MXPA00011087A - Benzocarbazole and indenoindole derived estrogenic agents - Google Patents

Abstract

The present invention relates to new substituted benzo[a]carbazoles and indenoindoles having general structures (I) or (II) which are useful as estrogenic agents, as well as pharmaceutical compositions and mehtods of treatment utilizing these compounds alone or in combination with one or more estrogens.

Description

ESTROGENIC AGENTS DERIVED FROM BENZOCARBAZOL AND INDENOINDOL DESCRIPTION OF THE INVENTION The present invention relates to novel indenoindole and benzocarbazole compounds which are useful as estrogenic agents, as well as with pharmaceutical compositions and methods of treatment using these compounds, alone or in combination with one or more estrogens.

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 or conjugated estrogens isolated from natural sources (ie, Premarin conjugated estrogens "from yeth-Ayerst). In some patients, the therapy may be contraindicated because of the non-opposing estrogen proliferative effects (estrogens are not provided in combination with progestins) and have been found on uterine tissue. This proliferation is associated with an increased risk of endometriosis and / or cancer Ref: 124425 endometrial The effects of unopposed estrogen on breast tissue is less clear, but it is worrisome. 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. For example tamoxifen (sold as tamoxifen citrate Novadex ™ by Zeneca Pharmaceuticals, Wilmington, Delaware), is a useful palliative for the treatment of breast cancer and has been shown to exert an effect similar to an 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. 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. The WO document 93/2337 (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 it does not describe such compounds having chains from the indole nitrogen having the same structure to those provided by the present invention. In his postmenopausal article Hormone replacement theraphy with estrogen periodically supplemented wi th antiestrogen, Am. J. Obstet, Gynecol. , Vol. 1 0, No. 7, 1981, pp. 787-792, Kauppila et al. describes her postmenopausal estrogen therapy study of 7-week estrogen regimens followed by treatment for 10 days with the antiestrogen clomiphene citrate. Also, in his Article Comparison of Megestrol Acetate and Clomiphene Ci tra te as Suplemental Medication in Posmenopausal Oestrogen Replacement Therapy, Arch. Gynecol. (1983) 23: 9-58, Kauppila et al., Describes in postmenopausal women combination therapies of estrogen with random supplementation of megestrol acetate or clomiphene citrate. The United States patent number, 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. The United States patentNo. 5,552, 01 (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; they are used in pharmaceutical formulations that optionally contain estrogen or prostegin. U.S. Patents 5,6 6,137 and 5,591,753 (both issued to Black et al.) Describe methods for treating osteoporosis with formulations of arylbenzothiophene compounds of the raloxefin type together with a progestin that is selected from medroxyprogesterone, norethindrone or norethynodrel, or pharmaceutically acceptable salts thereof. U.S. Patent No. 5,550,107 (Labrie) 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, so less an inhibitor of sex steroid formation, especially 17β-hydroxysteroid dehydrogenase and aromatase activity, at least one inhibitor of prolactin secretion, one inhibitor of growth hormone secretion and one inhibitor of ACTH secretion. U.S. Patent No. 5,672,609 (Bryant et al.) Discloses pyridine compounds useful in treating the syndrome postmenopausal 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. The indenoindoles and bezocarbazoles, as shown in Figures I and II, have not been reported for compounds of the type described which present the side chain of the indole nitrogen as described in the present invention. See Ger. Offen., DE 3821148 Al 891228 and WO 96/03375 describe indenoindoles and benzocarbazoles which do not have or claim the basic side chains of this invention. In addition, see Segall, et al, Eur. J. Med. Chem., 30 no. # 2 165-169 (1995) for benzocarbazoles with estrogenic / antiestrogenic activity.

DESCRIPTION OF THE INVENTION The indenoindoles and benzo [a] carbazoles of the general structure type shown in Figures (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, and are capable of antagonizing the effects of 17β-estradiol (in an infection test by luciferase) and at the same time show little intrinsic estrogen agonist activity when dosed alone. The present invention includes compounds of the formulas in Figures I and II below: n where Ri is selected from H, OH or the straight or branched chain Cl-C12 esters (or straight chain or branched or cyclic alkyl ethers thereof, halogen or benzyloxy; or halogenated ethers including trifluoromethyl ethers) and trichloromethyl; R2, R3, R4, R5 and R6 are independently selected from H, OH or the C ^ C ^ esters (straight or branched chain or alkyl ethers of (straight or branched chain or cyclic thereof, halogens or halogenated ethers including trifluoromethyl ether and trichloromethyl ether, cyano, C 1 -C 6 alkyl (straight or branched chain), benzyloxy or trifluoromethyl, with the proviso that when R 1 is H, R 2 is not OH. n 'is 1 or 2; n is 2 to 4; And it is selected from a) the portion: wherein R7 and R8 are independently selected from the group of H, C ^ C alkyl, phenyl, or combined with - (CH2) P-, where p is an integer from 2 to 6, so as to form a ring , the ring optionally forms a methylene bridge and the ring is optionally substituted by up to three substituents which are selected from hydroxyl, halo, C 1 -C 6 alkyl, trihalomethyl, C 1 -C 6 alkoxy, trihalomethoxy, C 5 -C 10 alkylthio, alkylsulfinyl of Cj-C, Cj-C alkylsulfonyl, hydroxyalkyl of Cj-C ,, -C02H, CN, -CONH (Cj-C4 alkyl), -NH2-, Cj-C alkylamino, Cj-dialkylamino -C ,, -NHS02Ci-C, alkyl, -NHCOalkyl of Cj-C4 and -NOs; or b) a saturated, unsaturated or partially unsaturated five-membered heterocycle containing up to 2 heteroatoms which are selected from the group consisting of -0-, -NH-, -N (C1-C4 alkyl) -, -N =, ( in which case the heterocycle may be linked via nitrogen) and -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 Cj-C, trihalomethyl, CJ-CJ alkoxy, trihalomethoxy, C 1 -C 6 acyloxy, C 1 -C alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 1 hydroxyalkyl phenyl optionally substituted by 1-3 C 1 -C, C 1 -C 2 alkyl, -CN-, -CONHR, -, -NH 2, C 1 -C 8 alkylamino, dialkyl (Cj-C,) amino, -NHSOJRÍ, - NHCOR1; -N02; OR; c) a saturated, unsaturated or partially unsaturated six-membered heterocycle containing up to 2 heteroatoms which are selected from the group consisting of -0-, -NH-, -N (Cj-C alkyl,), -N = (in whose case the heterocycle may be linked via nitrogen) and -S (0) ", -, 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, C 1 -C 4 alkoxy, trihalomethoxy, Ci-C acyloxy, C 1 -C 4 alkylthio, C 1 C alkylsulfinyl, C 2 -C 6 alkylsulfonyl, hydroxyalkyl C ^ C ,,, phenyl optionally substituted with 1-3 alkyl of -C02H, -CN-, -CONHRj-, -NH2-, C ^ C alkylamino, dialkyl (C ^ C,) amino, -NHSOjR; -, -NHCORÍ-, -N02; or d) a seven-membered, saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms that are selected from the group consisting of -0-, -NH-, -N (C 1 -C 4 alkyl) -, -N =, (in which case the heterocycle may be linked via nitrogen), and -S (0) n-, where m is an integer of 0-2, optionally substituted with 1-3 substituents that are independently selected from the group consisting of of hydrogen, hydroxyl, halo, C 1 -C 4 alkyl, trihalomethyl, C 1 -C 2 alkoxy, trihalomethoxy, C 1 C 5 acyloxy, C 1 C alkylthio, C 1 -C 1 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C ,,, hydroxyalkyl of Cj-C ,, optionally substituted phenyl with 1-3 of C 1 -C 4 alkyl, -C0 2 H, -CN, -CONHR, -, -NH 2, C 1 C 1 alkylamino, dialkyl (0, -0,) amino, -NHS02R,, -NHCOR, , -N02; Or e) a bicyclic heterocycle containing 6-12 carbon atoms either bridging or fused and containing up to two heteroatoms which are selected from the group consisting of -0-, -NH-, -N (Cl- C4) -, (in which case the heterocycle may be linked via nitrogen) and -S (0) m-, where m is an integer of 0-2, optionally substituted with 1-3 substituents that are independently selected from group consisting of hydroxyl, halo, Cj-C4 alkyl, trihalomethyl, C, -C4 alkoxy, trihalomethoxy, C, -C "acyloxy, Cj-alkylthio, C, -C4-alkylsulfinyl, C-CJ-alkylsulfonyl , hydroxyalkyl of 0, -0, phenyl optionally substituted with 1-3 of C1-C1 alkyl, -C02H, -CN, -CONHRj, -NH2, C, -C4 alkylamino, dialkyl (C, -C4) amino , -NHS02R ,, -NHCOR ,, -N02; (for example R, is C, -C4 alkyl); and pharmaceutically acceptable salts thereof.

