MXPA97002866A

MXPA97002866A - Estrogeni agents

Info

Publication number: MXPA97002866A
Application number: MXPA/A/1997/002866A
Authority: MX
Inventors: Paul Miller Chris; David Collini Michael; Dinh Tran Bach
Original assignee: American Home Products Corporation
Priority date: 1996-04-19
Filing date: 1997-04-18
Publication date: 1999-04-06

Abstract

The present invention relates to new compounds of 3- [4- (Phenyl-Indol-1-ylmethyl) -phenyl] -acrylamide and to new compounds of 2-phenyl-1- [4- (amino-1-yl -alk-1-ynyl) -benzyl] -1H-in dol-5-ol which are useful as estrogenic agents, as well as pharmaceutical compositions and treatment methods using these compounds, the compounds have the general formulas given below: wherein Z is selected from -CH-CH-CY or -C = C- (CH2) n

Description

ESTROGENIC AGENTS FIELD OF THE INVENTION The present invention relates to new compounds of 3- [4- (2-Phenyl-Indol-l-ylmethyl) -phenyl] -acrylamide and to new compounds of 2-phenyl-l- [4- (amino-1-yl- alk-1-inyl) -benzyl] -lH-indol-5-ol which are useful as estrogenic agents, as well as to pharmaceutical compositions and methods of treatment using these compounds.

BACKGROUND OF THE INVENTION The use of a hormone replacement therapy for the prevention of bone loss in postmenopausal women is well documented above.

The normal protocol requires estrogen supplementation using such formulations containing estrone, estriol, ethinyl estradiol or conjugated estrogens isolated from natural sources (Wyeth-Ayerst Premarin). In some patients, therapy may be contraindicated due to the proliferative effects of non-opposing estrogens (Estrogens are not given in combination with progestins) that they have on the uterine tissue. This proliferation is associated with an increased risk of endometriosis Ref. 24476 and / or endometrial cancer. The effects of unopposed estrogen on breast tissue is less clear, but it is interesting. The need for estrogens which can maintain the bone replacement effect while minimizing the proliferative effects on the uterus and chest is evident. Certain non-steroidal antiestrogens have been shown to maintain bone mass in the ovariectomized rat model as well as in human clinical trials. Tamoxifen, for example, is a useful palliative for the treatment of breast cancer. It has been shown to exert an effect similar to the estrogen agonist on bone, in humans. However, it is also a partial agonist in the uterus and this is the reason why there is something of interest in it. Raloxifene, a benzothiophene antiestrogen, has been shown to stimulate uterine growth in the ovariectomized rat to a degree smaller than Tamoxifen while maintaining the capacity of bone replacement. An adequate review of selective tissue estrogens is: Tissue-Selective Actions of Estrogen Analogs, Bone Vol. 17, No. 4, October 1995, 181S-190S. The use of the indoles as estrogen antagonists has been reported by Von Angerer, Chemical Abstracts, Vol. 99, No. 7 (1983), Abstract No. 53886u.

Also, see, J.Med. Chem. 1990, 2635-2640; J.Med. Chem. 1987, 30, 131-136. See also Ger.Offen., DE 3821148 Al 891228 and WO 96/03375. Additionally, see WO, A, 93 23374 (Otsuka Pharmaceutical Factory, Inc.). Von Angerer's work is limited to aliphatic chains linked or linked to the indole nitrogen and then bonded or bonded to the basic amine (or amide) or, benzyl groups that do not possess the basic amine. The Otsuka (Japanese) world patent consists of compounds related to the present invention except R ~ (as shown in formula I) which is defined as -SR wherein R is alkyl. Additionally, there are no indole nitrogen chains in their patent with the same structure as some given in the present invention, either by claim or by example. A related patent, W0 A 93 10741 describes the 5-hydroxyindoles. The patent W0 A 95 17383 (Kar Bio AB) describes aliphatic chain compounds. The patent W0 A 95 17383 (Karo Bio AB) describes indole antiestrogens with long straight chains. Another related patent, No. W0 A 93 10741 describes the 5-hydroxyindoles with a wide range of side chains. Patent No. W0 93/23374 (Otsuka Pharmaceuticals, Japan) describes compounds that share structural similarities with those of the present invention, except with the structure referred to as R "in the present formulas I and II, below, which is defined as the thioalkyl and the reference does not describe such compounds having chains from the indole nitrogen having the same structure as those provided by the present invention.

DESCRIPTION OF THE INVENTION Compounds of the general structural type shown in formulas (I) and (II) are estrogen agonists / antagonists useful for the treatment of diseases associated with estrogen deficiency. The compounds of the present invention show strong binding to the estrogen receptor. These compounds have proven that they will be antiestrogens with a small intrinsic estrogenicity. In a three-day ovariectomized rat model, the compounds of the formula (I) are capable of antagonizing the effects of 17 B -estradiol while showing a small uterine stimulation when dosed alone. The present invention includes the compounds of the formulas (I) and (II), which are given below: wherein: it is selected from H, OH or the esters with C, -C, ° l ° s alkyl ethers thereof, or halogen; R ?, R, R ,, Fr, and Rfi are independently selected from H, OH or the esters with C, -C, or the alkyl ethers thereof, halogen, o, alkyl with C, -C, or trifluoromethyl, with the proviso that when n is 2 or 3; X is selected from H, alkyl with C.-C, o, nitro, trifluoromethyl, halogen; Z is selected from -CU-CH-C-Y -C = £ C- (CH2) rr ?.

And it is selected from: a) the portion: R7 Rβ wherein R, and RR are independently selected from the group of H, alkyl with C, -C, phenyl or combined by - (CH -,) p-, where p is an integer from 2 to 6, for To form a ring, the ring is optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, alkyl with C.-C, trihalomethyl, alkoxy with C.-C, trihalomethoxy, alkylthio with C.- C, -C, C, -C, alkylsulfonyl, alkylsulfinyl with C, -C, hydroxy (C, -C ^ alkyl, -C02H, -CN, -CONHICj-C ^, "Hj, alkylamino with C.-C, dialkylamino with C.-C ,, -NHS02 (C1-C4), -NHC0 (C1-CA), and -N02. b) a saturated, unsaturated or partially unsaturated heterocycle of five, six or seven elements, containing up to two heteroatoms selected from the group consisting of -0-, -NH-, -N (CC, alkyl) -, -N = , and -S (0) m-, where m is an integer from 0-2 optionally substi-tuted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl with C, -C, , trihalomethyl, alkoxy with C.-C ,, trihalomethoxy, acyloxy with C- | -C ,, alkylthio with C.-C ,, alkylsulfinyl with C.-C ,, alkylsulfonyl with C.-C ,, hydroxy (C, -C,) alkyl, phenyl substituted with from 1 to 3 groups (C.C,) alkyl, -CO ^ H-, -CN-, -CONHRj-, -NH2-, (Cj-C ^) alkylamino, diCJ -C ^ alkylamino, -NHS02R1-, -NHC0R1-, -N02-; c) a bicyclic ring system consisting of a five or six element heterocyclic ring fused to a phenyl ring, the heterocyclic ring contains up to two heteroatoms selected from the group of -0-, -NH-, -N (CC, alkyl ) -, and -S (0) -, where m is an integer from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl with C, -C, , trihalomethyl, alkoxy with C.-C ,, trihalomethoxy, acyloxy with C.-C ,, alkylthio with C.-C ,, alkylsulfinyl with C.-C ,, alkylsulfonyl with C.-C ,, hydroxy (C. C,) alkyl, phenyl substituted with from 1 to 3 groups (C, -C,) alkyl, -C02H-, -CN-, -C0NHR1-, -NH2 ~, (C ^ C ^ alkylamino, di (C1-C4) ) alkylamino, -NHS02R1-, -NHC0R1-, ~ N02, and pharmaceutically acceptable salts thereof.

