MXPA01008912A - N-substituted indolines as estrogenic agents - Google Patents

Abstract

The present invention provides compounds of formula (I) wherein R1 is H or benzyl;R2 is H, -OH, or -O-benzyl;R3, R4, and R5 are independently selected from H, halogen, cyano, C1-C6 alkyl (straight chain or branched), trifluoromethyl, -OH or the C1-C12 esters (straight chain or branched) or C1-C12 alkyl ethers (straight chain or branched or cyclic) thereof, or C1-C6 halogenated ethers;R6 is H or C1-C6 alkyl;R7 is C1-C6 alkyl;n is 2 to 3;Y is O or S;and X is the moiety -NR'R'wherein R'is selected from C1-C6 lower alkyl or X is one of the moieties (A), (B), (C), or (D);or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions and methods utilizing the compounds for treating or preventing disease states or syndromes which are caused or associated with an estrogen deficiency or an excess of estrogen utilizing these compounds.

Description

N-SUBSTITUTED INDOLINES AS ESTROGENIC AGENTS Field of the Invention The present invention concerns new N-substituted indolines compounds, which are useful as estrogenic agents, as well as pharmaceutical compositions, methods of treatment using these compounds and processes for preparing them. Background of the Invention Estrogen replacement therapy has been established as the selection treatment in women for the prevention of osteoporosis [C. Christiansen R. Lindsay, Estrogen, Bone Less and Preservation, Osteroporosis International, 1, 15-21 (1990)]. The problem with similar therapies is that the proliferative effects on the uterus can take place and be associated with endometriosis and / or endometrial cancer. Although less clear, similar estrogen replacement therapies have been implicated in increasing the incidence of breast tumor formation. Non-steroidal anti-estrogen drugs such as tamoxifen have been used in the treatment of breast cancer. Tamoxifen has been shown to exert an estrogen-like effect on bone in humans while acting as an antagonist in uterine tissue. However, it concerns a little to the demonstration of partial agonist effects in the uterus. An anti-estrogen drug REF: 132334 Recently, Raloxifene, Lilly's benzothiophene, is a non-steroidal anti-estrogen that appears to be more tissue selective. While possessing the ability to regenerate bone, it has been shown that it stimulates uterine development in animal models at a lower level than Tamoxifen. A review on the selective tissue action of estrogen receptor modulators has recently appeared. [T. A. Grese and J. A. Dodge In "Ann. Rep. In Med. Chem." J. A. Bristol, Ed. Academic Press, New York, 1996, p. 181]. The use of indoles as estrogen antagonists has been reported by Von Angerer, Chenical Abstracts, Vol. 99, No. 7 (1983), abstract No. 53886u. Also, see, 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.

The compounds described in the present invention possess moderate binding to the estrogenic receptor (ER) and have a potential use in the treatment of osteoporosis, prostatic hypertrophy, breast cancer and endometrial cancer. Description of the Invention The N-substituted indolines of this invention are tissue-selective estrogen agonists / antagonists useful for the treatment of diseases associated with estrogen deficiency. They include compounds of the formula: 0) fl) wherein: Ri is H or benzyl; R2 is H, -OH, or -O-benzyl; R3 R / and R5 are independently selected from H, halogen, cyano, Ci-Cd alkyl (straight chain or branched), trifluoromethyl, -OH or the C? -C_.2 esters (right or branched chain) or C? -CX2 alkyl esters (straight chain or branched or cyclic) thereof, or halogenated C? -C6 ethers, preferably halogenated C? -C3 ethers, which include trifluoromethyl ether and trichloromethyl ether; R6 is H or Ci-Ce alkyl; R7 is C6C6 alkyl; n is 2 to 3; And it is O or S; and X is wherein R 'is selected from lower alkyl C __-C6, the same or different, or X is cyclic portion selected from: or a salt thereof, pharmaceutically acceptable. Examples of C1-C12 esters of the OH group are C2-C? 2 alkyl ester such as 0C (= 0) C? -C6 alkyl esters. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl and n-butyl. Examples of Re and R7 are methyl. Among the most preferred compounds of this invention are those wherein Y is O. Preferably n is 2. Preferably R3, R4, and R5 are independently selected from H, OH or halogen. It will be understood that the number of carbons in the alkyl groups of portions R6 and R7 can be independently selected from each other. The invention includes acceptable salt forms, formed by addition reaction with either organic or inorganic acids. Inorganic acids such as hydrochloric acid are useful, 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, succinic acid, methanesulfonic acid, acid • Toluenesulfonic acid, naphthalenesulfonic acid, camphor sulfonic acid, benzenesulfonic acid. It is known that compounds having a basic nitrogen can be complexed with many different acids (both protic and non-protic) and it is usually preferred to administer a compound of this invention, in the form of an acid addition salt. 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 suitably reactive alkylating agent such as an alkyl halide or benzyl halide. The compounds of this invention possess at least one asymmetric center and therefore the compounds can exist and be isolated in a number of optically active stereoisomeric forms. This invention encompasses compounds of formula I, in some form optically active or mixtures thereof, for example racemates. Standard separation techniques can be used to isolate particular enantiomeric or diastereomeric forms. For example, a racemic mixture can be converted to a mixture of optically active diastereomers by reaction with a single enantiomer of a "resolving agent" (e.g., by formation of diastereomeric salts or formation of a covalent bond). The resulting mixture of optically active diastereoisomers can be separated by standard techniques (eg crystallization or chromatography) and individual optically active diastereoisomers, then treated to remove the "resolving agent", thus releasing the enantiomer alone from the compound of the invention. Chiral chromatography can also be used (using a chiral support, eluent or apparent ionic agent), to directly separate enantiomeric mixtures.

The compounds of the invention are partial estrogen agonists and exhibit high affinity for the estrogenic receptor. Unlike many estrogens, however, many of these compounds do not cause increases in wet uterine weight. These compounds are anti-estrogenic in the uterus and can completely antagonize the trophic effects of estrogen agonists in uterine tissue. Due to the tissue-selective nature of these compounds, they are useful for treating or preventing in mammalian syndromes or disease states that are caused or associated with an estrogenic deficiency or an excess of estrogen. The compounds of the present have the ability to behave similarly to estrogen agonists for cholesterol abatement and prevent bone loss. These compounds are useful for treating many diseases resulting from excess or deficiency of estrogen including osteoporosis, prostatic hypertrophy, male 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 cancer, CNS cancers, among others. Additionally, these compounds can be used for hormone replacement therapy in post-menopausal women or in other estrogen deficiency states where estrogen supplementation would be beneficial. The compounds of this invention can also be used in methods of treatment for