MXPA99001761A - Naphthyl compounds, intermediates, compositions, and methods of use - Google Patents

Abstract

The invention are naphthyl compounds of formula (I), wherein R1 is -H, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or sustituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl);R2 is -H, -F, -Cl, -OH, -O(C1-C4 alkyl), -OCOAr where Ar is phenyl or substituted phenyl, -O(CO)OAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl);R3 and R4 are, independently, -H, -F, -Cl, CH3, -OH, -O(C1-C4 alkyl), OCOAr where Ar is phenyl or substituted phenyl, -OCO(C1-C6 alkyl), -O(CO)O(C1-C6 alkyl), or -OSO2(C4-C6 alkyl), with the proviso that both R3 and R4 cannot be hydrogen;n is 2 or 3;and R5 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino;or a pharmaceutically acceptable salt or solvate thereof, their intermediates, compositions and method of use.

Description

NAFTILO COMPOUNDS, INTERMEDIARIES, COMPOSITIONS AND METHODS OF USE DESCRIPTION OF THE INVENTION Osteoporosis describes a group of diseases that arise from various etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and the resulting fracture of bone is the inability of the skeleton to provide adequate support for the body. One of the most common types of osteoporosis is associated with menopause. Most women lose from approximately 20% to approximately 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after cessation of menses. This rapid loss is generally associated with an increase in bone resorption and formation. However, the restoring cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among • postmenopausal women. REF. 29188 There are an estimated 25 million women in the United States alone who are affected with this disease. The results of osteoporosis are personally harmful, and also explain a great economic loss due to its chronicity and the need for long-term and extensive support (hospitalization and nursing home care) due to the consequences of the disease. This is especially true in older patients. Furthermore, although osteoporosis is not generally thought to be a life-threatening condition, 20% to 30% of the mortality rate is related to hip fractures in older women. A high percentage of this mortality rate can be directly associated with postmenopausal osteoporosis. The most vulnerable tissue in the bone for the effects of postmenopausal osteoporosis is trabecular bone. This tissue is often referred to as cancellous or cancellous bone and is particularly concentrated near the ends of the bone (near the joints and joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which are interconnected with each other, as well as the more solid and dense cortical tissue which constitutes the outer surface and the central axis of the bone. This interconnected network of trabeculae gives lateral support to the external cortical structure, and is critical for the biomechanical resistance of the entire structure. In postmenopausal osteoporosis, it is mainly the net resorption and loss of the trabeculae that leads to bone failure and fracture. In light of the loss of trabeculae in postmenopausal women, it is not surprising that most common fractures are those associated with bones that are highly dependent on trabecular support, for example, the vertebrae, the neck of the bones that they carry the weight, such as the femur and the forearm. Of course, hip fracture, Colles fractures, and vertebral crush fractures are hallmarks of postmenopausal osteoporosis. __ The generally accepted method for the treatment of postmenopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, the patient's compliance with therapy is low, mainly because estrogen treatment often produces undesirable side effects. An additional method of treatment could be the administration of a bisphosphonate compound, such as, for example Fosamax® (Merck &Co., Inc.). Throughout premenopausal time, most women have a lower incidence of cardiovascular disease than men of the same age. After menopause, however, the rate of cardiovascular disease in women increases slowly until it equals the rate observed in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen's ability to regulate serum lipid levels. The nature of estrogen's ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can up-regulate low-density lipid (LDL) receptors in the liver to eliminate excess cholesterol . In addition, estrogen seems to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health. It has been reported in the literature that serum lipid levels in postmenopausal women who have estrogen replacement therapies return to the concentrations found in the premenopausal state. In this way, estrogen would seem to be a onable tment for this condition. However, the side effects of estrogen replacement therapy are not acceptable for many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent that regulates serum lipid levels in a manner analogous to estrogen, but which is devoid of the side effects and risks associated with estrogen therapy. In response to the clear need for new pharmaceutical agents that are capable of alleviating the symptoms of, among others, postmenopausal syndrome, the present invention provides naphthyl compounds, pharmaceutical compositions thereof, and methods for using such compounds for tment of postmenopausal syndrome and other pathological conditions related to estrogen, such as those mentioned below. Thus, it would be a significant contribution to the art to provide the novel substituted naphthyl compounds useful, for example, in the inhibition, "tment, or prevention of disease states as set forth herein. the compounds of the formula I: wherein R1 is -H, -OH, -0 (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (C0) 0Ar where Ar is phenyl or substituted phenyl, -0C0 ( alkyl of 1 to 6 carbon atoms), -0 (CO) 0 (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms); R2 is -H, -F, -Cl, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (CO) Ar where Ar is phenyl or substituted phenyl , -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) 0 (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms); R3 and R4 are, independently, -H, -F, -Cl, -CH3, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -OCO (alkyl) 1 to 6 carbon atoms), -O (CO) O (alkyl of 1 to 6 carbon atoms), or -OS0 (alkyl of 4 to 6 carbon atoms), with the proviso that R3 and R4 can not be hydrogen; n is 2 or 3; and R 5 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino; or a pharmaceutically acceptable salt or solvate thereof. Also provided by the present invention are intermediate compounds that are useful for the preparation of the pharmaceutically active compounds of the present invention.

The present invention further provides pharmaceutical formulations containing the compounds of formula I, optionally containing an effective amount of an additional therapeutic agent selected from the group consisting of estrogen, progestin, bisphosphonate, parathyroid hormone (PTH), and subcombinations thereof. . The present invention also provides the methods of using the compounds of the formula I. Intermediate compounds useful in the synthesis of the compounds of the formula I are also provided, and include the compounds of the formula II: II wherein: Rla is -H or -OR6 in which R6 is a hydroxyl protecting group; R2a is -H, -F, -Cl, -OH, -0 (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (C0) 0Ar where Ar is phenyl or substituted phenyl , -OCO (alkyl of 1 to 6 carbon atoms), -O (CO) O (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms); R 3a is -H, -F, -Cl, or -OR 7 in which R 7 is a hydroxyl protecting group; R 4a is -H, -F, -Cl, -CH 3, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (CO) OAr where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -O (CO) O (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms), with the condition that R3a and R4a can not be hydrogen; R5 is -OH, -CO, or -0 (C0) W; and W is -H or alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt or solvate thereof.

