MXPA00011170A - Compositions comprising 2-phenyl-indole compounds and estrogen formulations - Google Patents

Abstract

The present invention relates to the use of 3-[4-(2-phenyl-Indol-1-ylmethyl)-phenyl]Acrylamide compounds and 2-phenyl-1-[4-(amino-1-yl-alk-1-ynyl)benzyl]-1H-indol-5-ol compounds which are useful as estrogenic agents, as well as pharmaceutical compositions and methods of treatment utilizing these compounds, the compounds having general formula (I) or (II).

Description

COMPOSITIONS THAT COMPRISE 2-FENILINDQL COMPOUNDS AND FORMULATIONS OF ESTROGEN DESCRIPTION OF THE INVENTION The present invention relates to the use of 3- [4- (4-phenyl-indol-1-methyl) -phenyl] -acrylamide compounds and 2-phenyl-1- [4- (amino-1-yl-alkyl) compounds. l-inyl) -benzyl] -1H-indol-5-ol which are useful as selective modulators of estrogen receptor, together with estrogens, as well as pharmaceutical compositions and methods of treatment which utilize these compounds.

Background of the Invention The use of hormone replacement therapies for the prevention of bone loss in post-menopausal women is well-founded. The normal protocol requires estrogen supplementation using formulations such as estrone, estriol, ethinylestradiol, 17β-estradiol, esterified estrogens or conjugated estrogens isolated from natural sources (ie Premarin conjugated estrogens "from yeth-Ayerst) or synthetic estrogens. some patients, the therapy may be contraindicated due to the non-oppositive estrogen proliferative effects (estrogens are not: 124426 provide in combination with progestins) and have been found on interim tissue. This proliferation is associated with an increased risk of endometriosis or endometrial cancer, or both. The effects of unopposed estrogen over breast tissue is less clear, but it is disturbing. The need for estrogen which can maintain the effect of bone saving while minimizing the proliferative effects on the uterus and breast is evident. It has been shown that certain non-steroidal antiestrogens maintain bone mass in the ovariectomized rat model as well as in clinical trials in humans. Tamoxifen (sold as tamoxifen citrate Novadex ™ by Zeneca Pharmaceuticals, Wilmington, Dela), for example, is a useful palliative for the treatment of breast cancer and has been shown to exert an effect similar to the estrogen agonist in bone in humans However, it is also a partial agonist in the uterus and in this case it is of some concern. Raloxifene, a benzothiophene antiestrogen, has been shown to stimulate uterine growth in the ovariectomized rat to a lesser degree than tamoxifen and at the same time maintain the ability to save bone. An adequate review of tissue-selective estrogens can be found in the article "Tissue-Selective Actions of Estrogen Analogs", Bone Vol. 17, No. 4 of October 1995, 181S-190S. The use of indoles, estrogen antagonists has been reported by Von Angerer, Chemical Abstracts, Vol. 99, No. 7 (1983). Abstract No. 53886u. See also J. Med. Chem. 1990, 33, 2635-2640; J. Med. Chem. 1987, 30, 131-136. See also Ger. Offen., DE 3821148 to 891228 and WO 96/03375. These compounds of the prior art share structural similarities with the present compounds, but are functionally different. For compounds containing a basic amine, there is no phenyl group to rigidify the side chain. WO A 95 17383 (Karo Bio AB) describes indole antiestrogens with long linear chains. Another related patent, WO A 93 10741 describes 5-hydroxyindoles with a wide range of side chains. WO 93/23374 (Otsuka Pharmaceuticals, Japan) discloses compounds that share structural similarities with those of the present invention, except with the structure referred to as R3 in the present formulas I and II below, which is defined as thioalkyl and the reference does not disclose such compounds having chains from the indole nitrogen having the same structure to those provided by the present invention. In his article Postmenopausal Hormonal replacement theraphy wi th estrogen periodically supple ented wi th antiestrogen, Am. J. Obstet, Gynecol. , Vol. 140, No. 7, 1981, pp. 787-792, Kauppila et al. describes his postmenopausal estrogen therapy study of estrogen regimens of 7 weeks followed by treatment for 10 days with the antiestrogen clomiphene citrate. In addition, in his article Comparaison of Megestrol Acétate and Clomiphene Ci treat as Supplemental Medication in Postmenopausal Oestrogen Replacement Therapy, Arch. Gynecol. (1983) 234: 49-58, Kauppila et al., Describes in postmenopausal women combination therapies of estrogen with random supplementation of megestrol acetate or clomiphene citrate. U.S. Patent No. 4,894,373 (Young) describes the use of antiestrogens, including clomiphene and its isomers, citrates and derivatives, in the absence of estrogen to treat menopausal symptoms and treat or prevent osteoporosis. U.S. Patent No. 5,552,401 (Cullinan et al.) Discloses benzothiophene compounds as being useful for the treatment of various medical indications associated with postmenopausal syndrome and uterine fibroid disease, endometriosis and proliferation of smooth muscle cells in the aorta. , the compounds are used in pharmaceutical formulations that optionally contain estrogen or prostegin. U.S. Patents 5,646,137 and 5,591,753 (both issued to Black et al.) Disclose methods for treating osteoporosis with formulations of arylbenzothiophene compounds of the raloxefin type together with a progestin that is selected from medroxyprogesterone, norethindrone or norethinodrel, or pharmaceutically acceptable salts thereof. U.S. Patent No. 5,550,107 claims an invention comprising the treatment of breast or endometrial cancer with an antiestrogen together with at least one compound selected from the group of an androgen, a progestin, at least one inhibitor of the formation of sex steroids, especially 17β-hydroxysteroid dehydrogenase and aromatase activity, at least one inhibitor of prolactin secretion, an inhibitor of growth hormone secretion and an inhibitor of ACTH secretion. U.S. Patent No. 5,672,609 (Bryant et al.) Discloses pyridine compounds useful in treating postmenopausal syndrome and formulations that therefore contain estrogen or progestin. U.S. Patent No. 5,534,527 (Black et al.) Describes the use of aroylbenzothiophenes and oestrogens in the inhibition of bone loss.

