Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-21
2003-08-19
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S311000
Reexamination Certificate
active
06608203
ABSTRACT:
This invention relates to novel tetrahydroisoquinoline compounds that are useful as estrogen agonists and antagonists, and the pharmaceutical uses thereof.
BACKGROUND OF THE INVENTION
The value of naturally occurring estrogens and synthetic compositions demonstrating “estrogenic” activity has typically 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, but is not limited to, 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 postpartum lactation (Goodman and Gilman, The Pharmacological Basis Of Therapeutics (7th Ed.), Macmillan Publishing Company, 1985, pages 1421-1423). Accordingly, there has been increasing interest in finding newly synthesized compounds and new uses for previously known compounds that are demonstrably estrogenic, that 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 desirable to procure compounds having demonstrable estrogen-like function, but which are devoid of unwanted 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 treated chronically with active estrogens, it is not clinically advisable to treat osteoporosis in intact women with fully active estrogens for prolonged periods.
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 injuries cost the nation over $10 billion per year. Hip fractures are the most serious, with 5-20% of patients dying within one year, and over 50% of the 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 3-fold over the next 60 years, and one study estimates 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 that 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 remains concern about possible increased risk of breast cancer with the use of estrogen.
Black et al., in EP 0605193A1, report that estrogen, particularly when taken orally, lowers plasma levels of LDL and raises plasma levels of the beneficial high density lipoproteins (HDLs). Thus, estrogen can be an effective therapy for hypercholesterolemia. However, as discussed supra, long-term estrogen therapy has been implicated in a variety of disorders, including an increase in the risk of uterine and breast cancer, causing many women to avoid this treatment. Recently suggested therapeutic regimens, that seek to lessen the cancer risk, such as administering combinations of progestogen and estrogen, cause the patient to experience unacceptable bleeding. Furthermore, combining progestogen with estrogen seems to blunt the desired serum cholesterol effects of estrogen. The significant undesirable effects associated with estrogen therapy support the need to develop alternative therapies for hypercholesterolemia that have the desirable effect on serum LDL but do not cause undesirable effects.
There is a need for improved estrogen agonists that exert selective effects on different tissues in the body. Tamoxifen, or 1-(4-&bgr;-dimethylaminoethoxyphenyl)-1,2-diphenyl-but-1-ene, is an antiestrogen that has a palliative effect on breast cancer, but is reported to have estrogenic activity in the uterus. Gill-Sharma et al.,
J. Repr. Fert.,
99:395 (1993), discloses that tamoxifen at 200 and 400 mg/kg/day reduces the weights of the testes and secondary sex organs in male rats.
Recently it has been reported (Osteoporosis Conf. Scrip No. 1812/13, p. 29 (Apr. 16-20, 1993)) that raloxifene, or 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. (Jordan et al.,
Breast Cancer Res. Treat.,
10(1):31-36 (1987)).
Neubauer et al.,
The Prostate,
23:245 (1993), teaches that raloxifene treatment of male rats produced regression of the ventral prostate.
Raloxifene and related compounds are described as antiestrogenic and antiandrogenic materials that are effective in the treatment of certain mammary and prostate cancers. See U.S. Pat. No. 4,418,068 and Jones et al.,
J. Med. Chem.,
27:1057-66 (1984).
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 that are useful as antifertility agents, and also suppress the growth of mammary tumors.
Lednicer et al.,
J. Med. Chem.,
12:881 (1969), describes estrogen antagonists of the structure
wherein R
2
is phenyl or cyclopentyl and R
3
is H, —CH
2
CHOHCH
2
OH, or
Bencze et al.,
J. Med. Chem.,
10:138 (1967), prepared a series of tetrahydronaphthalenes intended to achieve separation of estrogenic, antifertility, and hypocholesterolemic activities, although they were only partially successful in doing so. These structures have the general formula:
wherein R
1
is H or OCH
3
, R
2
is H, OH, OCH
3
, OPO(OC
2
H
5
)
2
, OCH
2
CH
2
N(C
2
H
5
)
2
, OCH
2
COOH, or OCH(CH
3
)COOH, and R
3
is H or Cl.
U.S. Pat. No. 3,234,090 discloses compounds having estrogenic and antifungal properties, as well as procedures for the preparation of these compounds. The described compounds have the formula:
in which Ph is a 1,2-phenylene radical, Ar is a monocyclic carbocyclic aryl group substituted by tertiary amino-lower alkyl-oxy, in which the tertiary amino is separated from the oxy by at least two carbon atoms, R is hydrogen, an aliphatic radical, a carbocyclic aryl radical, a carbocyclic aryl-aliphatic radical, a heterocyclic aryl radical, or a heterocyclic aryl aliphatic radical, the group of the formula —(C
n
H
2n-2
)— stands for an unbranched alkylene radical having from three to five carbon atoms and carrying the groups Ar and R, salts, N-oxides, salts of N-oxides, or quaternary ammonium compounds thereof.
U.S. Pat. No. 3,277,106 refers to basic ethers with estrogenic, hypocholesterolemic, and antifertility effects, those ethers having the formula:
in which Ph is a 1,2-phenylene radical, Ar is a monocyclic aryl radical substituted by at least one amino-lower alkyl-oxy group in which the nitrogen atom is separated from the oxygen atom by at least two carbon atoms, R is an aryl radical, and the portion —(C
n
H
2n-2
)— stands for lower alkylene forming with Ph a six- or seven-membered ring, two of the ring carbon atoms thereof carry the groups Ar and R, salts, N-oxides, salts of
Cameron Kimberly O.
Chesworth Richard
DaSilva-Jardine Paul A.
Day Robert F.
Lefker Bruce A.
Benson Gregg C.
Pfizer Inc.
Richardson Peter C.
Seaman D. Margaret
Wichtowski John A.
LandOfFree
Tetrahydroisoquinoline compounds as estrogen... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Tetrahydroisoquinoline compounds as estrogen..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tetrahydroisoquinoline compounds as estrogen... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3096781