bone loss, which can result from an imbalance in the formation of new bone tissue and the resorption of older tissues of individuals, leading to a net loss of bone. Said bone depletion is found in a range of individuals, particularly in post-menopausal women who have undergone hysterectomy, those who receive or who have received prolonged corticosteroid therapies, those who have experienced gonadic dysgenesis, and those who suffer from Cushing's syndrome. Special needs for bone replacement can also be controlled using these compounds in individuals with bone fractures, defective bone structures, and those who received bone-related surgeries and / or prosthetic implantation. In addition to the problems described above, these compounds can be used in treatments for osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalisteresis, multiple myeloma and other forms of cancer that have effects of deterioration on bone tissues. The methods of treating the diseases listed herein, of course, comprise administering to an individual in need of such treatment, 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 compounds herein, and / or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers, excipients, etc. It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the disease and the individual being treated and will be subject to the judgment of the practicing physician involved. It is preferred that administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved. The effective administration of these compounds can be given at an effective dose of about 0.1 mg / day to about 1,000 mg / day. Preferably, the administration will be from about 10 mg / day to about 600 mg / day in a single dose or divided into two or more doses. Said doses can be administered in any useful way to direct the active compounds of the present to the bloodstream of the recipient, which includes, orally, parenterally (which includes intravenous, intrperitoneal and subcutaneous injections), and transdermally. For the purposes of this disclosure, transdermal administrations are understood to include, all administration through the body surface and the internal coatings of body passages that include mucosal and epithelial tissues. Said administrations can be carried out, using the compounds of the present invention, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal). Oral formulations containing the active compounds of this invention may comprise some conventionally used oral forms, including tablets, capsules, buccal forms, lozenges, tablets, and liquids, suspensions or oral solutions. The capsules may contain mixtures of the active compounds with inert fillers and / or diluents such as pharmaceutically acceptable starches (eg, corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as celluloses. crystalline and microcrystalline, flours, jellies, gums, etc. Useful tablet formulations can be made by conventional compression methods, wet granulation or dry granulation and use pharmaceutically acceptable diluents, binders, lubricants, disintegrants, suspension or stabilizers including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. Oral formulations of the present may utilize timed release or standard delay formulations to alter the absorption of the active compounds. Formulations for suppositories can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used. This invention also provides processes for preparing the compounds of formula (I), said processes comprising the following: a) alkylating a compound of the formula: (II) wherein Ri, R2, R3, R6 and R7, are as defined above, with a compound of the formula: (ip) wherein n, R4, R5, Y and X are as defined above, to give a compound of formula I; or b) reacting a compound of formula (TV) wherein Y, Ri, R2, R3, R4, Rs > Re and R7 are as defined above and hal represents a halogen, for example, chlorine or bromine, with an amine of the formula: H-X (V) wherein X is as defined above, to give a compound of formula (I) ), or c) debenzylating a compound of formula I, wherein Ri is optionally substituted benzyl and / or R 2 is optionally substituted benzyloxy, to give a compound of formula I wherein Ri is hydrogen and / or R 2 is hydroxy, or e) esterify a compound of formula I, wherein at least one of R3, R4, or R5 is hydroxy to an ester derived therefrom. The methods for carrying out processes a) -> e) above are known in the art and / or are illustrated in the following reaction schemes. The compounds of this invention can be prepared by methods known in the art. For example, the indoline principle or nucleus can be prepared by the general methods of Reaction Schemes 1 and 2, below.

Reaction Scheme 1 Reaction Scheme 2 (Example 7) Dioxane / MβOH 8 (Example No. 9) n-l 10 (Execute No. 11) a-2 The synthesis of the compounds of this invention can be achieved by deprotonation, then alkylation of the core mold 1 or 6 using the sodium salt of hexamethyldisilyl amide and the desired side chain. (Reaction Schemes 1 and 2) 1 R = H 6 R = OBn Example No. 1 (Compound No. 1, in Reaction Scheme 1) 5-Benzyloxy-3,3-dimethyl-2-phenyl-2,3-dihydro-1H-indole The protected dihydro-indoles 1 and 6, exposed previously, they were used as the core mold to synthesize compounds 3 (Example No. 3), 5 (Example No. 6), 8 (Example No. 9) and 10 (Example No. 11). These material molds were prepared using the general method described by Letcher, R. M. et al., J. Chem. Soc. Perkin Trans., 1993, Vol. Pp. 939-944. For example, the mold 1 was prepared from 4-benzyloxyphenyl hydrazine and isobutyrophenone. to a solution of 4-benzyloxy-phenyl hydrazine HCl (2.5 g, 11.7 mmol) and isobutyrophenone (2.1 g, 14.0 mmol) in 20 ml of toluene, acetic acid (cat) was added and the resulting solution was refluxed with azeotropic removal of H20 for 14 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting semi-solid was taken up in acetic acid and refluxed for 12 hours. The reaction mixture was cooled to room temperature and concentrated. The semi-solid residue was taken up in ether and neutralized with K2CO3. The ether layer was dried and concentrated. The resulting solid imine was dissolved in THF-MeOH (6: 1), cooled to 0 ° C and NaBH 4 (0.53 g, 13.2 mmol) was added. The solution was allowed to warm to room temperature and stirred for 0.5 hours. The reaction mixture was poured into 15% HCl and made basic with K2CO3. The organic layer was separated, washed with brine, dried over NaSO 4, and concentrated. The crude product was purified by column chromatography (SiO2, hexane-ethyl acetate (9: 1) .The desired template, 1, was isolated as an orange semi-solid (2.9 g, 75%): H NMR (CDC13) dd 0.7 (s, 3H), 1.4 (s 3H), 3.85 (s.HID), 4.8 (s .IH), 5.0 (s, 2H), 6.62 (s, 1H), 6.67 s, ), 6.8 (dd, ÍH), 7.3-7.5 (m, 10.H); 13C-NMR (CDC13) d 24.3 (q), 26.3 (q), 45.5 (s) 71.0 (t), 74.9 (d), 110.4 (d), 110.9 (d), 113.0 (d), 127. 4, 127.5, 127.6, 127.8. 128, 128.5 (d), 137.6 (s), 139.7 (s), 139.9 (s), 143.4 (s), 152.9 (s); IR (film) 3390, 3040, 2980, 1490, 1050 cm "1; mass spectrum m / e 330 (M + l); CHN cale, for C23H23NO Example No. 2 (Compound No. 2 of Reaction Scheme 1) 5-Benzyloxy-3,3-dimethyl-2-phenyl-l-4- (2-piperidin-1-yl-ethoxy) -benzill-2, 3 -dihydro-lH-indole To a solution of 5-benzyloxy-indoline 1 (0.2 g, 0.61 mmol) and ethoxy piperidine benzylbromide 11 (0.18 g, 0.61 mmol) in 3 ml THF at -78 ° C, 1.53 ml (1.53 mmol, 1M, NaHNDSA-THF, 2.5 eq.) Were added. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was then poured into water, extracted with EtAc. The organic layer was dried with MgSO 4 and concentrated. The product was purified by flash chromatography (15% EtOAc-hexane) to give the desired N-alkylated indoline 2, as a yellow foam.