Further provided by the present invention are the intermediate compounds of formula III which are useful for preparing the pharmaceutically active compounds of the present invention: III wherein: Rla is -H or -OR5 in which R5 is a hydroxyl protecting group; R2a is -H, -F, -Cl, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -O (CO) O (alkyl of 1 to 6 carbon atoms), or -OS02 (alkyl of 4 to 6 carbon atoms); R3 and R4 are, independently, -H, -F, -Cl, -CH3, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -O (CO) O (alkyl) from 1 to 6 carbon atoms), or -OS02 (alkyl of 4 to 6 carbon atoms), with the proviso that R3 and R4 can not both be hydrogen. Further provided by the present invention are the intermediary compounds of formula IV which are useful for preparing the pharmaceutically active compounds of the present invention: IV wherein: Rla is -H or -OR6 in which R6 is a hydroxyl protecting group; R2a is -H, -F, -Cl, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) O (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms); R 3a is -H, -F, -Cl, or -OR 7 in which R 7 is a hydroxyl protecting group; R4a is -H, -F, -Cl, -CH3, -OH, -0 (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (C0) 0Ar where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) 0 (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms), with the proviso that R3a and R4a can not be hydrogen; R8 is -OH or -OCO (alkyl of 1 to 6 carbon atoms); wherein the dotted line represents the optional unsaturation; or a pharmaceutically acceptable salt or solvate thereof. Also provided by the present invention are the intermediate compounds of the formula VI which are useful for the preparation of the pharmaceutically active compounds of the present invention: saw wherein: Rla is -H or -OR6 in which R6 is a hydroxyl protecting group; R2a is -H, -F, -Cl, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -O (CO) O (alkyl of 1 to 6 carbon atoms), or -OS02 (alkyl of 4 to 6 carbon atoms); R 3a is -H, -F, -Cl, or -OR 7 in which R 7 is a hydroxyl protecting group; R 4a is -H, -F, -Cl, -CH 3 -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (CO) OAr where Ar is phenyl or substituted phenyl. -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) 0 (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms), with the proviso that R3a and R4a can not both be hydrogen; and Q is a leaving group; or a pharmaceutically acceptable salt or solvate thereof. The general terms used in the description of the compounds described herein have their usual meanings. For example, "C 1 -C 4 alkyl" refers to linear or branched aliphatic chains of 1 to 4 carbon atoms including methyl, ethyl, propyl, isopropyl, n-butyl, and the like; and "alkyl of 1 to 6 carbon atoms" encompasses the groups included in the definition of "alkyl of 1 to 4 carbon atoms" in addition to the groups such as pentyl, isopentyl, hexyl, and the like. The term "substituted phenyl" refers to a phenyl group having one or more substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 3 carbon atoms, hydroxyl, nitro, chloro, fluoro, tri (chloro or fluoro) methyl, and the like. "Alkoxy of 1 to 4 carbon atoms" refers to an alkyl group of 1 to 4 carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, n-propoxy, and isopropoxy, butoxy and the like. Of these alkoxy groups of 1 to 4 carbon atoms, methoxy is highly preferred. The term "inhibits" includes its generally accepted meaning, which includes prohibition, prevention, restriction, and diminution, arrest, or progression of reversion, severity, or improvement of a symptom or resultant effect . Preferred embodiments of the present invention are l- [4- [2- (l-piperidinyl) ethoxy] phenoxy] -2- (3-hydroxyphenyl) -6-hydroxynaphthalene hydrochloride, for example, where R1 and R3 are hydroxyl, R5 is piperidinyl, and the hydrochloride salt thereof; and l- [4- [2- (l-piperidinyl) ethoxy] phenoxy] -2- (3-methoxyphenyl) -6-hydroxynaphthalene hydrochloride, for example, where R 1 is hydroxyl, R 3 is methoxy, R 5 is piperidinyl, and the hydrochloride salt thereof. Illustrative compounds of the present invention include, but are not limited to the following: l- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (3-methoxy phenyl) -6-methoxynaphthalene hydrochloride, l- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (3-methoxy phenyl) naphthalene hydrochloride, l- [4- [2- (1-piperidinyl) ethoxyphfenoxy] -2-hydrochloride - (3-hydroxy phenyl) -6-hydroxynaphthalene, l- [4- [2- (1-piperidinyl) ethoxyphfenoxy] -2- (3-hydroxyphenyl) naphthalene hydrochloride, l- [4- [2- ( 1-piperidinyl) ethoxy-phenoxy] -2- (3-hydroxyphenyl) -6-methoxynaphthalene, and l- [4- [2- (1-piperidinyl) ethoxy-phenoxy-2- (3-methoxy-phenyl) -6-hydroxynaphthalene hydrochloride. The starting material for the preparation of the compounds of the present invention are the compounds of the formula III: III wherein: Rla is -H or -OR5 in which R5 is a hydroxyl protecting group; R2a is -H, -F, -Cl, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (CO) OAr where Ar is phenyl or substituted phenyl , -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) 0 (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms); R3a and Ra are, independently, -H, -F, -Cl, -CH3, -OH, -0 (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, 0 (C0) Ar where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) O (alkyl of 1 to 6 carbon atoms), or -OS02 (alkyl of 4 to 6 carbon atoms) ), with the proviso that R3a and Ra can not be hydrogen. Compounds of the formula III wherein at least two of the substituents R2a, R3a, and Ra are hydrogen, are well known in the art, and are prepared essentially as described by Boyle et al., In U.S. Patent No. 4,910,212 which it is incorporated by reference herein. See, also, Collins, D.J. and collaborators, Aust. J. Chem., - 41: 745-756 (1988); and Collins, D.J. and collaborators, Aust. J. Chem., 37: 2279-2294 (1984). In the preparation of the compounds of the present invention, in general, a ketone of the formula III is flavored, providing a phenol of the formula IVc, which is then reacted with a 4-halobenzaldehyde to give a biaryl ether of the formula lia, which, in turn, is converted to a phenol of the formula Ilb. This synthetic route is as shown below in Scheme I, and Rla, R2a, R3a and R4a are as defined above.

SCHEME I In the first step of the present process, a compound of formula III is converted to a phenol of formula IVc by means of a three-step protocol, essentially as described by Wang, G., et al., M. Syn, Commun. ., 21: 989 (1991). In essence, a ketone of the formula III is enolized upon refluxing a solution of an acetylenic ester solvent in the presence of an acid catalyst. The resulting enolacetate is directly converted to a naphthalacetate which is then hydrolyzed to a phenol of formula IVc. In the conversion of a ketone of the formula III to its respective enol aceto, various known acid catalysts can be used. Preferably, non-aqueous acids are preferred, and particularly, p-toluenesulfonic acid is preferred. A preferred acetylenic ester solvent could be isopropenyl acetate. When running at reflux, the present reaction takes from about 6 to about 48 hours to complete. The enol product of this reaction is not isolated, but after completion of the reaction, the resulting solution is treated with an appropriate oxidant and heated to reflux optimally for about 1 to about 3 hours. Suitable oxidants for this second phase of the first reaction step shown in Scheme I are limited to those known in the art, which can lead to the removal of hydrogen from a saturated system to give an aromatized system. Such oxidants include, for example, dehydrogenation catalysts such as platinum, palladium, and nickel, elemental sulfur and selenium, and quinones. For the present application, quinone oxidants, especially 2, 3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) are preferred. Approximately 1 to 2 equivalents of DDQ per equivalent of substrate will boost the present phase of the process. The product resulting from the present phase, a 1-naphtholyester, is then subjected to hydrolysis to provide a compound of formula IVc, thereby completing the first step of the process shown in Scheme I. The present hydrolysis step is achieved by acidic or basic hydrolysis medium of the substrate in a polar protic solvent such as water or one or more solvents containing an alcohol such as methanol or ethanol. A cosolvent such as tetrahydrofuran (THF) or dioxane may also be added to the solution, to help solubility. Suitable bases for this phase include sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. Suitable acids include, for example, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like. A preferred acid could be hydrochloric acid. This final phase of the first step shown in Scheme I, above, could be run at room temperature and run in a short period of time, typically from 1 to about 12 hours. The termination of the present reaction can be determined by standard chromatography techniques such as thin layer chromatography. In the second step of Scheme I, a phenol of the formula IVc is first reacted with a base, followed by the addition of a 4-halobenzaldehyde or 4-halobenzoketone, in a polar aprotic solvent, under an inert atmosphere such as nitrogen, to give a biaryl ether of the formula lía. This reaction is well known in the art and is carried out essentially as described by Yeager, G.., Et al., Synthesis, 63 (1991). More particularly, 1 equivalent of a compound of the formula IVc is first treated with at least 1 equivalent of an alkali metal hydride or alkali metal carbonate in a suitable solvent, followed by a dropwise addition of a 4-halobenzaldehyde in the same solvent that is used with the substrate. The appropriate solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the reaction. N, N-dimethylformamide (DMF), especially the anhydrous form thereof, is preferred. Preferably, sodium hydride is used as the required base, and 4-fluorobenzaldehyde is used as the preferred 4-halobenzaldehyde. The temperature used in this step of the present process should be sufficient to effect the termination of this reaction, without promoting the formation of undesirable byproducts. A preferred temperature range for this reaction is from about 30 ° C to about 100 ° C. Under the preferred reaction conditions, a compound of formula Ia will be prepared by means of the preferred process in about 24 to about 48 hours. The final reaction shown in Scheme I, the conversion of the aldehyde portion of a compound of the formula lia to a phenol group, thereby forming a compound of the formula Ilb, is known in the art as an oxidation of Bayer-Villiger . See, for example, Fiesers, L. et al., Reagents for Organic Synthesis, 1: 467, Wiley (New York, 1967); Hassall, C.H., Organic Reactions, 9: 73-106 '(Wiley, New York, 1967). In general, the present reaction involves the combination of a benzaldehyde with a peracid such as peracetic acid or m-chloroperbenzoic acid in an inert solvent such as chloroform or methylene chloride. The product of this reaction, a formate ester, can then be easily hydrolyzed to the desired phenol. See, for example, Yeager et al., Supra; Godfrey, I.M. and collaborators, J. Chem. Soc. Perkins. Trans. 1: 1353 81974); and Rué, R. and collaborators, Bull. Soc. Shim. Fr. , 3617 (1970). For the present reaction, a preferred variation is described by Matsumoto, M. et al., J. Org. Chem., 49: 4741 (1984). This method involves the combination of a benzaldehyde of the formula "lia" with at least 1 to about 2 equivalents of 30% hydrogen peroxide in an alcohol solvent, and in the presence of a catalytic acid. Under these conditions, the phenol is formed directly, and therefore the need for an additional hydrolysis step is eliminated. The preferred solvent and the preferred acid catalyst for the present reaction, is methanol and concentrated sulfuric acid, respectively. Under the preferred reaction conditions, the transformation from a compound of the formula lia to a compound of the formula 11b is complete after stirring for about 12 to about 48 hours at room temperatures. The compounds of the formula II, lia, and Ilb are useful as intermediates in the preparation of the pharmaceutically active compounds of the formula I of the present invention. After the preparation of a compound of the formula Ilb, it is reacted with a compound of the formula V R5- (CH2) nQ V wherein R5 and n are as defined above, and Q is a leaving group, such as, for example, mesylate, tosylate, chlorine, or bromine, with bromine which is preferred, to form a compound of the formula The compound of the formula la is then deprotected, when the hydroxyl protecting groups R5 and / or R6 are present, to form a compound of the formula Ib. These steps of the process are shown in Scheme II below.

