KR19990077157A - Use of Centroman L-Enantiomers for the Preparation of Pharmaceutical Compositions for the Treatment or Prevention of Breast Cancer - Google Patents

Abstract

The present invention provides a novel use of Centroman's l-enantiomer or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prevention of breast cancer.

Description

Use of Centroman L-Enantiomers for the Preparation of Pharmaceutical Compositions for the Treatment or Prevention of Breast Cancer

Breast cancer is the most common malignant tumor and the leading cause of cancer death in women. This causes about 20% of cancer deaths in women. However, despite years of intensive research and new types of treatment, the age-controlled mortality from breast cancer in the Western world has substantially stabilized over the past 30 years. The term "breast cancer" refers to cancer that occurs in the ducts and glandular structures of the breast. Breast cancer is rare in women who have had ovaries removed, and ovarian resection before age 35 reduces the risk by one third. Women who have their first child before 18 have only one-third of the risks compared to women who have not had their first child by age 30. Growth of breast cancer is associated with the presence of estrogens. Therefore, the treatment of breast cancer is to block the source of estrogen by ovarian resection or hysterectomy. An alternative to this surgical approach is endocrine therapy whereby an estrogen antagonist is used to reduce estrogen concentration at the target site.

Centcroman is a nonsteroidal compound known to have antiestrogens activity. It is used in India as an oral contraceptive (see, eg, Salman et al., US Pat. No. 4,447,622; Singh et al., Acta Endocrinol. (Copenh) 126 (1992), 444-450; Grubb, Curr. Opin) Obstet.Gynecol. 3 (1991), 491-495; Sankaran et al., Contraception 9 (1974), 279-289; see Indian Patent Specification No. 129187). Centcroman has also been studied as an anticancer agent for the treatment of advanced breast cancer (Misra et al., Int. J. Cancer 43 (1989), 781-783). Recently, centromman as a racemate has been found as a potential cholesterol lowering agent that has been shown to significantly lower serum concentrations (S.D. Bay et al., J. Min. Bon. Res. 9 (1994), 394). However, there is no disclosure where the isolated C-enantiomer of Cencroman is useful in the treatment of breast cancer.

Today, there is a need in the art for compositions and methods useful and safe for the treatment or prevention of breast cancer.

It is an object of the present invention to provide compounds that can be effectively used for the treatment or prevention of breast cancer.

The present invention is directed to centcroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidine-1) for the treatment and prevention of patients suffering from breast cancer. -Yl) ethoxy) phenyl] -7-methoxychroman), and the use of the isolated l-enantiomer or a pharmaceutically acceptable salt thereof. The present invention also encompasses pharmaceutical compositions consisting of Centroman's l-enantiomers or pharmaceutically acceptable salts thereof and methods of using the aforementioned compounds and pharmaceutical compositions thereof.

The present invention is directed to centcroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidine-) for the preparation of a pharmaceutical composition for the treatment or prevention of breast cancer. Isolated l-enantiomer of 1-yl) ethoxy) phenyl] -7-methoxychroman) or a pharmaceutically acceptable salt thereof.

3,4-diarylchromans are described in US Pat. No. 3,340,276 to Carney et al., US Pat. No. 3,822,287 to Boolger and Ray et al., J. Med. Chem. 19 (1976), 276-279, the contents of which are incorporated herein by reference. The conversion of cis isomers to trans structures by organometallic catalyzed rearrangements is disclosed in US Pat. No. 3,822,287. Optically active d- and l-enantiomers are described in US Pat. No. 4,447,622 to Salman et al., Incorporated herein by reference, by forming acidic hydrolytic acid-acidic salts to produce the desired enantiomer. Can be prepared as disclosed.

The l-enantiomer of Centroman in the present invention may be prepared in the form of acid addition salts, including pharmaceutically acceptable salts, in particular salts of organic and inorganic acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid addition salts include salts such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Acid addition salts can be obtained as direct products of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing a suitable acid, and the salt is isolated by evaporating the solvent or by separating the salt and the solvent by other means.