XH-NMR (CDC13) d 0.79 (s, 3H), 1.34 (s 3 H), 1.4 (m, 2H), 6 (, 4H), 2.5 (m, 4H), 2. 8 (t, 2H), 3.82 (d, AB q, ÍH), 1 (t, 2H), 4.2 (s, ÍH), 4.25 (d, AB q, ÍH), 5.0 (s, ÍH), 6.33 (d, ÍH), 6.6 ( dd, HH), 6.7 (dd, HH), 6.8 (d, 2H), 7.2, (d, 2H), 7.3-7.45 (m, 10H); 13C-NMR (CDCl3) d 24.18 (t), 25.05 (q), 25.9 (t), 26.0 (q), 44.5 (s), 51.5, 55.0, 57.9. 65.9, 70.9 (t), 80.5 (d). 109.0. 110.7, 112.5, 114.4. 127.53, 127.55, 127.7, 128.1, 128.5, 128.6 (d), 130.6, 137.6, 137.7, 140.4, 145.3, 152.6, 157.72 (s); mass spectrum m / e 547 (M + l).

Example No. 3 (Compound No. 3 of Reaction scheme 1) 3,3-dimethyl-2-phenyl-1-f4- (2-piperidin-1-yl-ethoxy) -benzyl-2, 3-dihydro-1H -indol-5-ol To a solution of the N-alkylated indoline 2 (0.14 g, 0.26 mmole) in 8 ml (THF-EtOH-AcOH, 5: 2: 1) was added 0.14 g (10% Pd / C). ) followed by 0.25 ml of cyclohexadiene (10 eq). The reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was filtered through celite, concentrated. The residue was taken up in EtOAc, washed with NaHCO3. The organic layer was dried with MgSO 4 and concentrated. The product was purified by flash chromatography (8% MeOH-methylene chloride) to give the desired phenolic indoline 3. 1H-NMR (CDC13) d 0.65 (s, 3H), 1255 (s, 3H), 1.3-1.5 (m, 6H), 2.4 (m, 6H), 2.65 (m, 2H), 3.7 (d, AB q, ÍH), 4.1 (m, ÍH), 4.25 (d, AB q, ÍH), 6.28 (d, ÍH) , 6.4 (dd, ÍH), 6.5 (S, ÍH), 6.8, (d, 2H), 7.1 (d, 2H), 7.3-7.45 (, 5H), 8.6 (S, ÍH); mass spectrum m / e 457 (M + l). Example No. 4 (Compound No. 3 (Salt HCl) of Reaction Scheme 1) 3,3-dimethyl-2-phenyl-1-r 4 - (2-piperidin-1-yl-ethoxy) -] - benzyl 2 , 3-dihydro-lH-indol-5-ol (HCl) A solution of phenolic indoline 3 (0.043 g, 0.11 mmol) in 2 ml of Et20-THF (4-1) is treated with 1.2 eq (1M HCl / Et20). The reaction mixture was then stirred for 2 hours, concentrated to give the desired HCl salt. Example No. 5 (Compound No. 4 of Reaction Scheme 1) l- [4- (2-Azepan-1-yl-ethoxy) -benzyl-5-benzyloxy-3,3-dimethy1-2-pheny1-2, 3-dihydro-lH-indole Prepare as described above for compound 2. -NMR (CDCI3) d 0.8 (s, 3H), 1.35 (s, 3H) H), 1.65 (, 8H), 2.8 (m, 9H), 3.0 (t, 2H), 3.8 (AB q, ÍH), 4.1 (t, 2H), 4.2 (s, ÍH), 4.3 (AB q, ÍH), 4.95 (s, 2H). 6.35 (d, HH), 6.65 (dd, HH), 7.5 (s, 1H), 6.85 (d, 2H), 7.2 (d, 2H), 7.25-7.5 (m, 10H); mass spectrum m / e 561 (M + l). Example No. 6 (Compound No. 5 of Reaction Scheme 1) l- [4- (2-Azepan-1-yl-ethoxy) -benzyl-3,3-dimethyl-2-phenyl-2,3-dihydro- 1H-indol-5-ol was prepared as described for compound 3. XH-NMR (DMSO-d6) d 0.6 (5, -3H), 1.15. (S, 3H), 1.4 (, 8H), 2.6 (, 4H), 2.7 (, 2H), 3.55 (ABq, ÍH), 3.8 (7.2H), 3.9 (S, ÍH), 4.05 (ABq, ÍH) , 6.15 (d, ÍH), 6.25 (d, ÍH), 6.35 (S, ÍH); 6.7 (D, 2H), 7.0 (d, 2H), 7.2-7.4 (.5H), 8.5 (S, ÍH); mass spectrum m / e 471 (M + l). Example 7 (Compound No. 6 of Reaction Scheme 2) 5-Benzyloxy-2- (4-benzyloxy-f ni1) -3,3-dimethy1-2.3-dihydro-1H-indole The title compound was prepared using the general method described by Letcher, RM and collaborators, J.

Chem. Soc. Perkin Trans., 1993, Vol. I, pp. 939-944 (See Example No. 1, above) from 4-benzyloxyphenyl hydrazine and (4-benzyloxy) -phenyl isopropyl ketone. XH-NMR (CDC13) d 0.7 (s, 3H), 1.35 (s, 3H), 3.85 (br. S, ÍH), 4.5 (S, ÍH), 5.0 (s, 2H), 5.1 (s, 2H) , 6.6 (d, ÍH), 6.7 (s, ÍH), 6.75 (s, ÍH), 6.95 (d, 2H), 7.25-7.5 (, 12H). 13C-NMR (CDCI3) d 24.2, 26.2 (q), 45.5 (s), 70.0, 71.0 (t), 74.5 (d), 109.4, 110.9, 112.9, 114.3, 127.5, 127.6, 127. 8, 127.9, 128.5, 128.6, (d), 132.2, 137.04, 137.6, 139. 