SCHEME II Ib where: Rla, R2a, R3a, R4a, R5 and n are as defined above; Rlb is -H or -OH; R3b is -H, -OH or halo; or a pharmaceutically acceptable salt or solvate thereof. In the first step of the process shown in Scheme II, the alkylation is carried out by means of standard procedures. The compounds of the formula V are commercially available or are prepared by methods well known to one of ordinary skill in the art. Preferably, the hydrochloride salt of a compound of formula V, particularly 2-chloroethylpiperidine hydrochloride, is used. In general, at least about 1 equivalent of the substrate of the formula Ilb is reacted with 2 equivalents of a compound of the formula V in the presence of at least about 4 equivalents of an alkali metal carbonate, preferably cesium carbonate, and a solvent appropriate. The solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the reaction.

N, N-dimethylformamide, especially the anhydrous form thereof, is preferred. The temperature employed in this step should be sufficient to effect the termination of this alkylation reaction. Typically, the room temperature is sufficient and preferred. The present reaction is preferably run under an inert atmosphere, particularly nitrogen. Under the preferred reaction conditions, this reaction will run to completion in about 16 to about 20 hours. The progress of the reaction can be checked periodically by means of standard chromatography techniques. As an alternative for the preparation of the compounds of the formula la, a compound of the formula Ilb is reacted with an excess of an alkylating agent of the formula VII as further illustrated in Scheme III below: Q '- (CH2) n - Q "VII where n is 2 or 3, and Q' and Q" are each the same or different leaving groups, in an alkaline solution.

SCHEME III wherein Rla, R2a, R3a, R4a; R5 and n are as defined above. Suitable leaving groups include sulfonates, such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropylsulfonate, 4-methoxybenzenesulfonate, 4-nitrobéncensulfonate, 2-chlorobenzenesulfoant, triflate, and the like, halogens such as bromine, chlorine, and iodine, and others. related outgoing groups. Halogens are preferred leaving groups and bromine is especially preferred.

An alkaline-preferred solution for this alkylation reaction contains potassium carbonate in an inert solvent such as, for example, methyl ethyl ketone (MEK) or DMF. In this solution, the 4-hydroxyl group of the benzoyl portion of a compound of the formula Ilb exists as a phenoxide ion which displaces one of the leaving groups of the alkylating agent. This reaction is most favorable when the alkaline solution containing the reagents is brought to reflux and allowed to run to completion. When MEK is used as the preferred solvent, the reaction times range from about 6 hours to about 20 hours. The reaction product from this step is then reacted with an equivalent or excess of 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, or 1- hexamethyleneimine, by means of standard techniques, to form the compounds of the formula la. The reaction can be facilitated with the addition of a strong base, such as a tertiary alkylamine, or an inorganic base, such as K2C03, Cs2C03, and the like. Preferably, the hydrochloride salt of the piperidine is reacted with the alkylated compound of the formula Ilb in an inert solvent, such as anhydrous dimethylformamide, with cesium carbonate (Cs2CO3), and heated to a temperature in the range of about 60. ° C to approxily 110 ° C. When the mixture is heated to a preferred temperature of about 90 ° C, the reaction only takes about 30 minutes to about 1 hour. However, changes in reaction conditions will influence the amount of time this reaction needs to be run until completion. Of course, the progress of this reaction step can be verified periodically by standard chrography techniques. The hydroxyl compounds of the formula I are obtained by the cleavage, when present, of the hydroxyl protecting groups R6 and R7 of the compounds of the formula la, by means of well-known procedures. Numerous reactions for the foron and removal of such protecting groups are described in a number of standard works including, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973).; Green, T.W., Protective Groups in Organic Synthesis, Wiley, (New York, 1981); and The Peptides, Vol. I. Schrooder and Lubke, Academic Press (London and New York, 1965). Methods for the non-regioselective removal of the preferred R6 and / or R7 hydroxyl protecting groups, particularly methyl, are essentially as described in Examples 2 and 4, below. The compounds of the formula I in which R1 and R3 are methoxy and hydroxy, respectively, are obtained by selective cleavage of the 3'-methoxy group (see: Example 5, infra). In general, the process for cleaving or cleaving a methoxy group on the 3 'position, involves the combination of the 6,3'-dimethoxy substrate with a demethylation reagent selected from the group of boron tribromide, boron trichloride or triiodide of boron or with A1C13 and various thiol-type reagents, such as EtSH. The reaction is conducted under an inert atmosphere such as nitrogen, with one or more moles of the reactant per mole of the methoxy group to be cleaved. The appropriate solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the demethylation reaction. Halogenated solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, or aromatic solvents such as benzene or toluene are preferred. The temperature used in this reaction of the present process should be sufficient to effect the termination of the demethylation reaction. However, it is advantageous to keep the temperature below 0 ° C in order to maximize the selectivity for the cleavage of the 3'-methoxy group and to avoid the formation of undesirable byproducts, especially the 6,3-dihydroxyl analog product which arises from excessive demethylation. Under the preferred reaction conditions, a selectively dealkylated product will be formed after stirring the reaction for about 1 to 24 hours. A preferred variation involves the use of boron tribromide in the amount of about 1.5 moles with one mole of the 6,3'-dimethoxy substrate in dichloromethane, under a nitrogen atmosphere at a temperature of -20 ° C per 1 to 4 hours. The compounds of the formula I in which R1 and R3 are hydroxyl and methoxy, respectively, are prepared by a regioselective complementary cleavage of the 6-methoxy group (see: Example 6, below). The procedure for the regioselective cleavage of a methoxy group on position 6 involves the combination of the 6,3'-dimethoxy substrate with a demethylation reagent chosen from the group of alkali metal thioalkyl compounds, such as sodium thiomethylate, lithium thiomethylate. , sodium thioethylate, lithium thioethylate, sodium 2-propantiolate, lithium 2-methylpropan-2-thiolate, and the like. The reaction is conducted under an inert atmosphere such as nitrogen, with one or more moles of the reactant per mole of the methoxy group to be cleaved. The appropriate solvents for this reaction are those solvents or mixture of solvents that remain inert throughout the demethylation reaction. Solvents that facilitate bimolecular nucleophilic displacement reactions, such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), dimethylsulfoxide (DMSO), or N-methylpyrrolidinone (NMP), especially the anhydrous forms of they are the preferred ones. The N, N-dimethylformamide anhydrous is especially preferred. A temperature of about 80 ° C to 120 ° C is required to effect the completion of the demethylation reaction. However, it is necessary to minimize the temperature in order to maximize the selectivity for cleavage of the 6-methoxy group while avoiding the formation of undesirable byproducts and especially the 6,3'-dihydroxyl compound that could arise from excessive demethylation. Under the preferred reaction conditions, a selectively dealkylated product will be formed after stirring the reaction for about 2 to 8 hours. A preferred variation involves the use of lithium thioethylate in the amount of about 15 moles with one mole of the 6,3'-dimethoxy substrate in anhydrous dimethylformamide under a nitrogen atmosphere at a temperature of 107 ° C for 5 hours. Other preferred compounds of the formula I are prepared by replacing the hydroxyl portions in the 6 and / or 3 'position, when present, with a portion of the formula -O-CO- (alkyl of 1 to 6 carbon atoms) ), or -0-S02- (alkyl of 4 to 6 carbon atoms) by means of well-known procedures. See, for example, U.S. Patent No. 4,358,593. When a group -O-CO (alkyl of 1 to 6 carbon atoms) is desired, a mono- or dihydroxy compound of the formula I is reacted with an agent such as acyl chloride, bromide, cyanide, or azide, or with a suitable anhydride or mixed anhydride. The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quiniline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine, and the like. The reaction can also be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethyl sulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, and the like, to which at least one equivalent of an acid scavenger has been added ( except as noted below), such as a tertiary amine. If desired, acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine can be used. See, for example, Haslam et al., Tetrahedron, 36: 2409-2433 (1980). The present reactions are carried out at moderate temperatures, in the range of about -25 ° C to about 100 ° C, often under an inert atmosphere such as nitrogen gas. However, the ambient temperature is usually adequate for the reaction to run. The acylation of a hydroxyl group in position 6 and / or in the 3 'position can also be carried out by means of acid-catalyzed reactions of the appropriate carboxylic acids, in inert organic solvents. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid, and the like, are used. The aforementioned R1 and / or R3 groups of the compounds of the formula I can also be provided by the formation of an active ester of the appropriate acid, such as the esters formed by such known reagents as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N -hydroxysuccinimide, and 1-hydroxybenzotriazole. See, for example, Bull. Chem. Soc. Japan, 38: 1979 (1965), and Chem. Ver., 788 and 2024 (1970). Each of the above techniques that provide the -O-CO- (alkyl of 1 to 6 carbon atoms) portions are carried out in solvents as discussed above. Those techniques that do not produce an acid product in the course of the reaction do not explain the use of an acid scavenger in the reaction mixture. When a compound of the formula I is desired in which the hydroxyl group in the 6-position and / or the 3'-position of a compound of the formula I is converted to a group of the formula -0-S02- ( 4 to 6 carbon atoms), the mono- or dihydroxy compound is reacted with, for example, a sulfonic anhydride or an appropriate sulphonic acid derivative such as a sulfonyl chloride, bromide, or sulfonylammonium salt, as noted by King and Monoir, J. Am. Chem. Soc, 97: 2566-2567 (1975). Such reactions are carried out under conditions as given above in the discussion of the reaction with the acid halides, and the like. The term "solvate" represents an aggregate comprising one or more molecules of the solute, such as a compound of the formula I, with one or more molecules of the solvent. Although the free base form of the compounds of the formula I can be used in the methods of the present invention, it is preferred to prepare and use a pharmaceutically acceptable salt form. The term "pharmaceutically acceptable salt" refers to either the acid addition or base salts which are known as non-toxic and are commonly used in the pharmaceutical literature. The pharmaceutically acceptable salts generally have improved solubility characteristics compared to the compound from which they are derived, and are thus often more suitable for formulation as liquids or emulsions. The compounds used in the methods of this invention, primarily form pharmaceutically acceptable acid addition salts, with a wide variety of organic and inorganic acids, and include the physiologically acceptable salts which are frequently used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like acids. Salts derived from organic acids, such as mono- and dicarboxylic aliphatic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts include in this manner the salts of acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β -hydroxybutyrate, butin-1, -diioate, hexin-1, 4-dioate, caproate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxyalate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monoacid phosphate, diacid phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate , p-toluenesulfonate, xylene sulfonate, tartrate, and the like. A preferred salt is the hydrochloride salt. The pharmaceutically acceptable acid addition salts are typically formed by the reaction of a compound of the formula I with an equimolar or excess amount of an acid. The reagents are generally combined in a mutual solvent such as diethyl ether or ethyl acetate. The salt is normally precipitated from the solution within about one hour to 10 days, and can be isolated by filtration, or the solvent can be removed by conventional means. The present invention further provides pharmaceutically acceptable formulations for administration to a mammal, including humans, in need of treatment, which comprises an effective amount of a compound of the formula I and a pharmaceutically acceptable diluent or carrier. As used herein, the term "effective amount" means an amount of compound of the present invention that is capable of inhibiting, alleviating, improving, treating, or preventing additional symptoms in mammals, including humans, suffering from shortages of estrogen, for example, in menopause and oophorectomy, or inappropriate stimulation with estrogen such as uterine fibrosis or endometriosis, or suffering from proliferation of aortal smooth muscle cells or restenosis. In the case of estrogen-dependent cancers, the term "effective amount" means the amount of compound of the present invention that is capable of alleviating, improving, inhibiting cancer development, treating, or preventing cancer and / or its symptoms. in mammals, including humans. By "pharmaceutically acceptable formulation" is meant that the carrier, diluent, excipients and salt must be compatible with the active ingredient (a compound of formula I) of the formulation, and not harmful to the container thereof. The pharmaceutical formulations can be prepared by methods well known in the art. For example, the compounds of this invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules and the like. Examples of excipients, diluents and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as agar agar, calcium carbonate, and sodium bicarbonate; agents for delaying dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; absorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols. The final pharmaceutical forms can be: pills, tablets, powders, troches, syrups, sprays, sachets, sachets, elixirs, suspensions, emulsions, ointments, suppositories, sterile injectable solutions, or sterile packaged powders, and the like, depending on the type of excipient used. In addition, the compounds of this invention are well suited for formulation as sustained release dosage forms. The formulations may also be constituted so that they release the active ingredient only or preferably at a particular site of the intestinal tract, possibly over a period of time. Such formulations could involve coatings, wraps, or protective matrices which can be made from polymeric substances or waxes. The particular dose of a compound of formula I required to treat, inhibit, or prevent the symptoms and / or disease of a mammal, including humans, suffering from the above diseases according to this invention, will depend on the particular disease of the symptoms and the severity. The dose, administration routes, and frequency of dosing are best decided by the attending physician. In general, the accepted and effective doses will be from 15 mg to 1000 mg, and more typically from 15 mg to 80 mg. Such doses will be administered to a patient in need of treatment one to three times a day or as often as necessary for efficacy, and for periods of at least two months, more typically for at least six months, or chronically. As a further embodiment of the invention, the compounds of the formula I can be administered together with an effective amount of an additional therapeutic agent, including but not limited to estrogen, progestin, benzothiophene compounds having even raloxifene, naphthyl compounds having antiestrogenic activity, bisphosphonate compounds such as alendronate and tiludronate, parathyroid hormone (PTH), including the truncated and / or recombinant forms of PTH such as, for example, PTH (1-34), .calcitonin, bone morphogenic proteins (BMPs), or combinations thereof. The different forms of these additional therapeutic agents available, as well as the various utilities associated therewith and the applicable dosage regimens, are well known to those of skill in the art. Various forms of estrogen and progestin are commercially available. As used herein, the term "estrogen" includes those compounds that have estrogenic activity and estrogen-based agents. Useful estrogenic compounds in the practice of the present invention include, for example, estradiol, estrone, estriol, equilin, equilenin, estradiol cypionate, estradiol valerate, ethynyl estradiol, polyestradiol phosphate, estropipate, diethylstilbestrol, dienestrol, chlorotrianisene, and mixtures thereof. Estrogen-based agents include, for example, 17-α-ethinylestradiol (0.01-0.03 mg / day), mestranol (0.05-0.15 mg / day), and conjugated estrogenic hormones such as Premarin® (Wyeth-Ayerst; 0.2-2.5). mg / day). As used herein, the term "progestin" includes compounds that have, progestational activity such as, for example, progesterone, norethynodrel, norgestrel, megestrol acetate, norethindrone, progestin-based agents, and the like. Progestin-based agents include, for example, medroxyprogesterone such as Provera® (Upjohn, 2.5-10 mg / day), norethylnodrel (1.0-10.0 mg / day), and norethindrone (0.5-2.0 mg / day). A preferred estrogen-based compound is Premarin®, and norethylnodrel and norethindrone are preferred agents based on progestin. The method of administration of each agent based on estrogen and progestin is consistent with that known in the art. The following formulations are given for purposes of illustration, and are not intended to be limiting in any way. The total active ingredients in such formulations comprise from 0.1% to 99.9% by weight of the formulation. The term "active ingredient" means a compound of the formula I.