DESCRIPTION OF THE INVENTION The present invention provides pharmaceutical formulations and methods for using them, comprising compounds of formulas (I) and (II), in the following, together with estrogens, preferably together with one or more pharmaceutically acceptable carriers or excipients. Among the uses of Present formulations are alleviating the symptoms of postmenopausal syndrome in women, which include perimenopausal and postmenopausal symptoms. The present formulations and methods of treatment can be used to minimize undesirable side effects of estrogen treatment or therapy and can be used to minimize the amounts of estrogen needed for a particular regimen. The compounds of the general structure type shown in formulas (I) and (II) are estrogen agonists / antagonists useful for the treatment of diseases associated with estrogen deficiency and are described in EP-A-0802184, the content of which is incorporated in the present as a reference in its entirety. The compounds used in the present invention show strong binding to the estrogen receptor and are able to antagonize the effects of 17β-estradiol and at the same time show little uterine stimulation when dosed alone. The present invention includes compounds of formulas (I) or (II), in the following: where: R? is selected from H, OH or the Ci-C alkyl esters thereof, or halogen R2, R3, R4, R5 and R6 are independently selected from H, OH or the alkyl esters or ethers of Cj-C , of the same, halogen, cyano, C1-C6 alkyl or trifluoromethyl, with the proviso that when Rx is H, R2 is not OH. X is selected from H, Cj-Ce alkyl, cyano, nitro, trifluoromethyl, halogen; Z is selected from: -CH = CH- n is 2 or 3; And it is selected from a) the portion: wherein R7 and R8 are independently selected from the group of H, -Cj alkyl, phenyl or combined with - (CH2) p-, where p is an integer from 2 to 6, so as to form a ring, the ring is optionally substituted by up to three substituents which are selected from idroxyl, halo, Ci-Q alkyl, trihalomethyl, C 1 -C alkoxy, trihalomethoxy, C 1 -C 4 alkylthio, C 1 -C alkylsulfinyl, C 1 alkylsulfonyl, C4, hydroxyalkyl of C ^ C ,,, -C02H, CN, -CONH (C-C4 alkyl), -NH2-, C ^ C alkylamino, Cj-C-dialkylamino, -NHS02alkyl of Cj-C, , -NHCOalkyl of CL-C4 and -N02; b) a saturated, unsaturated or partially unsaturated heterocycle of five, six or seven members containing up to two heteroatoms which are selected from the group consisting of -O-, -NH-, -N (Cj-C alkyl,) -, -N = in which case the ring can be linked via nitrogen) and -S (0) _-, where m is an integer of 0-2, optionally substituted with 1-3 substituents that are independently selected from hydroxyl, halo, C 1 -C 6 alkyl, trihalomethyl, alkoxy Ci-d, trihalomethoxy, acyloxy of C [-C4, alkylthio of dC ,,, alkylsulfinyl of Cj-Cj, alkylsulfonyl of Cj-C4, hydroxyalkyl of Cj-C ,, -C02H, -CN-, -CONHR! -, -NH2, Cinylamino, dialkyl (dQ) amino, -NHSORj, -NHCOR ^ -N02 and phenyl optionally substituted with 1-3 C] .- C4 alkyl groups, wherein R is as defined above, or Cj-Cj alkyl, - c) a bicyclic ring system consisting of a five- or six-membered heterocycle ring fused to a phenyl ring, the heterocyclic ring contains up to two heteroatoms which is selected from -O-, -NH- , -N (CLd alkyl), -N = and -S (0) m-, wherein m is an integer of 0-2, optionally substituted with 1-3 substituents that are independently selected from the group consisting of hydroxyl , halo, C 1 -C 4 alkyl, trihalomethyl, dC 4 alkoxy, trihalomethoxy, C 1 -Cy acyloxy, C 1 -C 4 alkylthio, C 1 C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, , -C02H, -CN-, -CONHRi-, -NH2-, alq u-amino acid of d-C ,,, dialkyl (C? - C4) amino, -NHSOjRi-, -NHCORi-, -N02, and phenyl optionally substituted with 1-3 C1-C4 alkyl groups; (for example Rx is as defined above or Cj-C alkyl,), and pharmaceutically acceptable salts thereof.

The most preferred formulations and treatment methods of this invention are those that have or that they use, together with one or more pharmaceutical carriers or excipients: a) one or more estrogens; and b) one or more compounds that are selected from general structures I or II, above, wherein: R x is selected from H, OH or the Cj-Q esters, or alkyl ethers thereof, halogen; R2, R3, R4, R5 and R6 are independently selected from H, OH or the Cj-C, esters, or alkyl ethers thereof, halogen, cyano, or trifluoromethyl alkyl, with the proviso that when R? is H, R2 is not OH; X is selected from H, CJ-CJ alkyl, cyano, nitro, trifluoromethyl, halogen; And it's the portion R "° I R7 and R8 are independently selected from H, C-C6 alkyl or, combined with - (CH2) p-, where p is an integer from 2 to 6, so as to form a ring, the ring is optionally substituted by up to 3 substituents which are selected from hydroxyl, halo, C 1 -C 4 alkyl, trihalomethyl, C 1 -C 6 alkoxy, trihalomethoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl -C4, hydroxyalkyl of C ^ C ,, -C02H, -CN, -CONH (C ^ C alkyl,), -NH2, alkylamino of dQ, dialkylamino of C1-C1, -NHS02 (alkyl of ^ -0.), -NHCO (Cx-C4 alkyl) and -N02. The rings formed by concatenated R7 and R8, mentioned above, may include, but are not limited to aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneamine rings. It is further preferred that when R7 and R8 are concatenated together, the ring formed in this manner is optionally substituted with 1-3 substituents that are selected from a group containing Q-Cj alkyl., trifluoromethyl, halogen, hydrogen, phenyl, nitro, -CN. The compounds of formulas (I) and (II) are partial estrogen agonists and show high affinity for the estrogen receptor. However, unlike many estrogens, 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 for treating or preventing mammalian disease states or syndromes which are caused or associated with an estrogen deficiency. This tissue selectivity allows its use for desirable estrogenic activity in certain tissues, such as bone, and at the same time limits its activity in others, for example in the uterine tissue.

Estrogens useful in the formulations of this invention include estrone, estriol, equilin, estradiene, equilenin, ethinylestradiol, 17β-estradiol, 17o-dihydroequilenin, 17β-dihydroequilenin (U.S. Patent No. 2,834,712), 17a-dihydroequilin, 17β-dihydroequilin , menstranol and conjugated estrogenic hormones such as the Premarin ™ products from Wyeth-Ayerst Laboratories'. They can also be used in the present formulations and phytoestrogen methods such as equol or enterolactone. A preferred embodiment of this invention comprises pharmaceutical compositions and methods of treatment utilizing conjugated estrogenic hormones such as those of the "Premarin" products of Wyeth Ayerst Laboratories with 1 or more compounds of formula (I) or (III) included herein. Esterified estrogens such as those sold by Solvay Pharmaceuticals Inc. under the tradename Estratab ™ can also be used for the following compositions. Salts of the applicable estrogens are also preferred for the use of the present invention, more preferably sodium salts. Examples of these preferred salts are estrone sodium sulfate, equilin sodium sulfate, sodium alkale dihydroequiline sulfate, sodium 17alpha-estradiol sulfate, delta 8, 9-sodium dehydroestrone sulfate, sodium equilenin sulfate, 17beta dihydroequiline sulfate sodium, 17alpha sodium dihydroequilenine sulfate, 17beta-estradiol sodium sulfate, 17beta-dihydroequilenine sodium sulfate, estrone sodium 3-sulfate, equilin 3-sodium sulfate, 17alpha-dihydroequiline 3-sodium sulfate, 3beta hydroxyster 5 (10), 7-dien-17-one 3- sodium sulfate, 5alpha-Pregnan-3beta-20R-diol 20-sodium sulfate, 5alpha-Pregnan-3beta, 16alpha-diol-20 -one-3-sodium sulfate, delta (8, 9) -dehydroestrone 3 -sulfate sodium, estra-3beta, 17alpha-diol sodium 3-sulfate, 3beta-hydroxyestr-5 (10) -en-17-one-3-sulfate sodium, or 5alpha-Pregnan-3beta, 16alpha, 20R-triol 3- sodium sulfate. Preferred salts of estrone include, but are not limited to, the sodium and piperate salts. The present compounds of formulas (I) and (II) are tissue-selective compounds that have the ability to behave as estrogen agonists, for example by lowering cholesterol and preventing bone loss, or as similar estrogen antagonists. Therefore, these compounds in the present formulations are useful for treating many discomforts including osteoporosis, prostatic hypertrophy, infertility, breast cancer, endometrial hyperplasia, endometrial cancer, endometriosis, cystic glandular hyperplasia, uterine hyperplasia, cervical hyperplasia, benign prostatic hyperplasia , cardiovascular disease, contraception, Alzheimer's disease and melanoma. The formulations of this invention can also be used to treat bone loss resulting from secondary osteoporosis, including categorized as endocrine in nature, including that resulting from glucocorticoid excess, hyperparathyroidism, hyperthyroidism, hypogonadism, hyperprolactinemia and diabetes mellitus. Bone loss can also be induced by medications such as that resulting from heparin treatments, alcohol consumption or the use of tobacco, barbiturates or corticosteroids. Drug-induced bone loss can also be the basis for treatment with gonadotropin releasing hormone (GnRH or LHRH) or synthetic GnRH antagonists or agonists, such as injectable leuprolide acetate and sold by TAP Pharmaceuticals Inc. by LUPRONMR, or the goserelin acetate implant sold by Zeneca Pharmaceuticals under the trade name Zoladex ™ *. Such bone loss can also result from the immobilization of chronic individual renal failure, malabsorption syndrome, liver disease, chronic obstructive pulmonary disease, rheumatoid arthritis or sarcoidosis. Additionally, these formulations can be used for hormone replacement therapy in postmenopausal women or in other estrogen deficiency states where estrogen supplementation may be beneficial. The symbiotic activity of the compounds and estrogen or estrogens of the present methods of treatment are particularly of interest in solving the undesired consequences of estrogen therapy, such as external bleeding and / or stimulation. excessive endometrial, which can lead to endometrial hyperplasia or endometriosis. Therefore, these formulations can be used in methods to treat or prevent excessive uterine estrogen stimulation in a mammal. Estrogens regulate many physiological processes.