Within the scope of the compounds described above are the preferred compounds of formulas I or II wherein R ,, R2, R3, R4, R5, Rs, X, n 'and n are as defined above, and Y is selected from saturated heterocycles of five, six, seven or eight members, or bicyclic structures with the heteroatoms and substituents described in groups b) ae) in the above. Among the Y groups preferred additionally of this subset are those shown below, each unsubstituted or optionally substituted by the substituents described in the foregoing.

The most preferred compounds of this invention are those having the above general structures I or II, wherein: R, is selected from H, OH or the esters or alkyl ethers of C, -C4 thereof, halogen; R2, R3, R4, R5 and R6 are independently selected from H, OH or the esters or alkyl ethers of C, -C4 thereof, halogen, cyano, C, -C6 alkyl or trifluoromethyl, with the proviso that when R , is H, R2 is not OH; And it's the portion: R, and R, are independently selected from the group of H or 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 optionally forms a methylene bridge and the ring is optionally substituted by up to three substituents selected from hydroxyl, halo, C, -C 4 alkyl, trihalomethyl, C 1 -C 4 alkoxy, trihalomethoxy, C, -C 4 alkylthio, alkylsulfinyl of C, -C 4, C, -C 4 alkylsulfonyl, hydroxyalkyl of C, -C 4, -C0 2 H, CN, -CONH (Ci-C alkyl,), -NH 2 -, C, -C 4 alkylamino, dialkylamino of C , -C4, -NHS02C1-C4 alkyl, -NHCOalkyl of C, -C4 and -N02; and pharmaceutically acceptable salts thereof. The rings formed by concatenated R7 and RB, mentioned in the above, may include but are not limited to aziridine, azetidine, pyrrolidine, piperidine hexamethyleneimine or heptamethyleneimine rings. The most preferred compounds of the present invention are those having structural formulas I or II in the foregoing, wherein R is OH; R2-R6 are as defined in the above; and Y is the portion and R, and R, are concatenated together as - (CH2) r-, where r is an integer from 4 to 6, to form a ring that optionally forms a bridge with methylene and optionally substituted by up to three substituents that are selected of hydroxyl, halo, C, -C 4 alkyl, trihalomethyl, C 1 -C 4 alkoxy, trihalomethoxy, C, -C 4 alkylthio, C, -C 4 alkylsulfinyl, C, -C 4 alkylsulfonyl, C, -C 4 hydroxyalkyl, -C02H, CN, -CONHtCi-C,), -NH2-, C-C4 alkylamino, C-C4-dialkylamino, -NHS02 of C, -C4, -NHCO of C, -C4 and -N02; and the pharmaceutically acceptable salts thereof. Compounds of general formulas are also included within the subsets of compounds of this invention: wherein R ,, R2, R3, R4, R5, R6, R7, Ra, Y, r, n, n 'and p are as defined in the groups described above. The examples of the variables in the formulas in the above are independent or collectively: n is 2; R, is hydroxyl or benzyloxy; R2 is hydrogen; X is -CH = CH- or CH2; R3 is hydrogen; R 4 is methoxy, hydroxyl or benzyloxy; R5 is hydrogen; R6 is hydrogen; And it is piperidin-1-yl or azepan-1-yl. This invention includes acceptable salt forms made from the addition reaction with inorganic or organic acids. Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid as well as organic acids such as acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid are useful. , succinic acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid. It is known that compounds possessing a basic nitrogen can form complexes with many different acids (both protic and non-protic) and are usually preferred to administer a compound of this invention in the form of an acid addition salt. Additionally, this invention includes quaternary ammonium salts of the compounds herein, which can be prepared by reacting the nucleophilic amines of the side chain with a suitable reactive alkylating agent such as alkyl halide or benzyl halide.

This invention also provides processes for preparing the compounds of formula (I) and (II), which process includes: a) reacting a compound of formula (III) or (IV) (III) (IV) where R, _, and X are as defined in the above, if necessary any reactive group is protected, with a compound of the formula: (V) wherein Y is as defined in the above and hal is a halogen, for example Cl or Br, and R5 and R6 are as defined in the above and, if necessary, review any protecting group; or b) reacting a compound of the formula: (SAW) wherein R, .β and X are as defined in the above and Hal is a halogen, for example Cl or Br, if necessary any reactive group must be protected with a compound of formula wherein R7 and Rβ are as defined in the foregoing. c) hydrogenating a compound of formula I or II wherein R, and / or R 4 is benzyloxy to provide a corresponding compound of formula I or II wherein R, and / or R 4 is OH. • 15 These reactions are discussed more broadly in the following.

Methods The synthesis of the compounds described in this invention is carried out by simply heating either an indanone or a tetralone with an appropriately substituted phenylhydrazine and a protic acid to provide the desired hydrazone which is then cured by further heating with additional 25 a Lewis acid (for example ZnCl2). He indenoinol or benzo [a] carbazole can then be alkylated by deprotonation with a suitable strong base (for example NaH) and then treated with the desired side chain. The general reaction scheme for the synthesis of these compounds is illustrated in reaction scheme 1. This concept is illustrated in reaction scheme 2 specifically for the synthesis of compound 6. The synthesis of side chain 11 is shown in the scheme of reaction 3.

Reaction Scheme 1 X = CH2, CH2CH2 2- Deprotection if necessary as described in figures i and 2 Reaction Scheme 2 [5111-70-6] [51145-58-5] 2008-75-5] [26815-04-3] NaBU / MeOH 10 In the reaction scheme 4 the synthesis of benzo [a] carbazoles (19 to 22) is shown. Tetrahydone 14 hydrazone is formed from the condensation reaction between 6-methoxy-1-tetralone 12 ([1078-19-9] Aldrich Chemical Company) and 4-benzyloxyphenylhydrazine 13 [51145-58-5] in the presence of ethanol and catalytic acetic acid. The hydrazone is then cyclized in the presence of zinc chloride in acetic acid to provide the unsubstituted benzo [a] carbazole N 15. The benzo [a] carbazole can then be alkylated in the same manner as that shown in Reaction Schemes 1 or 2, or alternatively as shown in Reaction Scheme 4, with 4- (2-chloroethoxy) benzyl bromide 17 as the alkylating agent. The chloride is displaced with piperidine or hexamethyleneimine for the examples given using DMF as the solvent and potassium iodide to facilitate the reaction. The substituted compounds 19 and 20 are then hydrogenated with cyclohexadiene and a palladium / carbon catalyst to provide compounds 21 and 22.

Reaction Scheme 4 13 14 [1078-19-9] [51145-58-5] ZnCt AcOH ] (n = 2) 22 (n = 2) The compounds of formulas (I) and (II) are partial estrogen agonists and show high affinity for the estrogen receptor. Unlike many estrogens, these compounds are not expected to cause substantial increases in wet uterine weight, which is evidenced by their low agonism in the luciferase infection assay. Additionally, these compounds compete with estrogen for the estrogen receptor and are therefore capable of antagonizing the effects of estrogen on target tissues. Due to the tissue-selective nature of these compounds, they are useful for treating or preventing in a mammalian disease state or syndrome which are caused or associated with an estrogen deficiency or an excess of estrogen. In particular, 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 disease states or syndromes in the mammal which are caused or are associated with an estrogen deficiency. This tissue selectivity allows its use for desirable estrogenic activity in certain tissues, such as bone, while limiting activity in others, such as uterine tissue. Mixed estrogen agonists / antagonists are useful for treating or preventing many diseases, which result from excess or deficiency of estrogen and include osteoporosis, prosthetic hypertrophy, male pattern baldness, ovarian cancer, infertility, breast cancer, endometrial cancer, cardiovascular disease, contraception, Alzheimer's disease, cognitive decline and other CNS disorders, as well as certain cancers that include melanoma, prostate cancer, colon cancers, CNS cancers and uterine cancer among others. Additionally, these compounds can be used for hormone replacement therapy in postmenopausal women or in other estrogen deficiency states where supplementation with estrogen may be beneficial. The compounds of this invention can also be used in treatment methods for bone loss, which may result from an imbalance of the individual formation of new bone tissues and 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, those who receive or who have received prolonged corticosteroid therapies, those who have experienced adrenal dysgenesis and those who suffer from Cushings' syndrome. Special needs for bone substitution can also be resolved using these compounds in individuals with bone fractures, defective bone structures, and those receiving bone-related surgeries or prosthetic implantation, or both. In addition to the problems described above, these compounds can be used in treatments for osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalasia, osteohalisteresis, multiple myeloma and other forms of cancer that have harmful effects on bone tissue. The methods for treating the diseases included herein are understood to comprise the 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 utilizing one or more of the present compounds, and / or salts pharmaceutically acceptable thereof, together with one or more carriers, excipients, etc., pharmaceutically acceptable.

