Tamoxifen, 1-(4-&bgr;-dimethylaminoethoxyphenyl)-1,2-diphenyl-but-1-ene, is an antiestrogen which has a palliative effect on breast cancer, but is reported to have estrogenic activity in the uterus.
Recently it has been reported (Osteoporosis Conference Scrip No. 1812/13 Apr. 16/20, 1993, p29) that raloxifene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, mimics the favorable action of estrogen on bone and lipids but, unlike estrogen, has minimal uterine stimulatory effect. (Breast Cancer Res. Treat. 10(1). 1987 p 31-36 Jordan, V.C. et al.)
Raloxifene as well as ethers and esters thereof and related compounds are described as antiestrogen and antiandrogenic materials which are effective in the treatment of certain mammary and prostate cancers. See U.S. Pat. No. 4,418,068 and Charles D. Jones, et al., J. Med. Chem. 1984, 27, 1057-1066.
Jones, et al in U.S. Pat. No. 4,133,814 describe derivatives of 2-phenyl-3-aroylbenzothiophene and 2-phenyl-3-aroylbenzothiophene-1-oxides which are useful as antifertility agents as well as suppressing the growth of mammary tumors.
Related 2-phenyl-3-aroylbenzothiophenes have also been claimed to modulate the clearance of antibody coated cells from the circulation of mammals, thus providing a method of treating autoimmune disease, U.S. Patent No. 5,075,321.
SUMMARY OF INVENTION
This invention provides compounds of the formula
wherein
A, B and Z are independently
(a) —CH═,
(b) —CR
4
═,
(c) ═N—;
X is
(a) —S—,
(b) —O—,
(c) —NH—,
(d) —NR
2
—,
(e) —CH
2
CH
2
—,
(f) —CH
2
CH
2
CH
2
—,
(g) —CH
2
O—,
(h) —OCH
2
—,
(i) —CH
2
S—,
(j)
(k) —SCH
2
—,
(l) —N═CR
2
—,
(m) —R
2
C═N—;
Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of halo, hydroxy, C
1
-C
4
alkyl, C
1
-C
4
alkoxy,
 and R
1
SO
2
NH—;
(b) C
1
-C
8
alkyl, said alkyl groups being optionally substituted with 1-3 substituents independently selected from the group consisting of
 and R
1
SO
2
NH—;
(c) C
3
-C
8
cycloalkyl, optionally substituted with 1-2 substituents independently selected from the group consisting of —OH,—R
1
,
 and R
1
SO
2
NH—;
(d) C
3
-C
8
cycloalkenyl, optionally substituted with 1-2 substituents independently selected from the group consisting of —OH,
 and R
1
SO
2
NH—;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR
2
— and —S(O)
n
—, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, aryl (C
1
-C
4
)alkyl,—CO
2
H, —CN, —CONHOR
1
, —SO
2
NHR
1
, —NH
2
, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, —NHSO
2
R
1
,—NHCOR
1
, —NO
2
, and -aryl;
a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR
2
— and —S(O)
n
— optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, aryl (C
1
-C
4
)alkyl,—CO
2
H, —CN, —CONHOR
1
, —SO
2
NHR
1
, —NH
2
, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, —NHSO
2
R
1
,—NHCOR
1
, —NO
2
, and -aryl;
(g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR
2
— and —S(O)
n
—, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, aryl (C
1
-C
4
)alkyl,—CO
2
H, —CN, —CONHOR
1
, —SO
2
NHR
1
, —NH
2
, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, —NHSO
2
R
1
, —NHCOR
1
, —NO
2
, —OH, and -aryl;
D is
(a) —CO—,
(b) —CR
2
R
3
—,
(c) —CONH—,
(d) —NHCO—,
(e) —CR
2
(OH)—,
(f) —CONR
2
—,
(g) —NR
2
CO—,
E is
(a) a single bond;
(b) phenyl, or phenyl substituted with up to three substituents independently selected from the group consisting of hydrogen, halo, C
1
-C
4
alk

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