Formulation 1: Gelatin capsules Ingredient Quantity (mg / capsule) Active Ingredient 0.1-1000 NF 0-500 Starch Fluid Starch Powder 0-500 Fluid Silicone 350 0-15 centistokes The ingredients are mixed, passed through a No. 45 mesh American sieve, and filled into capsules of hard gelatin.

Formulation 2: Tablets Ingredient Quantity (mg / tablet) Active Ingredient 2.5-1000 Starch 10-50 Cellulose, microcrystalline 10-20 Polyvinylpyrrolidone (as 10% solution 5 in water) Sodium carboxymethyl cellulose 5 Magnesium stearate 1 Talc 1-5 The active ingredient, starch, and cellulose are pass through a No. 45 mesh American sieve, and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the powders, which are then passed through a No. 14 mesh American sieve. The granules produced in this way are dried at 50-60 ° C and passed through the filter. US No. 18 mesh sieve. Sodium carboxymethylcellulose, magnesium stearate, and talc, previously passed through a No. 60 mesh US sieve, are added to the above granules and mixed thoroughly. The resulting material is compressed in a tabletting machine to produce the tablets.

Formulation 3: Aerosol Ingredient Weight% Active Ingredient 0.25 Ethanol 29.75 Propellant 22 70.00 (Chlorodifluoromethane) Total 100.00 The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device . The required amount is then fed to a stainless steel vessel and diluted with the rest of the propellant. The valve units are then adjusted to the container.

Formulation 4: Suppositories Ingredient Weight Active Ingredient 150 mg Fatty Acid Glycerides 3000 mg saturated The active ingredient is passed through a No. 60 mesh American sieve and suspended in the fatty acid glycerides, which had previously been heated to their point of fusion. The mixture is emptied into a suppository mold and allowed to cool.

Formulation 5: Suspension Suspensions each containing 0.1-1000 mg of a compound of formula I per 5 ml dose.

Ingredient Weight Active Ingredient 0.15-1000 mg Sodium Carboxymethylcellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml (0.1 M) Flavor q.s.