8, 143.4, 152.9, 158.3 (s): mass spectrum m / e 436 (M + l). Example No. 8 (Compound No. 7 of Reaction Scheme 2) 5-benzyloxy-2- (4-benzyloxy-phenyl) -3,3-dimethyl-1- [4- (2-piperidin-1-yl-ethoxy ) -benzyl] -2,3-dihydro-lH-indole Prepared as described above for compound 2 1 H-NMR (CDCL3) d 0.75 (s, 3H), 1.2 (s, 3H), 1.6-1.8 (m, 6H), 2.75 (t, 2H), 3.2-3.85 (, 4H), 4.05 (t.2H), 4.7 (br.s, ÍH), 4.35 (br. s), 5.0 (s, 2H), 5.1 (s, 2H), 6.3, (d, 2H), 6.5 (m.2H), 6.6 (d, 2H) ), 6.85 (d.2H). 6.95 (d, 2H), 7.05 (d, 2H). 7.2-7.5 (, 8H), 7.5 (br.s.1 H). Example No. 9 (Compound No. 8 of Reaction Scheme 2) 2- (4-hydroxy-phenyl) -3,3-dimethyl-l-f4- (2-piperidin-1-yl-ethoxy) -bencill-2 , 3-dihydro-lH-indol-5-ol was prepared as described above for compound 3. XH-NMR (DMSO) d 0.75 (s, 3H), 1.2 (s, 3H), 1.6-1.8 (m. 6H), 2.75 (t.2H), 3.2-3.85 (m, 4H), 4.05 (t.2H), 4.7 (br.s, ÍH), 4.35 (br. S. 2H), 6.3 (d.2H) . 6.5 (m, 2H), 6.6 (d, 2H), 6.85 (d.2H), 7.05 (d.2H), 7.5 (br. mass spectrum m / e 473 (M + l). Example No. 10 (Compound No. 9 of Reaction Scheme 2) 5-benzyloxy-2- (4-benzyloxy-phenyl) -3,3-dimethyl-1- [4- (2-Azepan-1-yl-ethoxy ) -benzyl-2,3-dihydro-lH-indole Prepared as described above for compound 2. 1 H-NMR (CDC13) d 0.8 (s 3 H), 1.35 (s 3 H), 1.6-1.8 (m , 6H), 2.8 (br.s, 4H) 3.1 (t, 2H), 3.8 (AB q, ÍH), 4.1 (t 3H), 4. 25 (AB q. ÍH), 4.95 (s 2H), 5.1 (s, 2H), 6.3 (d. ÍH), 6.6 (d.1M), 6.75 (s. ÍH), 6.8 (d, 2H), 6.95 (, 3H), 7.1 (d, ÍH), 7. 2 (d.2H), 7.3 (m, 8H), 7.55 (d, HH), 8.1 (d, HH). Example No. 11 (Compound No. 10 of Reaction Scheme 2): l-f4- (2-Azepan-1-yl-ethoxy) -benzyl-2- (4-hydroxy-phenyl) -3,3-dimethyl- 2-phenyl-2,3-dihydro-lH-indol-5-ol was prepared as described above for compound 3 XH-NMR (CDCl3) d 0.8 (s, 3H). 1.15 (s, 3H), 1.6 (t.2H), 1. 7 (m, 4H), 3.1 (m.2H). 3.3-3.5 (m.4H), 4.2 (t, 2H), 4.3-4.5 (m2H), 6.7 (d, 4H), 6.8 (d, 4H) 6.9 (d, 2H), 2.1 (d, 2H) , 7.3 (br. S, ÍH). Example No. 12 (Compound No. 11 of Reaction Scheme 2) l-2- (-chloromethyl-phenoxy) -ethyl-piperidine This material was prepared from the amino alcohol l- [2- (4-Hydroxymethyl-phenoxy) - ethyl] piperidine by treatment with thionyl chloride in THF at or ° C. The resulting solid was used without further purification. ^ -NMR (CDC13) d 1.7-1.9 (m, 6H), 2.5 (br. S, 4H), 2.7 (t, 2H), 4.1 (t, 2H), 4.6 (s, 2H), 6.9 (d, 2H), 7.3 (d, 2H). 12.1 (br s, ÍH). Example No. 13 (Compound No. 12 of Reaction Scheme 2) l- [2- (4-Chloromethyl-phenoxy) -ethyl] -Azepane This material was prepared from the aminoalcohol l- [2- (4-Hydroxymethyl-phenoxy) ) -ethyl] azapine by treatment with thionyl chloride in THF at 0 ° C. The resulting solid is used without further purification. XH-NMR (CDCl 3) d 1.7 (m, 2H), 1.9 (m, 4H), 2.2 (m, 2H), 3.1 (m, 2H), 3.4 (7, 2H), 3.6 (t.2H), 6.9 (d, 2H), 7.3 (d, 2H), 12.5 (ÍH). Receptor Binding Assay Objective: To identify compounds that compete with 17β-estradiol for binding to the estrogen receptor (ER). The mode widely accepted for estrogenic action is via its high affinity to the receptor protein. Compounds that demonstrate an ability to bind to the ER can then regulate physiological processes associated with estrogenic action. Procedure: Preparation of the Receptor: CHO cells were cultured that overexpress the estrogen receptor in plates of 150 mm2 in DMEM + 10% dextran-coated carbon, fetal bovine serum was separated. The plates were washed twice with PBS and once with 10 mM Tris-HCl, pH 7.4, 1 mM EDTA. The cells were harvested by scraping the surface and then the cell suspension was placed on ice. The cells were disrupted with a portable motorized tissue grinder using two 10 second pulses. The crude preparation was centrifuged at 12,000 X g for 20 minutes, followed by a rotation of 60 minutes at 100,000 X g to produce a ribosome-free cytosol. The cytosol or hyaloplasm is frozen and stored at -80 ° C. The protein concentration