Rings formed by a concatenated or chained R7 and R, mentioned above, may include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, or hexamethyleneamine rings. It is further preferred that, when R-, and RR are chained together as - (CH2) p-, the ring thus formed is optionally substituted with 1-3 substituents selected from a group containing an alkyl with C, -C, trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN. The most preferred compounds of the present invention are those having structural formulas I or II, above, wherein R. is OH; R2 ~ Rt are as defined above; X is selected from the Cl group, N02, CN, CF ", or CHg-, and Y is the portion and R-- and R "are chained together as - (CH") -, where p is an integer from 4 to 6, to form a ring optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, alkyl with C.sub.3 -C trihalomethyl, alkoxy with C.sub.C, trihalomethoxy, alkylthio with C.sub.1 -C.sub.silylsulfinyl with C.sub.C.sub.2, alkylsulfonyl with C.sub.1 -C.sub.hydroxy (C, -C,) alkyl, -C02H, -CN, -C0NH (C1-C4) alkyl, -NH ,,, (C ^ C ^ alkylamino, diCJ-C ^ alkylamino, -NHSO ^ Cj-C ^, -NHCOÍCj- C ^ alkyl, and ~ N02, and the pharmaceutically acceptable salts thereof The invention includes acceptable salt forms formed from the reaction by addition with either organic or inorganic acids.Inorganic acids such as hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid also useful as organic acids such as acetic acid, propionic acid, acid citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, are useful. It is known that compounds possessing a basic nitrogen can form complexes with many different acids (both protic and non-protic) and it is usually preferred to administer a compound of this invention in the form of an acid addition salt. The compounds of the invention are partial estrogen agonists and exhibit a high affinity towards the estrogen receptor. Unlike many estrogens, however, these compounds do not cause increases in wet uterine weight. These compounds are antiestrogenic in the uterus and can completely antagonize the trophic effects of estrogen agonists in uterine tissue. These compounds are useful in the treatment or prevention of mammalian disease states or syndromes which are caused or are associated with an estrogen deficiency. The present compounds have the ability to behave in a similar way to estrogen agonists by lowering cholesterol and preventing bone loss. Therefore, these compounds are useful for treating many diseases including osteoporosis, prostatic hypertrophy, infertility, breast cancer, endometrial cancer, cardiovascular disease, contraception, ßhezheiner's disease and melanoma. Additionally, these compounds may be used for the replacement therapy of hornones in postmenopausal women or in other estrogen deficiency states where estrogen supplementation may be beneficial. The compounds of this invention can also be used in treatment methods for bone loss, which can result from an imbalance in an individual's formation of new bone tissues and resorption of older tissues, leading to a net loss of bone . Such bone depletion leads to a range of individuals, particularly post-menopausal women, women who have undergone hysterectomy, those who receive or who have received prolonged corticosteroid therapies, those who experience gonadal dysgenesis, and those who suffer from the syndrome. Cushing. Special needs for bone replacement can also be solved by using these compounds in individuals with bone fractures, defective bone structures, and those who undergo surgeries related to bone and / or prosthetic implant. In addition to those problems described above, these compounds can be used in treatments for osteoarthritis, Paget's disease, osteomalacia, osteohalistresis, endometrial cancer, multiple myelomas and other forms of cancer that have detrimental effects on bone tissues. The methods of treatment of the diseases listed herein are understood to include administration to an individual in need of such treatment., of a pharmaceutically effective amount of one or more of the compounds of this invention or a pharmaceutically acceptable salt thereof. This invention also includes pharmaceutical compositions that use one or more of the present compounds, and / or pharmaceutically acceptable salts thereof, in the company of one or more carriers, excipients, pharmaceutically acceptable, etc. It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the disease and the individual being treated and will be subject to the judgment of the physician involved. It is preferred that the administration of one or more of the compounds here begin at a low dose and subsequently increase until the desired effects are achieved. The effective administration of these compounds can be provided at a dose from about 0.1 mg / day to about 1,000 mg / day. Preferably, the administration will be from about 50 mg / day to about 600 mg / day in a single dose or in two or more divided doses. Such doses may be administered in any manner useful to direct the active compounds from here to the blood flow of the patient, including the oral, parenteral (including intravenous, intraperitoneal and subcutaneous), and transdermal routes. For the purposes of this disclosure, transdermal administrations are understood to include all administrations throughout the body surface and internal coatings of body passages including epithelial and mucosal tissues. Such administrations can be carried out using the present compounds, or 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 may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions and solutions. The capsules may contain mixtures of the active compound (s) with inert fillers and / or diluents, such as pharmaceutically acceptable starches (eg, corn starch, potato or tapioca), sugars, artificial sweetening agents. , powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional dry compression, wet granulation, or granulation methods, and utilize pharmaceutically acceptable diluents, binders, lubricants, disintegrants, suspending or stabilizing agents, but are 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, silicates in complex form, calcium carbonate, glycine , dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. The oral formulations herein may use time-release or delayed-release, standard formulations to alter the absorption of the active compound (s). Suppository formulations can 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, such as polyethylene glycols of various molecular weights, can also be used. The compounds of this invention can be synthesized in a general sense in accordance with Schemes 1 and 2, which are given below.

Scheme 1 The synthesis of the initial indole of Scheme 1 is effected by heating a properly substituted aniline (1) with an appropriately substituted alpha-bromophenylpropiophenone (2), in a suitable high-boiling solvent, such as DMF. The product is then rented with a 4-bromobenzyl bronto to give the substituted indole (3). At this point, the deprotection of the phenols is pered (ßi are present). Normally, the phenols are protected as benzylic ethers and can be split or conveniently separated with TMSI. The acrylamides are joined using the conditions of the Heck reaction in either Et ~ N or Et N / CH ^ CN pure.

Scenario 2 The synthesis of the initial indole of Scheme 2 can be effected by heating an aniline (1) appropriately substituted with an appropriately substituted alpha-bromophenylalkyl-phenyl (2), in a suitable high-boiling solvent, such as DMF. The product is then alkylated with the 4-iodobenzyl bromide to give the substituted indole (3). At this point, the deprotection of the phenols is made (if present). Normally, the phenols are protected as benzylic ethers and can be split or conveniently separated with TMSI. The propargylamines can then be attached to the phenyl iodide. Propargylamines are typically prepared from an alkynyl bromide or alkynyl tosylate by substitution with the appropriate amine. The substitution reaction is done in situ, without isolating the propargylamine. The compounds substituted in the 3-position with different alkyl groups can be prepared by first preparing the substituted indole in the 3-position with -H. The indole can be halogenated, ylated, etc., then hydrophilically, to give other 3-substituted compounds. The solvents used the reactions here were anhydrous Aldrich Sure Seal without further purification. The reagents were typically from Aldrich and were used without further purification. All reactions were carried out under a nitrogen atmosphere. Chromatography was pered using a 230-240 mesh silica gel (Merck Grade 60, Aldrich Chemical Company). Thin layer chromatography was carried out with Silicon Gel 60 F2 plates, from EM Science. The H-NMR spectra were obtained on a Bruker AM-400 instrument in DMSO and the chemical shifts were reported in ppm. The melting points were determined on a Thomas-Hoover apparatus and are uncorrected. The IR spectra were recorded on a Perkin-Elmer diffraction grating or on Perkin-Elmer 784 spectrophotometers. The mass spectra were recorded on Kratos MS 50 or Finnigan 8230 mass spectrometers. The elemental analyzes were obtained with a Perkin elemental analyzer. -Elmer 2400. The values of the analysis are within the range of 0.4% of the theoretical. The present invention is further illustrated by the following non-limiting examples.

