MXPA97005219A - Use of 3,4-difenil-chromanos for the manufacture of a pharmaceutical composition for the treatment of profilaxis of disorders ginecologi - Google Patents

Abstract

The present invention provides the new uses of compounds of the general formula I wherein R1, R4 and R5 are individually hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (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 or prophylaxis of gynecological disorders, including endometriosis, dysfunctional bleeding, endometrial cancer, polycystic ovarian syndrome and anovulatory bleeding, and also for thinning the endometrium

Description

USE OF 3,4-DIFENIL-CHROMIANS FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OR PROPHYLAXIS OF GYNECOLOGICAL DISORDERS 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 gynecological disorders, especially endometriosis, dysfunctional bleeding, endometrial cancer, polycystic ovary syndrome and anovulatory bleeding and prophylaxis thereof. In addition, this invention also relates to the use of the compounds of the general formula I for the induction of endometrial thinning, for example, before surgeries on the uterus. The present invention also encompasses pharmaceutical compositions comprising these compounds and these methods for using the compounds and their pharmaceutical compositions.

BACKGROUND OF THE INVENTION A number of endocrine disorders in the breast and reproductive organs in women are associated with impaired stimulation with estrogen on the involved tissues.

REF: 25035 Endometriosis is a disorder characterized by an appearance of endometrial tissue outside the uterine cavity. This tissue is sensitive to cyclic stimulation with estradiol, which occurs during the normal menstrual cycle. Symptoms include dysmenorrhea, dyspareunia, infertility, abdominal pain, obstipation, and mechanical ileus. The current treatment of endometriosis is surgery or medical suppression of ovarian function by continuous or cyclic treatment by a combination of estrogen and gestagen, or gestagen alone or a suppression with a synthetic testosterone derivative similar to gestagen. Surgery is expensive and only appropriate when endometriosis is localized. Estrogen / gestagen in different combinations is associated with bleeding disorders, while treatment with danazol is expensive and is associated with side effects and such as menopausal syndrome and virilization. An objective of the present invention is to provide compounds that can be used effectively in the treatment or prophylaxis of endometriosis. Dysmenorrhea in ovulatory cycles and dysfunctional uterine bleeding in anovulatory cycles are disorders that are characterized by transient impairments of the hypothalamic-pituitary-ovarian synchronic patterns necessary for regular ovulatory cycles. Dysfunctional uterine bleeding can result from either a sudden withdrawal of estrogen with a penetrating bleeding after prolonged stimulation with estrogen. In common the pathogenesis of these disorders therefore includes the abnormal stimulation of endometrial estrogen. Currently, the treatment of these disorders involves different oral estrogen contraceptive regimens, which may be associated, after bleeding disorders and syndrome similar to menopause. A further objective of the present invention is to provide compounds that can be used effectively in the treatment or prophylaxis of dysfunctional bleeding. A further objective of the present invention is to provide the compounds that can be effectively used in the treatment or prophylaxis of anovulatory bleeding. Surgical techniques such as endometrial ablation and resection are becoming increasingly er. women with dysfunctional uterine bleeding as an alternative to hysterectomy. This allows women to be treated as daily patients, and reduces the period of convalescence from six weeks to two or three days. It is estimated that dysfunctional uterine bleeding affects 20% of women during their reproductive years. The pre-thinning of the endometrium creates the optimal surgical conditions by reducing the extortion of the fluid, a condition potentially would be in the ablation surgery, currently only has been authorized for this indication the danazol, which is expensive and is associated with side effects such as enopáusicos symptoms and virilization. Thus, a further object of the invention is to provide compounds that can be used effectively for endometrial thinning, for example, prior to surgery on the uterus. Endometrial cancer is the most common gynecological malignancy in the United States, and its incidence is increasing. Some patients are at risk of developing endometrial carcinoma and include obese, diabetic, hypertensive and infertile patients; those with ovulation failure and dysfunctional bleeding; estrogen users for a long time, and those like severe degree of endometrial hyperplasia. The common denominator for many risk factors is estrogenic stimulation in excess. In addition to different possibilities in the treatment of the different risk factors underlying the development of carcinomas at the level of the endometrium. Yet another objective of the present invention is to provide the compounds that can be used effectively in the treatment or endometrial prophylaxis. The polycystic ovaries are characterized by multiple follicular cysts or cystic follicles which vary in degree of luteinization of the internal teak and different degrees of estrogen overproduction. This will result in constant and prolonged endometrial estrogen stimulation, which causes infertility and increases the risk of different bleeding disorders and the risk of developing endometrial carcinoma. The treatment of polycystic ovaries is generally driven by a desire for pregnancy by the patient, and the therapy constitutes either surgery or medical induction of ovulation. If this proves to be successful, the patient treated with oral estrogen contraceptives which, however, can lead to different bleeding disorders and after prolonged treatment increase the risk of developing endometrial carcinoma. Yet another objective of the present invention is to provide the compounds that can be used effectively in the treatment or prophylaxis of polycystic ovarian syndrome. The centcrous anus is a non-steroidal compound that is known to have antiestrogenic activity. This is in use in India as an oral contraceptive (see, for example, Salman et al., American Patent Specification No. 4,447,622; Singh et al., Endocrinal Acta (Copenh) 126 (1992), 444-450; Grubb, Curr Opin Obstet Gynecol 3 (1991), 491-495; San aran et al., Contraception 9 (1974), 279-289; Hindu Patent Specification No. 129187). The centchromat has also been investigated as an anticancer agent for the treatment of advanced breast cancer (Mísra et al., Int J Cancer 43 (1989), 781-783), recently, the centchromate as a racemate, has been found as a potent product. pharmaceutical to decrease cholesterol, expressed by a significant decrease in serum concentrations (SD Bain et al., J. Min Bon Res 9 (1994), S 394).