The present invention also provides pharmaceutical formulations and methods for using them, comprising compounds of formulas (I) and (II) together with one or more estrogens, preferably together with one or more pharmaceutically acceptable carriers or excipients. Among the uses of the present estrogen formulations is alleviating the symptoms of postmenopausal syndrome in women including perimenopausal and postmenopausal symptoms. The present formulations and methods of treatment can be used to minimize the undesirable side effects of estrogen treatment or therapy and can be used to minimize the amounts of estrogen needed for a particular regimen. Estrogens useful in the formulations of this invention include estrone, equilin, equilenin, ethinylestradiol, 17β-estradiol, dihydroequilenin, 17β-dihydroequilenin (U.S. Patent No. 2,834,712), menstranol and conjugated estrogen hormones such as Premarin's products. from Wyeth-Ayerst Laboratories' as well as the sulfated esters of these oestrogens Also useful in the present formulations are sodium sulphate, sodium equilin sulfate, sodium alkale dihydroequiline sulfate, sodium 17alpha-estradiol sulfate, delta 8.9 - sodium dehydroestrone sulfate, sodium equilenin sulfate, sodium 17beta-dihydroequiline sulfate, sodium 17alpha dihydroequilenin sulfate, sodium 17beta-estradiol sulfate, sodium 17beta-dihydroequilenine 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, 17alpha-Pregnan-3 -beta, 16alpha-diol, sodium 20-ona-3-sulfate, delta (8, 9) -dehydroestrone 3-sodium sulfate, estra-3beta, sodium 17alpha-diol 3-sulfate, 3beta-hydroxy-sulfate Sodium 5 (10) -en-17-one-3-sulfate, or 5alpha-Pregnan-3beta, 16alpha, 20R-triol 3-sodium sulfate. Esterified estrogens such as those sold by Solvay Pharmaceuticals, Inc. under the tradename Estratab "* can also be used with the present formulations.The preferred salts of estrone, include, but are not limited to, the sodium and piperate salts. phytoestrogens such as equol or enterolactoma can also be used in the present formulations and methods.The mammalian metabolic conjugates of estrogens in the following, such as the sulfates or glucuronics thereof, are those that are preferred.A particularly preferred embodiment of this invention comprises pharmaceutical compositions and methods of treatment using conjugated estrogenic hormones such as Premarin ™ products from Wyeth-Ayerst Laboratories with one or more compounds of the formulas (I) or (II) included herein. 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 comprise one or more estrogens and are useful for treating many ailments including osteoporosis, prosthetic hypertrophy, infertility, breast cancer, endometrial hyperplasia, endometrial cancer, endometriosis, cystic glandular hyperplasia, uterine hyperplasia, Cervical hyperplasia, benign prosthetic hyperplasia, cardiovascular disease, contraception, Alzheimer's disease and melanoma. Such formulations of this invention can also be used to treat bone loss resulting from secondary osteoporosis, including that 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 may also be the rationale for hormone-releasing hormone treatment. gonadotropin (GnRH or LHRH) or synthetic GnRH antagonists or agonists, such as injectable leuprolide acetate and sold by TAP Pharmaceuticals Inc. by LUPRON ™, or the goserelin acetate implant sold by Zeneca Pharmaceuticals under the tradename Zoladex "8. bone loss can also result from the immobilization of the individual, chronic renal failure, malabsorption syndrome, liver disease, chronic obstructive pulmonary disease, rheumatoid arthritis or sarcoidosis.In addition, the compounds of formula (I) and (II) in formulations that comprise one or more estrogens may be used for hormone replacement therapy in postmenopausal women or in other estrogen deficiency states where estrogen supplementation may be beneficial Synthetic activity of the compounds and estrogen or estrogens of the present methods of treatment are particularly interesting in solving the consequences not desired estrogen therapy, such as heavy bleeding and / or excessive endometrial stimulation, which can lead to endometrial hyperplasia. 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 primary target tissues for oestrogens include the reproductive tract (ovary, uterus), breast tissue, 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 and stroke), the skeletal system (maintenance of bone mass, risk reduced 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 tissue and cardiovascular system where the combination 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.

Estrogen comprises formulations of this invention that can also be used in methods of treatment for bone loss, osteoarthritis, Paget's disease, osteomalacia, osteohalisteresis, endometrial cancer, multiple myeloma and other forms of cancer that have harmful effects on bone tissues such as It is described before. 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 will be monitored to obtain the desired result with the minimum of estrogen or estrogen required. 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, the administration will be from about 1 mg / day to approximately 600 mg / day in a single dose or in two or more divided doses. Most preferably, it will administer a daily dose of between about 1 mg / day and about 150 mg / day. Such doses may be administered in any way useful in targeting the active compounds herein to the bloodstream of the receptors including the oral, parenteral (including intravenous, intraperitoneal and subcutaneous) injections, and transdermally. 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 one or more estrogens and one or more of the active compounds of the formulas (I) and (II) can comprise any conventionally used oral form including tablets, capsules, mouth forms, troches, dragees and oral fluids, suspensions or solutions. The capsules may contain mixtures of the active compound or compounds with inert fillers and / or diluents such as pharmaceutically acceptable starches (for example corn starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses such as crystalline and microcrystalline celluloses, flours, gelatins, 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 or estrogens used in this invention will be administered in 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 0.3 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 menstranol a daily dosage can be from about 1 μg to about 0.15 mg / day, and a dosage from about 1 μg to about 0.03 mg / day, preferably between about 5 μg and about 0.15 mg / day of ethinyl estradiol can be used for ethinylestradiol. . The estrogens and compounds of these formulations can 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, agents that improve the suspension, thickeners, colors, viscosity regulators, stabilizers or osmoregulators. 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. 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 petroleum 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 suppositories, 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 may be packaged compositions, for example packaged powders, flasks, ampoules, pre-filled syringes 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 compounds of formulas (I) and (II) and the estrogen or oestrogens of the present formulations can be - 4? -administer in separate dosage units such as separate pills, tablets, powders, etc. or they can be combined in a formulation. When optimum dosages for the compounds of formulas (I) and (II) and 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.

Experimental part Aldrich Sure Seal "" Solvents, anhydrous without further purification can be used for the reactions described herein and can be obtained from Aldrich Chemical Company. All reactions are carried out under a nitrogen atmosphere. Chromatography is performed using 230-400 mesh silica gel (Merck Grade 60, Aldrich Chemical Company). Thin layer chromatography is carried out with silica gel 60 F254 plates from EM Science. The 'H NMR spectra are obtained in a Bruker AM-400 instrument in DMSO and the chemical shifts are reported in ppm. The melting points were determined in a Thomas-Hoover apparatus and are uncorrected. The IR spectra were recorded on a Perkin-Elmer diffraction grating or on spectrophotometers Perkin-Elmer 784. Mass spectra were recorded on a Kratos MS 50 or Finnigan 8230 mass spectrometer. Elemental analysis is obtained with a Perkin-Elmer 2400 elemental analyzer. The compounds for which CHN is reported are within 0.4% of the theoretical value for the given formula. The nomenclature of the compound is typically obtained by using the Beilstein Autonom ™ program.

Synthesis of indenoindoles and benzocarbazoles Table 1 Example No. 1 (Intermediary # 3 and reaction scheme 2) (5-methoxy-l-indanon (4-benzyloxyphenyl) -hydrazone A solution of 4-benzyloxyphenylhydrazine [51145-58-5] * (10.0 g, 51 mmol) and 5-methoxyindanone [511-70-6] ** (9 g, 55 mmol) and a few drops of AcOH in 100 ml of EtOH is heated at reflux for 1 h. The reaction is then cooled and precipitated out of a solid. The solid is filtered to provide 14 g of a tan solid (80%). 'H NMR (DMSO) 11.88 (s, 1 H), 7.48 (d, 1 H, J = 8.4 Hz), 7.43-7.32 (m, 5 H), 7.08 (d, 2 H, J = 9.0 Hz), 6.88 (m, 3 H), 6.81 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 5.17 (s, 2 H), 3.75 (s, 3 H), 3.03 (t, 2 H, J = 6.6 Hz), 2.73 (t, 2 H, J = 6.5 Hz); IR (KBr) 3350, 1520, 1250 cm "1; CHN calculated for C23H22N202. * Prepared by the method provided in Miyadera T. and Kosower EM; J. Med. Chem 15 (1972) 339-340 using 4-benzyloxyaniline (Aldrich Chemical) as the initial material.

