MXPA97005218A - Use of the 3,4-difenil-chromians for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of idiopathic gynecomassia or physiology - Google Patents

Abstract

The present invention provides new uses of the compounds of the general formula (I) wherein R1, R4 and R5 are individually hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy (tertiary amino) (lower alkoxy), and R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment of prophylaxis of idiopathic or physiological gynecomastia.

Description

USE OF THE 3,4-DIFE IL-CHROMANOS FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR TREATMENT OR PROFILAXIS OF IDIOPATHIC OR PHYSIOLOGICAL GYNECOMASTIA FIELD OF THE INVENTION The present invention relates to the use of the compounds of the general formula I for the treatment of patients suffering from idiopathic or physiological gmecomastia. and prophylaxis of it. The present invention also encompasses the pharmaceutical compositions comprising in these compounds and methods for using the compounds and their pharmaceutical compositions.

BACKGROUND OF THE INVENTION Gynecomastia is characterized by an increased amount of breast tissue in men. A central problem in the evaluation of breast tissue in adult males is the separation of what is normal from the abnormal. In autopsy data (Anderson JA &Groora JB, Acta Pathol Microbiol Immunol Scand 90: 191, 1982) the incidence of active gynecomastia is between 5% and 9% .. However, it has been reported (Nutall FQ, J Clin Endocpnol Metab 48: 338, 1979; Niewoehner CV &Nutall REF: 25034 FQ, A J-Med 77: 635, 1984) that approximately 40% of normal men and 70% of hospitalized men have palpable breast tissue. The reason for this discrepancy is unclear, but it may suggest that it may be difficult to distinguish true breast tissue from adipose tissue masses without breast tissue (lipomastia). Alternatively, a true increase in the incidence of gynecomastia may occur, or the autopsy data may underestimate the frequency of palpable breast tissue. Histologically, early gynecomastia is characterized by proliferation in the fibroblastic stromal breast and the duct system, which lengthens, bulges and doubles. As gynecomastia, progressive fibrosis and hyalization persist; they are associated with the progression of epithelial proliferation. Eventually, the number of ducts decreases. The resolution occurs due to the reduction in size and epithelial content with the gradual disappearance of the ducts, leaving hyaline bands that sooner or later disappear. The growth of the breast in men, as in women, is mediated by estrogen and results from the disturbances of the normal ratio of active androgen to estrogen in the plasma or within the breast itself. -The formation of estradiol in the normal man occurs mainly by the conversion of circulating androgens to estrogens in the peripheral tissues; The normal ratio of testosterone production to estradiol in adult males is approximately 100: 1 (6 mg versus 45 μg), and the normal ratio of the two plasma hormones is approximately 300: 1. Feminization results when there is a significant decrease in this effective proportion, as a result of decreased production or action of testosterone, increased production of estrogen, or both processes occurring simultaneously. The predominant manifestation of feminization in males is the enlargement of the breast. Enlargement of the male breast can occur as a normal physiological phenomenon at certain stages of life, or as a result of different pathological conditions. Physiological gynecomastia occurs in neonates and adolescents as transient enlargements of the breast, which usually disappear spontaneously within a few weeks to years, usually without leaving palpable changes. The gynecomastia of aging occurs in otherwise healthy males. Forty percent or more of elderly men - they have gynecomastia. One likely explanation is the increase with age in the conversion of androgen to estrogen in extraglandular tissues. Abnormal liver function or drug therapy can be causes that contribute to gynecomastia in such males. Pathological gynecomastia can result from one of three mechanisms: deficiency in the production or action of testosterone (with or without a secondary increase in the production of estrogen), increase in the production of estrogen or drugs. When the primary cause of over-estrogenization can be identified and corrected, the breast enlargement usually decreases quickly and sooner or later it disappears. However, in a number of cases no cause can be found and gynecomastia is called idiopathic or physiological. These cases can some people at certain stages of life, cause tremendous psychological disturbances. The cause in these cases is always an increased proportion of estrogen / testosterone.There may be an increased risk of developing breast cancer under these circumstances.The surgery is undesirable in these otherwise healthy males.The most rational way to treat Gynecomastia could be the inhibition of the underlying excessive stimulation of L breast tissue by estrogen, endogenous, and induce atrophy of breast tissue.The centromantal is a non-steroidal compound known to have antiestrogenic activity.This is in use in India as a oral contraceptive (see, for example, Salman et al., US Patent Specification No. 4,447,622; Singh et al., Endocrinal Acta (Copenh) 126 (1992), 444-450; Grubb, Curr Op n Obstet Gynecol 3 (1991), 491-495; Sankaran et al., Contraception 9 ^ (1974), 279-289; Hindu Patent Specification No. 129187). Centromano has also been investigated as an anticancer agent for the treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781-783). Recently, it has been found that centromano as a racemate is potent as a pharmaceutical for lowering cholesterol, expressed by a significant decrease in serum concentrations (S.D. Bain et al., J Min Bon Res 9 (1994), S 394). * US Patent 5,280,040 discloses methods and pharmaceutical compositions for reducing bone loss using 3,4-diarylchromans and their pharmaceutically acceptable salts.