U.S. Patent No. 5,280,040 describes the methods and pharmaceutical compositions for reducing bone loss using 3,4-diarylchromans and their pharmaceutically acceptable salts.

BRIEF DESCRIPTION OF THE INVENTION It has surprisingly been found that the compounds of the general formula I as set forth in claims 1-7, can be used in the treatment or prophylaxis of patients suffering from gynecological disorders, especially endometriosis, dysfunctional bleeding, endometrial cancers, of polycystic ovary and anovulatory bleeding. Furthermore, it has surprisingly been found that the compounds of the general formula I as set out in claim 7 can be used for the induction of endometrial thinning.

DETAILED DESCRIPTION OF THE INVENTION The present invention is based in part on the discovery that a representative 3, 4-diarylchroman, centroman (3, 4-trans-2,2-dimethyl-3-phenyl-4- [p- (beta-pyrrolidinetoxy) phenyl) ] -7-methoxychroman) is effective against endometriosis, dysfunctional bleeding, anovulatory bleeding and polycystic ovarian syndrome, among others in rats. These animal models mimic the premenopausal condition and are generally recognized models of the aforementioned indications. These data thus indicate that 3, 4-diarylchromans are useful as therapeutic agents against endometriosis, dysfunctional bleeding, anovulatory bleeding and polycystic ovary syndrome in mammals, including primates such as humans. The present invention is further based in part on the discovery that a 3, 4-diarylchromanc representing, the cent-roman (3, 4-trans-2, 2-dimethyl-3-phenyl-4- [p- (beta-pyrrolidinetoxy ) phenyl] -7-methoxy chroman) is effective against endometrial cancer, among others, these animal models mimic the peri-menopausal condition and are generally recognized models of endometrial cancer., These data indicate that the 3, 4-diarylchromans are useful as therapeutic agents against endometrial cancer in mammals, including primates such as humans. In addition, the present invention is based in part on the discovery that a representative 3, 4-diarylchroman, centchroman is effective as an agent for thinning the endometrium, for example, before surgery on uterine tissues, among others, in rats. These animal models mimic the premenopausal condition and are generally recognized models of endometrial hyperplasia. These data thus indicate that the 3, 4-diarylchromans are useful as agents for the induction of thinning of the endometrium, for example, before surgery. Within the present invention, the compounds of the formula I as set forth in claims 1-7, are used for the indications set forth herein, in the patient. Within the formula IR ", 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 lower alkyl. present, 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, tert-butyl, n-amyl , sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethyl-ilbutyl and the like The term "lower alkoxy" includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, 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, for example, piperidine, pyrrolidine, N-methylpiperazine or morpholine. Preferred compounds include those in which R 'is lower alkoxy; R * - and R3 are lower alkyl, especially methyl; R4 is hydrogen; and R5 is (tertiary amine) (lower alkoxy) of the polymethyleneimine type. Within the particularly preferred embodiments R 'is in the 7-position and is lower-alkoxy, particularly methoxy; each of R and R! is methyl, R "is hydrogen and R ^ 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 It is preferred to use the compounds of the formula I in the trans configuration These compounds can be used as racemic mixtures, or the isolated enantiomers of 1 can be used. The trans 1-enanlomers are more preferred. the