** Purchased from Aldrich Chemical Company Example No. 2 (Intermediary No. 4 in Reaction Scheme 2) 2 - . 2-methoxy-8-benzyloxy-5.10-dihydro-ineno TI.2-b] indole A solution of 5-methoxy-1-indanone (4-benzyloxyphenyl) idrazine (# 3 from the previous step) (14 g, 41 mmol) and ZnCl 2 (14 g, 100 mmol) in 70 ml of AcOH is heated to 110 °. C for 30 min. The reaction is then poured into water, extracted with EtOAc. The organic layer is dried with MgSO 4 and concentrated. The product is purified by flash chromatography (eluent 20% EtOAc / hexane) to give a yellow solid. The solid is stirred in ether and filtered to provide 2.3 g of an off-white solid (17%). p.f. = 189 -193 ° C, * H NMR (DMSO) 11.28 (s, 1 H), 7.41 (m, 5 H), 7.32 (m, 2 H), 7.17 (d, 1 H, J = 2.4 Hz), 7. 1 0 (d, 1 H, J = 2.4 Hz), 6.89 (dd, 1 H, J = 8.4 Hz, 2.4 Hz), 6.75 (dd, 1 H, J = 8.6 Hz, 2.4 Hz), 5. 1 0 (s, 2 H), 3.78 (s, 3 H), 3.60 (s, 2 H); MS at m / z 342 (M *).

Example No. 3 (Intermediary No. 5 in Reaction Scheme 2) 8-benzyloxy-2-methoxy-5- T4- (2-piperidin-1-l-ethoxy) -benzyl] -5,10-dihydro-indene TI.2-bl indole Compound # 11 (see procedure in the following) (5.0 g, 23.9 mmol) in 40 ml of DMF is cooled to 0 ° C and treated with NaH (60% dispersion in mineral oil, 1.15 g, 28.8 mmol) and stirred for 15 minutes. The resulting solution is treated with indenoindole # 4 (4.0 g, 11.7 mmole) followed by an additional equivalent of NaH (60% dispersion in mineral oil, 0.47 g, 11.7 mmole). The reaction is allowed to reach room temperature (rt) and is stirred for 2 hours. The reaction mixture is poured into water and extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The concentrate is chromatographed on silica gel (ethyl acetate / hexanes, 7: 3) and then with 100% ethyl acetate which gives a brown solid which is triturated with methanol to give 3.2 g of an off-white solid: pf = 102-105 ° C; l NMR (DMSO) 7.52 (d, 1 H, J = 8.4 Hz), 7.43 (m, 5 H), 7.36 (m, 1 H), 7.18 (d, 1 H, J = 2.2 Hz), 7.13 (d , 1 H, J = 2.4 Hz), 7.04 (d, 2 H, J = 8.6 Hz), 6.85 (dd, 1 H, J = 8.3 Hz, 2.4 Hz), 6.80 (m, 3 H), 5.58 (s , 2 H), 5. 10 (S, 2 H), 3.93 (t, 2 H, J = 5.9 Hz), 3.77 (s, 3 H), 3.64 (s, 2H), 2.55 (t, 2 H, J = 5.9 Hz), 2.34 (m, 4H), 1.42 (m, 4 H), 1.33 (m, 2 H), IR (KBr) 2950, 1460.1250 crn "1; EM at m / z 559 (M *) Example No. 4 (Product No. 6, in Reaction Scheme 2) 2-methoxy-5- [4- (2-piperidin-1-yl-ethoxy) -benzyl-5,10-dihydro-indene TI. 2 -b] indole-8-ol A solution consisting of indenoindole # 5, 1.6 g of 10% Pd / C and 8 ml of cyclohexadiene and THF / EtOH (about 1: 1) is stirred at rt for 18 hours after which time the reaction mixture is filtered off. through Celite, concentrate and triturate with methanol to provide 2.2 g of a white solid: mp = 144-146 ° C; aH NMR (DMSO) 8.74 (s, 1 H), 7.48 (d, 1 H, J = 8.4 Hz), 7.29 (d, 1 H, J = 8.8 Hz), 7.16 (d, 1 H, J = 2.2 Hz ), 7.04 (d, 2 H, J = 8.8 Hz), 6.82 (m, 4 H), 6.55 (dd, 1 H, J = 8.8 Hz, 2.2 Hz), 5.53 (s, 2 H), 3.93 (t , 2 H, J = 6.0 Hz), 3.76 (s, 3 H),, 3.60 (s, 2 H), 2.55 (t, 2 H, J = 5.9 Hz), 2.34 (m, 4 H), 1.43 ( m, 4 H), 1.33 (m, 2 H); IR (KBr) 3400, 2910, 1460, 1250 cm "1; MS m / z 469 (M *). CHN calculated for C30H32N2O3 +.5 H20 +.4 ethanol.

Example No. 5 (Intermediary No. 9 in Reaction Scheme 3) 4 - (2-piperidine-ethoxy-bßncyl aldehyde To a well-stirred suspension of p-idroxybenzaldehyde [123. 08 - 0] (83.5g, 0.68 moles) and K2C03 (224 g, 1.6 moles) in 1 1 of DMF, 1- (2-chloroethyl) piperidine [2008-75-5] (120 g, 0.65 moles) is added. The reaction mixture is refluxed for 2 h with vigorous mechanical stirring. After 2 h, the reaction mixture is filtered through Celite, diluted with 2 1 EtOAc and washed with water (3 x 500 ml). The organic layer is concentrated to provide 147 g of aldehyde # 9 [138351-15-2] as a yellow oil: H NMR (CDC13) 9.87 (s, 1 H), 7.81 (d, 2 H, J = 8.7 Hz) , 7.02 (d, 2 H, J = 8.7 Hz), 4.14 (t, 2 H, J = 6.1 Hz), 2.98 (t, 2 H, J »6.1 Hz), 2.78 (m, 4 H), 1.66 - 1.61 (m, 8 H).

Example No. 6 (Intermediary No. 10 in Reaction Scheme 3) 4- (2-piperidin-ethoxy) -benzyl alcohol To a stirred solution of aldehyde # 9 (115 g, 0.49 mol) in 0.36 1 of MeOH at 0 ° C are added portions of NaBH 4 (9.44 g, 0.25 mol). The reaction is allowed to stir for 30 minutes and then poured into water and extracted with CH2C12 and then dried over MgSO,. The solution is concentrated to provide 91.6 g of an oil which crystallizes upon letting settle: * H NMR (CDC13) 7.23 (d, 2 H, J = 8.5 Hz), 6.80 (d, 2 H, J 8.5 Hz), 4.56 (s, 2 H), 3.99 (t, 2 H, J = 6.1 Hz), 2.69 (t, 2 H, J 6.1 Hz), 2.47 (m, 4 H), 1.60 - 1.25 (m, 6 H); 13 C NMR (DMSO) 158.2, 135.3, 128.7, 114.8, 66.4, 63.4, 58.3, 55.3, 26.4, 24.8.

Example No. 7 (Compound No. 11 in Reaction Scheme 3) (4-Sloromethyl-phenoxy) -ethyl-pjperidine hydrochloride A solution of # 10 alcohol (61.3 g, 0.26 moles) in 0.5 1 of THF is cooled to 0 ° C and bubbled through it HCl gas. Bubbling is continued until thickening is no longer observed. The ice bath used to cool the reaction is removed and S0C12 (29 ml, 0.39 mole) is added and then the mixture is heated to 50 ° C until the mixture becomes clear. The reaction mixture is cooled to -3 ° C and stirred for 30 minutes. A white solid is precipitated and filtered and dried to provide 72 g of # 11 chloride: X H NMR (DMSO) 11.0 (broad s, 1 H), 7.39 (d, 2 H, J = 8.5 Hz), 6.99 (d, 2 H, J = 8.5 Hz), 4.74 (s, 2 H), 4.46 (m, 2 H), 3.45 (m, 4 H), 2.69 (m, 2 H) , 1.90-1.20 (m, 6 H).

Example No. 8 (a) Intermediary No. 14 in the Reaction Scheme 4) (5-methoxy-l-tetralone- (4-benzyloxyphenyl) -hydrazone A solution of 6-methoxy-l-tetralone [1078-19.9] * (14.8 g, 84 mmol) and 4-benzyloxyphenylh? Drazine [5111-70-6] ** (15.0 g, 70.0 mmol) and a few drops of AcOH in EtOH, it is refluxed for 1 h. The reaction is then cooled and a solid precipitated out. The solid is filtered to provide 21.5 g of # 14: m.p. = 86 - 91 ° C; * H NMR (DMSO) 8.8 (S, 1 H), 8.00 - 6.50 (m, 12 H), 5.00 (s, 2 H), 3.82 (s, 3 H), 2.80 - 2.65 (m, 4 H), 1.90 (t, 2 H, J = 6.0 Hz). * Aldrich Chemical Company ** Prepared by the method provided in Miyadera T. AND Kosower E. M.; J. Med. Chem 15 (1972) 339-340 using 4-benzyloxyaniline (Aldrich Chemical) as the starting material.