EXAMPLE 1 -Benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1H-indole One vessel was charged with 4-benzyloxyaniline (45 g, 0.23 mole), 4'-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 mole), and DMF (50 ml). The reaction is refluxed 30 minutes and then cooled to room temperature and then partitioned between EtOAc (250 mL) and IN HCl (aq) (100 mL). The EtOAc is washed with NaHCO3 (aq) and brine, dried over MgSO ,. The solution is concentrated and the residue is taken up in CH2C12 and hexanes were added to precipitate 25 g of a crude solid. The solid is dissolved in CH? C12 and evaporated on silica gel and subjected to chromatography using CH2Cl2 / Hexane (1: 5) to give 9.2 g of a tan solid (33%): Mp = 150-152 °. C; NMR XH (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.48 (d, 4 H, J = 7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d , 1 H, J = 7.0 Hz), 7.13 (d, 2 H, J = 8.8 Hz), 7.08 (d, 1 H, J = 2.2 Hz), 6.94 (dd, 1 H, J = 8.8, 2.4 Hz) , 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm "1; MS m / z 419.

EXAMPLE 2 -Benzyloxy-2- (4-fluoro-phenyl) -3-methyl) -lH-indole The title compound was prepared in a manner similar to (3): PP = 132 ° C; H? (DMSO) 11.0 (s, 1 H), 7.68-7.64 (m, 2 H), 7.49-7.47 (m, 2 H), 7.41-7.31 (m, 5 H), 7. 23 (d, 1 H, J = 8.8 Hz), 7.10 (d, 1 H, J = 2.4 Hz), 6.82 (d, 1 H, J = 8.8, 2.4 Hz), 5.11 (s, 2 H), 2.34 (s, 3 H); MS The m / z 331; CHN calc.paraC22H18FNO.

EXAMPLE 3 -Benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl) -l-ylmethyl- (4-phenylbromide -indole) A solution of 60% NaH (0.17 g, 7.1 mmol) in DMF (2 mL) is cooled to 0 ° C and treated by a dropwise addition of benzyloxyindole 1 (2.5 g, 5.94 mmol) in DMF (10 mL). ). After 15 minutes, 4 '-bromobenzyl bromide (1.63 g, 6.53 mmol) in DMF (10 ml) was added dropwise. The reaction is stirred for 5 minutes at 0 ° C and then at room temperature for an additional 20 minutes. The reaction mixture is diluted with ether (300 ml) and washed with NH4C1 (2x25 ml) then with NaHCOg (1x25 ml), and brine (25 ml). The organic extracts are dried over MgSO4 and concentrated. The residue is crystallized from THF / Hexanes to give 2.7 g (77%) of 2: P.f. (Melting point) = 144-146 ° C; H NMR (CDClg) 7.51-7.36 (m, 8 H), 7.34 (d, 4 H, J = 8.6 Hz), 7.20 (d, 2 H, J = 8.8 Hz), 7.15 (d, 1 H, J = 2.4 Hz), 7.03-7.00 ( m, 3 H), 6.89 (dd, 1 H, J = 8.8, 2.4 Hz), 6.80 (d, 2 H, J = 8.6 Hz), 5.14 (s, 2 H), 5.12 (s, 2 H), 5.09 (s, 2 H), 2.25 (s, 3 H); IR (KBr) 3400, 3020, 1600 cm "1; EM at m / z 587.

EXAMPLE 4 -Benzyloxy -2 - (4-f 1-uoro-f-enyl) -3-methyl) -l-ylmethyl- (4-f n i lb) -indole The title compound was prepared si thousand to compound 5. Pf = 139-139.5 ° C; RHN (DMSO) 7.49-7.46 (m, 2 H), 7.41-7.37 (m, 6 H), 7.33-7.27 (m, 4 H), 7.24 (d, 1 H, J = 8.8 Hz), 7.16 (d 1 H, J = 2.2 Hz), 6.84 (dd, 1 H, J = 8.8, 2.4 Hz), 6.73 (d, 1 H, J = 8.6 Hz), 5.2 ($, 2 H), 5.12 (s, 2 H), 2.15 (s, 3 H); IR (KBr) 2920, 1630 cm "1; MS m / z (499/501, Br presents CHN cal for C ^ HaBrFNO.

EXAMPLE 5 2- (4-hydroxyphenyl) -3-methyl) -1-ylmethyl- (4-phenyl bromide) -indol-5-ol A solution consisting of 5 (0.5 g, 0.85 mmol) in CH2C12 (10 ml) is treated by dropwise addition with 3.5 eq. of TMSI (0.47 ml, 3.0 mmol) at room temperature. After a couple of hours, the reaction is stopped, 2.2 eq. of TMSI and the reaction is refluxed for 5 hours. The reaction is cooled to 0 ° C and the methanol is added slowly to quench the reaction. The reaction is diluted with ether (25 ml) and washed with NaHCO 3 (25 ml), 10% Na 2 SO 3 (25 ml), and salt-die. The ether layer is dried over MgSO 4 and concentrated on silica gel. Chromatography with EtOAc / hexanes (1: 4 to 1: 1) gave 0.25 g of 3 (71%): Mp = 83-86 ° C; WN H (CDCLj) 2 H's of phenols applio (> 10), s 7.35 (d, 2 H, J = 9.0 Hz), 7.15 (d, 2 H, J = 8.8 Hz), 7.01 (dd, 1 H, J = 2.4, 0.4 HZ), 6.86 (d, 2 H, J = 8.8 HZ), 6.80 (d, 1 H, J = 8.6 Hz), 6.72 (dd, 1 H, J = 8.6, 2.4 Hz), 5.10 (s, 2 H), 4.88 (s, 1 H), 4.50 (s, 1 H), 2.21 (s, 3 H); MS m / z 407/409 contains Br, IR 3390, 2900, 1600 cm'1; CHN cal.for C22H? 8BrNO2 + 0.25 EtOAc.

EXAMPLE 6 2- (4-fluoro-phenyl) -3-methyl-yl) -l-ylmethyl- (4-phenyl bromide) -indole-5-ol The title compound was prepared if my compound was layered and a foam was isolated. H NMR (DMSO) 8.79 (s, 1 H), 7.39-7.34 (m, 4 H), 7.32-7.30 (m, 3 H), 7.11 (d, 1 H, J = 8.8 Hz), 6.85 (d, 1 H, J = 2.2 Hz), 674 (d, 1 H, J = 2.4 Hz), 6.63 (dd, 1 H, J = 8.6, 2.2 Hz), 5.16 (s, 2 H), 2.11 (s, 3 H); IR (KBr) 3400, 2900, 1630 cm'1; MS m / z 409/411 contains Br.

General Procedure for Indole Acryllanides A solution of Example 3 in Et ~ N is treated with tri-o-tolylphosphine (10% mol), and acrylamide (1.25 eq.) Is completely purged with N2 and added Pd (0Ac) 2 (2.5% mo l) . The reaction is heated to 100-110 ° C in a sealed tube until it is completed by CCD analysis. The crude reaction product is concentrated by lowering the temperature and either directly crystallized or chromatographed on silica gel.

EXAMPLE 7 (IN. N-Diethyl-3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-l-ylmethyl-phenyl-acrylamide P.f. = 160-165 ° C; ! H NMR 9.67 (s, 1 H), 8.72 (s, 1 H), 7.50 (d, 2 H, J = 8.1 Hz), 7.37 (d, 1 H, J = 15.4 Hz), 7.17 (d, 2 H, J - 8.3 Hz), 7.06 (d, 1 H, J = 8.8 Hz), 6.97 (d, 2 H, J = 15.4 Hz), 6.86-6.82 (m, 5 H), 6.58 (dd, 1 H , J = 8.6, 2.2 Hz), 5.19 (sa, 2 H), 3.47-3.42 (, 2 H), 3.34-3.30 (m, 2 H), 2.09 (s, 3 H), 1.10 (t, 3 H , J = 7.0 Hz), 1.03 (t, 3 H, J = 7.0 Hz); IR (KBr) 3300, 2950, 1660, 1580 cm -1; MS (el) m / z 454; CHN cal.for C29H30N2O3 + O.I5 CH2Cl2 + 0.30 H2O.