There remains a need in the art for compositions and methods that are useful in the treatment or prophylaxis of idiopathic or physiological gynecomastia. An objective of the present invention is to provide the compounds that can be used effectively in the treatment or prophylaxis of idiopathic or physiological gynecomastia.

BRIEF DESCRIPTION OF THE INVENTION It has surprisingly been found that the compounds of the general formula I, as set forth in claim 1, can be used in the treatment or prophylaxis of idiopathic or physiological gynecomastia.

DETAILED DESCRIPTION OF THE INVENTION The present invention is based in part on the discovery that a representative 3,4-diarylchroman, centromanic (3,4-trans-2,2-dimethyl-3-phenyl-4- [p- (beta-pyrrolidinoethoxy) phenyl) ] -7-methoxychroman) is effective against idiopathic or physiological gynecomastia, among others in rats. These animal models - are generally recognized models of idiopathic or physiological gynecomastia. These data thus indicate that 3,4-diarylchromans are useful as therapeutic or preventive agents against idiopathic or physiological gynecomastia in mammals, including primates such as humans. Within the present invention, the compounds of the formula I as set forth in claim 1 are used for idiopathic or physiological gynecomastia in a patient. Within the formula I, Rl, R4 and R5 are individually hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R2 and R3 are individually hydrogen or a lower alkyl. As used herein, the term "lower alkyl" includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, ter- butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like. The term "lower alkoxy" includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as ethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butroxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy and the like-. "Halogen" includes chlorine, fluorine, bromine, and iodine. The tertiary amino radical can be a dialkylamine such as a dimethyl, diethyl, dipropyl, dibutyl or a polymethyleneimine group, for example, piperidine, pyrrolidine, N-methylpiperazine or morpholine.

Preferred compounds include those in which R 1 is lower alkoxy; R2 and R3 are lower alkyl, especially methyl; R4 is hydrogen; and R5 is (tertiary amino) (lower alkoxy) of the polymethyleneimine type. Within the particularly preferred embodiments, R1 is in the 7-position and is lower-alkoxy, particularly methoxy; each of R2 and R3 is methyl, R4 is hydrogen and R5 is in the 4-position and is a radical (tertiary amino) (lower alkoxy) such as pyrrolidinoethoxy. To be included by this invention are all pharmaceutically acceptable salts of the aforementioned compounds of the formula I. It is preferred to use the compounds of the formula I in the transconfiguration. These compounds can be used as racemic mixtures, or the isolated d- or 1- enantiomers can be used. Trans-1-enantiomers are more preferred. A particularly preferred compound for use within the present invention is the centromano having the formula IV as set forth in the claims below. Although only one enantiomer is shown, it will be understood that formula IV used herein to designate the transconfiguration of the 3- and 4-phenyl groups and that the d- and 1- enantiomers, as well as the racemic mixture, are included. The 3, 4-diary Lchromans are prepared according to known methods, such as those described in the US Patent Specification No. 3,340, 276 to Carney et al., US Patent Specification No. 3,822,287 to Bolger, and Ray et al., J Med Chem 19 (1976), 276-279, the contents of which are incorporated by reference herein. The conversion of the ci s isomer to the trans configuration by means of rearrangement catalyzed by organometallic base, is described in the US Patent Specification No. 3,822,287. The optically active d and 1- enantiomers can be prepared as described by Salman and co-workers, in US Patent Specification No. 4,447,622 (incorporated by reference herein) by forming an optically active acid salt which is subject to alkaline hydrolysis to produce the desired enantiomer.