Example No. 8 (b) (Intermediary No. 15 in Reaction Scheme 4) 3 - . 3-methoxy-8-benzyloxy-5, 11-dihydro-6H-benzo Such carbazole A flask containing h-drazone # 14 (23 g, 61.7 mmol), ZnCl 2 (21.0 g, 154.4 mmol) and 100 mL of AcOH is heated at 95 ° C for 10 minutes. The reaction is allowed to reach rt and the product is precipitated out of the reaction mixture. The product is washed with ether and filtered giving 21 g of product # 15 as a solid cinnamon: p.f. = 182 -185 ° C; * H NMR (DMSO) 11.19 (s, 1 H), 7.59-7.36 (m, 6 H), 7.26 (d, 1 H, J = 8.7 Hz), 7.08 (d, 1 H, J = 2.3 Hz), 6.94 - 6.87 (m, 2 H), 6.79 (dd, 1 H, J = 8.7 Hz, 2.4 Hz), 5.14 (S, 2 H), 3.81 (s, 3 H), 2.99 (t, 2 H, J = 7.1 Hz), 2.86 (t, 2 5 H, J = 6.1 Hz).

Example No. 9 (Intermediary No. 17 in Reaction Scheme 4) Bromide of 4- (2-chloroethoxy) benzyl To the 4- (2-chloroethoxy) benzyl alcohol # 16 [11172-87-lp] (6.4 g, 34.3 mmol) in 100 ml of dioxane at 0 ° C is slowly added thionyl bromide (7.13 g, 34.3 mmol). The The reaction is carried out at 0 ° C after 5 min. The reaction mixture is diluted with 200 ml of ether and washed with H20 (1 x 30 ml) and then with NaHCO3 (2 x 25 ml) and 30 ml of brine. The organic extract is dried over MgSO4 and concentrated. The crude product is purified by chromatography on silica gel (EtOAc / hexanes: 1: 6) to provide 5.0 g (58%) of the desired product # 17 as a white solid: m.p. = 64 - 66 ° C; H NMR (DMSO) 7.37 (d, 2 H, J 8.8 Hz), 6.93 (d, 2 H, J = 8.8 Hz), 4.68 (s, 2 H), 4.24 (t, 2 H, J 5.0 Hz), 3.93 (t, 2 H, J = 5.3 Hz); MS m / z 248 (M *). f25 Example No. 10 (Intermediary No. 18 in Reaction Scheme 4) 11- 14- (2-Chloroethoxy) -benzyl-8-benzyloxy-3-methoxy-5, 11- 5 dihydro-6H-benzo [Tal carbazole Benzo [a] carbazole # 15 (10 g, 28.1 mmol) in DMF is cooled to 0 ° C and treated with NaH (1.66 g, 41.5 mmol) and stirred for 10 minutes. This solution is then added to a The solution of 4- (2-chloroethoxy) benzyl bromide # 17 (11.2, 45.0 mmol) in DMF was added and the reaction was stirred at 0 ° C for 5 minutes and then allowed to stir at rt for 20 minutes. The reaction is worked up by suspension with water and extracted with ethyl acetate. The ethyl acetate is washed with brine and is dried over MgSO4. The reaction mixture is concentrated to leave 15 g of product as a crude oil which is used as such for the following reaction: * H NMR (DMSO) 7.52-6.82 (m, 13 H), 6.80 (dd, 1 H, J = 8.4 Hz, 2.6 Hz), 6.75 (dd, 1 H, 8.8 Hz, 2.4 Hz), 5.56 (s, 2 H), 5.11 (s, 2 H), 4.20 (t, 2 H, 0 J = 6.0 Hz), 3.90 (t, 2 H, J = 6.2 Hz), 3.73 (s, 3 H), 2.92 - 2.75 (m, 4 H).

Example No. 11 (Compound No. 19 in Reaction Scheme 4) '25 3-methoxy-8-benzyloxy-11-T4- (2-piperidin-1-yl-ethoxy) -benzyl-5-dihydro-6H-benzo-carbazole Intermediate # 18, 11- [4-chloroethoxy) -benzyl] -8-benzyloxy-3-methoxy-5,11-dihydro-6H-benzo [a] carbazole, (6 g, 11.5 mmol) in DMF is treated with Kl (2.5 g, 15.0 mmol) and 12 ml of piperidine, and heated at 65 ° C for 18 hours. The reaction is worked up by pouring the crude reaction mixture into water and extracting with ethyl acetate. The ethyl acetate layer is washed with aqueous NaHCO 3, brine and dried over MgSO 4. The resulting material is chromatographed on silica gel using 100% CH2C12, CH2Cl2: MeOH (98: 2), CH2Cl2: MeOH (96: 4) as the eluting solvents. 3.2 g of the product are isolated as an oil: 'H NMR (DMSO) 7.52-7.12 (m, 8 H), 6.98-6.82 (m, 5 H), 6.80 (dd, 1 H, J = 8.4 Hz, 2.6 Hz ), 6.73 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 5.56 (s, 2 H), 5.11 (s, 2 H), 3.98 (t, 2 H, J = 6.0 Hz), 3.70 (s, 3 H), 2.85 - 2.78 (m, 2 H), 2.75 (s, 2 H), 2.60 (t, 2 H, J = 6.5 Hz), 2.42 - 2.38 (m, 4 H), 1.70 - 1.58 (m, 4 H), 1.58 - 1.35 (m, 2 H).

Example No. 12 (Compound No. 20 in Reaction Scheme 4) 11- [4- (2-azepan-l-yl-ethoxy) -benzyl-8-benzyloxy-3-methoxy-5,11-dihydro-6H-benzo [al carbazole] # 20 is prepared analogously to # 19, except that the amine used is hexamethyleneimine. The product is isolated as an oil: * H NMR (DMSO) 7.52-7.12 (m, 8 H), 6.98-6.82 (m, 5 H), 6.80 (dd, 1 H, J = 8.4 Hz, 2.6 Hz), 6.73 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 5.56 (s, 2 H), 5.10 (s, 2 H), 3.97 (t, 2 H, J = 6.0 Hz), 3.73Í ?, 3 H), 2.85 - 2.70 (m, 6 H), 2.68 - 2.62 (m, 4 H), 1.70 - 1.43 (m, 8 H).

Example No. 13 (Compound No. 21 in Reaction Scheme 4) 3 - . 3-methoxy-11-T4- (2-piperidin-1-yl-ethoxy) -bencill -5.11- dihydro-6H-benzo [a] carbazole-8-ol 3.2 g of compound # 19 is dissolved in THF / EtOH (30 ml, 1: 1) and treated with 1.2 g of 10% Pd / C and 8 ml of cyclohexadiene. The reaction is stirred at rt for 3 h and then filtered through Celite and concentrated. The crude product is precipitated from methanol to provide 1.3 g of # 21 as a white solid: m.p. = 141 - 143 ° C, lH NMR (DMSO) 8.75 (s, 1 H), 7.27 (d, 1 H, J = 8.5 Hz), 7.09 (d, 1 H, J = 8.5 Hz), 7. 00 6.90 (m, 3 H), 6.84 (d, 2 H, J = 8.8 Hz), 6.80 (d, 1 H, J = 2.4 Hz), 6.70 (dd, 1 H, J = 8.4 Hz, 2.6 Hz), 6.58 (dd, 1 H, 8.8 Hz, 2.4 Hz), 5.45 (s, 2 H), 3.98 (t, 2 H, J = 6.0 Hz), 3.70 (s, 3 H), 2.89 (t, 2 H, J = 6.6 Hz) 2.75 (t, 2 H, J = 6.5 & g., ^ and »and ^ ~ ^".

Hz), 2.60 (t, 2 H, J = 6.5 Hz), 2.40 - 2.30 (m, 4 H), 1.53 - 1.40 (m, 4 H), 1.39 - 1.30 (m, 2 H); MS [M + H] observed at m / z = 483; CHN calculated for C31H34N203 +.60 H20.

Example No. 14 (Compound No. 22 in Reaction Scheme 4) 11- 14- (2-azepan-1-yl-ethoxy) -benzyl-3-methoxy-5, 11-dihydro-6H-benzo Such carbazole-8-ol The reaction is carried out analogously to that described for the synthesis of Example # 21: p.f. = 115-118 ° C; H NMR (DMSO) 8.74 (s, 1 H), 7.27 (d, 1 H, J = 8.5 Hz), 7.08 (d, 1 H, J = 8.5 Hz), 7.0-6.90 (m, 3 H), 6.84. (d, 2 H, J = 8.8 Hz), 6.80 (d, 1 H, J = 2.4 Hz), 6.71 (dd, 1 H, J 8.5 Hz, 2.6 Hz), 6.58 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 5.48 (s, 2 H), 3.94 (t, 2 H, J = 6.0 Hz), 3.72 (s, 3 H), 2.87 (t, 2 H, J = 6.6 Hz), 2.80 - 2.73 (ra, 4 H), 2.64 - 2.60 (m, 4 H, J = 4.4 Hz), 1.60 - 1.45 (m, 8 H); IR (KBr) 3400, 2900, 1500, 1250; MS BAR m / z 495 (M-H) "; CHN calculated for C32H36N203 +.33 CH30H.

Reaction Scheme 5 The benzocarbazoles of Reaction Scheme 5 are prepared analogously to the dihydro compounds, however, the added step of oxidizing the dihydrocarbazole intermediate 20 using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) is inserted in the sequence.