The main target tissues for estrogen include the reproductive tract (ovary, uterus, vagina), breast tissue, the skeletal and cardiovascular system as well as the central nervous system (CNS). The reduction in circulating estrogens produces numerous changes. There is a suspension of reproductive function with associated amenorrhea, uterine atrophy and increased vaginal dryness (lack of keratinization). The breast tissue becomes relatively quiescent. There is an increase in the rate of bone loss (2-7%) compared to the normal of 0.5-1.0% / year observed in all individuals over 35 years of age. There is a change in the lipid profile which increases in low density lipoprotein (LDL) and decreases in high density lipoprotein (HDL) commonly measured as an associated increased risk of a cardiovascular event (heart attack or stroke) . Changes in the central nervous system include an increase in vasomotor symptoms (hot flushing) and potential changes in learning and memory.

Estrogen replacement therapy (ERT) normalizes some of these changes, particularly those associated with the cardiovascular system (reduced LDL, increased HDL, reduced risk of heart attack), the skeletal system (maintenance of bone mass, reduced risk of fractures). ) and the central nervous system (reduction in the frequency and severity of hot flushing). Although the reproductive tract responds, not everything is positive. On the positive side, vaginal dryness is relieved. However, negative uterine responses include hypertrophy and hyperplasia along with some bleeding similar to menstrual bleeding. The breasts are also affected and there are data that correlate exogenous estrogen therapy with an increased risk of breast cancer. Currently, women with intact uteri are generally not prescribed estrogen alone, but estrogen in combination with a progestin to reduce uterine stimulation. Although the risks of endometrial cancer are reduced to treated levels without hormone, the other side effects of progestins reduce compliance in women on hormone replacement. The tissue-selective estrogen (TSE) compounds of this invention provide positive skeletal and cardiovascular alterations similar to those of estrogens, without the negative effects associated with the uterus. and the breasts. The combinations of TSE and estrogen derive the positive effects of estrogen on the CNS, bone and cardiovascular system with the combination that provides complementary or additive effects in the bone and cardiovascular systems. The main variable is the ability of TSEs to block the estrogenic influence in the uterus and breasts, which are the two main negative effects of non-opposite estrogens. The formulations of this invention can also be used in methods of treatment for bone loss, which may result from an imbalance of the individual formation of new bone tissues and the resorption of older tissues, leading to a net loss of bone. Such bone suppression results in a range of individuals, particularly postmenopausal women, women who have undergone hysterectomy / oophorectomy, those receiving or who have received prolonged corticosteroid therapies, those who have experienced adrenal dysgenesis and those who suffer from Cushings's syndrome. The special needs for bone substitution can also be resolved using these formulations in individuals with bone fractures, defective bone structures and those who undergo bone-related surgeries or prosthetic implantation, or both. In addition to the problems described above, these formulations can be used in treatments for osteoarthritis, disease of Paget 's, osteomalasia, osteohalisteresis, endometrial cancer, multiple myeloma and other forms of cancer that have harmful effects on the bone tissue. The methods for treating the discomforts included herein are understood to comprise administration to an individual in need of such treatment of a pharmaceutically effective amount of one or more of the compounds of the formulas (I) and (II) or a pharmaceutically salt acceptable thereof, together with a therapeutically desirable amount of an estrogen. This invention also includes pharmaceutical compositions that use one or more of the present compounds, 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 of formulas (I) and (II) will vary according to the discomfort and the individual being treated and will be submitted to the judgment of the practicing physician involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and increase until the desired effects are obtained. Similarly, it will be understood that the dosage or dosages of the estrogen or estrogens used in the present formulations will be selected according to conventional methods. It is further preferred that the dosage It will be monitored to obtain the desired result with the minimum of estrogen or estrogen needed. The effective administration of these compounds of formulas (I) and (II) can be delivered at a dose of about 0.01 mg / day to about 1000 mg / day. Preferably, administration will be from about 1 mg / day to about 600 mg / day in a single dose or in two or more divided doses. More preferably, a daily dose of between about 1 mg / day and about 150 mg / day will be administered. Such doses may be administered in any way useful in directing the active compounds herein to the recipient including the oral, parenteral (including intravenous, intraperitoneal and subcutaneous injections, implants, etc.), intravaginal and transdermal routes. For purposes of this disclosure, transdermal administrations are understood to include all administrations across the body surface and the inner linings of the 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 the formulas (I) and (II) can comprise any conventionally used oral form including tablets, capsules, buccal forms, troches, dragees and liquids, suspensions or oral 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 starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses such as crystalline celluloses and microcrystalline, flours, jellies, gums, etc. Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and diluents, binders, lubricants, disintegrants, suspension improving agents or pharmaceutically acceptable stabilizers can be used, which include, but are not limited to, they are limited to magnesium stearate, stearic acid, talcum, sodium laurisulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, arginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. Oral formulations herein may use standard formulations of delay or release over time to alter the absorption of the active compound or compounds.

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. It will be understood that the estrogen of this invention will be administered in the dosages of conventional regimens, according to the tolerance of the recipient and the particular treatment or maintenance protocol that is desired. The compounds of formulas (I) and (II) herein, will be administered in an amount necessary to agonize or antagonize the estrogen or estrogen activity of the formulation to the desired level. When conjugated estrogens, USP, are used, it is preferred that the daily dosage is from 0.1 mg to 5.0 mg, more preferably from approximately 0.3 mg to approximately 2.5 mg, and much more preferably from approximately 0.3 to approximately 1.25 mg / day. . For mestranol or ethinylestradiol, a daily dosage may be from about 1 μg to about 0.15 mg / day, and a dosage of 1 μg to about 0.3 mg / day for ethinylestradiol, preferably between about 0.2 μg to about 0.15 mg / day may be used. of ethinylestradiol.

