MXPA01008911A - N-SUBSTITUTED BENzOYL INDOLES AS ESTROGENIC AGENTS. - Google Patents

Abstract

The present invention provides compounds of formula (A) wherein R1, R2 and R3 are independently selected from hydrogen, halogen, C1-C6 alkoxy, -CF3, -NO2, cyano, C1-C6 alkyl, trifluoromethyl, -OH or the C1-C12 esters (straight chain or branched) or C1-C12 alkyl ethers thereof, or C1-C6 halogenated ethers, preferably C1-C3 halogenated ethers, including trifluoromthyl ether and trichloromethyl ether; R4 and R5 are independently selected from H or benzyl, the benzyl group being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, -CF3, or halogen; X is H, C1-C6 alkyl, or CF3; Z is O or S; n is 2 or 3; Y is selected from: a) a moiety of the formula -NR'R' wherein R' is C1-C6 lower alkyl; or b) a moiety selected from the group of (B), (C), (D) or (E); or a pharmaceutically acceptable salt thereof, as well as pharmaceutical formulations and methods of treating or preventing disease states or syndromes which are caused or associated with an estrogen deficiency or an excess of estrogen utilizing these compounds.

Description

BENZOIL-N-SUBSTITUTE INDIANS USEFUL AS ESTROGENIC AGENTS The present invention relates to novel N-substituted benzoyl-indole compounds which are useful as estrogenic agents, as well as to pharmaceutical compositions and methods of treatment which use these compounds and processes for preparing them.

BACKGROUND OF THE INVENTION Estrogen replacement therapy has been well established as the treatment of choice in women for the prevention of osteoporosis. [C. Christiansen, R. Lindsay, Estrogen, Bone Loss and Preservation (Estrogen, Bone Tissue Loss and Conservation), Osteoporosis International, 1, 15-21 (1990)]. The drawback of this therapy is that when estrogen is administered alone, that is, without the opposite effects of the progesters, proliferative effects could result in the uterus and therefore the patient could be put at risk of developing endometrial cancer. Although less clearly, estrogen replacement therapy has been implicated in the increase REF: 132333 "of the incidence of breast tissue tumor formation In the treatment of breast cancer, non-steroidal antiestrogenic drugs, such as tamoxifen, have been used.The drug is also known to maintain the bone tissue mass, acting as a estrogen agonist in the replacement of bone tissue, however it is also an agonist in uterine tissue.A newer antiestrogenic drug, raloxifene from Lilly laboratories, is an antiestrogenic non-steroidal type that appears to be more tissue selective. The desirable property of replenishing bone tissue has been shown to stimulate the growth of the uterus in animal models to a lesser extent than tamoxifen.Furthermore, recent clinical data do not reveal endometrial hyperplasia. of tissue of estrogen analogues [GL Evans and RT Turner, Tissue Selective Act ions of Estrogen Analogs ( Selective Actions of Tissue of Estrogen Analogues), Bone, 17, No. 4, 1815-1905 (1995)]. The use of indoles as estrogen antagonists has been reported by Von Angerer, Chemical Abstracts, Vol. 99, No. 7 (1983), Abstract (Excerpt) No. 53886u. See also J. Med. Chem. 1990, 33, 2635-2640; J. Med. Chem. ^ & ÍAM? ^ - * atJí- * á? & l & * &** Wlt? F. ***. * Z ... * *? * '*, * * _- > ,? . * ím *. »~ *? I * M *** M d ** J ^ * r ** ** &**. **** - *» ** M - ^^^ 1987, 30, 131-136. See also Ger. Offen., DE 3821148 to 891228 and WO 96/03375. These prior art compounds share some structural similarities with the compounds of the present invention, but are different in their functionality. For compounds containing a basic amine, there is no phenyl group to stiffen the side chain. The reported data for these compounds indicate that these could have a weaker binding to the estrogen receptor than that of the compounds of the present invention and that the compounds containing basic side chains have a certain amount of uterotrophic effect in the rat uterus. WO A 95 17383 (Kar Bio AB) describes indole antiestrogens with long straight chains. Another related patent, WO A 93 10741, discloses 5-hydroxyindole with a generic descriptor incorporating other side chains. The patent E.U.A. No. 5,496,844 (Inai, et al.) Teaches substituted N-indole-type compounds having potent antiestrogenic activity which are useful in the treatment of estrogen-dependent diseases, such as anovulatory infertility, prostate hypertrophy, osteoporosis, cancer of breast, cancer of the endometrium and melanoma. Jones et al., In their article An ti estrogens. twenty-one Structure-Acti vi ty Studi es en a Seri es de 3 -Aroyl -2- arylbenzo [b] thiophene Derivati ves Leading to [6 -Hydroxy-2 - (4 -hydroxyphenyl) benzo [b] - thi in -3 -yl ] [4 - [2 - (1-piperidinyl) ethoxy] -phenyl] me thanone Hydrochioride (LY156758), to Remarkably Effective Estrogen Antagonist wi th Only Minimal In trinsec Estrogenici ty (Antiestrogens) 21 Structure-Activity Studies in a Series of 3-aryl-2-arylbenzo [b] thiophene Derivatives that lead to [6-hydroxy-2- (4-hydroxyphenyl) benzohydrochloride] [b] -thien-3-yl] [4- [2- (1-piperidinyl) ethoxy] -phenyl] -methanone (LY156758), a remarkably effective estrogen antagonist which only has minimal intrinsic estrogenic character), J. Med. Chem. 1984, 27, 1057-1066, describe a series of 3-aroyl-2-arylbenzo [b] thiophene derivatives that act as antiestrogens of the non-steroid type. The compounds described in the present invention are mixed estrogen agonists / antagonists and have potential use in the treatment of osteoporosis, endometriosis, prostate hypertrophy, breast cancer and endometrial cancer.