Example No. 15 Hydrazone 19 in the Reaction Scheme 5) A solution consisting of 4-benzyloxyphenylhydrazide 18 (8 g, 37.3 mmol), 4-benzyloxytetralone 17 (11.3 g, 44.8 mmol), 5 drops of AcOH in 100 ml of EtOH is heated at reflux for 3 hours, during which time all reagents are in solution.

The reaction is cooled to 0 ° C and the product is separated by precipitation and separated by filtration. 9.5 g of the product 20 are isolated as a white solid: m.p. 102-104 ° C. We find that the product is best used immediately because the product settles at room temperature and results in a change in color.

Example No. 16 (Dihydrobenzocarbazole 20 in Reaction Scheme 5) 3, 8-bis-benzyloxy-5, 11-dihydro-6H-benzo [to carbazole Hydrazone 19 (7.5 g, 16.7 mmol) is dissolved in 50 ml of AcOH and treated with ZnCl2 (5.7 g, 42 mmol) and then heated at 105 ° C for 15 minutes, during which time the whole is in solution. The reaction is allowed to reach room temperature and is worked by division of the reaction mixture between Et20 and H20. The product 20 which is not soluble in any of the layers, is isolated by filtration of the biphasic mixture. The product is isolated as 5.6 g of a white solid: m.p. 177-180 ° C; EM APCI 430 (M-H).

Example No. 17 (Benzocarbazole-5 in Reaction Scheme 5) 3. 8-bis-benzyloxy-IIH-benzo [a] carbazole The dihydrocarbazole (5.1 g, 11.9 mmol) in 50 ml of benzene is treated with DDQ (3.2 g, 14 mmol) and refluxed for 3 hours. The crude reaction mixture is partitioned between EtOAc and H20 and the product which is not soluble in any of the layers, is separated by filtration. The crude precipitate in this manner is triturated with Et20 to provide the desired material 21 as 3.4 g of a light gray solid m.p. 244-248 ° C; EM on 429 Example No. 18 (Benzocarbazole alkylated 22 in Reaction Scheme 5) 3, 8-bis-benzyloxy-11-T4- (2-piperidin-l-yl-ethoxy) -benzyl-HH-benzo [a] carbazole Benzocarbazole 21 (1.2 g, 2.8 mmol) is placed in 30 ml of DMF (the initial material appears insoluble in this solvent) and is cooled to 0 ° C and treated with NaH (60% dispersion in mineral oil, 300 mg , 7.8 mmol) and stirred at 0 ° C for 15 minutes. The side chain of piperidine-oxybenzyl chloride is added (0.97 g, 3.3 mmol) and the reaction is stirred an additional 15 minutes at 0 ° C followed by 1 h at rt. The reaction is partitioned between EtOAc and H20 and the product, which is insoluble in none of the layers, is separated by filtration. The product is triturated with Et20 to provide 1.3 g of the desired product 6 as a white solid: m.p. 171-173 ° C; MS (+) ESI 647 (M + H).

Example No. 19 15 (Alkylated Benzocarbazole 23 in Reaction Scheme 5) 11- [4- (2-azepan-1-yl-ethoxy) -benzyl-3,3-bis-benzyloxy-11H-benzo [a] carbazole The benzocarbazole 23 is prepared analogously to benzocarbazole 22: p.f. 175-177 ° C; EM ESI. { +) 661 (M + H).

Example No. 20 (Benzocarbazole 24 in Reaction Scheme 5) '25 11- T4- (2-piperidin-l-yl-ethoxy) -benzyl] -HH-benzo [a] carbazole - 3.8-diol A solution consisting of 1.15 g of benzocarbazole protected in THF / EtOH (75:25) is treated with 4.5 ml of cyclohexadiene and 0.45 g of 10% Pd / C and allowed to stir at room temperature overnight. The solution is filtered through Celite and subjected to chromatography on silica gel (10% MeOH / CH2C12) to provide the product which is Triturate with Et20 to return to the product as a light gray solid: m.p. 249-251 ° C; * H NMR (DMSO) 8 9.68 (s, 1 H), 9.05 (s, 1 H), 8.21 (d, 1 H, J = 9.2 Hz), 8.04 (d, 1 H, J = 8.5 Hz), 7.48 (d, 1 H, J = 2.2 Hz), 7.46 - 7.40 (m, 2 H), 7.26 (d, 1 H, J = 2.4 Hz), 6.70 - 6.96 (m, 3 H), 6.89 (dd, 1 H, J = 8.7 Hz, 2.2 Hz), 6.83 (d, 2 H, J = 8.6 Hz), 5.92 (s, 2 H), 3.95 (t, 2 H, J = 5.8 Hz), 2.63 - 2.55 (m, 2 H), 2.42 - 2.33 (m, 4 H), 1.50 - 1.42 (m, 4 H), 1.38 - 1.29 (, 2 H); ESI ES (+) 467 (M + H).

Example 21 (Benzocarbazole 25 in Reaction Scheme 5) 11- T4- (2-azepan-1-yl-ethoxy) -benzyl-lH-benzo [a] carbazole 3,8-diol '25 The benzoj iEsazol 25 is prepared in a manner analogous to benzocarbazole 23: p.f. 204-206 ° C; H NMR (DMSO) 9.7 (broad s, 1 H), 9.1 (br S, 1 H), 8.21 (d, 1 H, J = 9.2 Hz), 8.04 (d, 1 H, J = 8.5 Hz), 7.48 (d, 1 H, J = 2.2 Hz), 7.46 - 7.40 (m, 2 H), '7.26 (d, 1 H, J = 2.39 Hz), 7.02 - 6.97 (m , 3 H), 6.88 (dd, 1 H, J = 8.7 Hz, 2.1 Hz), 6.82 (d, 2 H, J = 8.6 Hz), 5.92 (s, 2 H), 3.92 (t, 2 H, J = 6.0 Hz), 2.76 (t, 2 H, J 6.0 Hz), 2.65 - 2.57 (m, 4 H), 1.57 - 1.48 (m, 8 H); ESI ES (+) 481 (M + H).

Biological data Enzyme of ßno ia vitro receptor Preparation of the receiver CHO cells that overexpress the estrogen receptor are grown in 150 mm2 containers in DMEM + 10% dextran-coated activated charcoal, purified fetal bovine serum. The plates are washed twice with PBS and once with 10 mM Tris-HCl, pH 7.4, 1 mM EDTA. The cells are harvested by scraping the surface 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 minutes followed by centrifugation for 60 minutes at 100,000 g to produce a ribosome-free cytosol. The cytosol is then frozen and stored at -80 ° C. The protein concentration of the cytosol is estimated using the BCA assay with the standard reference protein.

Union test conditions The competition test was performed on 96-well plates (polystyrene *) which binds < 2.0% of [3H] -17β-estradiol introduced total, and each data point is recovered in triplicate. Aliquots of 100 μg / μl of the receptor preparation are placed per well. A saturating dose of 2.5 nM [3H] 17ß-estradiol + competitor (or buffer) in a volume of 50 μl is added in the primary competition when evaluating competitors of lOOx and 500x, only [3H] 17β-estradiol 0.8 nM is used. . 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 carbon (activated charcoal 5% coated with 69 K 0.05% dextran) are added to each well and the plate is immediately centrifuged at 99 g for 5 minutes at 4 ° 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, the wells contain radioactivity and cytosol, but are not processed with activated carbon and are included to quantify the amounts of available isotope. In addition, wells containing radioactivity but without cytosol are processed with activated carbon to estimate the non-removable MPE of [3H] 17β-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 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 charcoal)) 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.

Table 2 Estrogen receptor binding 2X VIT ERE infection test Maintenance and treatment of cells 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). Cells are plated at a density of 5000 cells / well in 96-well plates containing 200 μl medium / well.

Transfection of calcium phosphate Indicator DNA (Promega pGL2 plasmid containing two battery copies of ERE vitellogenin in the front of the minimal thymidine kinase promoter that activates the luciferase gene) is combined with the B- expression plasmid. galactosidase 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 The DNA (20 μG) is dissolved in 500 μl of 250 mM sterile CaCl 2 and added dropwise to 500 μl of 2 X HeBS (NaCl) 0. 28 M, 50 mM HEPES, 1.5 mM Na2HP04, pH 7.05) and incubate 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, 1 M 17β-estradiol, 1 μM compound or 1 μM + 17β-estradiol compound. 1 nM (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.

Ensavo de lusiferasa 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 15 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 luciferan 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.