The compounds of this invention may be formulated pure or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, the route of administration chosen and the standard pharmacological practice. The pharmaceutical carrier can be solid or liquid. A solid carrier can include one or more substances which also act as flavoring agents, lubricants, solubilizers, suspension improving agents, fillers, fluidizing agents, compression aids, binders or tablet disintegrating agents; It can also be an encapsulating material. In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, waxes with low melting point and ion exchange resins. . Liquid carriers are used to prepare solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent or a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspension improving agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (which partially contains additives as in the above, for example cellulose derivatives, preferably a solution of sodium carboxymethylcellulose), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives, lecithins and oils (for example fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in compositions in sterile liquid form for parenteral administration. The liquid carrier for pressurized compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds of this invention can also be administered orally either in the form of a liquid or solid composition. The compounds of this invention can be administered rectally or vaginally in the form of a conventional suppository, creams, gels, etc. For administration by intranasal or intrabronchial inhalation or by insufflation, the compounds of this invention can be formulated in an aqueous or partially aqueous solution which can then be used in the form of an aerosol. The compounds of this invention can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is not toxic to the skin and allows the delivery of the agent for systemic absorption in the the bloodstream via the skin. The carrier can take many of the forms such as creams and ointments, pastes, gels and occlusive devices. The creams and ointments can be a viscous liquid or semi-solid emissions, either oil-in-water or water-in-oil. Also suitable are pastes made of absorbent powders dispersed in petroleum or hydrophilic oil containing the active ingredient. Various occlusive devices may be used to release the active ingredient into the bloodstream such as a semipermeable membrane that covers a reservoir containing the active ingredient with and without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. Dosage requirements vary with the particular compositions used, the route of administration, the severity of the symptoms presented and the particular subject being treated. Treatment will usually start with small dosages less than the optimal dose of the compound. Subsequently the dosage will be increased until the optimum effect is reached under the circumstances; the precise dosages for oral, parenteral, transdermal, rectal or vaginal suppository administrations, by nasal or intrabronchial administration and other administrations will be determined by the physician who performs the administration based on the experience with the individual subject treated. Preferably, the pharmaceutical composition is in unit dosage form, for example as tablets or capsules. In such form, the composition is subdivided into a unit dose containing appropriate amounts of the active ingredient; the unit dosage forms can be packaged compositions, for example packaged powders, flasks, ampoules, syringes pre-filled or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate amount of any such compositions in package form. The compound or compounds of formula (I) and (II) and the estrogen or oestrogens of the present formulations can be administered in separate dosage units such as separate pills, tablets, powders, etc. or they can be combined in a formulation. When the optimal dosages for the compounds of formulas (I) and (II) and the estrogens of these formulations have been determined, it may be preferable to incorporate both a single formulation for ease of administration. It should also be understood that the formulations herein may or may not include other pharmaceutically active components. The process for preparing a compound of formula (DM or (II)) comprises one or more of the following: a) reacting a compound of formula where R.-R6 and X are as defined in the above with an acrylamide of formula wherein Y is as defined above, to provide a compound of formula (I) wherein Z is -CH = CH-COY; or b) reacting a compound of formula where RÍ-RÍ and X are as defined in the above, with a compound of formula == (CHa ^ -Y wherein n and Y are as defined in the foregoing to provide a corresponding compound of formula I, wherein Z is Conveniently, the compounds of this invention can be synthesized in a general sense in accordance with Reaction Schemes 1 and 2, below.

REACTION SCHEME 1 The initial indole synthesis of Reaction Scheme 1 is carried out by heating an aniline (1) appropriately substituted with an alpha-bromophenylpropiophenone. (2) appropriately substituted in a solvent with a suitable high boiling point, such as DMF. The product is then alkylated with 4-bromobenzyl bromide to provide the substituted (3) indole. At this point, the deprotection of the phenols is performed (if present). Typically, the phenols are protected by benzyl ethers and can be conveniently prepared with TMSI. The acrylamides are coupled using the Heck reaction conditions in either Et3N or Et3N / CH3CN.

REACTION SCHEME 2 The initial indole synthesis of the Reaction Scheme 2 can be carried out by heating an aniline (1) appropriately substituted with an appropriately substituted alpha-bromophenylalkyl-phenyl (2) in a solvent with a suitable high boiling point, such as DMF. The product is then alkylated with 4-iodobenzyl bromide to provide the substituted (3) indole. At this point, the deprotection of the phenols is performed (if present). Normally the phenols are protected as benzyl ethers and can be conveniently separated with TMSI. The propargylamine can then be coupled to the phenyl iodide. Propargylamines are typically prepared from alkyl bromide or alkynyl tosylate by substitution with the appropriate amine. The substitution reaction is carried out in situ, without isolating the propargylamine. Compounds substituted at the 3-position with groups other than alkyl can be prepared by preparing first the indole substituted in the 3 position with -H. The indole can then be halogenated electrophilically, formily, etc., to provide other substituted compounds in the 3-position. The solvents used for the reactions are Aldrich Sure Seal ™ anhydrous without further purification. The reagents were typically from Aldrich and are used without further purification. All reactions were carried out under a nitrogen atmosphere. Chromatography was performed using 230-400 mesh silica gel (Merk Grade 60, and Aldrich Chemical Company). Thin-layer chromatography was performed with silica gel plates 60 F254 from EM Science. H NMR spectra were obtained on a Bruker AM-400 instrument in DMSO, and chemical shifts are reported in ppm. The melting points were determined in a Thomas-Hoover apparatus and are uncorrected. The IR spectra are recorded in a Perkin-Elmer diffraction grating or in Perkin-Elmer 784 spectrophotometers. The mass spectra were recorded in Kratos MS 50 or Finnigan 8230 mass spectrometers. The elemental analysis was obtained with a Perkin-Elmer elemental analyzer. 2400. The analysis values are within 0.4% of the theoretical.

EXAMPLE 1 -Benzyloxy -2- (4-benzyloxy-phenyl) -3-methyl-1H-indole A flask is charged with 4-benzyloxyaniline (45 g, 0. 23 moles), 4'-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 moles) and 50 1 of DMF. The reaction is refluxed for 30 minutes and then cooled to rt and then divided between 250 ml EtOAc and 100 ml aqueous IN HCl. The EtOAc is washed with aqueous NaHCO 3 and brine, dried over MgSO 4. The solution is concentrated and the residue is taken up in CH2C12 and hexanes are added to precipitate out 25 g of a crude solid. The solid is dissolved in CH2C12 and evaporated on silica gel and subjected to chromatography using CH2Cl2 / hexane (1: 5) to provide 9.2 g of a tan solid (33%): m.p. = 150-152 ° C; 'H RMH (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; EM the m / z 419.

EXAMPLE 2 -Benzyloxy-2- (4-fluorophenyl) -3-methyl) -lH-indole The title compound is prepared in a manner similar to (3): p.f. = 132 ° C; * H NMR (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 (dd, 1 H, J = 8.8, 2.4 Hz), 5.11 (s, 2 H), 2.34 (s, 3 H); MS m / z 331; CHN calculated for C22H18FNO.

EXAMPLE 3 -benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl) -1-ylmethyl- (4-phenyl bromide) -indole A solution of 60% NaH (0.17 g, 7.1 mmol) in 20 ml of DMF is cooled to 0 ° C and treated by dropwise addition of benzyloxyindole 1 (2.5 g, 5.94 mmole) in 10 ml of DMF. After 15 min, 4 '-bromobenzyl bromide (1.63 g, 6.53 mmol) in 10 ml of DMF is added dropwise. The reaction is stirred for 5 min at 0 ° C and then at rt for an additional 20 min. The reaction mixture is diluted with 300 ml of ether and washed with NH 4 Cl (2 x 25 ml) then with NaHCO 3 (1 x 25 ml) and 25 ml of brine. 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. = 144-146 ° C; H NMR (CDC13) 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, MS at m / z 587.