DESCRIPTION OF THE INVENTION The present invention provides N-substituted indols of the formula (I): Formula (I) wherein Ri 2 and 3 are independently selected from hydrogen, halogen, C 1 -C 2 alkoxy (straight or branched chain or cyclic), -CF 3, -N0 2, cyano, C 1 alkyl- C6 (straight or branched chain), trifluoromethyl, -OH or the C? -C? 2 esters (straight chain or branched) thereof, or the halogenated ethers of Ci-Cß, preferably the halogenated ethers of C ? -C3, including trifluoromethyl ether and trichloromethyl ether; R and R5 are independently selected from H or benzyl, the benzyl group being substituted i. *. A ¿,?, ix? * i - L *. * i * < Í¡IÁ * > It is optionally optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 or halogen; X is H, C? -C6 alkyl or CF3; Z is 0 or S; n is 2 or 3; And it is selected from: a) a portion of the formula: R '/ -N \ R' wherein R 'is lower alkyl of C? -C6 same or different; or b) a portion that is selected from the group of or a pharmaceutically acceptable salt thereof. Examples of Ri, R2 and R3 when esters are C2-C2 alkyl esters such as -0 (C = 0) (C6-C6 alkyl). í, -? ¿* I? -., * Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl and n-butyl. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The uses of R? and R2 are H, C? -C6 alkyl, C? -C6 alkoxy, -CF3 and N02. The examples of R3 and R4 are H. An example of X is methyl. A preferred group of this invention is that of those compounds of the formula I in which R x, R 2 and R 3 are independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -CF 3, or -N02; and R4, R5, X, Z, n and Y are as defined above, or a pharmaceutically acceptable salt thereof. Another group of preferred compounds of this invention is those in which Z is oxygen and R x, R 2, R 3 and R are H, or a pharmaceutically acceptable salt thereof. Preferably R5 is H. Among the most preferred compounds of these generic and sub-generic groups are those in which Y is a piperidine ring. This invention includes acceptable salt forms formed from the addition reaction with acids whether inorganic or organic. Acids are useful tt .- * l, ¡, zm *. ',. * J ... inorganic such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and nitric acid as well as acids organic acids such as acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphor sulfonic acid and benzenesulfonic acid. Among the preferred salts of the compounds of the present invention are the HCl, HBr and acetate salts. The compounds of the invention are partial estrogen agonists and exhibit a high affinity for the estrogen receptor. Nevertheless, unlike many estrogens, many of these compounds do not cause the increase in uterine weight on a wet basis that is normally associated with natural or synthetic estrogens. These compounds are antiestrogenic in the uterus and antagonize the trophic effects of agonists in uterine tissue. In addition, the compounds could be used as estrogen agonists in bone tissue. Due to the selective tissue nature of these compounds, they are useful in the treatment or prevention of "í * s ^ 1 * !? ' pathologies or syndromes in a mammal which are caused or are associated with an estrogen deficiency or with an excess of estrogen The compounds of the present invention have the ability to behave as estrogen agonists by reducing cholesterol and preventing the loss of bone tissue These compounds are useful for treating various diseases resulting from an excess or deficiency of estrogen including osteoporosis, prostate hypertrophy, male pattern baldness, ovarian cancer, infertility, breast cancer, endometrial cancer, cardiovascular disease, contraception, Alzheimer's disease, cognitive decay and other CNS disorders, as well as certain types of cancer, including melanoma, prostate cancer, colon cancers, CNS cancers, etc. In addition, these compounds can be used for Hormone replacement therapy in post-menopausal women or in other states of estrogen deficiency in which it would be beneficial to supplement estrogen. The compounds of this invention could also be used in methods for treating the loss of bone tissue, which could result from an imbalance in the formation of new bone tissues and the resorption of old tissues in an individual, which leads