Color c.s. Purified water to a total of 5 ml total A compound of formula I is passed through a No. 45 mesh American sieve and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid solution, the flavoring, and the color are diluted in water and added, and the mixture is stirred well. Additional water is added to carry the formulation to the final volume. The following examples and preparations are provided to better elucidate the practice of the present invention and should not be construed in any way as limiting the scope thereof. Those skilled in the art will recognize that various modifications may be made without departing from the spirit and scope of the invention. All publications and patent applications mentioned in the specification are indicative of the level of those of experience in the art to which the present invention pertains.

EXAMPLES The NMR data (Magnetic Resonance Nuclear) for the following Examples were generated in a GE NMR instrument of 300 Megahertz, and anhydrous d-6 DMSO was used as the solvent, unless otherwise indicated.

Preparation 1 Uric acid 2, 4-di- (3-methoxy phenyl) A solution of 50.68 g (305 mmol) of the 3-methoxy phenylacetic acid in 1.4 1 of anhydrous tetrahydrofuran was prepared and cooled to -70 ° C under a nitrogen atmosphere. Slowly 400 ml of 1.6 M n-butyllithium (640 mmol) were added and the solution left stirring for two hours at -70 ° C. A solution of 72.1 g (335 mmol) of 2- (3-methoxyphenyl) ethyl bromide in 100 ml of tetrahydrofuran was then added, and the reaction was allowed to proceed for sixteen hours, while heating slowly to room temperature. The solvent was removed by evaporation in vacuo. The residue was redissolved in a solution of 50 ml of 5 N NaOH and 450 ml of water, and stirred for one hour. The aqueous solution was extracted three times with ether. The aqueous solution was acidified with the addition of 150 ml of 5 N HCl and the product was extracted three times with chloroform. The organic extracts were combined, washed with brine and dried by filtration through anhydrous sodium sulfate. The solvent was removed by evaporation. This produced 90 g of the title compound as a clear oil.

Preparation 2 2- (3-methoxyphenyl) -6-methoxy-l-tetralone A solution of 90 g (300 mmol) of 2,4-di- (3-methoxyphenyl) butyric acid in 1.5 1 of methylene chloride was prepared, and 62.4 g were slowly added. (300 mmol) of PC15 (phosphorus pentachloride). The reaction mixture was heated to reflux under a nitrogen atmosphere for four hours. The solvent was removed by evaporation. The residue was stirred with 100 ml of aqueous sodium hydrogen carbonate and the suspension was extracted three times with chloroform. The combined organic extracts were washed with brine, dried with sodium sulfate, and evaporated to dryness. The product was crystallized from 2-propanol at -70 ° C and then twice from methanol at -70 ° C. This produced 65 g of the title compound as a color burned solid with a melting point of 81-82 ° C.

* Preparation 3 l-acetyloxy-2- (3-methoxyphenyl) -6-methoxy-3, 4-dihydronaphthalene A suspension of 47 g (167 mmol) of 2- (3-methoxyphenyl) -6-methoxy-1-tetralone and 4.7 g of the p-toluenesulfonic acid monohydrate in 470 ml of isopropenyl acetate was prepared. The reaction mixture was heated to reflux for forty-eight hours under a nitrogen atmosphere. The reaction was allowed to cool and 10 g of sodium hydrogen carbonate was added, the solution was emptied into 500 ml of an aqueous solution of sodium hydrogen carbonate. The aqueous solution was extracted three times with 200 ml portions of ethyl acetate. The combined organic extract was washed with brine, dried with sodium sulfate, and evaporated to a dark oil. This produced 52.7 g of the title compound.

Preparation 4 l-Acetyloxy-2- (3-methoxyphenyl) -6-methoxynaphthalene A solution of 52.7 g (162 mmol) of l-acetyloxy-2- (3-methoxyphenyl) -6-methoxy-3,4-dihydronaphthalene and 36.9 g (162 mmol) of DDQ in 500 ml of p-dioxane was prepared. The solution was heated to reflux for two hours under a nitrogen atmosphere. The reaction was allowed to cool and the solvent was removed by evaporation. The residue was extracted by stirring in chloroform for sixteen hours, then filtered to remove the insoluble material. The chloroform extract was further purified by chromatography on a column of silica gel eluted with chloroform. This resulted in a red oil, which was suspended in methanol and crystallized at -70 ° C. This produced 46.5 g of the title compound as a low melting point solid.

Preparation 5 l-hydroxy-2- (3-methoxyphenyl) -6-methoxynaphthalene A suspension of 46.5 g of 1-acetyloxy-2- (3-methoxyphenyl) -6-methoxynaphthalene and 40 ml of 5N hydrochloric acid in 400 ml of methanol was prepared. The reaction mixture was heated to reflux for eleven hours. The reaction mixture was evaporated to a clear oil. This yielded 38.6 g of the title compound. PMR: (CDC13) 8.19 ppm (d, J = 9.1 Hz, 1H); 7.51-6.94 ppm (m, 8H); 5.91 ppm (s, 1H); 3.94 ppm (s, 3H). MS (MASS SPECTRUM): m / e = 280 (M) FD EA: Calculated for C? 8H? 603: C, 77.12; H, 5.75 Found: C, 76.91; H, 5.81.

Preparation 6 l-h.-hydroxy-2- (3-methoxy phenyl) naphthalene In a manner analogous to Preparations 1-5, the title compound was prepared. PMR: 8.30 ppm (m, 1H); 7.80 ppm (, 1H); 7.57-7.45 ppm (m, 4H); 7.40 ppm (d, J = 7.1 Hz, 1H); 7.35 ppm (d, J = 6.0 Hz, 1H); 7.06 ppm (s, 1H); 6.97 ppm (dd, J = 6.0 Hz, 1H); 6.00 ppm (s, 1H); 3.90 ppm (s, 1H). MS: m / e = 250 (M) FD EA: Calculated for C? 7H? 4O2-0.21 mol EtOAc: C, 79.52; H, 5.93 Found: C, 79.72; H, 5.63 Preparation 7 1- (4-formylphenoxy) -2- (3-methoxyphenyl) -6-methoxynaphthalene A solution of 9.8 g (35 mmol) of l-hydroxy-2- (3-methoxyphenyl) -6-methoxynaphthalene in 490 ml of DMF was prepared under a nitrogen atmosphere, and 1.47 g (36.8 mmol) was added slowly to this solution. of 60% sodium hydride in mineral oil. After ten minutes, 7.5 ml (70 mmol) of 4-fluorobenzaldehyde was added, and the reaction mixture was heated at 70 ° C for sixty-four hours. The reaction mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was dried with sodium sulfate and chromatographed on a column of silica gel eluted with hexyl acetate-hexane (1: 9) (v / v). The final product was further purified by crystallization from methanol. This yielded 2.4 g of the title compound as a burnt-colored solid, m.p. 145-146 ° C. PMR: (CDC13) 9.80 ppm (s, 1H); 7.79 ppm (d, J = 9.2 Hz, 1H); 7.75 ppm (d, J = 8.8 Hz, 1H); 7.67 ppm (d, J = 8.9 Hz, 2H); 7.58 ppm (d, J = 8.4 Hz, 1H); 7.31-7.05 ppm (m, 5H); 6.86-6.75 ppm (m, 3H); 3.95 ppm (s, 3H); 3.72 ppm (s, 3H). MS: m / e = 384 (M) FD EA: Calculated for C25H2o04: C, 78.11; H, 5.24. Found: C, 78.26; H, 5.33.

Preparation 8 1- (4-for-ilphenoxy) -2- (3-methoxy-phenyl) -naphthalene In a manner similar to that used in Preparation 7, the title compound was prepared.

PMR: (CDC13) 9.90 ppm (s, 1H); 7.90-7.83 ppm (m, 2H); 7. 70 ppm (d, J = 8.0 Hz, 1H); 7.35-7.20 ppm (m, 4H); 7. 58-7.43 ppm (m, 2H); 7.58 ppm (d, J = 8.4 Hz, 1H); 7.10 ppm (m, 2H); 6.80 ppm (d, J = 8.0 Hz, 2H); 3.80 ppm (s, 3H). MS: m / e = 354 (M) FD EA: Calculated for C24H? 8O3-0.2 mol EtOAc: C, 86.06; H, 5.31. Found: C, 80.17; H, 5.29.