use within the present invention, is the centcroman having formula IV as set forth in claim 17. Although only one enantiomer is shown, it will be understood that formula IV is used herein to designate the trans configuration of the groups 3- and 4-phenyl, and that the d- and 1- enantiomers, as well as the racemic mixture, are included. They are based on known methods, such as those described in 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 cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is described in US Patent Specification No. 3,822,287. The optically active d- and 1- enantiomers can be prepared as described by Salman et al. In US Patent Specification No. 4,447,622 (incorporated by reference herein) by the formation of an optically active acid salt, which it is subjected to alkaline hydrolysis to produce the desired enantiomer. Within the present invention, the 3,4-diarylchromans can be prepared in the form of pharmaceutically acceptable salts, especially the acid addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as fumaric acid, formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, citric acid, benzoic acid, salicylic acid and similar. 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 a suitable solvent containing the appropriate acid, in the salt it is isolated by evaporation of the solvent or the salt and the solvent are otherwise separated. The 3, 4-diari chromans and their salts are useful within human and veterinary medicine, for example, in the treatment of patients suffering from gynecological disorders especially endometriosis, dysfunctional bleeding, endometrial cancer, polycystic ovarian syndrome and anovulatory bleeding, and also for the induction of endometrial thinning. 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 of according to conventional methods. The formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. and can be provided in forms such 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 Remington's Pharmaceutical Sciences. Gennaro et al., Mack Publishing Co., Easton, PA, 1990. Oral administration is preferred. In this way, the active compound is prepared in a form suitable for oral administration, such as a tablet or capsule. Typically, a pharmaceutically acceptable salt of the compound is combined with a carrier and molded into a tablet. Suitable carriers in this regard include starch, sugars, calcium 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 of such amount that provides a clinically significant effect against gynecological disorders especially endometriosis, dysfunctional bleeding, endometrial cancer, polycystic ovary syndrome and anovulatory bleeding or for the induction of endometrial thinning. 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 week. In an alternative, these may be provided as controlled release formulations appropriate for the dermal implant. The implants are formulated to provide the release of the active compound over the desired period of time, which may be up to several years. Controlled release formulations are described for example in Sanders et al., J Pharm 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 centchroman as a racemic mixture and as 1-centchroman and d-centchroman. In addition, a preferred compound is 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-hydroxychroman. The most preferred compound is isolated 1-centchroman (l-3,4-trans-2, 2-dimethyl-3-phen? L-4- [p- (beta-pyrrolidino-ethoxy) phenyl] -7-methoxy chroman) . Examples of pharmaceutically acceptable 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 fumaric acid, formic 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 realizing the invention in various forms thereof.