EXAMPLE 4 -Benzyloxy-2- (4-fluoro-phenyl) -3-methyl) -1-ylmethyl] - (4-phenyl bromide) -indole The title compound is prepared in a manner similar to compound 5. p.p. = 139-139.5 ° C; l NMR (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 (s, 2 H), 5.12 (s) , 2 H), 2.15 (s, 3 H) -, IR (KBr) 2920, 1630 crn "1; MS m / z (499/501, Br present); CHN calculated for C2sH23BrFNO.

EXAMPLE 5 2- (4-hydroxyphenyl) -3-methyl) -1-methylmethyl- (4-phenyl bromide) indole-5-ol A solution consisting of 5 (0.5 g, 0.85 mmol) in 10 ml of CH2C12 is treated by the dropwise addition of 3.5 equivalents of TMSI (0.47 ml, 3.0 mmol) at rt. After a a couple of hours, the reaction is stopped, so that 2.0 additional equivalents of TMSI are added and the reaction is refluxed for 5 h. The reaction is cooled to 0 ° C and methanol is slowly added to suspend the reaction. The reaction is diluted with 25 ml of ether and washed with 25 ml of NaHCO, 25 ml of 10% Na 2 SO 3 and brine. The ether layer is dried over MgSO4 and concentrated on silica gel. Chromatography with EtOAc / hexanes (1: 4 to 1: 1) gives 0.25 g of 3 (71%): m.p. = 83-86 ° C; H NMR (CDC13) 2 H of broad phenols (> 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 containing Br; IR 3390, 2900, 1600 cm- '; CHN calculated for C22H1BBrN02 + 0.25 EtOAc.

EXAMPLE 6 2- (4-Fluoro-phenyl) -3-methyl) - (4-phenyl bromide) -indol-5-ol The title compound is prepared in a manner similar to compound 7 and isolated as a foam; * 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), 6.74 (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-MS m / z 409/411 containing Br.

General Procedure for Indolacrylamides A solution of Example 3 in Et3N is treated with tri-o-tolylphosphine (10 mole%) and acrylamide (1.25 mole) is carefully purged with N2 and Pd (0Ac) 2 (2.5 mole%) is added. The reaction is heated to 100-110 ° C in a sealed tube until it is finished, determined by CCD analysis. The crude reaction product is reduced by concentration and directly crystallized or chromatographed on silica gel.

EXAMPLE 7 (IN. N-Diethyl-3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-1-ndol-1-ylmethyl] -phenyl] -acrylamide p.f. = 160-165 ° C; X 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 (broad s, 2 H), 3.47-3.42 (m, 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 crn "1; MS (el) m / z 454; CHN calculated for C29H30N2O3 + 0.15 CH2C12 + 0.30 H20.

EXAMPLE 8 1 (E) -N-tert-butyl-3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methylo-ndol-l-ylmethyl-eneyl] -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 calculated for C29H30N203 + 0.4 H20 EXAMPLE 9 (E) -Pyrrolidino-3- (4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenyl) -acrylamide P.f. = 170-175 ° C; lH NMR 9.67 (s, 1 H), 8.71 (s, 1H), 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 (s broad, 2 H), 3.56 (t, 2H, 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 calculated for C29H28N203 + 0.1 MeOH + 1.3 H20.

EXAMPLE 10 (E) -N, N-dimethyl-3-. { 4- [5-hydroxy-phenyl) -3-methyl-indol-l-ylme] -phenyl) -acrylamide p.f. = 278-280 ° C; 2 H NMR (DMSO) 9.65 (s, 1 H), 8.70 (s, 1 H), 7.50 (d, 2 H, 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 = 15.6 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 calculated for C27H26N203 + 0.5 H20.

EXAMPLE 11 (IN. N-dibutyl-3-. { 4- [5-hydroxy-2- (4-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -acrylamide p.f. = 126-128 ° C, JH NMR (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 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- '; CHN calculated for C33H38N203.

EXAMPLE 12 (E) -N-Butyl N 1 -methyl-3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indo-1-ylmethyl} phenyl) -acrylamide p.f. = 240-242 ° C-, * H NMR (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 calculated for C30H32N203 + 0.2 H20.

EXAMPLE 13 (E) -Morfolino-3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indole} -1-ylmethyl) -f nyl) -acylamide p.f. = 165-167 ° C, 2 H NMR (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 14, 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 (, 2 H), 3.59-3.53 (m, 6 H), 2.11 (s, 3 H); IR (KBr) 3330, 1650, 1620, 1580 cm 1; MS (bar) M / Z 469 (M + H *); CHN calculated for C29H28N204 + 0.5 H20.

EXAMPLE 14 (E) -3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmethyl] phenyl) -acrylamide mp = 161-163DC, XH NMR (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. 1 0 (s, 3) H); IR (KBr) 3320, 3180, 1660, 1580 crn "1; MS (BAR) m / z 399 (M + H *); CHN calculated for C25H22N203 + 1.3 H20.

EXAMPLE 15 (IN. Methyl-3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmet-yl] -phenyl} -acylamide p.f. = 155-158 ° C; aH NMR (DMSO) 9.64 (s, 1 H), 8.70 (s, 1 H), 7.99 (c, 1 H, J = 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. 1 0 (S, 3 H); IR (KBr) 3400, 1660, 1620 cm "1; MS m / z 412; CHN calculated for C26H24N203 + 0.4 H20.

EXAMPLE 16 (IN. N-Dibutyl-3-. 4 - [5-hydroxy-2- (4-fluoro-phenol) -3-methyl-indol-1-ylme-1-yl] -phenyl) -acrylamide p.f. = 180 ° C; JH NMR (DMSO) 8.77 (s, 1 H), 7.48 (d, 2 H, J = 8.4 Hz), 7.4 1 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 (m, 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- 7- EM at m / z 512; CHN calculated for C33H37N202.

EXAMPLE 17 (E) -N-Butyl. N '-Methyl-3-. { 4- [5-hydroxy-2-. { 4-fluoro-enyl) -3-methylindol-1-ylmethyl] -phenyl) -acrylamide-p.f. = 153-153.5 ° C; ? NMR (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- '; EM on M / z 470; CHN calculated for C30H31FN2O2.

EXAMPLE 18 -Benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-lH-? Ndol A flask is charged with 4-benzyloxyaniline (45 g, 0.23 mmol), 4'-benzyloxy? -2-bromophenylpriopiphenone (21 g, 0.066 mol) and 50 ml of DMF. The reaction is refluxed for 30 minutes and then cooled to rt and then divided between 250 ml EtOAc and 100 ml IN aqueous HCl. The EtOAc is washed with aqueous NaHCO 3 and brine, dried over MgSO 4. The The solution is concentrated and the residue is taken up in CH2C12 and hexanes are added to precipitate out 25 g of a crude solid. The solid is dissolved in CH2C12 and evaporated on silica gel and subjected to chromatography using CH2Cl2 / hexane (1: 5) to provide 9.2 g of a tan solid (33%): m.p. = 150-152 ° C; 'H EMN (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 "; MS m / z 419.