to an net loss of bone tissue. Such bone depletion occurs in a range of individuals, particularly in post-menopausal women, women who have undergone hysterectomy, those who receive or have received long-term corticosteroid therapies, those who have dysgenesis of the gonads, and those who suffer from Cushing's syndrome. Special needs can also be met regarding the replacement of bone tissue using these compounds in individuals who have broken bones, defective bone structures and those who undergo bone-related surgeries and / or prosthetic implants. In addition to those problems described above, these compounds can be used in treatments for osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalistresis, multiple myeloma and other forms of cancer that have harmful effects on bone tissues. It is understood that methods for treating the diseases listed in the present invention comprise administering to an individual in need of such treatment, a pharmaceutically acceptable amount of one or more of the compounds . < - »8M * * - of this invention or a pharmaceutically acceptable salt thereof. This invention also includes pharmaceutical compositions that use one or more of the compounds of the present invention, and / or the pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers, excipients, etc. It is understood that the dosage, regimen and mode of administration of these compounds will vary in accordance with the disease and with the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that administration of one or more of the compounds of the present invention be initiated at low doses and increased until the desired effects are obtained. Effective administration of these compounds could be given at an effective dose from about 0.1 mg / day to about 1,000 mg / day. Preferably, administration will be from about 10 mg / day to about 600 mg / day in a single dose or in two or more divided doses. Such doses could be administered in any way that is useful for targeting the active compounds of the present invention to the bloodstream of the recipient, including orally, parenterally. (which includes intravenous, intraperitoneal and subcutaneous injections) and transdermally. For the purposes of this description, transdermal administrations are understood to include all administrations through the body surface and the internal coatings of the body passages including the epithelial and mucosal tissues. Such administrations could be carried out using the compounds of the present invention, or the pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal). Oral formulations containing the active compounds of this invention could comprise any of the oral forms used in conventional manner, including tablets, capsules, forms for mouth application, troches, lozenges, oral liquids, suspensions and topical solutions. The capsules may contain mixtures of the active compound or compounds with inert fillers and / or diluents such as pharmaceutically acceptable starches (eg, corn, potato or cassava starches), sugars, artificial sweetening agents, powdered celluloses , such as crystalline and microcrystalline celluloses, flours, .., ***** .-, ....,.-... irti r t'i Ifo-ri- - "• *** ^ áfer -" • * - --- .. « . *** - * - * f- M¿ | ajtt jellies, gums, etc. Useful formulations for tablets could be made by conventional methods of compaction, wet granulation or dry granulation using pharmaceutically acceptable diluents, binders, lubricants, disintegration, suspension or stabilization agents, including but not limited to magnesium stearate, stearic acid, talcum, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, sulfate calcium, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. The oral compositions of the present invention could use delayed-release or time-release formulations to alter the absorption of the active compound or compounds. The suppository formulations could be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the melting point of the suppository, and glycerin. Water-soluble suppository bases could also be used, such as polyethylene glycols of various molecular weights. . ta ** f * fiL * ... **. . ! ,.? ^^ ^.? .. * .-. ^. í ^^^ .., .. ^^,. ^ jí *? i ?? ^. ^. < í *.? ^ * a í? í.