of the cytosol is estimated using the BCA assay with BSA as the standard reference protein. Conditions of the Linkage Test: The comparison test was carried out on a 96-well plate (polystyrene *) which links <; 2.0% of the total input of [3H] -17β-estradiol. Each data point was obtained in triplicate, 100 μg / 100 μl of the receptor preparation was diluted per well. A saturation dose of 2.5 nM [3H] 17β-estradiol + comparator (or regulator) in a volume of 50 μl was added in the preliminary comparison when the comparison concentrations XlOO and X500 were evaluated. For an IC50 determination, 12 comparator concentrations were evaluated, only 0.8 nM of [3H] 17β-estradiol was used. The plate was incubated at room temperature for 2.5 hours. At the end of this incubation period, 150 μl of cooled dextran-coated carbon was added to ice (5% of activated carbon coated with 0.05% dextran 69K) / well and the plate was centrifuged immediately at 900 X g for 5 minutes at 4 minutes. ° C. 200 μl of the supernatant solution was removed for scintillation counting. Samples were counted at 2% or 10 minutes, whichever occurred first. * Because polystyrene absorbs a small amount of [3H] 17-ß-estradiol, the wells containing radioactivity and cytosol, but which are not processed with carbon, were included in the small amount of available isotope. Also, wells containing radioactivity but not cytosol were processed with carbon to estimate DPM without removing [3H] 17β-estradiol. 96-well Corning # 25880-96 plates were used because, among those examined, they proved to bind the lowest amount of estradiol. Analysis of Results Minute-per-minute (CPM) radioactivity counts were automatically converted to minute disintegrations (DPM) by means of the Scintillation Counter "Beckman LS7500 Scintillation Counter", which uses a set of blanked standards to generate an H # for each sample . To calculate the% of estradiol that binds in the presence of 100 or 500 times comparator, the following formula was applied: ((MPD of the sample - DPM not removed by carbon / (DPM of estradiol - DPM not removed by carbon)) X 100% =% bound oestradiol For the generation of IC50 curves, the% link was plotted Vs. [Composite] IC50s were generated for compounds that exhibited> 10% comparison to a 500-fold comparator ( X 500) of concentration Reference Compounds: The reference compounds and those of Examples Nos. 4, 6, 9 and 11 were evaluated and their concentration of IC50 was determined.The concentration of these compounds required to displace 50% of [ 3H] 17β-estradiol is: Estradiol: 0.08 μM Example No. 4: 0.8 μM Tamoxifen: 4.5 μM Example No. 6: 1.0 μM Raloxifene: 0.04 μM Example No. 9 0.31 μM 17a-dihydroequilin: 0.15 μM Example No. 11: 0.35 μM 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 (17)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula:
1. OR)
2. (I) wherein: Ri is H or benzyl; R2 is H, -OH, or -O-benzyl; R3, R4, and Rs are independently selected from H, halogen, cyano, C _ - C6 alkyl (right or branched chain), trifluoromethyl, -OH or the C _ - C? 2 esters (right or branched chain) or C? ~ C 2 alkyl ethers (straight chain or branched or cyclic) thereof, or halogenated C α -C 6 ethers, R 6 is H or C α -C 6 alkyl; R7 is Ci-Cβ alkyl; n is 2 to 3; And it is O or S; and X is
3. -N "R ' wherein R 'is selected from lower alkyl Ci-Cß, the same or different, X is a portion selected from: or a pharmaceutically acceptable salt thereof,. 2. A compound as claimed in claim 1, characterized in that Y is O, or a pharmaceutically acceptable salt thereof. 3. A compound as claimed in the claim 1 or claim 2, which is characterized in that n is 2 and R3, R4, and R5 are independently selected from H, OH or halogen; or a pharmaceutically acceptable salt thereof.