EXAMPLES Test 1 The competitive antiestrogenic action of centchroman has been demonstrated in uterine tissue from sexually mature, normal Sprague-Dawley rats. Twenty sexually mature Sprague-Dawley female rats (200-225 g) were obtained from the Mollegaards breeding center, Ll Skensved, Denmark. The rats were housed in hanging metal cages in groups of two, and had access to 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 5 treatment groups, of 4 rats each, and daily oral treatment with the test compound was initiated. The test compound was given 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. of the dosing period the animals were weighed and sacrificed by asphyxia with CO., the uterus was removed through an intermediate line incision, and the wet weight of the uterus was determined after gentle drying on a towel. Table I below shows the comparative results between treated rats.Ch treatment with centroman in sexually mature rats with intact ovaries induces significant hypoplasia of the uteri.

Table I From this observation it can be concluded that the centchroman acts as an antagonist for the normal stimulating effect of estrogen on the uterus. This was supported by subsequent microscopy, which revealed an endometrium to rófico in these rats.

It is noted that in relation to this date, the best method known to 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 (23)

1. The use of the compounds of the general formula I character Iz-aJoa because P, R4 and R 'are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower akoxy or tertiary amino) (lower alkoxy); and R 'and R' 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 gynecological disorders.

2. The use according to the claim of the compounds of the general formula I characterized in that R ", R4 and R 'are individually hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower akoxy or (tertiary amino) (lower alkoxy), and R' and R, are individually hydrogen or lower alkyl, or 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 endometriosis.

3. The use according to claim 1 of the compounds of the general formula I characterized in that R, R4 and R ~ are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R and R 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 dysfunctional bleeding.

4. The use according to claim 1 of the compounds of the general formula I characterized in that R-, R4 and R 'are individually hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R 'and R! 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 endometrial cancer.

5. The use according to claim 1 of the compounds of the general formula I characterized in that R-, R "and R: are individually hydrogen, hydroxyl, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy), and R" and R '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 polycystic ovarian syndrome.

6. The use according to claim 1 of the compounds of the general formula I characterized in that R ", R1 and R" are individually hydrogen, hydroxyl, halogen, tp fluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R2 and R3 are individually hydrogen 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 anovulatory bleeding.

7. The use according to claim 1 of the compounds of the general formula I characterized in that R-, R "and R" are individually hydrogen, hydroxy, halogen, tri fluoromethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy); and R 'and R ~ are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier for thinning the endometrium.

8. The use according to any of claims 1 to 8, characterized in that R * in the compound used is lower akoxy, R2 and Rs is lower alkyl, R "is hydrogen and R5 is (tertiary amino) (lower alkoxy).

9. The use of the compound according to any of claims 1 to 8, characterized in that R is methoxy.

10. The use of the compound according to any of claims 1 to 9, wherein R "is methyl.

11. The use of the compound according to any of claims 1 to 10, wherein RJ is methyl.

12. The use of the compliant compound cor. any of claims 1 to 11, wherein R is hydrogen.

13. The use of the compound according to any one of claims 1 to 12, wherein R is a group as set forth in the following formula II: (II)

14. The use according to any of claims 1 to 13, characterized in that the compound is an enantiomer of d or 1 isolated.

15. The use according to any of claims 1 to 14, characterized in that the compound has the formula. General III as set forth below: and the substituents are as defined in claim 1 above.

16. The use according to any of the preceding claims, characterized in that the compound is an isolated enantiomer 1.

17. The use according to any of claims 1 to 15, characterized in that the compound is centchroman having the formula IV as set forth below:

18. The use according to claim 17, characterized in that the compound is an isolated d or 1 enantiomer.

19. The use according to claim 17, characterized in that the compound is an isolated enantiomer 1.

20. The use according to any of claims 1 to 19, characterized in that the composition is in a form suitable for oral administration.

21. The use according to any of claims 1 to 20, characterized in that the compound is administered as a dose in a range of about 0.001 to 75, preferably in the range of about 0.01 to 75, more preferably in the range of about 0.01 up to 50, and especially in the range of approximately 0.1 to 25 mg / kg of the patient per day.

22. The use according to any of claims 1 to 21, characterized in that the composition is administered one or more times per day or week.

23. The use according to any of claims 1 to 21, characterized in that the composition is in the form of a dermal implant.