- Within the present invention, 3,4-diarylchromans can be prepared in the form of pharmaceutically acceptable salts, especially acid addition salts, including salts of organic acids and mineral 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, acid benzoic acid, salicylic acid and the like. Suitable inorganic acid addition salts include salts of hydrochloric, hydrobromic, sulfuric and phosphoric acids and the like. The acid addition salts can be obtained as the direct products of the synthesis of the compound. In the alternative, the free base can be dissolved in an appropriate solvent containing the appropriate acid, and the salt isolated by evaporation of solvent or the salt and solvent are otherwise separated. The 3, 4-diarylchromans and their salts are useful in human and veterinary medicine, for example, in the treatment of patients suffering from idiopathic or physiological gynecomastia. For use within the present invention, the 3,4-diarylchromans and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier, to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal or transdermal administration, according to the conventional methods. The formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc., and may be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release, dermal implants, tablets, etc. One of skill in this art can formulate the compounds in an appropriate manner, and in accordance with accepted practices, such as those described in Remingtop's Pharmaceutical Sciences, Gennaro, of., Mack Publishmg Co., Easton, PA, 1990. Oral administration is preferred. In this way, the active compound is prepared in a form suitable for oral administration, such colloid, a tablet or capsule. Typically, a pharmaceutically acceptable salt of the compound is combined by a carrier and molded into a tablet. Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate, and the like. Such compositions may also include one or more auxiliary substances such as wetting agents, emulsifiers, preservatives, stabilizers, coloring additives, etc. The pharmaceutical compositions are administered one or more times per day or week. An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against idiopathic or physiological gynecomastia. Such amounts will depend, in part, on the particular condition to be treated, the age, weight, and general health of the patient, and other factors evident to those skilled in the art. The pharmaceutical compositions can be administered in unit dosage form one or more times per day or per week. In the alternative, these can be provided as controlled release formulations, appropriate for dermal implantation. The implants are formulated to provide liberation of the active compound over the desired period of time, which may be up to several years. Formulations of controlled composition are described, for example, in Sanders et al., J Phar Sci 73 (1964), 1294-1297, 1984; US Patent Specification No. 4,489,056; and US Patent Specification No. 4,210,644, which are incorporated by reference herein. The following examples are offered by way of illustration, not limitation. Examples of preferred compounds are the centromano as a racemic mixture and a 1-centromano and d-centromano. further, 3, 4-trans-2, 2-dimethyl-3-phenyl-4- [4- (2-pyrrolidin-1-yl) ethoxy) phenyl] -7-hydroxychroman is a preferred compound. A more preferred compound is trans-1-centroman (l-3,4-trans-2, 2-dimethyl-3-finel-4- [p- (beta-pyrrolidinoethoxy) phenyl] -7-methoxy chroman). Examples of pharmaceutically acceptable acid addition salts are salts with non-toxic acids, either inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, or organic acids such as formic acid, fumaric acid, acetic acid , propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulfonic acid and malonic acid. The present invention is further illustrated by the following examples, which, however, are not to be considered as limiting the scope of protection. The features described in the foregoing description and in the following examples may, either separately and in any combination thereof, be material for the embodiment of the invention in various forms thereof.