4. 4. A compound of claim 1, which is characterized in that it is 5-benzyloxy-3,3-dimethyl-2-phenyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -2, 3- dihydro-1H-indole, or a pharmaceutically acceptable salt thereof.
5. 5. A compound of claim 1, characterized in that it is 3, 3-dimethyl-2-phenyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -2, 3-dihydro-1H- Indole-5-ol or a pharmaceutically acceptable salt thereof.
6. 6. A compound of claim 1, characterized in that it is l- [4- (2-azepan-l-yl-ethoxy) -benzyl] -5-benzyloxy-3, 3-dimethyl-2-phenyl-2, 3-dihydro-1H-indole or a pharmaceutically acceptable salt thereof.
7. 7. A compound of claim 1, characterized in that it is l- [4- (2-azepan-l-yl-ethoxy) -benzyl] -3,3-dimethyl-2-phenyl-2,3-dihydro- lH-indol-5-ol or a pharmaceutically acceptable salt thereof.
8. 8. A compound of claim 1 which is characterized in that it is 5-benzyloxy-2- (4-benzyloxy-phenyl) -3,3-dimethyl-2,3-dihydro-1H-indole or a pharmaceutically acceptable salt thereof .
9. 9. A compound of claim 1, characterized in that it is 5-benzyloxy-2- (4-benzyloxy-phenyl) -3,3-dimethyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] 2, 3-dihydro-lH-indole or a pharmaceutically acceptable salt thereof.
10. 10. A compound of claim 1, which is characterized in that it is 2- (4-hydroxy-phenyl) -3,3-dimethyl-1- [4- (2-piperidin-1-yl-ethoxy) benzyl] -2 , 3-dihydro-lH-indol-5-ol or a pharmaceutically acceptable salt thereof.
11. 11. A compound of claim 1, which is characterized in that it is 5-benzyloxy-2- (4-benzyloxy-phenyl) -3,3-dimethyl-1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2,3-dihydro-lH-indole or a pharmaceutically acceptable salt thereof.
12. 12. A compound of claim 1, characterized in that it is l- [4- (2-azepan-l-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3,3-dimethyl- 2-phenyl-2,3-dihydro-lH-indol-5-ol or a pharmaceutically acceptable salt thereof.
13. 13. A pharmaceutical composition which is characterized in that it comprises a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
14. 14. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing bone loss in a mammal.
15. 15. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing disease states or syndromes that are caused or associated with an estrogen deficiency in a mammal.
16. 16. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing cardiovascular disease in a mammal.
17. 17. A process for preparing a compound of formula 1 as claimed in claim 1, or a pharmaceutically acceptable salt thereof which is characterized in that it comprises the following: a) alkylating a compound of the formula: 1) wherein Ri, R2, R3, R6 and R7, are as defined above, with a compound of the formula: (ip) wherein n, R4, R5, Y and X are as defined above, to give a compound of formula I; or b) reacting a compound of formula (IV) wherein Y, Ri, R2, R3, R4, R5, R6 and R7 are as defined above and hal represents a halogen, for example, chlorine or bromine, with an amine of the formula: H - X (V) wherein X is as defined above, to give a compound of formula (I), or c) to debenzylate a compound of formula I, wherein Ri is optionally substituted benzyl and / or R 2 is optionally substituted benzyloxy, to give a compound of formula I in where R ± is hydrogen and / or R 2 is hydroxy, or e) esterifying a compound of formula I, wherein at least one of R 3, R, or R 5 is hydroxy, to an ester derived therefrom.