EXAMPLE 8 l (E) -N-tert-butyl-3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-me-thiyl-indol-1-ylmethyl] -phenyl-3-acrylamide P.f. = 168-170 ° C; * H NMR 9.66 (s, 1 H), 8.71 (s, 1 H), 7.66 (s, 1 H), 7.34 (d, 2 H, J = 8.3 Hz), 7.24 (d, 1 H, J = 15.8 Hz), 7.15 (d, 2 H, J = 8.3 Hz), 7.05 (d, 1 H, J = 8.6 Hz), 6.85-6.82 (m, 5 H), 6.59-6.56 (m, 1 H), 6.55 (d, 1 H, J = 16.0 Hz), 5.18 (s, 2 H), 2.11 (s, 3 H), 1.28 (s, 9 H); IR (KBr) 3350, 2950, 1660, 1620; MS (el) m / z 454; CHN cal.for C29H30N2O3 + 0.4H2O EXAMPLE 9 (E) -Pyrrolidino-3- j 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-l-ylmethyl] -phenyl-J-acrylamide P.f. = 170-175 ° C; ! H NMR 9.67 (s, 1 H), 8.71 (s, 1 H), 7.49 (d, 2 H, J = 8.1 Hz), 7.35 (d, 1 H. J = 15.4 Hz) .7.16 (d.2) H, J = 8.6 Hz) .7.05 (d, 1 H, J = 8.8 Hz), 6.88-6.81 (m, 6 H), 6.57 (dd, 1 H, J = 8.6, 2.2 Hz), 5.19 (sa. , 2 H), 3.56 (t, 2 H, J = 6.6 Hz), 3.35 (m, 2 H), 2.11 (s, 3 H), 1.87 (p, 2 H, J = 7.0 Hz), 1.77 (p, 2 H, J = 7.0 Hz); MS m / z 452; CHN cal.for + 0.1 MeOH + 1.3 H2O.

EXAMPLE 10 (IN. N-Dimethyl-3- {4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmethyl-phenyl-acrylamide P.f. = 278-280 ° C; H fMN (DMSO) 9.65 (s, 1 H), 8.70 (s, 1 H), 7.50 (d.2H.

J = 8.1 Hz), 7.33 (d, 1 H, J = 15.4 Hz), 7.15 (d, 2 H, J = 8.6 Hz), 7.07 (d.1 H, J = . 6 Hz), 7.05 (d, 1 H, J = 8.8 Hz), 6.85-6.80 (m, 5 H), 6.57 (dd, 1 H, J = 8.6, 2.4 Hz), 5.19 (s, 2 H), 3.09 (s, 3 H), 2.88 (s, 3 H), 2.11 (s, 3 H); MS at m / z 426; IR (KBr) 3410, 3220, 1650, 1580 cm -1; CHN cal.for C ^ Has ^ Os + 0.5 H2O.

EXAMPLE 1 1 (E) -N. N-Dibutyl-3- C 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-1-indol-1-ylmethyl] -phenyl-acrylamide P.f. = 126-128 ° C, 1W (DMSO) 9.65 (s, 1 H), 8.70 (s, 1 H), 7.48 (d, 2 H, J = 8.3 Hz), 7.36 (d, 1 H. J = 15.2 Hz), 7.16 (d, 2 H, J = 8.6 Hz), 7.05 (d, 1 H, J = 8.6 Hz), 6.97 (d, 1 H, J = 15.2 Hz), 6.86-6.81 (m, 5 H) ), 6.57 (dd, 1 H, J = 8.8, 2.4 Hz), 5.19 (s, 2 H), 3.39 (t, 2 H, J = 7.0 Hz), 3.29 (t, 2 H, J = 7.2 Hz) , 2.11 (S, 3 H), 1.48-1.43 (M, 4 H), 1.29-1.20 (M, 4 H), 0.87 (t, 6 H, J = 7.2 Hz); MS at m / z 510; IR (KBr) 3300, 2920, 2900, 2850, 1650, 1625, 1580 cm'1; CHN cal.para EXAMPLE 12 (E) -N-butyl. N'-methyl-3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) • 3-methyl-indol-1-ylmethyl] -phenyl J -acrylamide P.f. = 240-242 ° C; ^ (DMSO) 9.66 (s, 1 H), 8.70 (s.1 H), 7.50 (d, 2 H, J = 8.1 Hz), 7.38-7.32 (m, 1 H), 7.16 (d, 2 H, J = 6.8 Hz), 7.06-7.01 (m, 2 H), 6.85-6.81 (m, 5 H), 6.57 (dd, 1 H, J = 8.6, 2.2 Hz), 5.19 (s, 2 H), 3.44 , 3.33 (2 t, 2 H, J = 7.2 Hz), 3.06, 2.87 (2 s, 3 H). 2.11 (s, 3 H), 1.45 (m 2 H). 1.24 (p, 2 H, J = 7.5 Hz), 0.87 (t, 3 H. J = 7.2 Hz); MS at m / z 468; IR (KBr) 3300, 1660, 1590 cm'1; CHN cal.for C3oH32N2O3 + 0.2 H2O.

EXAMPLE 13 (E) -Morfolino-3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indole-1-ylmethyl-phenyl-acrylamide, P.f. Kti (DMSO) 9.66 (s.1 H) .8.71 (s, 1 H) .7.52 (d, 2 H, J = 8.1 Hz), 7.39 (d, 1 H, J - 15.4 Hz), 7.15 (d, 2 H, J = 8.6 Hz), 7.12 (d.1 H. J = 15.4 Hz) .7.06 (d, 1 H. J - 8.6 Hz) .6.85-6.81 (m, 5 H), 6.57 (dd.1 H, J = 8.6, 2.2 Hz), 5.19 (s, 2 H), 3.65-3.64 (m.2 H), 3.59-3.53 (m, 6 H), 2.11 (s, 3 H); IR (KBr) 3330, 1650, 1620. 1580 cm-1; M (FAB) m / z 469 (M + H +); CHN cal.for CajHaNjO-, + 0.5 H2O.

EXAMPLE 14 (E) -3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenyl-3"-acrylamide P.f. = 161-163 ° C, H m (DMSO) 9.65 (s, 1 H), 8.70 (s.1 H), 7.48 (s, 1 H), 7. 37 (d.2 H, J = 8.35 Hz), 7.30 (d, 1 H, J = 15.8 Hz), 7.14 (d, 2 H, J = 8.35 Hz). 7.04 (d, 2 H, J = 8.6 Hz), 6.85-6.81 (m, 5 H), 6.57 (dd, 1 H, J = 8.8, 2.4 Hz), 6.48 (d, 1 H, J = 15.8 Hz), 5.18 (s, 2 H), 2.10 (s, 3 H); IR (KBr) 3320, 3180, 1660, 1580 cm'1; MS (FAB) m / z 399 (M + H +); CHN cal.for C25H22N2O3 + 1.3 H2O.

EXAMPLE 15 (IN. Methyl-3-f 4- [5-hydroxy-2- (4-hydroxy-f-enyl) -3-methyl-indol-l-ylmethyl] -phenyl-3-acrylamide P.f. = 155-158 ° C; NMR (DMSO) 9.64 (s, 1 H), 8.70 (s.1 H), 7.99 (c, 1 H, J = 4.4 Hz), 7.37 (d.2 H, J = 8.1 Hz) .7.30 (d, 1 H, j = 15.8 Hz), 7.14 (d, 2 H, J = 8. 6 Hz), 7.03 (d, 1 H, J - 8.6 Hz), 6.85-6.81 (m, 5 H), 6.57 (dd, 1 H, J = 8.6, 2.4 Hz), 6.48 (d.1 H, J = 15.8 Hz) .5.18 (s, 2 H), 2.66 (d, 3 H, J = 4.6 Hz) .2.10 (s, 3 H); IR (KBr) 3400, 1660, 1620 cm-1; EM mz 412; CHN cal.for C ^^ NzOs + 0.4 H2O.

