Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ether doai
Patent
1998-10-08
2000-03-14
Cook, Rebecca
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ether doai
A61K 3140
Patent
active
060373792
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the use of Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol for lowering serum total or LDL cholesterol or increasing serum HDL cholesterol.
It has been demonstrated that elevated levels of serum cholesterol associated with low density lipoproteins (LDL) are a major contributing factor in the development and progression of atherosclerosis. Low serum HDL cholesterol is an independent risk factor for atherosclerosis. Therefore it is desirable to provide a method for reducing serum total cholesterol or LDL cholesterol levels combined with an increasing effect on HDL cholesterol levels in patients with hypercholesterolemia or at risk of developing hypercholesterolemia.
Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol, also known as (deaminohydroxy)toremifene, having the chemical structure represented by formula, ##STR1## is a metabolite of known antiestrogen drug toremifene. Toremifene is currently used clinically for the treatment of estrogen receptor positive breast cancer.
Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol has been earlier described e.g. in Sipila, H. et al., "Metabolism of toremifene in the rat", J. Steroid Biochem., 36, 3, 211-215, (1990), in Kangas, L., "Biochemical and pharmacological effects of toremifene metabolites", Cancer Chemother. Pharmacol., (1990), 27, 8-12, in Anttila, M. et al., "Pharmacokinetics of toremifene", J. Steroid Biochem., 36, 3, 249-252, (1990), in Simberg, N. et al, "In vitro and in vivo binding of toremifene and its metabolites in rat uterus", J. Steroid Biochem., 36, 3, 197-202, (1990), in Bishop, J. et al., "Phase I clinical and pharmacokinetics study of high dose toremifene in postmenopausal patients with advanced breast cancer", Cancer Chemother. Pharmacol., 30, 174-178 (1992) and in the applicant's International Patent Application No. PCT/FI95/00475. It was shown that this compound is active in producing the release of TGF-.beta. but is devoid of significant hormonal activity.
Now it has been found that Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)-phenoxy]ethanol is active in lowering serum total and LDL cholesterol and increasing serum HDL cholesterol. Since this compound lack significant hormone associated side effects, it is especially suitable for lowering serum total or LDL cholesterol or increasing serum HDL cholesterol, as well as in the treatment or prevention of atherosclerosis.
The invention provides a method of lowering serum total or LDL cholesterol levels or increasing serum HDL cholesterol levels, which method comprises administering to a patient in need of such treatment an effective amount of Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol.
The invention also provides a method for the prevention or treatment of atherosclerosis, which method comprises administering to a patient in need of such treatment an effective amount of Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol.
The present invention also provides the use of Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol in the manufacture of a medicament for use in lowering serum total or LDL cholesterol levels or increasing serum HDL cholesterol levels.
The invention also provides a pharmaceutical composition for use in lowering serum total or LDL cholesterol levels or increasing serum HDL cholesterol levels comprising an effective amount of Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol.
The invention also provides the use of Z-2-[4-(4chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol in the manufacture of a medicament for the prevention or treatment of atherosclerosis.
The compound of the invention may be administered in a variety of ways including orally, parenterally or transdermally using conventional forms of preparations, such as capsules, tablets, granules, powders, suppositories, injections, patches, suspensions and syrups. The term "effective amount" means an amount of compound of the invention which is capable of lowering serum total or LDL cholesterol levels or increasing serum HDL cholesterol levels. The c
REFERENCES:
patent: 4996225 (1991-02-01), Tiovola et al.
CA 114:220854, Kangas, Cancer Chemother. Pharmacol, 27 (1), 8-12, 1990.
Drugnl AN 95:1133 R&D Focus Drug News, Jul. 10, 1995.
"Biochemical and Pharmacological Effects of Toremifene Metabolites", Lauri Kangas, Cancer Chemother Pharmacol, 1990, vol. 27, pp. 8-12.
"Tamoxifen and Toremifene Lower Serum Cholesterol by Inhibition of .increment..sup.8 -Cholesterol Conversion to Lathosterol in Women with Breast Cancer" H. Gylling et al. Journal of Clinical Oncology, Dec. 1995; vol. 13, No. 12, pp. 2900-2905.
"Pharmacokinetics of Toremifene", M. Anttila et al., J. Steroid Biochemistry, 1990, vol. 36, No. 3, pp. 249-252.
"Metabolism of Toremifene in the Rat", H. Sipila et al., J. Steroid Biochemistry, 1990, vol. 36, No. 3, pp. 211-215.
"In Vitro and In Vivo Binding of Toremifene and its Metabolites in Rat Uterus", N. Simberg et al. J. Steroid Biochemsitry, 1990, vol. 36, No. 3, pp. 197-202.
"Phase I Clinical and Pharmokinetics Study of High-Dose Toremifene in Postmenopausal Patients with Advanced Breast Cancer", James Bishop et al., Cancer Chemother Pharmacol, 1992, vol. 30, pp. 174-178.
DeGregorio Michael
Harkonen Pirkko
Kangas Lauri
Mantyla Eero
Miettinen Tatu
Cook Rebecca
Orion Corporation
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