Preparation 9 1- (4-hydroxyphenoxy) -2- (3-methoxyphenyl) -6-methoxynaphthalene 2. 3 g (6 mmol) of 1- (4-formylphenoxy) -2- (3-methoxyphenyl) -6-methoxynaphthalene was suspended in 15 ml of methanol and 1.7 ml (9 mmol) of 30% hydrogen peroxide were added. To the stirred mixture, 0.76 ml of concentrated sulfuric acid was slowly added. An additional 30 ml of methanol was added and the reaction was allowed to proceed for forty-eight hours. The reaction was neutralized with sodium hydrogen carbonate solution and extracted with chloroform. The chloroform was washed with brine, dried over sodium sulfate, and chromatographed on a column of silica gel eluted with chloroform. This yielded 1.6 g of the title compound as an amorphous, burnt-colored powder, m.p. 125-126 ° C. PMR: 8, .9 ppm (s, 1H); 7.78 ppm (d, J = 8.1 Hz, 1H); 7.70 ppm (d, J = 9.0 Hz, 1H); 7.57 ppm (d, J = 8.4 Hz, 1H); 7.39 ppm (t, J = 9.0 Hz, 1H); 7.19-7.05 (m, 3H); 6.80 ppm (d, J = 8.9 Hz, 1H); 6.50 ppm (q, J = 8.9 Hz, 4H); 3.85 ppm (s, 3H); 3.64 ppm (s, 3H). S: m / e = 372 (M) FD EA: Calculated for C 24 H 20 O: C, 77.40; H, 5.41. Found. C, 77.69; H, 5.30.

Preparation 10 l- (4-hydroxyphenoxy) -2- (3-methoxy phenyl) naphthalene In a manner similar to that used in Preparation 9, the title compound was prepared and isolated as a clear oil. PMR: (CDC13) 7., 90 ppm (d, J = 8.0 Hz, 1H); 7.87 ppm (d, J = 7.0 Hz, 1H); 7.80 ppm (d, J = 8.0 Hz, 1H); 7.60 ppm (d, J = 8.0 Hz, 1H); 7.50-7.40 ppm (m, 3H); 7.10 ppm (, 2H); 6.80 ppm (d, J = 8.0 Hz, 1H); 6.60 ppm (s, 4H); 4.40 ppm (s, 1H); 3.70 ppm (s, 3H). MS: m / e = 342 (M) FD EA: Calculated for C23H? 8O3-0.5 mol EtOAc: C, 77.70; H, 5.74. Found: C, 77.93; H, 5.82.

Example 1 L- [4- [2- (1-piperidinyl) ethoxy-phenoxy] -2- (3-methoxy-phenyl) -6-methoxy-naphthalene hydrochloride A solution of 1.5 g (4 mmol) of 1- (4-hydroxyphenoxy) -2- (3-methoxy phenyl) -6-methoxynaphthalene in 40 ml of dimethylformamide was prepared. To this solution were added 920 mg (5 mmol) of chloroethylpiperidine hydrochloride and 5.2 g (16 mmol) of Cs2CO3, the reaction was stirred at room temperature under a nitrogen atmosphere for sixteen hours. The solvents were removed by evaporation and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water, then with brine, dried with sodium sulfate, and evaporated to dryness. The residue was dissolved in 10 ml of methanol and 1 ml of 5N hydrochloric acid was added. The solvents were removed by evaporation and the product crystallized from ethyl acetate. This yielded 1.8 g of the title compound as a white solid, m.p. 161-162 ° C. PMR: 10.43 ppm (broad s, 1H); 7.81 ppm (d, J = 8.3 Hz, 1H); 7.67 ppm (d, J = 9.0 Hz, 1H); 7.59 ppm (dd, J = 8.8, 1.1 Hz, 1H); 7.41 ppm (d, s, 1H); 7.24 ppm (t, J = 7.8 Hz, 1H); 7.18-7.06 ppm (m, 3H); 6.88-6.75 ppm (m, 3H); 6.59 ppm (dd, J = 8.8, 1.1 Hz, 2H); 4.22 ppm (t, J = 4.3 Hz, 2H); 3.85 ppm (s, 3H); 3.65 ppm (s, 3H); 3.47-3.22 ppm (m, 4H); 2.98-2.79 ppm (m, 2H); 1.83-1.57 ppm (m, 5H); 1.39-1.22 ppm (m, 1H). MS: m / e = 483 (M-HC1) FD EA: Calculated for C3? H33N04-HCl: C, 71.60; H, 6.59; N, 2.69. Found: C, 71.87; H, 6.43; N, 2.76.

Example 2 L- [4- [2- (1-piperidinyl) ethoxy-phenoxy-2- (3-methoxy-phenyl) -naphthalene hydrochloride In a manner similar to that used in Example 1, the title compound was prepared and isolated as a white crystalline powder, m.p. 145 ° C. PMR: (CDC13) 7.90 ppm (dd, J = 8.0 Hz, 2H); 7.80 ppm (d, J = 9.0 Hz, 1H); 7.60 ppm (d, J = 8.0 Hz, 2H); 7.48-7.44 ppm (m, 3H); 7.20 ppm (d, J = 7.0 Hz, 2H); 7.10 ppm (d, J = 7.0 Hz, 2H); 6.80 ppm (d, J = 9.0 Hz, 1H); 6.60 ppm (s, 3H); 4.40-4.30 ppm (m, 2H); 3.70 ppm (s, 3H); 3.60-3.50 ppm (m, 1H); 3.20 ppm (m, 2H); 2.80-2.60 ppm (, 2H); 2.30-2.10 ppm (, 2H); 1.90-1.80 ppm (m, 3H); 1.70-1.60 ppm (m, 2H); 1.50-1.30 ppm (m, 1H). MS: m / e = 453 (M-HCl) FD EA: Calculated for C30H3? NO3-HCl: C, 73.53; H, 6.58; N, 2.86. Found: C, 73.31; H, 6.73; N, 3.05.

Example 3 L- [4- [2- (1-piperidinyl) ethoxy-phenoxy-2- (3-hydroxyphenyl) -6-hydroxynaphthalene hydrochloride A solution of 1.5 g (2.9 mmol) of l- [4- [2- (l-piperidinyl) ethoxy-phenoxy-2- (3-methoxyphenyl) -6-methoxy-naphthalene hydrochloride in 30 ml of methylene chloride was prepared and the solution it was cooled to 0 ° C under a nitrogen atmosphere. To this solution was added 1.09 ml (2.89 g, 11.5 mmol) of boron tribromide (BBr3) and the reaction was allowed to proceed for two hours at 0 ° C. The reaction was quenched by the addition of aqueous sodium hydrogen carbonate solution (50 ml). The reaction mixture was extracted with chloroform. The organic layer was washed with brine, dried with sodium sulfate and evaporated to dryness. The residue was suspended in tetrahydrofuran and filtered. To the filtrate, 1 ml of 5N hydrochloric acid was added and the solvents were removed by evaporation. This produced 0.99 g of the title compound as an amorphous color-burned powder. PMR: 9.90 ppm (s, 1H); 9.88 ppm (broad s, 1H); 9.3 ppm (s, 1H); 7.65 ppm (d, J = 8.4 Hz, 1H); 7.60 ppm (d, J = 8.8 Hz, 1H); 7.45 ppm (d, J = 8.7 Hz, 1H); 7.17 ppm (s, 1H); 7.14-7.01 ppm (m, 2H); 6.99-6.92 ppm (m, 2H); 6.77 ppm (d, J = 8.8 Hz, 2H); 6.68-6.54 ppm (m, 3H); 4.18 ppm (t, J = 4.7 Hz, 2H); 3.47-3.18 ppm (m, 4H); 2.98-2.81 ppm (, 2H); 1.81-1.58 ppm (, 5H); 1.38-1.22 ppm (m, 1H). MS: m / e = 455 (M-HC1) FD EA: Calculated for C29H29N04-HC1; C, 70.80; H, 6.15; N, 2.85. Found: C, 70.68; H, 6.29; N, 2.65.

Example 4 L- [4- [2- (1-piperidinyl) ethoxy-phenoxy-2- (3-hydroxy-phenyl) -naphthalene hydrochloride In a manner similar to that used in Example 3, the title compound was prepared and isolated as a white crystalline solid, m.p. 194- 195 ° C. PMR: (MeOD-d4) 7.96-7.84 ppm (m, 2H); 7.80 ppm (d, J = 8.0 Hz, 1H); 7.50 ppm (d, J08.0 Hz, 1H); 7.50-7.40 ppm (m <3H); 7.12-7.09 ppm (dd, J = 8.0 Hz, 1H); 7.00-6.90 ppm (m, 2H); 4.70 ppm (s, 1H); 4.20-4.10 ppm (m, 1 HOUR); 3.50-3.40 ppm (m, 2H); 3.40-3.20 ppm (m, 4H); 1. 90-1.70 ppm (m, 4H); 1.80-1.60 ppm (m, 2H). MS: m / e = 439 (M-HC1) FD EA: Calculated for C29H29N03-HC1: C, 73.17; H, 6.35; N, 2.94. Found: C, 72.88; H, 6.31; N, 2.90.