EXAMPLE 16 (IN. N-Dibutyl-3-. { - [5-hydroxy-2- (4-f luoro-f-enyl) -3-methyl-indol-l-il-methyl-phenyl-acrylamide P.f. = 180 ° C; H RW (DMSO) 8.77 (s, 1 H), 7.48 (d, 2 H, J = 8.4 Hz), 7.41-7.38 (m, 3 H), 7.38-7.29 (m.3 H), 7.13 (d, 1 H. J = 8.8 Hz), 6.97 (d, 1 H. J = 15.4 Hz), 6.85 (d, 1 H, J = 2.4 Hz), 6.80 (d, 2 H, J = 8.1 Hz), 5.2 ( s, 2 H), 3.40-3.36 (m, 2 H), 3.30-3.27 (m, 2 H), 2.10 (s, 3 H), 1.50-1.40 (, 4 H), 1.29-1.21 (m, 4 H), 0.86 (t, 6 H. J = 7.2 Hz); IR (KBr) 3180, 2950, 2900.2850, 1650, 1590 cm "1; MS m / z 512; CHN cal.for C33H37N2O2.

EXAMPLE 17 (E) -N-Butyl. N'-Methyl-3- i - [5-hydroxy-2- (4-fluoro-phenyl) -3-methyl-indol-l-ylmethyl] -phenyl J- -acrylamide P.f. = 153-153.5 ° C; H NM (DMSO) 8.77 (s, 1 H), 7.50 (d, 2 H, J = 8.1 Hz), 7.42-7.36 (m, 2 H) .7.35-7.28 (m.3 H) .7.13 (d, 1 H, J - 8.8 Hz), 7.03 (dd, 1 H, J = 15.4, 2.6 Hz), 6.84 (d, 1 H, J = 2.4 Hz), 6.80 (d, 2 H, J = 8.1 Hz), 6.62 (dd, 1 H, J = 8.8, 2.4 Hz), 5.21 (s, 2 H), 3.44, 3.41 (2 t, 2 H, J = 7.0 Hz) .3.06, 2.87 (2 s, 3 H), 2.10 (s, 3 H), 1.49-1.42 (m, 2 H), 1.27-1.20 (m, 2 H), 0.86 (t, 3 H); IR (KBr) 3300, 2950, 2860, 1645, 1580 cm'1; MS at m / z 470; CHN cal.for C3oH3? FN2O2.

EXAMPLE 18 -Benzyloxy-2- (4-benzyl-1-phenyl) -3-methyl-1H-indole One vessel was charged with 4-benzyloxyaniline (45 g, 0.23 moles), 4'-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 moles), and DMF (50 ml). The reaction is refluxed for 30 minutes and then cooled to room temperature and then partitioned between EtOAc (250 mL) and IN HCl (aq) (100 mL). The EtOAc is washed with NaHCO3 (aq) and brine, dried over MgSO ,. The solution is concentrated and the residue is taken up in CH2C12 and hexanes are added to precipitate 25 g of a crude solid. The solid is dissolved in CH C12 and evaporated on silica gel and subjected to chromatography using CH2Cl2 / Hexane (1: 5) to give 9.2 g of a tan solid (33%): M.p. = 150-152 ° C; NMR (Nuclear Magnetic Resonance Spectrum) H (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.48 (d, 4H, J = 7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J = 7.0 Hz), 7.13 (d, 2 H, J = 8.8 Hz), 7.08 (d, 1 H, J = 2.2 Hz), 6.94 (dd, 1 H, J = 8.8, 2.4 Hz), 5.16 (s, 2 H) .5.11 (s, 2 H) .2.33 (s.3 H); IR (KBr) 3470.2880.2820, 1620 cm'1; EM the m / z 419.

EXAMPLE 19 5-Benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl) -1-ylmethyl- (4-phenylioduro) -indole A solution of 4 (3.0 g, 7.4 mmol) in DMF (25 ml) is treated with NaH (60% dispersion, 0.21 g, 8.9 mmol) and stirred at room temperature for 15 minutes. 4-Iodobromobenzyl bromide (2.2 g, 7.4 mmol) is added and the reaction is stirred for 1 hour. The reaction mixture is poured into water and extracted with EtOAc, dried over MgSO, and concentrated. Trituration of the crude product with ether yielded 2.2 g of the product as a white solid: M.p. = 153-156 ° C; 1 H NMR (DMSO) 7.54 (d, 2 H, J = 8.6 Hz), 7.52-7.45 (m, 4 H), 7.37-7.29 (m, 6 H) .7.27 (d.2 H. J = 8.8 Hz), 7.17 (d, 1 H, J = 9.0 Hz), 7.13 (d, 1 H, J = 2.2 Hz), 7.10 (d, 2 H, J = 8.8 Hz), 6.81 (d, 1 H. J = 8.8, 2.4 Hz), 6.60 (d, 2 H. J = 8.3 Hz), 5.18 (s, 2 H), 5.12 (s, 2 H), 5.11 (s, 2 H), 2.15 (s, 3 H); EM at m / z 635.

EXAMPLE 20 2- (4-hydroxyphenyl) -3-methyl) -l-ylmethyl- (4-phenylioduro) -indole-5-ol A solution of 4 (2.2 g, 3.5 mmol) in CHClg is treated with iodotrimethylsilane (1.04 ml., 7.0 mmol) and the reaction is heated to reflux. After 2 h, 3 eq. of iodotrimethylsilane and the reaction is stirred at room temperature for 18 h. The reaction is quenched by adding MeOH (5 mL). The organic layer is washed with a 10% aqueous solution of Na 2 SO 3, HCl (IM) and dried, I will taste MgSO 4. The solution is concentrated and chromatographed on silica gel EtOAc / hexane (3: 7) to give 4a as a foam (1.2 g): H NMR 9.65 (s, 1 H), 8.71 (s, 1 H), 7.54 (d, 2 H, J - 8. 3 Hz), 7.12 (d, 2 H, J = 8.3 Hz), 7.02 (d, 1 H, J = 8.6 Hz), 6.84-6.80 (m, 3 H), 6.61 (d, 2 H, J = 8.3 Hz), 6.57 (dd, 1 H, J = 6.4 Hz), 5.12 (s, 2 H), 2.09 (s, 3 H); EM at m / z 455.

General Procedure for the Preparation of Indole Propargylamine The title compounds of Examples 21-23 were produced using a solution containing a 10-fold molar excess of a secondary amine in DMF cooled to 0 ° C and treated with propargyl bromide (3 eq 80% solution in toluene ). After 1 h at 0 ° C, the reactions are allowed to proceed at room temperature for 1 hour. The indole iodide (4a, 1 eq.) Is added followed by Cu (I) I (0.1 eq.) And Pd (PPh3) 2Cl2 (0.035 eq.). The reaction mixture is then stirred for 16-48 h and worked up by pouring it into water and extracting it in EtOAc. The EtOAc is concentrated and chromatographed on silica gel using EtOAc / hexane as eluent system.

EXAMPLE 21 2- (4-Hydroxy-phenyl) -3- "eti 1 -l- [4- (3-N, N-dimethyl-1-yl-prop-1-ynl 1) -benzyl] -lH-indole-5 -ol P.f. = 173-176 ° C; hi * f (DMSO) 9.64 (s, 1 H), 8.70 (s, 1 H), 7.25 (d, 2 H, J = 8.1 Hz), 7.12 (d.2 H. J - 8.3 Hz) .7.03 ( d, 1 H, J = 8.6 Hz), 6.83-6.78 (m, 5 H), 6.57 (dd.1 H, J = 8.8.2.4 Hz) .5.17 (s, 2 H), 3.39 (s, 2 H ), 2.19 (s, 6 H), 2.10 (s, 3 H); IR (KBr) 3390, 1490 c 1; MS es 411 (M + H +).