EXAMPLE 19 -Benzyloxy-2- (4-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl) -1- ylmethyl- (phenylioduro) -indole A solution of 4 (3.0 g, 7.4 mmol) in 25 ml of DMF is treated with NaH (60% dispersion, 0.21 g, 8.9 mmol) and stirred at rt for 15 minutes. 4-Iodobromobenzyl bromide (2.2 g, 7.4 mmol) is added and the reaction mixture is stirred for 1 hour. The reaction mixture is poured into water and extracted with EtOAc, dried over MgSO4 and concentrated. Trituration of the crude product with ether gives 2.2 g of the product as a white solid: m.p. = 153-156 ° C; 1? 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. 1 0 (d, 2 H, J = 8.8 Hz), 6.81 (dd, 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) -1-ylmethyl- (4-phenyiiodide) indol-5-ol A solution of 4 (2.2 g, 3.5 mmol) in CHC13 is treated with iodotrimethylsilane (1.04 mL, 7.0 mmol) and the reaction is heated to reflux. After an additional 2 h, 3 additional equivalents of iodotrimethylsilane are added and the reaction is stirred at rt for 18 h. The reaction is suspended by adding 5 ml of MeOH. The organic layer is washed with a 10% aqueous solution of Na 2 SO 3, IN HCl and dried over MgSO 4. The solution is concentrated and chromatographed on silica gel with EtOAc / hexane (3: 7) to provide 1.2 g of 4a as a foam: XH NMR 9.65 (s, 1 H), 8.71 (s, 1 H), 7.54 (d, 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 Indolpropargilamina The title compounds of examples 21-23 are 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 equivalents), 80% solution in toluene ). After 1 h at 0 ° C, the reactions are allowed to reach rt for 1 h. Indole iodide (4a, 1 equivalent) is added followed by 0.1 equivalent of Cu (I) I and 0.035 equivalent of Pd (PPh3) 2C12. The reaction mixture is then stirred for 16-48 h and worked by pouring into water and extracted into EtOAc. The EtOAc is concentrated and chromatographed on silica gel using EtOAC / hexane as eluent system. + EXAMPLE 21 2- (4-hydroxy-phenyl) -3-methyl-l- [4- (3-N, N-dimethyl-l-yl-prop-l-ynyl) -benzyl] -lH-indol-5-ol m.p. = 173-176 ° C; X H NMR (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 cm "1; MS 411 (M + H *).

EXAMPLE 22 2- (4-hydroxy-phenyl) -3-methyl-1- [4- (3-piperidin-1-yl-prop-1-ynyl) -benzyl] -lH-indol-5-ol p.f. = 1 18 - 123 ° C; 4_ NMR (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 MS m / z 450; CHN calculated for C30H30N2O2 + 0.25 H20 EXAMPLE 23 2- (4-Hydroxy-phenyl) -3-methyl-1- [4- (3-pyrrolidin-1-yl-prop-1-ynyl) -benzyl-1H-indol-5-ol (5c) mp = 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- - MS m / z 436; CHN calculated for C29H28N202 + 0. 7 H20 Biological Methods Estrogen receptor binding assay in vi tro Preparation of the receiver CHO cells are grown that overexpress the estrogen receptor in 150 mm2 containers in DMEM + fetal bovine serum purified with activated charcoal coated with 10% dextran. The plates are washed twice with PBS and once with 10 M Tris-HCl, pH 7.4, 1 mM EDTA. The cells are harvested by scraping the surface after the cell suspension is placed on ice. The cells are broken with a portable motorized tissue grinder using two 10-second discharges. The crude preparation is centrifuged at 12,000 g for 20 min followed by centrifugation at 60 minutes at 100,000 g to produce a ribosome-free cytosol. The cytosol is then frozen and stored at -80 ° C. The concentration of cytosol protein is estimated using the BCA assay with standard reference protein.

Union Testing Conditions The competition test is performed on a 96-well plate (polystyrene *) which binds < 2.0% of the total input of [3H] - 17 ß -estradiol and each data point is recovered in triplicate. Aliquots of 100 mg / 100 IU of the receptor preparation are placed per well. A saturation dose of 2.5 nM [3 H] 17β-estradiol + competitor (or buffer) is added in a 50 μl volume in the preliminary competition when evaluating 100 x and 500 x competitor, only [3H] 17β-estradiol is used 0.8 nM. The plate is incubated at room temperature for 2.5 h. At the end of this incubation period, 150 μl of ice-cold dextran-coated activated charcoal (activated charcoal 5% coated with 69K 0.05% dextran) added to each well is added and the plate is immediately centrifuged at 99 g for 5 minutes at 4 minutes. ° C. Then 200 μl of the supernatant solution is removed by scintillation counting. Samples are counted at 2% or 10 minutes, whichever comes first. Because polystyrene absorbs a small amount of [3H] 17β-estradiol, wells that contain radioactivity and cytosol but are not processed with activated carbon are included to quantify amounts of available isotope. In addition, wells containing radioactivity but not cytosol are processed with activated carbon to estimate the non-removable MPE of [3H] 17β-estradiol. Corning 96 well plates are used # 25880-96, because they have shown that they bind at least an amount of estradiol.

Analysis of the results The per minute (CPM) radioactivity counts were automatically converted to minute disintegrations (DPM) by the Beckman LS 7500 scintillation counter using a set of suspended standards to generate an H No. for each sample. To calculate the% binding of estradiol in the presence of 100 or 500 'times of competitor, the following formula was applied: ((Sample DPM-DPM not removed by activated carbon / (DPM of estradiol-DPM not removed by activated carbon)) x 100% =% estradiol binding For the generation of the IC50 curves, the union% versus compound% is plotted. IC50's are generated for compounds that show > 30% competition at a competitor concentration of 500x. 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).

Assay of alkaline phosphatase in Ishi awa cells Maintenance and treatment of cells: Ishikawa cells are maintained in DMEM / F12 (50%: 50%) containing phenol red + 10% fetal bovine serum and the medium is supplemented with 2 mM Glutamax, 1% Pen / Strap and 1 mM sodium pyruvate. Five days before the start of each experiment (cell treatment) the medium is changed to phenol-free red of DMEM / F12 + purified serum in activated charcoal coated with 10% dextran. On the day before treatment, the cells are harvested using 0.5% trypsin / EDTA and placed at a density of 5 x 10 '' cells / well in 96-well tissue culture plates. The test compounds are dosed at 10'6, 10"'and 108 M in addition to 10'6 M (compound) + 109 M 17β-estradiol to assess the ability of the compounds to function as antiestrogens. 48 h before the test Each 96-well plate contains a control of 17β-estradol.The same population for each dose is n = 8.

Alkaline phosphatase assay: At the end of 48 h, the medium is aspirated into the cells and washed three times with saline buffered with phosphate (PBS). 50 μl of lysis buffer is added to each well (0.1 M Tris-HCl, pH 9.8, Triton X-100 0.2%). The plates are placed at -80 ° C for a minimum of 15 minutes. The plates are reheated to 37 ° C followed by the addition of 150 μl of 0.1 M Tris-HCl, pH 9.8, containing 4 mM para-nitrophenylphosphate (pNPP) to each well (final concentration, 3 mM pNPP). Absorbance and dependent calculations are performed using the KineticCalc Application program (Bio-Tek Instruments, Inc., Winooski, VT). The results are expressed as the mean +/- S.D. (standard deviation) of the enzyme reaction rate (slope) averaged over the linear portion of the reaction kinetic curve (optical density readings every 5 minutes for 30 minutes of absorbance reading). The results for the compounds are summarized as percent of the response relative to 1 nM 17β-estradiol. Several compounds are tested for the estrogenic activity by the alkaline phosphatase method and the corresponding ED 50 values (95% C.l.) are calculated. The four included in the following are used as reference standards. 17ß-estradiol 0.03 nM 17a-estradiol 1.42 nM estriol 0.13 nM estrone 0.36 nM A description of these methods is described 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 (Ishika a Line). Cancer Research, 46: 2771-2774, and by Littlefield, B.A., Gurpide, E., Markiewicz, L., McKinley, B. and Hochberg, R.B. (1990). A simple and sensitive microtiter plate estrogen bioassay based on stimulation alkaline phosphatase in Ishikawa cells; Estrogen action of D5 adrenal steroids. Endocrinology, 6: 2757-2762. 2X VIT ERE infection test Maintenance _yi_ cell treatment Chinese hamster ovary (CHO) cells which have been stably transfected with the human estrogen receptor are maintained in DMEM + 10% fetal bovine serum (FBS). At 48 h before treatment, the growth medium is replaced with DMEM that lacks phenol red + 10% FBS purified with activated charcoal coated with dextran (treatment medium). The cells are seeded in plates at a density of 5000 cells / well in 96-well plates containing 200 μl medium / well.