Example 5 l- [4- [2- (1-piperidinyl) ethoxy-phenoxy-2- (3-hydroxyphenyl) -6-methoxynaphthalene A solution of l- [4- [2- (l-piperidinyl) ethoxy-phenoxy-2- (3-methoxyphenyl) -6-methoxynaphthalene hydrochloride (0.500 g, 0.96 mmol) in 20 ml of anhydrous methylene chloride under nitrogen atmosphere , it was cooled in an acetonitrile-dry ice bath at -20 ° C. Boron tribromide (1.44 mmol) was added dropwise in 3 minutes by syringe as a 1 M solution (1.44 ml) also in methylene chloride. The resulting mixture was allowed to warm to 0 ° C and was stirred for 2 hours. The reaction was then poured into a stirred solution of saturated sodium acid carbonate, cold (100 ml) and the crude product was extracted with ethyl acetate (4 x 25 ml).

The organic extracts were combined, dried (magnesium sulfate), and concentrated to an oily foam. The crude free base was purified by radial chromatography using methanol / methylene chloride 5/95. The appropriate fractions were combined and concentrated in vacuo to provide 220 mg (49%) of l- [4- [2- (l-piperidinyl) ethoxy-phenoxy-2- (3-hydroxyphenyl) -6-methoxynaphthalene as a white crystalline solid, pf 170-171 ° C. PNMR: d 9.36 (s, 1H); 7.77 (d, J = 8.6 Hz, 1H); 7.68 (d, J = 9.2 Hz, 1H); 7.53 (d, J = 8.6 Hz, 1H); 7.39 (d, j = 2.4 Hz, 1H); 7.09 (m, 2H); 6.93 (m, 2H); 6.69 (d, J-9.1 Hz, 2H); 6.61 (m, 1H); 6.52 (d, J = 9.1 Hz, 2H); 3.84 (t, J = 6.0 Hz, 2H); 3.83 (s, 3H); 2.51- (t, J = 6.0 Hz, 2H); 2.25-2.40 (m, 4H); 1.35-1.45 (m, 4H); 1.25-1.35 (m, 2H). Analysis Calculated for C3oH31? 4: C, 76.73; H, 6.65; N, 2.98. Found: C, 76.94; H, 6.83; N, 3.26. For the determination by PMR analysis of the demethylation site, the treatment of the product in DMSO solution with several equivalents of NaOD in DMSO produced the following changes in the chemical shifts: three signals corresponding to the two aromatic protons that are in the ortho position or, and a proton that is in position for the hydroxyl group in the 2-aryl portion, were displaced 0.59, 0.57 and 0.75 ppm in high field, respectively. In contrast, the signals attributable to the protons on the naphthalene portion at positions 5 and 7 were only slightly affected (displacement <0.2 ppm). The signals remaining in the product spectrum in DMSO remained essentially unchanged by the addition of NaOD. The shifts described above show that the OH group is placed on the 2-aryl ring and the remaining methoxy group is on the naphthalene ring (for example selective regioselective demethylation occurred in the 2- (3-methoxyphenyl) moiety).

Example 6 l- [4- [2- (1-piperidinyl) ethoxy-phenoxy-2- (3-methoxyphenyl) -6-hydroxynaphthalene A solution of ethanethiol (2.85 ml) in anhydrous dimethylformamide (25 ml) under nitrogen atmosphere was cooled in an ice bath and treated dropwise with 20.1 ml of 1.6 M n-BuLi in hexane. The resulting sol, which was about 0.22 M in lithium thioethylate (LiSEt) was allowed to warm to room temperature before use. To l- [4- [2- (1-piperidinyl) -ethoxyfenoxoxy-2- (3-methoxyphenyl) -6-methoxynaphthalene hydrochloride (0.550 g, 1.05 mmol) under nitrogen atmosphere, 70 ml (15.4 mmol) of LiSEt solution was added and the resulting reaction mixture was heated in an oil bath at 107 ° C for 5 hours. The resulting yellow solution was concentrated under reduced pressure to remove most of the solvent and the yellow oil concentrate was distributed between 300 ml of ethyl acetate and 1 N HCl (100 ml) to which 50 g of ice had been added. The extract of the ethyl acetate layer was washed with 4 portions of 25 ml of brine, dried over magnesium sulfate, filtered, and concentrated to a foul-smelling yellow oil. The crude material was purified in portions by radial chromatography which used 5% methanol in chloroform as the eluting solvent. The appropriate fractions were combined, concentrated, and dried in vacuo to provide 265 mg (53%) of the l- [4- [2- (l-piperidinyl) ethoxy-phenoxy] -2- (3-methoxy phenyl) -6- hydroxynaphthalene, like a gray foam. PMR (DMSO-de) d 9.90 (s, 1H); 7.66 (d, J = 8.0 Hz, 1H); 7. 63 (d, J = 8.6 Hz, 1H); 7.50 (d, J = 8.6 Hz, 1H); 7.25- 7.16 (m, 2H); 7.10-6.95 (m, 3H); 6.79 (m, 1H); 6.70 (d, J = 9.0 Hz, 2H); 6.54 (d, J = 9.0 Hz, 2H); 3.86 (t, J = 6.0 Hz, 2H); 3.64 (s, 3H); 2.52 (t, J = 6.0 Hz, 2H); 2. 25-2.40 (, 4H); 1.35-1.45 (m, 4H); 1.25-1.35 (m, 2H). MS (FD) m / e 470 (M +) Analysis Calculated for C30H3? NO: C, 76.73; H, 6.65; N, 2.98. Found; C, 75.89; H, 6.81; N, 3.01. In an experiment similar to that described in Example 5, the demethylation site was determined by PNMR analysis (Proton Nuclear Magnetic Resonance): treatment of the product in DMSO solution with several NaOD equivalents in DMSO produced the following changes in chemical shifts: Signals corresponding to the two aromatic protons at positions 5 and 7 of the naphthalene ring (as well as other protons on the naphthalene portion) were dramatically displaced in high field. In contrast, the signals attributable to the protons on the 2-aryl portion were only slightly affected (displacement less than 0.2 ppm). The signals remaining in the product spectrum in DMSO remained essentially unchanged by the addition of NaOD. The displacements described above show that the OH group is placed on the naphthalene ring and the methoxy group remaining on the 2-aryl portion (for example selective regioselective demethylation in the 7-methoxy group occurred). The following discussions illustrate the methods of use for compounds of formula I in experimental models or in clinical studies.

These examples are for illustration purposes and are not intended to be limiting in any way.

A. Osteoporosis: Experimental models of postmenopausal osteoporosis are known in the art. Relevant to this invention is the ovariectomized rat model which is provided in U.S. Patent No. 5,393,763. The compounds of the formula I could be active in this model and could demonstrate an effective treatment or prevention of bone loss due to lack of estrogen. An additional demonstration of the method of treatment or prevention of osteoporosis due to the lack of estrogen could be as follows: One hundred patients could be chosen, who are healthy postmenopausal women, aged between 45 and 60 years and who could normally be considered as candidates for estrogen replacement therapy. This includes women with an intact uterus, who have had a last menstrual period more than six months ago, but less than six years. The patients excluded for the study could be those who have taken estrogens, progestins, or corticosteroids six months before the study, or who have even taken bis-phosphonates. Fifty women (test group) could receive 15 to 80 mg of a compound of the formula I, for example, Formulation 1 (above), per day. The other fifty women (control group) could receive an equivalent placebo per day. Both groups could receive calcium carbonate tablets (648 mg) per day. The study is a double blind design. Neither the investigators nor the patients would know which group each patient is assigned to. A baseline examination of each patient includes quantitative measurement of calcium, creatinine, hydroxyproline, and urinary pyridinoline crosslinks. Blood samples are measured for serum levels of osteocalcin and bone-specific alkaline phosphatase. Baseline measurements would also include a uterine examination and determination of bone mineral density by photon absorptiometry. The study could continue for six months, and each of the patients could be examined for changes in the above parameters. During the course of treatment, patients in the treatment group may notice a decreased change in the biochemical markers of bone resorption, compared to the control group. Also, the treatment group could show little or no decrease in bone mineral density compared to the control group. Both groups could have similar uterine histology, indicating that the compounds of formula I have little or no uterotrophic effect.

B. Hyperlipidemia: Experimental models of postmenopausal hyperlipidemia are known in the art. Concerning this invention is the ovariectomized rat model which is detailed in the North American Patent No. 5,464,845. The data presented in Table 1 show the comparative results between ovariectomized rats, rats treated with 17-a-ethinylestradiol (EE2), and rats treated with certain compounds of this invention.

Although EE2 caused a decrease in serum cholesterol when orally administered at 0.1 mg / kg / day, it also exerted a stimulating effect on the uterus, so that the uterine weight of EE2 was substantially higher than the uterine weight of the ovariectomized animals. . This uterine response to estrogen is well recognized in the art. Not only did the compounds of the present invention reduce serum cholesterol in comparison to ovariectomized animals, but also the uterine weight was increased to a lesser degree than those to which they were administered EE2. Compared to the estrogenic compounds known in the art, the benefit of reducing serum cholesterol while decreasing the effect on uterine weight is unusual and desirable. As expressed in the following data, estrogenicity was also assessed by evaluating the response of eosinophil infiltration within the uterus. The compounds of this invention did not cause such a large increase in the number of eosinophils observed in the stromal layer of the uteri of ovariectomized rats. EE2 caused a substantial and expected increase in the infiltration of eosinophils.