EXAMPLE 22 2- (4-Hydroxy-phenyl) -3-methyl-1- [4- (3-piperidin-1-yl-prop-1-yl) -benzyl] -lH-indol-5-ol P.f. = 118-123 ° C; ^ Mi (DMSO) 9.65 (s, 1 H), 8.71 (s, 1 H), 7.24 (d, 2 H, J = 8.1 Hz), 7.12 (d, 2 H, J - 8.6 Hz), 7.02 (d , 1 H, J = 8.6 Hz), 6.83-6.80 (m, 5 H), 6.57 (dd, 1 H, J = 8.6, 2.2 Hz), 5.17 (s, 2 H), 3.39 (s, 2 H) , 2.41 (m, 4 H), 2.10 (s, 3 H), 1.48 (p, 4 H, J = 5.7 Hz), 1.36-1.33 (m, 2 H); IR (KBr) 3400, 2920, 1620, 1420 cm "1; EM The m / z 450; CHN cal.for C30H30N2O2 + 0.25 H2O EXAMPLE 23 2- (4-Hydroxy-phenyl) -3-meth i 11 - [4- (3-pyrrolidin-1-yl-prop-1-ynyl) -benzyl] -l H-indol-5 -ol (5c) P.f. = 174-176 ° C; RW (DMSO) 9.64 (s, 1 H), 8.70 (s, 1 H), 7.23 (d, 2 H, J = 8.3 Hz), 7.11 (d, 2 H, J = 8.6 Hz), 7.02 (d, 1 H, J = 8.8 Hz), 6.84 (m, 5 H), 6.57 (dd, 1 H, J = 8.6, 2.2 Hz), 5.17 (s, 2 H), 3.53 (s, 2 H), 2.53- 2.51 (m, 4 H), 2.09 (s, 3 H), 1.69-1.66 (m, 4 H); IR (KBr) 3400, 2920, 2900, 1620 cm'1; MS at m / z 436; CHN cal. For C ^ n ^ Oi + 0.7 H2O.

Biological Methods In Vitro Estrogen Receptor Binding Assay Preparation of the Receiver CHO cells overexpressing the estrogen receptor were grown on 150 mm * discs or plates in mineral carbon coated with DMEM + 10% dextran, with separate fetal bovine serum. The plates or discs were washed twice with PBS and once with 10 mM Tris-HCl, pH 7.4, 1 mM EDTA. The cells were collected by scraping the surface and then the suspension of the cells is placed on ice. The cells were altered or fragmented with a manual motorized tissue shredder, using two 10 second pulses. The crude preparation is centrifuged at 12,000 gravities for 20 minutes followed by a 60-minute turn or spin at 100,000 gravities to produce a ribosomal-free cytosol. The cytosol was then frozen and stored at -80 ° C. The protein concentration of the cytosol was estimated using the BCA assay with the standard reference protein.

Conditions of the binding test The competition test was carried out on a 96-well plate (polystyrene *) which binds or agglutinates < 2.0% of the total input of [H] -17 ß-estradiol and each data point was collected in triplicate. lOOuG / lOOul of the receptor preparation were taken as aliquots per cavity. A saturation dose of 2.5 nM of [H] 17 ^ -estradiol + competitor (or buffer) in a volume of 50 ul was added in the preliminary competition when lOOx and 500x of the competitor were evaluated, only 0.8 nM of the [H ] 17 D-estradiol were used. The plate or box is incubated at room temperature for 2.5 hours. At the end of this incubation period 150 ul of dextran-coated mineral carbon are added, cooled with ice (5% activated mineral carbon coated with 0.05% dextran 69K) to each well and the plate was centrifuged immediately at 99 gravities for 5 minutes at 4 ° C. 200 ul of the supernatant solution is then removed for scintillation counting. The samples were counted at 2% or 10 minutes, whichever occurs first. Because the polystyrene absorbs a small amount of the [H] 17 β -estradiol, the cavities containing radioactivity and cytosol, but not processed with the mineral coal were included to quantify the amounts of the available isotope. Also, the cavities containing the radioactivity but not the cytosol were processed with mineral coal to estimate the non-removable DPM of [H] 17β-estradiol. 96-well plates from Corning # 25880-96, were used because they have proven to bind or bind the least amount of estradiol.

Analysis of the results The counts per minute (CPM) of the radioactivity were automatically converted to disintegrated per minute (DPM) by the Beckman LS 7500 Twinkling Counter using a set of off or reduced standards to generate an H # for each sample. To calculate the% of the union or agglutination of estradiol in the presence of 100 times or 500 times of the competitor, the following formula was applied: ((DPM sample-DPM not removed by mineral coal) / (DPM estradiol-DPM not removed by mineral coal)) x 100% =% union or agglutination of estradiol For the generation of ICt-0 curves, the% binding or agglutination is plotted against the compound. The IC, -n are generated for the compounds that show > 30% competition at a 500x concentration of the competitor. For a description of these methods, see Hulme, E.C., ed. 1992. Receptor-Ligand Interactions: A Practical Approach. IRL Press, New York, (see especially chapter 8).

Alkaline Phosphatase Assay of the Ishikawa Cell Treatment and maintenance of cells: The Ishikawa cells were maintained in DMEM / F12 (50%: 50%) containing red phenol + 10% fetal bovine serum and the medium is supplemented with 2 mM Glutax, 1% Pen / Strap and 1 mM sodium pyruvate. Five days prior to the start of each experiment (treatment of the cells) the medium was changed to serum separated from the mineral coal coated with red phenol-DMEM / free F12 + 10% dextran. One day before treatment, cells were collected using 0.5% trypsin / EDTA and plated at a density of 5 X 10 cells / well in tissue culture plates of 96 wells. The com- 6 -ft test stations were dosed at 10, 10 and 10 M in addition to 10 -6 M (co-pay) + 10-9 M of 17β-o-estradiol to assess the ability of the compounds to function as antiestrogens. The cells were treated for 48 hours prior to the test. Each 96-well plate contained a control of 17β-estradiol. The population of the samples for each dose was n = 8.

Alkaline Phosphatase Assay: At the end of 48 h, the medium is aspirated and the cells were washed three times with a salted solution buffered with phosphate (PBS). 50 μl of the lysis buffer (0.1 M Tris-HCl, pH 9.8, 0.2% Triton X-100) are added to each well. The plates are placed at -80 ° C for a minimum of 15 minutes. The plates were thawed at 37 ° C followed by the addition of 150 μL of 0.1 M Tris-HCl, pH 9.8, containing 4 mM para-nitrofenilphosphate (pNPP) to each well (final concentration, 3 mM pNPP) . The slope and absorbance calculations were made using the KineticCalc Application program (Bio-Tek Instruments, Inc., Winooski, VT). The results are expressed as the average +/- S.D. of the speed of the enzyme reaction (slope) averaged over the linear portion of the kinetic reaction curve (optical density readings every 5 minutes during the 30 minute absorbance reading). The results for the compounds are summarized as the percentage of response related to 1 nM 17 β -estradiol. Several compounds were evaluated to test the estrogenic activity by the alkaline phosphatase method and the corresponding ED50 values (95% C.I.) were calculated. The four lists in what is given below, were used as reference standards: 17/6-estradiol 0.03 nM 17 < ? C-estradiol 1.42 nM estriol 0.13 nM estrone 0.36 nM A description of such methods is provided by Holinka, C.F., Hata, H., Kuramoto, H. and Gurpide, E. (1986) Effects of steroid hormones and antisteroids on alkaline phosphatase activity in human endometrial cancer cells (Ishikawa Line). Cancer Research, 46: 2771-2774, and by Littlefield, B.A., Gurpide, E., Markiewicz, L., McKinley, B. and by Hochberg, R.B. (1990) A simple and sensitive microtiter piate estrogen bioassay based on stimulation alkaline phosphatase in Ishikawa cells; Estrogen action of D5 adrenal steroids. Endocrinology, 6: 2757-2762.

Transfection assay 2X VIT ERE Treatment and Maintenance of Cells Chinese hamster's ovary (CHO) cells which have been stably transfected with the human estrogen receptor were maintained in DMEM + 10% fetal bovine serum (FBS). 48 hours prior to treatment, the growth medium was replaced with DMEM that lacks separate FBS of mineral coal coated with red phenol + 10% dextran (treatment medium). The cells were placed in plates or boxes at a density of 5000 cells / well in 96-well plates containing 200 U. L of the medium / well.