This invention also provides processes for preparing the compounds of the formula I, which processes comprise one of the following: a) acylating a compound of the formula: p wherein R3, R4, R5 and X are as defined above, with a compound of the formula: (III) or a reactive derivative thereof, for example acid halide in which n, Ri, R ?, Z and Y are as defined above, to give a compound of the formula I; or b) reacting a compound of the formula: THE I*. í, -M? *? a.1 BÜftliiT "'- - * - - -V. **** **! - - - * i * - *** * .. ***? .. . ^ J - uJ-.tlj ht (| pl! -l > --..- tJ- (IV) wherein X, Z, Ri, R2, R3, R4 and R5 are as defined above and hal represents a halogen, for example chlorine or bromine, with an amine of the formula: H-Y (V) wherein Y is as defined above, to give a compound of the formula I, or c) debenzylating a compound of the formula I in which R4 and / or R5 is optionally substituted benzyl to give a compound of the formula I in the which R4 and / or R5 are hydrogen, or e) esterifying a compound of the formula I in which at least one of R1 (R2 or R3 are hydroxy to an ester derivative thereof) The methods for carrying out the process of a) to e) above are known in the art and / or are illustrated in the following schemes.

The compounds of this invention can be prepared by methods known in the art. For example, starting or central indole can be prepared by the general method of reaction scheme 1, below.

REACTION SCHEME No. 1 DMF? (c) The synthesis of the initial indole for 5-benzoyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1H-indole is achieved by heating an alpha-bromo-ketone (b), suitably substituted, with the desired aniline (a) in DMF to form indole (c). Acid side chains can be prepared (aminoethoxy) benzoic acid of the compounds of the present invention by the general methods taught by Jones et al., J. Med. Chem., 1984, vol. 27, No. 8, pages 1057-1066 or as shown in reaction scheme No. 2 and coupled to the central characters by the method of reaction scheme No. 3.

REACTION SCHEME No .2 ? i * j Á -_? l. ? ** ,, * -.? £ Jt * ¡, .2,3 REACTION SCHEME No. 3 EXAMPLE No. [5-Benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-indol-1-yl] - [4- (2-piperidin-1-yl-ethoxy) -phenyl] -methanone To a frozen solution (-78 ° C) of 2.42 g (0.00577 mole) of the indole (c) starting, (5-benzyloxy-2- (4 - benzyloxy-phenyl) -3-methyl-lH-indole), in 60 ml of dry THF, under N2, 2.6 g (0.00866 mole) of acid chloride (h), (HCl salt of [4- ( 2-piperidm-l-yl-ethoxy) benzoyl]), and stirred at -78 ° C for 20 minutes. 22 ml (0.0216 mole) of sodium bis (trimethylsilyl) amide (1.0 M solution in THF) was added dropwise to the reaction mixture and stirred at -78 ° C for 30 minutes. Then the reaction mixture was brought to 0 ° C for 4 hours, and then to room temperature for 1 hour. To the crude reaction mixture was added 100 ml of ethyl acetate and washed with aqueous NaHCO 3 solution (2 x 50 ml). The organic phase was collected, washed with water (2 x 50 ml), with saturated brine, removed, dried with magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. When the crude product was subjected to HPLC it gave 1.25 g of a yellow solid. Melting point: 48-51 ° C; NMR XH (DMSO) 7.55-7.30 (, 11H), 7.24-7.16 (m, 5H), 6.94-6.88 (, 5H), 5.18 (s, 2H), 5.05 (s, 2H), 4.09 (t, 2H, J = 5.8 Hz), 2.19 (t, 2H, J = 5.8 Hz), 2.41-2.38 (m, 4H), 2.21 (s, 3H), 1.51-1.35 (m, 6H); IR 3440, 2900, 1610 cm "1; MS m / z 651 (M +); CHN calculated for C43H42N2O4-0. 25H20.