EXAMPLES Test 1 The competitive antiestrogenic action of the centromanic has been demonstrated in uterine tissue from sexually normal mature Sprague-Dawley rats. Twenty sexually mature female Sprague-Dawley rats (200-225 g) were obtained from the Mollegaards LI Skensved breeding center, Denmark. The rats were housed in metal hanging cages in groups of two and had access to libitum for food and water for a week. The ambient temperature was maintained at 20 ° ± 1.5 ° with a minimum relative humidity of 40%. the photoperiod in the room was 12 hours of light and 12 hours of darkness. After one week of the acclimation period the rats were randomly divided into five treatment groups of 4 rats each, and the daily oral treatment was started with the test compound. The test compound was administered in five doses (0 mg / kg / day, 5 mg / kg / day, 10 mg / kg / day 25 mg / kg / day or 75 mg / kg / day) for fourteen days. After the dosing period the animals were weighed and sacrificed by asphyxia with C0, the uteri were removed through an intermediate line incision, and the wet uterine weight was determined after gentle drying on a towel. The data shown in the following table I show the comparative results between the treated rats. Treatment with centromano in sexually mature rats with intact ovaries induces significant hypoplasia of the uteri.

Table 1 -From this observation it can be included that the centromano acts as an antagonist for the normal stimulating effect of estrogen in the uterus.

This was supported by subsequent microscopy, which revealed an errophic endometrium in these rats.

Test 2 Between 3 and 25 men who have gynecomastia are administered with a compound of the present invention. The amount of the compound administered is 0.1 to 1000 mg / day, and the administration period is 3 months.

The males are observed during the administration period, and up to 3 months after the discontinuation of the administration, for effects on gynecomastia.

Test 3 'The same procedure is used as in Test 1, except that the administration period is 6 months.

Test 4 The same procedure is used as in Test 1, except that if the administration period is 1 year.

Test 5 Prolonged estrogen stimulation is used to induce gynecomastia in sexually mature male rats. The animals are dosed with an estradiol 3-5 times per week, by injection of 2-4 months until gynecomastia arises. The consistent treatment of a treatment of the invention or the vehicle is administered daily 'for 3-20 weeks and then the animals' are sacrificed and the mammary glands harvested and analyzed for regression of gynecomastia.

Test 6 - The tissue from human mammary glands is harvested and maintained, in vitro, as primary non-transforming cultures. Surgical specimens are pushed through a sterile mesh or shirt, or alternatively separated from the surrounding tissue to produce a simple cell suspension. The cells are maintained in media containing 10% serum and antibiotic. The proportions of growth in the presence or absence of astrogen are determined. Cells are tested for their ability to respond to growth factors and growth hormone. The levels of steroid hormone receptors are evaluated weekly to determine if important cellular characteristics are maintained in vitro. Tissues from 5-25 patients are used.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (17)

1. The use of the compounds of the general formula I characterized in that R1, R4 and R5 are individually hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); / R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of idiopathic or physiological gynecomastia.
2. 2. The use according to claim 1, characterized in that Rl in the compound used is lower alkoxy, R2 and R3 are lower alkyl, R4 is hydrogen and R5 is (tertiary amino) (lower alkoxy).
3. 3. The use according to claim 1, characterized in that Rl is methoxy.
4. 4. The use according to claim 1, characterized in that R2 is methyl.
5. 5. The use according to claim 1, characterized in that R3 is methyl.
6. 6. The use according to claim 1, characterized in that R4 is hydrogen.
7. 7. The use according to claim 1, characterized in that R5 is a group as set forth in formula II below:
8. (II) -3. Use according to claim 1, face: because the compound is a d-1 or r-thiomer.
9. 9. The use according to claim 1, characterized in that the comp. has the general formula III as set forth below:
10. 10. The use according to any of the preceding claims, characterized in that said coirpuesto is an isolated 1-enantiomer.
11. 11. The use according to claim 1, characterized in that the compound is centchroman which has formula IV as set forth below:
12. 12. The use according to claim 11, characterized in that the compound is an isolated d- or 1-enantiomer.
13. 13. The use according to claim 11, characterized in that the compound is an isolated l-enantiomer.
14. 14. The use according to claim 1, characterized in that the composition is in a form suitable for oral administration.
15. 15. The use according to claim 1, characterized in that the compound is administered as a dose in a range of about 0.001 to 75, preferably in a range of about 0.01 to 75, more preferably in the range of about 0.01 to 50. and especially in the range of approximately 0.1 to 25 mg / kg of patient per day.
16. 16. The use according to claim 1, characterized in that the composition is administered one or more times per day or week.
17. 17. The use according to claim 1, characterized in that the composition is in the form of a dermal implant.