Transfection of calcium phosphate Indicator DNA is combined (Promega pGL2 plasmid containing two battery copies of ERE vitellogenin in the front of the minimal thymidine kinase promoter that activates the luciferase gene) with the β-galactosidase expression plasmid pCHUO (Pharmacia) and carrier DNA (pTZ18U) in the following relationship: μG of indicator DNA 5 μG of pCHUO DNA 5 μG of pTZ18U 20 μG of DNA / l ml of transfection solution μg DNA is dissolved in 500 μl of 250 mM sterile CaCl 2 and added dropwise to 500 μl 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 μl of this mixture of cells are added to each well and remain on the cells for 16 h. At the end of this incubation the precipitate is removed, the cells are washed with medium, fresh treatment medium is replaced and the cells are treated with either vehicle, 17ß-estradiol 1 uM, 1 μM compound or 1 μM compound + 1 nM 17β-estradiol (tests for estrogen antagonism). Each treatment condition is carried out in 8 wells (n = 8) which are incubated for 24 hours before the luciferase assay.

Luciferase assay After exposure for 24 h to the compounds, the medium is removed and each well is washed 2 X with 125 μl of PBS lacking Mg ** and Ca **. After removing the PBS, 25 μl of Promega lysis buffer is added to each well and allowed to sit at room temperature for 15 min, followed by min at -80 ° C and 15 min at 37 ° C. 20 μl of lysate is transferred to an opaque 96 well plate for evaluation of luciferase activity and 5 μl of remaining lysate is used for evaluation of B-galactosidase activity (transfection normalization). The luciferane substrate (Promega) is added in 100 μl aliquots to each well automatically by the luminometer and the light produced (relative light units) is read 10 seconds after the addition. Β-galactosidase assay To the 5 μl remnants of the lysate, 45 μl of PBS is added. Then 50 μl of the Promega B-galactosidase 2X assay buffer is added, mixed well and incubated at 37 ° C for 1 hour. A plate containing a standard curve (0.1 to 1.5 milliunits in triplicate) is installed for each experimental run. The plates are analyzed in a Molecular Devices spectrophotometric plate reader at 410 nm. The optical densities for the unknown sample are converted to milliunits of activity by mathematical extrapolation from the standard curve.

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

Uterotrophic / antiterotrophic bioassay in rat The estrogenic and antiestrogenic properties of the compounds were determined in an immature rat uterotrophic assay (4 days) which (as previously described by L.J. Black and R.L. Goode, Life Sciences, 26, 1453 (1980)). They are tested in groups of six immature Sprague-Dawley rats (females, 18 days old). The animals are treated by daily ip injection with 10 μg of compound, 100 μg of compound (100 μg of compound + 1 μg of 17β-estradiol) to verify antiestrogenicity and 1 μg of 17β-estradiol, with 50% DMSO / saline 50% as an injection vehicle. On day 4, the animals are sacrificed by asphyxiation by C02 and their uteri are removed and cut to remove the excess lipid, any fluid is removed and the wet weight is determined. A small section of a horn is sent to Histology and the rest is used to isolate total RNA in order to evaluate the complement component of expression 3.

Biological Results Estrogen Receptor Affinity (reported as RBA, 17 β-estradiol = 100) Compound RBA raloxifene 200 tamoxifen 1.8 Example 10 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 infection assay Activation compound activation% with 17 n-estradiol 1 nM 17β-estradiol 100. N / A Estriol 38% N / A Tamoxifen 0% 10% Raloxifene 0% 0% Example 10 1% 2% Example 7 4% Example 8 6% Example 9 6% Example 12 13% 24. Example 11 12. Example 13 171 Example 14 19% 57. Example 15 15% 31-Example 21 34% 341 Example 22 17% 19% Alkaline phosphatase assay in Ishikawa % Activation Activation Compound (compound + 17 n-estradiol 1 nM) 17β-estradiol 100% N / A Tamoxifen 0% 45% Raloxifene 5% 5% Example 10 6 19 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 10 μg 10.0 μg Tamoxifen 69.6 mg 71.4 mg Raloxifene 47.5 mg 43.2 mg control = 42.7 mg 1 μg 17ß-estradiol = 98.2 Compound 10 μg 10.0 μg 100 μg plus 1 μg of 17β-estradiol Example 7 47.8 mg 64.8 mg 75.4 control = 202 mg 1 μg 17β-estradiol = 80.2 mg Compound or μq 100 μq 100 μa plus 1 μg of 17 β-estradiol Example 12 36.9 mg 49.5 mg 63.1 control = 314 mg 1 μg 17β-estradiol = 89.0 mg Compound 10 μq 100 μq 100 μ plus 1 ua of 17B-estradiol Example 11 39.3 mg 59.8 mg 81.0 control = 245 g 1 μg 17β-estradiol = 90.8 mg Compound 10 u < 3 100 μq 100 μq plus 1 ua of 176 -estradiol Example 14 32.5 mg 56.4 mg 79.8 mg Example 15 40.4 mg 56.3 mg 69.3 mg control = 291 mg 1 μg 17β-estradiol = 95.5 mg Compound or μq 100 μq 100 μq plus 1 μq of 17 B-estradiol Example 21 56.0 mg 84.0 mg 77.6 mg control = 32.1 mg 1 μg 17β-estradiol = 90.2 mg Compound 10 to 100 μq 100 ua plus 1 ua of 17B-estradiol Example 22 55.6 mg 71.3 mg 66.8 mg control = 21.7 mg 1 μg 17β-estradiol = 82.8 mg 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.