Enrollment of luciferase infection (standards) Composition% activation 17ß-estradiol 100% estriol activity 38% raloxifene 0% activity Enzyme of β-qalactosidase 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 fraction 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 JPM 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 with 17β-estradiol for each plate. The percentage of activity compared to 17ß- Estradiol is calculated using the formula% = ((Estradiol-control) / (compound value) X 100. Table 3 Luciferase infection activity ^ áss-, As can be seen from the data in Table 2, the benzo [a] carbazoles (Examples 13 and 14) bind better to the ER receptor than the indenoindole of Example 4. From the infection test data from luciferase in Table 3, it can be seen that none of the compounds shows significant agonist activity on this promoter. Benzo [a] carbazoles show an ability to antagonize the effects of estradiol to baseline or near baseline levels. 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 (27)

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

1. A compound of formulas I or II wherein R is selected from H, OH or the esters or alkyl ethers of C, -C4 thereof, or halogen; R2, R3, R4, R5 and R6 are independently selected from H, OH or esters or alkyl ethers or halogenated alkyl ethers of 0, -0.2 thereof, halogen, cyano, alkyl Cj, -C6 or trifluoromethyl, with the proviso that when Rj is H, R2 is not OH; X is (CH2) n-o -CH = CH-; n1 is 1 or 2; n is 2-4; And it is selected from a) the portion: R7 and R are independently selected from the group of H or C, -C6 alkyl or phenyl, or combined with - (CH2) P-, where p is an integer from 2 to 6, so as to form a ring, the ring optionally forms a methylene bridge and the ring is optionally substituted by up to three substituents that are selected from hydroxyl, halo, alkyl of C, -C4, trihalomethyl, C, -C4-lalkoxy, trihalomethoxy, C-C4-alkylthio, C-C4-alkylsulfinyl, Cj-C4-alkylsulfonyl, C-C4 hydroxyalkyl, -C0.0H, CN , -CONH (C-C4 alkyl), -NH2-, C-C4 alkylamino, C-C4 dialkylamino, -NHS02 C, -C4 alkyl, -NHCOalkyl of C, -C4 and -N02; or b) a saturated, unsaturated or partially unsaturated five-membered heterocycle containing up to 2 heteroatoms which are selected from the group consisting of -0-, -NH-, -N (C-C4 alkyl) -, -N = y -S (0) m-, wherein m is an integer of 0-2, optionally substituted with 1-3 substituents which are independently selected from hydroxyl, halo, C, -C, alkyl, trihalomethyl, C-alkoxy, -C4, trihalomethoxy, C, -C4 acyloxy, C, -C4 alkylthio, C, -C4 alkylsulfinyl, C, -C4 alkylsulfonyl, C, -C4 hydroxyalkyl, phenyl optionally substituted with 1-3 alkyl, C, -C4, -C02H, -CN-, -CONHR, -, -NH2, C, -C4 alkylamino, dialkyl (C, -C4) amino, -NHS02R ,, -NHCOR ,, -N02; c) a saturated, unsaturated or partially unsaturated six-membered heterocycle containing up to 2 heteroatoms which are selected from the group consisting of -O-, -NH-, -N (C-alkyl, -Ca), -N = y- S (0) m-, wherein m is an integer of 0-2, optionally substituted with 1-3 substituents which are independently selected from the group consisting of hydroxyl, halo, C, -C 4 alkyl, trihalomethyl, alkoxy C, -C4, trihalomethoxy, acyloxy of C, -C4, C 4 -C 4 alkylthio, C 1 -C 1 alkylsulfinyl, C 1 -C 4 alkylsulfonyl C 1 -C 4 hydroxyalkyl, phenyl optionally substituted with 1-3 C, -C 4 alkyl, -C 0 2 H, -CN-, -CONHR , -, -NH2-, C, -C4 alkylamino, dialkyl (C, -C4) amino, -NHSOsR, -, -NHCOR, -, -N02; d) a seven-membered, saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms which are selected from the group consisting of -O-, -NH-, -N (C-C4 alkyl) -, -N = , and -S (0) m-, where 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, -C4 alkyl, trihalomethyl , C, -C 4 alkoxy, trihalomethoxy, C, -C 4 acyloxy, C, -C 4 alkylthio, C, -C 4 alkylsulfinyl, C, -C 4 alkylsulfonyl, C, C, hydroxyalkyl, phenyl, optionally substituted with 1 -3 alkyl of C, -C4, -C02H, -CN, -CONHR, -, -NH2, C, -C4 alkylamino, dialkyl (C, -C4) amino, -NHS02R ,, -NHCOR, and -N02; or e) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring containing up to two heteroatoms which are selected from the group of -O-, -NH-, -N (C-alkyl, - C4) -N = and -S (0) m-, wherein m is an integer of 0-2, optionally substituted with 1-3 substituents that are independently selected from hydroxyl, halo, C, -C4 alkyl, trihalomethyl, C, -C 4 alkoxy, trihalomethoxy, C, -C 4 acyloxy, C, -C 4 alkylthio, C, -C 4 alkylsulfinyl, C, -C 4 alkylsulfonyl, C, -C 4 hydroxyalkyl, phenyl optionally substituted with 1-3 of C, -C4 alkyl. -C02H, -CN, -CONHR ,, -NH2, C, -C4 alkylamino, dialkylamino of C, -C4, -NHS02R ,, -NHCOR1 and -N02; or pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, characterized in that Y is selected from: a) a saturated, unsaturated or partially unsaturated five-membered heterocycle containing up to 2 heteroatoms which are selected from the group consisting of -0-, -NH-, -N (C, -C4 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 hydroxyl, halo, C, -C 4 alkyl, trihalomethyl, C, -C 4 alkoxy, trihalomethoxy, C, -C 4 acyloxy, C, -C 4 alkylthio, C, -C 4 alkylsulfinyl, C, -C 4 alkylsulfonyl, hydroxyalkyl, C, -C4, phenyl optionally substituted with 1-3 of C, -C4 alkyl, -C02H, -CN-, -CONHR, -, -NH2, C, -C4 alkylamino, dialkyl (C, -C4) amino , -NHS02R ,, -NHCOR ,, -N02; c) a saturated, unsaturated or partially unsaturated six-membered heterocycle containing up to 2 heteroatoms that are selected from the group consisting of -0-, -NH-, -N (C-C4 alkyl), -N = and -S (0) m-, where m is an integer of 0- 2, optionally substituted with 1-3 substituents which are independently selected from the group consisting of hydroxyl, halo, C, -C 4 alkyl, trihalomethyl, C, -C 4 alkoxy, trihalomethoxy, C, -C 4 acyloxy, C 1 alkylthio , -C 4, C, -C 4 alkylsulfinyl, C, -C 4 alkylsulfonyl, C, -C 4 hydroxyalkyl, phenyl optionally substituted with 1-3 C, -C 4 alkyl, -C0 2 H, -CN-, -CONHR, -, -NH2-, C, -C4 alkylamino, dialkyl (C, -C4) amino, -NHS02R, -, -NHCOR, -, -N02; or d) a seven-membered, saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms that are selected from the group consisting of -0-, -NH-, -N (C-C4 alkyl) -, -N = , and -S (0) m-, where 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, -C4 alkyl, trihalomethyl , C, -C 4 alkoxy, trihalomethoxy, C, -C 4 acyloxy, C, -C 4 alkylthio, C, -C 4 alkylsulfinyl, C, -C 4 alkylsulfonyl, C, -C 4 hydroxyalkyl, phenyl optionally substituted by -3 alkyl of C, -C4, -C02H, -CN, -CONHR, -, -NH2, C, -C4 alkylamino, dialkyl (C, -C4) amino, -NHS02R ,, -NHCOR ,, -N02; or pharmaceutically acceptable salts thereof.

3. A compound according to claim 1, characterized in that: X is (CH 2) n n 'is 1 R, is selected from H, OH or the esters or alkyl ethers of C, -C 4 thereof, halogen; R2, R3, R4, R5 and R6 are independently selected from H, OH or the esters or alkyl ethers of C, -C4 thereof, halogen, cyano, C, -C6 alkyl or trifluoromethyl, with the proviso that when R , is H, R2 is not OH; And it's the portion: R7 and R8 are independently selected from the group of H or 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 optionally forms a methylene bridge and the ring is optionally substituted by up to three substituents which are selected from hydrogen, halo, C, -C 4 alkyl, trihalomethyl, C, -C 4 alkoxy, trihalomethoxy, C, -C 4 alkylthio, C alkylsulfinyl, , -C4, alkylsulfonyl of 0, -0, hydroxyalkyl of C, -C4, -C020H, CN, -CONH (C, -C4 alkyl), -NH2-, C, -C4 alkylamino, dialkylamino of C, -C, -NHS02alkyl of C, -C4, -NHCOalkyl of C, -C4 and -N02; or pharmaceutically acceptable salts thereof.