EXAMPLE No. 2 [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-l-yl3 - [4- (2-piperidin-1-yl-ethoxy) -phenyl] -metanone To a solution of 0.78 g (0.00120 mol) of [5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1H-mdol-1-yl] - [4- (2-piper? Din- 1-yl-ethoxy) -phenyl] -methanone (described above) in 5 ml of dry THF, and 5 ml of nitrous ethanol, under N2, were added 1.4 ml (0.0120 moles) of cyclohexadiene and 0.39 g (half of the mass of the benzyloxy starting material) of 10% Pd / C, and was stirred at room temperature overnight. The reaction mixture was filtered and evaporated to dryness in a rotary evaporator. To the crude product was added 100 ml of ethyl acetate. This organic phase was washed with water (2 x 50 ml), with saturated brine, was removed, dried with magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. When the crude product was subjected to HPLC it gave 0.30 g of a pale yellow solid. Melting point: 127-130 ° C; 1 H NMR (DMSO) 9.47 (s, 1H), 9.17 (s, 1H), 7.48 (d, 2H, J = 8.6 Hz), 7.21 (d, 1H, J = 8.8 Hz), 7.03 (d, 2H, J = 8.4 Hz), 6.90-6.85 (m, 3H), 6.69-6.62 (m, 3H), 4.07 (q, 2H, J = 5.8 Hz), 2.62 (t, 2H, J = 5.8 Hz), 2.40-2.39 (m, 4H), 2.15 (s, 3H), 1.52-1.47 (m, 6H); IR 3440, 2900, 1610 cm "1; MS m / z 471 (M +); CHN calculated for C29H30N2O4" 0.5 H20.

EXAMPLE No. 3 4- (2-piperidin-1-yl-ethoxy) -benzoyl chloride hydrochloride The title compound was prepared as described by Jones, Charles D., Journal of Medicinal Chemistry, 1984, vol. 27, No. 8, pages 1057-1066.

To a solution of the acid salt HCl 1 (1.0 g, 3.7 mmol) in 50 ml of chloroform at room temperature, a solution of thionyl chloride (0.3 ml, 4.4) was added.

L ** ji. *. , t.? et ~ t > d * i? a- *** J * ^^ - > ** ilN ** »¡n ^ - * J *? i-? «^^^ aaaaaaaa mmoles) in 10 ml of chloroform. The resulting solution is brought to 60 ° C for 6 hours. The reaction mixture is then allowed to cool to room temperature and is diluted with hexane. The reaction mixture is then cooled to 0 ° C and the HCl salt of the resulting acid chloride, 2, is isolated by filtration, dried and used without purification in the acylation step.

PROOF OF UNION / COMPETITION BY THE ESTROGEN RECEIVER Objective To identify compounds that compete with 17β-estradiol to bind to the estrogen receptor (ER). The most widely accepted mode for estrogenic action is through the high affinity receptor protein. Then compounds that demonstrate an ability to bind to ER could regulate the physiological processes associated with the action of estrogen.

Procedure Preparation of the receptor: CHO cells expressing in excess to the estrogen receptor were cultured in 150 mm2 boxes in DMEM + bovine fetal serum, purified with carbon coated with 10% dextran. The plates are washed twice with PBS and once with 10 mM Tris-HCl, pH 7.4, 1 mM EDTA. The cells are harvested by scraping the surface and then the cell suspension is placed on ice. The cells are broken with a motorized manual tissue grinder using two 10 second increments. The crude preparation is centrifuged at 12,000 x g for 20 minutes, followed by another 60 minute centrifugation at 100,000 x g to produce a ribosome-free cytosol. The cytosol is frozen and stored at -80 ° C. The protein concentration of the cytosol is estimated using the BCA test with BSA as the reference standard protein.