Claims (30)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A pharmaceutical composition characterized in that it comprises one or more estrogens and a compound having the structure: wherein: Ri is selected from H, OH or the alkyl esters of C3-C4 thereof, or halogen R2, R3, R4, R5 and R6 are independently selected from H, OH or the C3-C4 alkyl esters or ethers thereof, halogen, cyano, C ^ Cj alkyl or trifluoromethyl, with the proviso that when R? is H, R2 is not OH. n is 2 or 3, - X is selected from H, C1-C3 alkyl, cyano, nitro, trifluoromethyl, halogen; Z is selected from: -CH = CH-C-Y C = C (CH2) ñ-Y And it is selected from a) the portion: wherein R7 and R8 are independently selected from the group of H, d-C6 alkyl, phenyl or combined with - (CH2) P-, where p is an integer from 2 to 6, so as to form a ring, the ring is optionally substituted by up to three substituents which are selected from hydroxyl, halo, C 1 -C 4 alkyl, trihalomethyl, C 4 alkoxy > trihalomethoxy, d-C4 alkylthio, d-C4 alkylsulfinyl, d-d alkylsulfonyl, d-C4 hydroxyalkyl, -C02OH, CN, -CONH (C3- alkyl) C4), -NH2-, alkylamino of d-C4, dialkylamino of C3-C4, -NHS02alkyl of d-C4, -NHCOalkyl of d-C4 and -N02; b) a saturated, unsaturated or partially unsaturated heterocycle of five, six or seven members containing up to two heteroatoms which are selected from the group consisting of -O-, -NH-, -N (C1-C alkyl) -, - N = y -S (0) m-, where m is an integer of 0-2, optionally substituted with 1-3 substituents that are independently selected from hydroxyl, halo, alkyl of C 4 'trihalomethyl, C 1 alkoxy -C ^ trihalomethoxy, C1-C4 acyloxy, ^ - ^ alkylthio, C ^ -C ^ alkylsulfonyl, hydroxyalkyl of ^ -C ^, -C02H, -CN-, -CONffi ^ -, -NH2, C-alkylamino ^ C ^ dialkyl (0 ^ -04) amino, -NHS02R ?, NHCOR-L, -N02 and phenyl optionally substituted with 1-3 C1-C4 alkyl groups, c) a bicyclic ring system consisting of a five or six membered heterocycle ring fused to a phenyl ring, the heterocyclic ring contains up to two heteroatoms which is selected from -O-, -NH-, -N (? C4), and -S (0) m-, wherein m is an integer of 0-2, optionally substituted with 1-3 substituents that are independently selected from the group consisting of hydroxyl, halo, d-C4 alkyl, trihalomethyl, -d, trihalomethoxy alkoxy, C3-C4 acyloxy, C3-C4 alkylthio, alkylsulfinyl of d-C4, alkylsulfonyl of C1-C, hydroxyalkyl of C3-C4, -C02H, -CN-, -CONHRi-, -NH2-, alkylamino of d-C4, dialkyl (d-C4) amino, -imSO ^ -, -NHCOR ^, -N02, and phenyl optionally substituted with 1-3 alkyl groups of d-C4, - and pharmaceutically acceptable salts thereof.

2. A pharmaceutical composition, according to claim 1, characterized in that: Ri is selected from H, OH or the esters of d-C4 alkyl ethers thereof, halogen; R2, R3, R4, R5 and R6 are independently selected from H, OH or the C1-C1 esters or alkyl ethers thereof, halogen, cyano, C3-C6 alkyl or trifluoromethyl, with the proviso that when R is H, R2 is not OH; X is selected from H, C3-C6 alkyl, cyano, nitro, trifluoromethyl, halogen; And it's the portion R7 and RB are independently selected from H, d-C6 alkyl or, combined with - (CH2) p-, where p is a integer from 2 to 6, so as to form a ring, the ring is optionally substituted by up to 3 solvents which are selected from hydroxyl, halo, d-C4 alkyl / trihalomethyl, C3-C4 alkoxy, trihalomethoxy, dithioxythio -C4, C1-C4 alkylsulfinyl, d-alkylsulfonyl, d-C4 hydroxyalkyl, -C02H, -CN, -CONH (d-C4 alkyl), -NH2, d-C4 alkylamino, C1-C4 dialkylamino , -NHS02 (d-C4 alkyl), -NHCO (d-C4 alkyl) and -N02.

3. The pharmaceutical composition according to claim 2, characterized in that R7 and R8 are concatenated together as - (CH2) p- to form a ring wherein p is an integer from 2 to 6, the ring is optionally substituted with 1-3 substituents which are selected from d-C3 alkyl, trifluoromethyl, halogen, phenyl, nitro and -CN.

4. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and 5-benzyloxy-2- (4-fluorophenyl) -3-methyl) -lH-indole.

5. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and 5-benzyloxy-2- (4-benzyloxyphenyl) -3-methyl) -1-ylmethyl- (4-phenylbromide) -indole.

6. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and 5-benzyloxy-2- (4-fluoro-phenyl) -3-methyl) -1-ylmethyl- (4-phenylbromide) -indole.

7. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and claim 1 comprises one or more estrogens and 2- (4-hydroxyphenyl) -3-methyl) -1-ylmethyl- (4-phenyl bromide) - indole-5-ol

8. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and (E) -N, N-diethyl-3-. { 4- [5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -Acrylamide.

9. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and 1 (E) -N-tert-butyl-3 -. { 4 - [5-Hydroxy-2- (4-hydroxyphenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -Acrylamide.

10. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and (E) -pyrrolidino-3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -Acrylamide.

11. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and (E) -N, N-dimethyl-3-. { 4- [5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -Acrylamide.

12. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and (E) -N, N-dibutyl-3-. { 4- [5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -Acrylamide.

13. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and (E) -N-butyl N '-methyl-3-. { 4- [5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -Acrylamide.

14. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and (E) -morpholinin-3. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenyl} Acrylamide

15. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and (E) -3-. { 4- [5-hydroxy-2- (4-hydroxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -Acrylamide.

16. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and (E) .N, methyl-3-. { 4- [5-hydroxy-2- (4-hydroxyphenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -Acrylamide.

17. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and (E) -N, N-dibutyl-3-. { 4- [5-hydroxy-2- (4-fluorophenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -Acrylamide.

18. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and (E) -N-butyl, N 1 -methyl-3-. { 4- [5-hydroxy? -2- (4-fluorophenyl) -3-methyl-indol-1-ylmethyl] -phenyl} -Acrylamide.

19. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and 2- (4-hydroxyphenyl) -3-methyl-1- [4- (3-N, N-dimethyl-1-yl-propyl) 1-inyl) benzyl] -lH-indol-5-ol.

20. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and 2- (4-hydroxyphenyl) -3-methyl-l- [4- (3-piperidin-1-ylprop-1-ynyl) -benzyl] -lH-mdol-5-ol;

21. The pharmaceutical composition according to claim 1, characterized in that it comprises one or more estrogens and 2- (4-hydroxyphenyl) -3-methyl-1- [4- (3-pyrrolidin-1-ylprop-1-ynyl) -benzyl ] -lH-indol-5-ol.

22. A pharmaceutical composition, characterized in that it comprises one or more estrogens and a compound according to any of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

23. A pharmaceutical composition, according to any one of claims 1 to 22, characterized in that one or more estrogens are selected from equilin, equilenin, estradiene, ethinylestradiol, 17β-estradiol, 17alpha-dihydroequilenin, 17β-dihydrohelequinnin, menstranol, conjugated estrogens , estrone, sulfate of 17alpha-estradiol, deltad, 9-dehydroestrone, equol or enterolactone; or a pharmaceutically acceptable salt or ester thereof.

24. The pharmaceutical composition according to claim 23, characterized in that the pharmaceutically acceptable salt of one or more estrogens is a sodium salt.

25. A method for treating or preventing bone loss in a mammal, the method is characterized in that it comprises administering to a mammal in need thereof an estrogen and an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

26. A method for treating or preventing disease state or syndromes which are caused or are associated with an estrogen deficiency in a mammal, the method is characterized in that it comprises administering to the mammal in need thereof an estrogen and an effective amount of a compound of according to claim 1 or a pharmaceutically acceptable salt thereof.

27. A method for treating or preventing cardiovascular diseases in a mammal, the method is characterized in that it comprises administering to the mammal in need thereof an estrogen and an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

28. A method for treating or preventing diseases in a mammal, which results from the proliferation of normal development, tissue growth actions Endometrial or similar endometrial, the method is characterized in that it comprises administering to a mammal in need thereof an effective amount of an estrogen and an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

29. The method of treatment according to claim 28, characterized in that the disease is endometriosis.

30. A product, characterized in that it comprises a compound of formula (I) or (II), according to any of claims 1 to 21, or a pharmaceutically acceptable salt thereof, and one or more estrogens in combination for separate administration, in sequence or simultaneously.