Transfection of Calcium Phosphate The reporter DNA (pGL2 from Promega plasmid containing two serial copies of the ERE of vitellogenin in front of the minimal thymidine kinase promoter driving the luciferase gene) is combined with the B-galactosidase expression plasmid pCHUO (Pharmacia) and the carrier DNA (pTZ18U) in the following proportions: lOuG of reporter DNA 5uG of pCHllODNA 5uG of pTZ18U 20uG of DNA / 1 ml of transfection solution The DNA (20uG) is dissolved in 500 ul of 250 mM CaCl? sterile and added dropwise to 500 ul of 2 X HeBS (0.28 M NaCl, 50 mM HEPES, 1.5 mM Na2HP04, pH 7.05) and incubated at room temperature for 20 minutes. 20 ul of this mixture are added to each cell cavity and remained on the cells for 16 h. At the end of this incubation the precipitate was removed, the cells were washed with the medium, a fresh treatment medium was replaced and the cells were treated with any vehicle, 1 nM 1 iß -estradiol, luM of the compound or 1 uM of the compound + 1 nM of 17-estradiol (tests for estrogen antagonism). Each treatment condition was carried out on 8 cavities (n = 8) which were incubated for 24 h prior to the luciferase assay.

Luciferase assay After 24 h of exposure to the compounds, the medium was removed and each well was washed with 2 X with 125 ul of PBS lacking Mg and Ca. After removing the pBS, 25 ul of the lysis buffer Promega was added to each cavity and allowed to stand at room temperature for 15 minutes, followed by 15 minutes at -80 ° C and 15 minutes at 37 ° C. 20 ul of the lysate are transferred to an opaque 96-well plate for the evaluation of the luciferase activity and the remaining lysate (5 ul) was used for the evaluation of the B-galactosidase activity (normalized transfection). The luciferane substrate (Promega) was added in aliquots of 100 ul to each cavity automatically by the luminometer and the light produced (relative luminosity units) was read 10 seconds after the addition.

Test of B-Galactosidase The remaining 5 ul of the lysate were added 45 ul of PBS. Then 50 ul of the 2X assay buffer of the Promega B-Galactosidase are added, mixed well and incubated at 37CC for 1 hour. A plate containing a standard curve (0.1 to 1.5 milliunits in triplicate) is adjusted or adapted for each experimental run. The plates were analyzed on a molecular spectrophotometer plate reader Molecular Devices at 410 nm. Dptile densities for unknown substances were converted to 1 iunities of activity by mathematical extrapolation of the standard curve.

Analysis of the results The luciferase data were generated as relative luminosity units (RLUs) accumulated during a 10-second measurement and were automatically transferred to a JMP record (SAS Inc.) where the background RLUs were subtracted. The B-galactosidase values were automatically imported into the record or file and these values were divided into the RLUs to normalize the data. The average and standard deviations were determined from n = 8 for each treatment. The activity of the compounds was compared with the 17β-estradiol for each plate. The percentage of the activity when compared to the 17 β -estradiol was calculated using the formula% = ((Estradiol-control) / (value of the compound)) X 100. These techniques are described by Tzukerman, M.T., Esty, A., Santiso-Mere, D., Danielian, P., Parker, M.G., Stein, R.B., Pike, J.W. and McDonnel, D.P. (1994). The transactivational capacity of the human estrogen receptor was determined both by the cellular and promoter context and mediated by two functionally distinct intramolecular regions (see Molecular Endocrinology, 8: 21-30).

Uterotrophic / Anti-Uterotrophic Bioassay of the Rat The estrogenic and antiestrogenic properties of the compounds were determined in an immature rat uterotrophic assay (4 days) (as previously described by L.J. Black and R.L.Goode, Life Sciences, 26, 1453 (1980)). The immature Sprague-Dawley rats (females, 18 days old) were tested in groups of six. The animals were treated by ip injection daily with 10 uG of the compound, 100 uG of the compound, (100 uG of the compound + 1 uG of 17 fi -estradiol) to verify the antiestrogenicidad, and 1 uG of the 17 β -estradiol , with 50% of a salty solution / DMSO as the vehicle of the injection. On day 4 the animals were sacrificed by asphyxia with C0"and their uteri were removed and the excess lipid was removed, any fluid was removed and the wet weight was determined. A small section of a callus was subjected to histology and the rest was used to isolate the total RNA to evaluate the expression of the complement component 3 gene.

Biological Results Affinity of the Estrogen Receptor (reported as RBA: 17; ft-estradiol = 100) RBA compound raloxifene 200 tamoxifen 1.8 Example 10 20 Example 7 42 Example 8 40 Example 9 40 Example 12 114 Example 11 80 Example 13 27 Example 14 32 Example 15 53 Example 21 53 Example 22 23 Luciferase Assay for Infection Compound I Activation% (Activation with 1 nM 17 yß-estradiol 17 -. 17 -estradiol 100% N / A Estriol 38% N / A Tamoxifen 0% 10% Raloxifene 0% 0% Example 10 1% 2% Example 7 4% 8% Example 8 6% 78% Example 9 6% 8% Ex 12 12% 24% Example 11 8% 12% Example 13 8% 17% Example 14 19% 57% Example 15 15% 31% Example 21 34% 34% Example 22 17% 19% Ishika Alkaline Phosphatase Assay to Activation Compound% Activation (Compues 17 ß -estradiol 100% N / A tamoxifen 0% 45% Raloxifen 5% 5% Example 10 6% 19% Alkaline Phosphatase Assay (Cont.) Example 7 1% 9% Example 8 10% 22% Example 9 3% 11% Example 12 7% 16% Example 11 6% 11% Example 13 7% 9% Example 14 2% 14% Example 15 0% 5% Example 21 34% 34% Example 22 27% 23% 3-Day Ovariectomized Rat Model Compound 1 or! 100 > J_G Tamoxifen 69.6 mg 71.4 mg Raloxif in 47.5 mg 43.2 mg control = 42.7 mg 1 UG 17/9-estradiol = 98.2 Compound 10? / ?? G 100 «íu 100 0J2-tG plus l -? IiG 17 and £ -Estradiol Example 7 47.8 mg 64.8 mg 75.4 control = 20.2 mg IJuG \ 1 ß -estradiol = 80.2 mg Ovar rat Model Octectized (Cont.) Compound 10 / * C 100 / lG 100 JJLG plus 1 AG 17 g -Stradiol Example 12 36.9 g 49.5 mg 63.1 control = 31.4 mg l ^ ü 17 ^ -estradiol - 89.0 Compound 10L-G 100 / ¿G 100 UG plus l JJLG 17 ß -Estradiol Example 11 39.3 pg 59.8 mg 81.0 mg control - 24.5 mg l ^ XG 17S -estradiol - 90.8 mg Compound 10 ¿¿G 100Z¿G 100 JJLG plus 1 G \ 1 -Estradiol Example 14 32.5 mg 56.4 mg 79.8 mg Example 15 40.4 mg 56.3 mg 69.3 mg control = 29.1 mg l U-g \ 1 -estradiol = 95.5 Compound 10 G 100 / G 100 jUG + 1 ¿G 17/8 - estradiol Example 21 56.0 mg 84.0 mg 77.6 mg control = 32.1 mg - estradiol = 90.2 mg Example 22 55.6 mg 71.3 mg 66.8 mg control = 21.7 mg 1 μ \ 1 -estradiol = 82.8 mg It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is the one that results clear of the present description of the invention.