Centroman's l-enantiomer and salts thereof are useful in humans and veterinary medicine, for example in the treatment of patients suffering from breast cancer. For use in the present invention, the Centromann l-enantiomer or a pharmaceutically acceptable salt thereof is formulated with a pharmaceutically acceptable carrier, followed by parenteral, oral, nasal, rectal, subcutaneous or Provided is a medicament for intradermal or transdermal administration. Formulations may include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, and the like, and may be provided in the form of liquids, powders, emulsions, suppositories, liposomes, transdermal patches, sustained release skin implants, tablets, and the like. One of ordinary skill in the art would appreciate, in accordance with suitable methods and acceptable practice as disclosed in Remington's Pharmaceutical Sciences, Gennaro, ed., Mack Publishing Co., Easton, PA, 1990, the Centroman l-enantiomer or a pharmaceutical thereof. Alternatively, acceptable salts can be prepared.

Oral administration is preferred. Accordingly, the Centroman active l-enantiomer or a pharmaceutically acceptable salt thereof is prepared in a form suitable for oral administration such as tablets or capsules. Typically, the pharmaceutically acceptable salts of the l-enantiomers of Centroman are combined with the carrier and formulated into tablets. Suitable carriers in this regard include starch, sugar, dicalcium phosphate, calcium stearate, magnesium stearate and the like. Such compositions may further comprise one or more auxiliary substances such as wetting agents, emulsifiers, preservatives, stabilizers, coloring additives and the like.

A pharmaceutical composition containing a compound of Centroman's l-enantiomer or a pharmaceutically acceptable salt thereof is administered daily or more than once a week. An effective amount of such pharmaceutical composition is an amount that provides a clinically significant effect on breast cancer. Such amount depends in part on the particular condition being treated, age, weight and general health of the patient, and other factors will be apparent to those skilled in the art. A typical daily dosage will contain a nontoxic dosage range in which about 0.001 to about 75 mg / kg of a compound of the present invention is administered to a patient daily.

Pharmaceutical compositions containing Centroman's l-enantiomer or pharmaceutically acceptable salts thereof may be administered in unit dosage form daily or more than once a week. Alternatively, they may be provided as a sustained release preparation suitable for skin transplantation. Implants are formulated to provide release of the active compound for a desired period of time, which can be up to several years. Sustained release preparations are described, for example, in Sanders et al., J. Pharm. Sci. 73 (1964), 1294-1297, 1984; US Patent No. 4,489,056; And US Patent No. 4,210,644.

The invention is further illustrated by the following examples, which should not be construed as limiting the scope of protection.

The features described in the foregoing description and in the following examples may be elements for realizing the invention in various forms, separately and in any combination thereof.

exam

15-45 nude (thymic deficiency) mice undergo ovarian resection under phenobarbital anesthesia. After one week of recovery, estrogen sensitive human tumor cell lines (MCF7, mammalian cancer fibroblasts 7) are successively transplanted into each of these animals. Mice are then treated with placebo (negative control), 17-beta-estradiol (positive control), or test compound. Estrogen-stimulated tumor growth is assessed by measuring tumor size twice a week for a period of about 8 weeks.

Claims (7)

3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrroli) in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prevention of breast cancer Use of l-enantiomer or pharmaceutically acceptable salt thereof only of din-1-yl) ethoxy) phenyl] -7-methoxychroman. Use according to claim 1, characterized in that the composition is in a form suitable for oral administration. Use according to claim 1 or 2, wherein the compound is administered to the patient at a dosage of about 0.001 to 75 mg / kg daily. 4. Use according to any one of claims 1 to 3, wherein the composition is administered daily or at least once a week. 5. Use according to any one of claims 1 to 4, wherein the composition is in the form of a skin implant. The 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidine-) used in any one of claims 1 to 5 in an amount sufficient to treat or prevent breast cancer. A method of treating or preventing breast cancer, comprising administering to a patient a clinically effective amount of the l-enantiomer of 1-yl) ethoxy) phenyl] -7-methoxychroman or a pharmaceutically acceptable salt thereof. . As a method of treating or preventing breast cancer, a patient in need of such treatment is treated with 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl). Treatment of breast cancer characterized by administering a clinically effective amount of a compound of l-enantiomer or salt thereof and a pharmaceutically acceptable composition containing such compound. Or preventive measures.