Conditions of the joint test The competence test is carried out on a 96-well plate (polystyrene *) which joins < 2.0% of the total [3H] -17β-estradiol introduced. Each data point is collected in triplicate. Aliquots of 100 μg / 100 μl of the receptor preparation per cavity are taken. In the preliminary competition, a saturation dose of 2.5 nM [3H] -17ß-estradiol + the competitor (or buffer) is added in a volume of 50 μl, when evaluated The competitor concentrations of lOOx and 500x. For an IC50 determination, in which 12 concentrations of competitor are evaluated, only [3H] -17β-estradiol 0.8 nM is used. The plate is incubated at room temperature for 2.5 hours. At the end of the incubation period, 150 μl of ice cold dextran coated carbon (5% activated carbon coated with 0.05% dextran 69K) are added per cavity and the plate is immediately centrifuged at 900 x g for 5 minutes at 4 ° C. 200 μl of the supernatant solution is removed for flash counting. Samples are counted up to 2% or 10 minutes, whichever comes first. Because the polystyrene absorbs a small amount of [3 H] -17β-estradol, the cavities containing radioactivity and cytosol, but which were not processed with carbon, are included to quantify the amount of available isotope. In addition, the cavities containing radioactivity but not cytosol are processed with carbon to estimate the DPM of [3H] -17ß-estradol that can not be eliminated. Corning # 25880-96 96-well plates were used because they demonstrated the lowest amount of estradiol binding of all those tested.

Analysis of results Radioactivity per minute counts (CPM) are automatically converted to minute disintegrations (DPM) using the Beckman LS7500 Flash Counter using a set of attenuated patterns to generate a H # for each sample. To calculate the percentage of estradiol binding in the presence of 100 or 500 times of competitor, the following formula is applied: (DPM of the sample - DPM not eliminated by carbon / (DPM of estradiol - DPM not eliminated by carbon)) x 100% =% of estradiol binding To generate the IC50 curves, the% binding against concentration of the compound is plotted. The IC50 values are generated for compounds exhibiting > 10% competition at a competitor concentration of up to 500x.

Reference Compounds Several reference compounds have been evaluated and their IC50 concentration has been determined. The concentration of these compounds required to displace hiáekAá? dt L -? * i- j * * riJ .íÁ * í¿Jí¡ííí * -; ai ^ -6a-KJ 50% of [3H] -17ß-estradiol is: Estradiol: 0.08 μM Tamoxifen: 4.50 μM Raloxifene: 0.04 μM 17 -. 17 -dihydroequiline 0.15 μM Test results To demonstrate the usefulness of the compounds of this invention, the compound of Example No. 2 was evaluated against the tamoxifen standards, also called (Z) -2- [4- (1, 2-diphenyl-1-bu enyl) -phenoxy] -N, N-dimethylethanamine, and raloxifene, also called [6-Aryroxy-2- (4-hydroxy-phenyl) -benzo [b] thiophen-3-yl] - [4- (2-piperidm- 1-yl-ethoxy) -phenyl] -methanone. It is understood that 17β-estradiol, as a pattern, has 100% binding in the Receptor Binding Test.

IC50 Compound of the Transfection Test Proof of Receptor Binding Example 2.0 x 10"7 M Concentration% of control No. 2 1 x 10" ° M 1 x 10"6 M + E s t radi o l 1 nM 1 3 ÍÍLJL * Í? , < -_! you? é * .f- ******** ...... u? s ***! **, *. ****, - ^^ a. J-fcf - ^ »f ^» ^, a:; a ^ a '**' «'^^ Tamoxifen 4.5 x 10" 6 M Concentration% control 1 x 10"6 M 0 1 x 10 -6 M Estradiol 1 nM 10 Raloxi feno 4 x 10 'M Control concentration 1 x 10"B M 1 x 10" b M + Estradiol 1 nM 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 iú tiá-u? TO

Claims (14)

2. Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula: (i) in which Rx, R2 and R3 are independently selected from hydrogen, halogen, C? -C6 alkoxy, -CF3, -N02, cyano, C? -C6 alkyl (straight or branched chain) ), trifluoromethyl, -OH or the esters of C? -C? 2 (straight or branched chain), or the C? -C? 2 alkyl ethers (straight chain or branched or cyclic) thereof or halogenated ethers of C? -C6; R4 and Rs are independently selected from H or benzyl, the benzyl group optionally being substituted with C? -C6 alkyl, C? -C6 alkoxy, -CF3 or halogen; X is H, C? -C6 alkyl or ! k ** ?. j.A - ** -? »CF3; Z is O or S; n is 2 or 3; And it is selected from: a) a portion of the formula:
3. R '/ -N \ R' wherein R 'is lower alkyl of C? -C6 same or different; or b) a portion that is selected from the group of: or a pharmaceutically acceptable salt thereof. 2. - A compound according to claim 1, further characterized in that Ri and R2 are independently selected from hydrogen, C? -C6 alkyl, C? -C6 alkoxy, -CF3 and -N02 or a salt pharmaceutically acceptable thereof. 3. A compound according to claim 1 or claim 2, further characterized in that Z is oxygen.
4. 4. A compound according to any of claims 1 to 3, further characterized in that R3 and t? • * & R4 are H.
5. 5. A compound according to any of claims 1 to 4, further characterized in that Ri and R2 are H.
6. 6. A compound according to any of claims 1 to 5, further characterized in that n is 2.
7. 7. A compound according to any of claims 1 to 6, wherein Y is a piperidine ring, or a pharmaceutically acceptable salt thereof.
8. 8. A compound according to claim 1, which is [5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methylindol-1-yl] - [4- (2-piperidin-1-yl) -ethoxy) phenyl] -methanone.
9. 9. A compound according to claim 1, which is [5-hydroxy-2- (-hydroxy-phenyl) -3-methylindol-1-? L] - [4- (2-piperi in-l- il-ethoxy) phenyl] -methanone, or a pharmaceutically acceptable salt thereof.
10. 10. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing the loss of bone tissue in a mammal.
11. 11. - A method for treating or preventing conditions or pathological syndromes which are caused or are associated with an estrogen deficiency in a mammal, the method comprising administering to the mammal in need thereof, an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
12. 12. A method for treating or preventing cardiovascular disease in a mammal, the method comprising administering to a mammal in need therefor, an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
13. 13. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, according to claim 1, characterized in that it comprises one of the following: a) acylating a compound of the formula: above, with a compound of the formula (III) Íij, ¿j ,. ? U ** A ** t--: * &** ** '-. ** &** .. ** • -.- * ^ ... ~ - * ^. ¡^??? i l l l *** *** 3 3 .- 3 3 3 3 *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** *** "" "*** ***" "" "" "" "" "". or a reactive derivative thereof, for example acid halide in which n, R1, R2, Z and Y are as defined in claim 1, to give a compound of the formula I; or b) reacting a compound of the formula: (IV) in which X, Z, Rx, R2, R3, R4 and s are as defined in claim 1, and hal represents a halogen, for example chlorine or bromine, with an amine of the formula: H-Y (V) wherein Y is as defined in claim 1, to give a compound of the formula I, or c) to debenzylate a compound of the formula I as defined in claim 1, wherein R4 and / or R5 is (are) optionally substituted to give a compound of the formula I in which R4 and / or R5 are hydrogen, or e) esterifying a compound of the Formula I as defined in claim 1, wherein at least one of Ri, R2 or R3 are hydroxy to an ester derivative thereof.
14. 14. A pharmaceutical composition comprising a compound according to any of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. SUMMARY OF THE INVENTION The present invention provides compounds of the formula (A) wherein R :, R2 and R3 are independently selected from hydrogen, halogen, C-C6 alkoxy, -CF3, -N02, cyano, C: -C6 alkyl, trifluoromethyl, -OH or the esters of C: -C; 2 (straight chain or branched) or the C: -C12 alkyl ethers thereof, or the halogenated ethers of d-C, preferably the halogenated ethers of C? -C3, including the trifluoromethyl ether and the trichloroethyl ether; R 4 and R 5 are independently selected from H or benzyl, the benzyl group being optionally substituted with C alquiloC alquilo alkyl, C alco-C6 alkoxy, -CF 3 or halogen; X is H, C-C alkyl & or CF ..; Z is O or S; n is 2 or 3; Y is selected from: a) a portion of the formula -NR'R 'in which R' is lower alkyl of C: -C6; or b) a portion that is selected from the group of (B), (C), (D) í-t & *. *. *. ^? *? - < -'- * - > - - '> - or (E: 5 or a pharmaceutically acceptable salt thereof, as well as pharmaceutical formulations and methods for treating or preventing conditions or pathological syndromes that are caused or that are associated with an estrogen deficiency or an excess of estrogen using these compounds. . "** & - • - - * ^ H? ^ * ^^ ** - a, -. í -