4. A compound according to claim 1, characterized in that: X is (CH2) n, n 'is 1 R, is selected from H, OH or the esters or alkyl ethers of C, -C4 thereof, halogen; R2, R3, R4, R5 and R6 are independently selected from H, OH or the esters or alkyl ethers of C, -C4 thereof, halogen, cyano, C, -C6 alkyl or trifluoromethyl, with the proviso that when R , is H, R2 is not OH; And it's the portion: R7 and R8 are independently selected from the group of H or 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 optionally forms a methylene bridge and the ring is optionally substituted by up to three substituents that are selected from hydroxyl, halo, C, -C 4 alkyl, trihalomethyl, C, -C 4 alkoxy, trihalomethoxy, C, -C 4 alkylthio, C, -C 4 alkylsulfinyl, C, -C 4 alkylsulfonyl, C, hydroxyalkyl C4, -C02H, CN, -CONH (C-C4 alkyl), -NH2-, C-C4 alkylamino, C-C4 dialkylamino, -NHS02 C, -C4 alkyl, -NHCOalkyl, -C- C4 and -N02; or pharmaceutically acceptable salts thereof.

5. A compound according to claim 1, characterized in that: X is (CH2) ", n1 is 1 R, is OH; R2, R3, R4, R5 and R6 are independently selected from H, OH or the esters or alkyl ethers of C, -C4 thereof, halogen, cyano, C, -C6 alkyl or trifluoromethyl, and is the portion: R7 and R, are concatenated together as - (CH2) r-, where r is an integer from 4 to 6, to form a ring that optionally forms a bridge with methylene and optionally substituted by up to three substituents which are selected from hydroxyl, halo, C, -C4 alkyl, trihalomethyl, C, -C4 alkoxy, trihalomethoxy, C, -C4 alkylthio, C, -C4 alkylsulfinyl, C, -C1 alkylsulfonyl, C4, hydroxyalkyl of C, -C4, -C02H, CN, -CONH (C, -C4), -NH2-, C4-C4 alkylamino, dialkylamino of Ci-C ,, -NHS02 of C, -C4, - NHCO of C, -C4 and -N02; or the pharmaceutically acceptable salts thereof.

6. A compound according to claim 1, characterized in that: X is (CH2) ", n1 is 2 R, is OH; R2, R3, R4, R5 and R6 are independently selected from H, OH or the esters or alkyl ethers of C, -C4 thereof, halogen, cyano, C, -C6 alkyl or trifluoromethyl, and is the portion: R7 and R8 are concatenated together as - (CH2) r-, where r is an integer from 4 to 6, to form a ring that optionally forms a bridge with methylene and optionally substituted by up to three substituents which are selected from hydroxyl, halo, C, -C 4 alkyl, trihalomethyl, C, -C 4 alkoxy, trihalomethoxy, C, -C 4 alkylthio, C alkylsulfinyl, -C4, C, -C4 alkylsulfonyl, C, -C4, C020H, hydroxyalkyl, CN, -CONHtC, - ^), -NH2-, C, -C4 alkylamino, dialkylamino of C, -C4, -NHS02 of C, -C4, -NHCO of C, -C4 and -N02; or the pharmaceutically acceptable salts thereof.

7. The compound according to claim 1, characterized in that it is 8-benzyl-2-methoxy-5- [4- (2-piperidin-1-yl) ethoxy) -benzyl] -5,10-dihydro-indene [1, 2-b] indole; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, characterized in that it is 2-methoxy-5- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -5,10-dihydro-indene [1,2-b] indol-8-ol indole; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, characterized in that it is 11- [4- (2-azepan-1-yl-ethoxy-benzyl] -8-benzyloxy-3-methoxy-5,11-dihydro-6H-benzo [a] carbazolindole or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, characterized in that it is 11- [4- (2-azepan-1-yl-ethoxy) -benzyl] -3-methoxy-5, 11-dihydro-6H-benzo [a] carbazole- 8-olindol; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, characterized in that it is 3-methoxy-8-benzyloxy-11- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -5,1-dihydro-6H-benzo [ a] carbazolindole; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, characterized in that it is 3-methoxy-ll- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -5,11-dihydro-6H-benzo [a] carbazole- 8-olindol; or a pharmaceutically acceptable salt thereof.

13. A compound of the formula where: n is 2 to 4; R, is selected from H, OH or the esters or alkyl ethers of C, -C4 thereof, halogen; R2, R3, R4, R5 and R6 are independently selected from H, OH or the esters or alkyl ethers of C, -C4 thereof, halogen, cyano, C, -C6 alkyl or trifluoromethyl, with the proviso that when R , is H, R2 is not OH; And it's the portion: R7 and R8 are independently selected from the group of H or C alkyl, -C6, or combined with - (CH2) p-, where p is an integer from 2 to 6, so as to form a ring, the ring optionally forms a methylene bridge and the ring is optionally substituted by up to three substituents which are selected from hydroxyl, halo, C, -C "alkyl, trihalomethyl, C-C4 alkoxy, trihalomethoxy, C-C4 alkylthio, C, -C4 alkylsulfinyl, C, -C4 alkylsulfonyl, hydroxyalkyl, C, -C4, -C02H, CN, -CONH (C, -C4 alkyl), -NH2-, C, -C4 alkylamino, dialkylamino of C, -C4, -NHS02alkyl of C, -C4, -NHCOalkyl of C, -C4 and -N02; or pharmaceutically acceptable salts thereof.

14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, characterized in that Y is selected from:

15. The compound according to claim 13, characterized in that it is 11- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-benzo [a] carbazole-3,8-diol or a pharmaceutically acceptable salt of the same.

16. 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 therefor an effective amount of a compound of compliance with any of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

17. A method for treating or preventing disease states or syndromes, which are caused or associated with an estrogen deficiency in a mammal, the method is characterized in that it comprises administering to the mammal in need thereof an effective amount of a compound in accordance with any of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

18. 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 effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

19. A process for preparing a compound of formula (I) and (II) according to claim 1, characterized in that it comprises: a) reacting a compound of formula (III) or (IV) (III) (IV) wherein R, .4 and X are as defined in accordance with claim 1 and, if necessary, any reactive group is protected, with a compound of the formula: wherein Y is as defined in the above and hal is a halogen, for example Cl or Br, and R5 and R6 are as defined in accordance with claim 1 and, if necessary, review any protecting group; or b) reacting a compound of the formula: (SAW) wherein R, _6 and X are as defined in accordance with claim 1 and Hal is a halogen, for example Cl or Br, if necessary any reactive group must be protected, with a compound of formula ß-7 - * "Rs (VIII) wherein R7 and R8 are as defined in accordance with claim 1, and if necessary, any protecting group is removed; O well. c) hydrogenating a compound of formula I or II wherein Ri and / or R4 is benzyloxy to provide a corresponding compound of formula I or II wherein R, and / or R4 is OH.

20. A pharmaceutical composition, characterized by comprising a compound of formula (I) or (II), according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition, characterized in that it comprises a compound of formula (I) or (II), according to any of claims 1 to 15, or a pharmaceutically acceptable salt thereof and one or more estrogens and optionally a pharmaceutically acceptable carrier.

22. A pharmaceutical composition, according to claim 21, characterized in that the estrogen is selected from one or more of the following: equilin, equilenin, ethinylestradiol, 17β-estradiol, dihydroequilenin, 17β-dihydroequilenine estrone sodium sulfate, equilin sodium sulfate, 17alpha-dihydroequiline sodium sulfate, sodium 17alpha-estradiol sulfate, delta 8, 9-dehydroestrone sodium sulfate, equilenin sodium sulfate, 17beta- sodium dihydroequiline sulfate, 17alpha sodium dihydroequilenine sulfate, 17beta-estradiol sodium sulfate, 17beta-dihydroequilenine sodium sulfate, estrone 3 -sulfate sodium, equilin 3-sodium sulfate, 17alpha-dihydroequilin 3 -sulfate sodium, 3beta hydroxiestra 5 (10), 7-dien-17-one-3-sodium sulfate, 5alpha-Pregnan-3beta-20R-diol 20-sodium sulfate, 17alpha-Pregnan-3-beta, 16alpha-diol, 20-one-3 sodium sulfate, delta (8, 9) -dehydroestrone 3-sodium sulfate, estra-3beta, sodium 17alpha-diol 3-sulfate, 3beta-hydroxy-estr-5 (10) -en-17-one-3 Sodium sulfate, or 5alpha-Pregnan-3beta, 16alpha, 20R-triol 3-sodium sulfate, equol or enterolactone; or a pharmaceutically acceptable salt or ester thereof.

23. A pharmaceutical composition, according to claim 21, characterized in that lo = estrogens are conjugated with hormones is rogénicas.

24. 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, one or more estrogens and an effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

25. A method for treating or preventing disease state or syndromes which are caused or associated with a deficiency of estrogen in a mammal, the method is characterized in that it comprises administering a mammal in need thereof one or more estrogens and an effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

26. A method for treating or preventing cardiovascular diseases in a mammal, the method is characterized in that it comprises administering to a mammal in need thereof one or more estrogens and an effective amount of a compound according to any of claims 1 to 15 or a salt pharmaceutically acceptable thereof.

27. A product, characterized in that it comprises a compound of formula (I) or (ID according to any of claims 1 to 15 or a pharmaceutically acceptable salt thereof and one or more estrogens in combination for separate administration, sequentially or simultaneously .