Having described the invention as above, property is claimed as contained in the following

Claims

R E I V I N D I C A C I O N S

1. A compound, characterized because it has the structure: where: it is selected from H, OH, esters with C, -C, or the alkyl ethers thereof, or halogen; R2, R ~, R,, R, and Rfi are independently selected from H, OH or the esters with C.-C, or the alkyl ethers thereof, halogen, cyano, alkyl with C.-C ,, or trifluoromethyl , with the proviso that, when R. is H, R "is not OH; n is 2 or 3; X is selected from H, alkyl with C.-C, cyano, nitro, trifluoromethyl, halogen; Z is selected from O I -CH-CH- C-Y -C = C- (CH2) rt-Y. And it is selected from: a) the portion wherein R7 and Rft are independently selected from the group of H, alkyl with C.-C, phenyl or combined by - (CH2) p-, where p is an integer from 2 to 6, to form a ring , the ring is optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, alkyl with C.-C, trihalomethyl, alkoxy with C.-C, trihalomethoxy, alkylthio with C.-C, alkylsulfinyl with C ..- C, alkylsulfonyl with C? ~ C 'hydroxy (Cj-C ^) alkyl, -C02H, -CN, -C0NH (C.-C,) alkyl, -NH2, alkylamino with C.-C, , diCJ-C ^) alkylamino, -NHSO ^ Cj-C ^) alkyl, -NHC0 (C1-C4) alkyl, and -N02. b) a saturated, unsaturated or partially unsaturated heterocycle with five, six or seven elements, containing up to two heteroatoms selected from the group consisting of -0-, -NH-, -N (C.-C, alkyl) -, -N =, and -S (0) m-, wherein m is an integer from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl with C.- C, trihalomethyl, alkoxy with C.-C, trihalomethoxy, acyloxy with C.-C ,, alkylthio with C.-C ,, alkylsulfinyl with C.-C ,, alkylsulfonyl with C1-C4, hydroxy (Cj -C ^ alkyl-CO ^ -, -CN-, -CONHRj-, -NH2, (C1-C4) alkylamino, diCJ-C ^ alkylamino, -NHS02R1-, -NHC0R1-, -N0-, and phenyl optionally substituted with from 1 to 3 alkyl groups with (C.-C4); c) a bicyclic ring system consisting of a five or six element heterocyclic ring fused to a phenyl ring, the heterocyclic ring contains up to two heteroatoms selected from the group of -0-, -NH-, -N (C1C4) alkyl) -, and -S (0) -, wherein m is an integer from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl with C-C4 , trihalomethyl, alkoxy with C.-C4, trihalomethoxy, acyloxy with C.-C4, alkylthio with C, -C4, alkylsulfinyl with C, -C4, alkylsulfonyl with C.-C4, hydroxy (C1-C4) alkyl, -C02H -, -CN-, -C0NHR1-, -NH2 ~, alkylamino with (C1-C4), di ^ -C ^ alkylamino, -NHS02R1-, NHC0R1-, -NO, -, and phenyl optionally substituted with from 1 to 3 alkyl groups with (C.-C4); or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, characterized in that R, is selected from H, OH, or the esters with C, -C4 or the alkyl ethers thereof, halogen; R ?, R. R ,. T rfi are independently selected from H, OH or the steres with C.-C4 or the alkyl ethers of the Bisaos, haldgeno, cyano, alkyl with C.-C, or trifluoroacetic acid, with the proviso that, when .. is H, R2 is not OH; X is selected from H, alkyl with C, -C, cyano, nitro, trifluoromethyl, halogen; And it's the share R-, and RQ are independently selected from H, alkyl with C.-C ,, or combined by - (CH2) p-, where p is an integer from 2 to 6, to form a ring, the ring is optionally substituted by up to three substituents selected from the group of hydrogen, hydroxyl, halo, G.- alkyl, trihalomethyl, C.-C, alkoxy, trihalanetoxy, alkylthio with C, -C4, alkylsulfinyl with C.-C4, alkylsulfonyl with C1-C4, hydroxy (C- ^ C ^ alkyl) , -C02H, -CN, -C0NH (C1 ~ C4) alkyl, ~ NHg »alkylamino with C.-C4> dialkylamino with C1-C4, -NHS02 (C1-C4) alkyl, -NHC0 (C1 ~ C4) alkyl , and -N02.

3. A compound according to claim 3, characterized in that R7 and Rg are chained together as - (CH2) p- to form a ring, where p is an integer from 2 to 6, the ring is optionally substituted with 1-3 substituents selected from the group of alkyl with C.-C ,,, trifluoromethyl, halogen, hydrogen, phenyl, nitro, or -CN.

4. A compound according to claim 1, characterized in that it is 5-benzyloxy-2- (4-fluoro-phenyl) -3-methyl) -lH-indole.

5. A compound according to claim 1, characterized in that it is 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl) -l-ylmethyl- (4-phenylbromide) -indole.

6. A compound according to claim 1, characterized in that it is 5-benzyloxy-2- (4-fluoro-phenyl) -3-methyl) -l-ylmethyl- (4-phenylbromide) -indole.

7. A compound according to claim 1, characterized in that it is 2- (4-hydroxyphenyl) -3-methyl) -1-ylmethyl- (4-phenylbromide) -indol-5-ol.

8. A compound according to claim 1, characterized in that it is (E) -N, N-Diethyl-3- 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indole -l-ylmethyl] -phenyl and -acrylamide.

9. A compound according to claim 1, characterized in that it is 1 (E) -N-tert-butyl-3. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-yl-methyl] -phenyl-acrylamide.

10. A compound according to claim 1, characterized in that it is (E) -pyrrolidino-3- \ 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmethyl) ] -phenyl-acrylamide.

11. A compound according to claim 1, characterized in that it is (E) -N, N-Dimethyl-3-4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indole-1 -ylmethyl] -phenyl j-acrylamide.

12. A compound according to claim 1, characterized in that it is (E) -N, N-Dibutyl-3- 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indole-1- ilrae-til] -phenyl-acrylamide.

13. A compound according to claim 1, characterized in that it is (E) -N-Butyl, N'-methyl-3- "i 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3 -methyl-indol-1-ylmethyl] -phenyl-acrylamide.

14. A compound according to claim 1, characterized in that it is (E) -Morpholinin-3- "t 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indole-1-ylme- til] -phenyl J * -acrylamide.

15. A compound according to claim 1, characterized in that it is (E) -3- 4- [5-hydro-xi-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenyl "~ acrylamide.

16. A compound according to claim 1, characterized in that it is (E) -N, Methyl-3 - ^ - [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-methylmethyl ] -phenyl-acrylamide.

17. A compound according to claim 1, characterized in that it is (E) -N, N-Dibutyl-3-4- [5-hydroxy-2- (4-fluoro-phenyl) -3-methyl-indole-1 -ylmethyl] -phenyl-acrylamide.

18. A compound according to claim 1, characterized in that it is (E) -N-Butyl, N'-Methyl-3. { 4- [5-hydroxy-2- (4-fluoro-phenyl) -3-methyl-indol-1-ylmethyl] -phenyl-acrylamide.

19. A compound according to claim 1, characterized in that it is 2- (4-Hydroxy-phenyl) -3-methyl-1- [4- (3-N, N-dimethyl-1-yl-propyl) -inyl) -benzyl] -lH-indol-5-ol or a pharmaceutically acceptable salt thereof.

20. A compound according to claim 1; cation 1, characterized in that it is 2- (4-Hydroxy-phenyl) -3-methyl-l- [4- (3-piperidin-1-yl-prop-1-ynyl) -benzyl] -lH-indol-5 -ol or a pharmaceutically acceptable salt thereof.

21. A compound according to claim 1, characterized in that it is 2- (4-hydroxy-phenyl) -3-methyl-1- [4- (3-pyrrolidin-1-yl-prop-1-ynyl) -benzyl] -IH-indol-5-ol or a pharmaceutically acceptable salt thereof.

22. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing bone loss in a mammal.

23. The use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation is a medicament for treating or preventing disease states or syndromes which are caused or are associated with an estrogen deficiency in a mammal. .-

24. The use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for: treating or preventing cardiovascular disease in a mammal.

25. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.