The data presented in Table 1 reflects the response by treatment group.

Table 1 Compound Dose Weight Uterine Eosinophil Cholesterol No. mg / kg3% Inc "Serum Uterine% (Vmax) c Desc.d EE2e 0.1 138.8 * 174.3 * 88.1 * Example 1 0.01 9.6 2.1 12.1 0.1 21.9 4.8 55.6 * 1.0 35.8 * 4.8 66.5 * Example 2 0.1 42.7 * 4.5 59.6 * oase free) 1.0 43.8 * 7.8 66.2 * 10.0 37.2 * 4.5 59.0 * Example 3 0.1 10.4 4.8 26.3 * 1.0 15.3 3.0 45.7 * 10.0 3.9 1.2 22.9 Raloxifene 0.1 23.5 5.4 49.3 * mg / kg PO b Percent increase in uterine weight versus ovariectomized controls c eosinophil peroxidase, Vmax d Decrease in serum cholesterol versus ovariectomized controls in 17-a-ethynyl-estradiol f Raloxifene hydrochloride [2- ( 4-hydroxyphenyl) -6-hydroxybenzo [b] thien-3-ylJ [4- [2- (1-piperidinyl) ethoxy-phenyl-methanone (see: Jones, ibid.) • p < .05 • An additional demonstration of the method of treating hyperlipidemia due to estrogen deficiency could be as follows: One hundred patients could be chosen, who are healthy postmenopausal women, aged between 45 and 60 years, and who could normally be considered as candidates for estrogen replacement therapy. This could include women with an intact uterus, who have not had a menstrual period for more than six months, but less than six years. The patients excluded for the study could be those who have taken estrogens, progestins, or corticosteroids.

Fifty women (test group) could receive 15 to 80 mg of a compound of formula I, for example, using Formulation 1, per day. The other fifty women (control group) could receive an equivalent placebo per day. The study could be a double blind design. Neither the researchers nor the patients would know which group each patient is assigned to. A baseline examination of each patient could include serum determination of cholesterol and triglyceride levels. At the end of the study period (six months), each patient could have taken their serum lipid profile. Analysis of the data could confirm a decrease in serum lipids, for example, cholesterol and / or triglycerides, in the test group versus the control. From the foregoing, it will be noted that this invention is a well adapted to achieve all the purposes described hereinbefore, together with the advantages inherent in the invention. It will be understood that certain characteristics and subcombinations are useful, and can be used without reference to other characteristics and subcombinations. Because they can be made 16 many possible embodiments of the invention without departing from the scope thereof, it should be understood that all of the material described herein must be construed as illustrative and not in a limiting sense.

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 (20)

1. Having described the invention as above, the content of the following is claimed as property: 1. A compound of the formula I characterized in that R- is -H, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (C0) 0Ar where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) 0 (alkyl of 1 to 6 carbon atoms), or -OSO- (alkyl of 4 to 6 carbon atoms); R 'is -H, -F, -Cl, -OH, -0 (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (CO)? Ar where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) O (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms); R3 and R4 are, independently, -H, -F, -Cl, -CH3, -OH, -0 (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -OCO (alkyl) 1 to 6 carbon atoms), -O (CO) O (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms), with the proviso that only one of R2, R3 and R4 can be hydrogen; n is 2 or 3; and R 5 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino; or a pharmaceutically acceptable salt or solvate thereof.
2. 2. A compound according to claim 1, characterized in that R1 and R3 are each -OH.
3. 3. A compound according to claim 1, characterized in that R1 is hydroxyl and R is methoxy
4. 4. A compound according to claim 1, characterized in that R1 is methoxy and R3 is hydroxyl.
5. 5. A compound according to claim 1, characterized in that n is 2 and R5 is 1-piperidinyl.
6. 6. A compound according to claim 1, characterized in that the salt thereof is the hydrochloride salt.
7. 7. A compound according to claim 1, characterized in that R1 and R3 are each -OH, R5 is piperidinyl, n is 2, and the salt thereof is the hydrochloride salt.
8. 8. A compound according to claim 1, characterized in that R1 is hydroxyl, R3 is methoxy, R3 is piperidinyl, n is 2, and the salt thereof is the hydrochloride salt.
9. 9. A compound according to claim 1, characterized in that R1 is methoxy, R3 is hydroxyl, R5 is piperidinyl, n is 2, and the salt thereof is the hydrochloride salt.
10. 10. A compound according to claim 1, characterized in that it is selected from the group consisting of l- [4- [2- (1-piperidinyl) ethoxy-phenoxy] -2- (3-methoxyphenyl) -6-methoxynaphthalene hydrochloride, hydrochloride l- [4- [2- (1-piperidinyl) ethoxy-phenoxy-2- (3-methoxyphenyl) -naphthalene, l- [4- [2- (1-piperidinyl) ethoxy-phenoxy-2- (3-hydroxy-phenyl) -hydrochloride] 6-hydroxynaphthalene, l- [4- [2- (1-piperidinyl) ethoxy-phenoxy] -2- (3-hydroxyphenyl) naphthalene hydrochloride, l- [4- [2- (1-piperidinyl) ethoxy-phenoxy-2-hydrochloride (3-hydroxyphenyl) -6-methoxynaphthalene, and l- [4- [2- (1-piperidinyl) ethoxy-phenoxy] -2- (3-methoxy-phenyl) -6-hydroxynaphthalene hydrochloride.
11. 11. A pharmaceutical formulation, characterized in that it comprises a compound according to claim 1, in combination with a pharmaceutically acceptable carrier, diluent or excipient.
12. 12. A method for inhibiting bone loss or bone resorption, characterized in that it comprises administering to a patient in need thereof an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.
13. 13. A method according to claim 12, characterized in that bone loss or bone resorption is due to menopause or ovariectomy.
14. 14. A method of compliance, with claim 12, characterized in that the patient is a postmenopausal woman.
15. 15. A method for lowering serum cholesterol, characterized in that it comprises administering to a patient in need thereof an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.
16. 16. A compound of formula II II characterized in that: R is -H or -OR in which R is a hydroxyl protecting group; R2a is -H, -F, -Cl, -OH, -0 (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (C0) 0Ar where Ar is phenyl or phenyl substituted, -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) 0 (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of "4 to 6 carbon atoms); R 3a is -H, -F, -Cl, or -OR 7 in which R 7 is a hydroxyl protecting group; Ra is -H, -F, -Cl, -CH3, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (CO) OAr where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) 0 (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms), with the proviso that only one of R2a, R3 and R4a can be hydrogen; R5 is -OH, -COW, or -0 (CO) W; and W is -H or alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt or solvate thereof.
17. 17. A compound according to claim 16, characterized in that Rla is -OR6 and R2a is -OR7.
18. 18. A compound of formula III III characterized in that: Rla is -H or -OR5 in which R5 is a hydroxyl protecting group; R2a is -H, -F, -Cl, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (CO) OAr where Ar is phenyl or substituted phenyl , -OCO (alkyl of 1 to 6 carbon atoms), -O (CO) O (alkyl of 1 to 6 carbon atoms), or -OS02 (alkyl of 4 to 6 carbon atoms); , 3a and R are, independently, -H, -F, -Cl, -CH3, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, 0 (CO) Ar where Ar is phenyl or substituted phenyl, -OCO (alkyl) 1 to 6 carbon atoms), -O (CO) O (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms), with the proviso that only one of R2a, R3a , and R4a can be hydrogen.
19. 19. A compound of formula IV IV characterized in that: Rla is -H or -OR6 in which R6 is a hydroxyl protecting group; R2a is -H, -F, -Cl, -OH, -0 (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) O (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms); R 3a is -H, -F, -Cl, or -OR 7 in which R 7 is a hydroxyl protecting group; , 4a is -H, -F, -Cl, -CH3, -OH, -O (alkyl 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (CO) OAr where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -O (CO) O (alkyl of 1 to 6 carbon atoms), or -OS02 (alkyl of 4 to 6 carbon atoms), with the proviso that only one of R2a, R3a and R4a can be hydrogen; R8 is -OH or -OCO (alkyl of 1 to 6 carbon atoms); or a pharmaceutically acceptable salt or solvate of the same.
20. 20. A compound of formula VI VI characterized in that: Raa is -H or -OR6 in which R6 is a hydroxyl protecting group; R2a is -H, -F, -Cl, -OH, -0 (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (C0) 0ar where Ar is phenyl or substituted phenyl , -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) 0 (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms); R 3a is -H, -F, -Cl, or -OR 7 in which R 7 is a hydroxyl protecting group; R4a is -H, -F, -Cl, -CH3, -OH, -O (alkyl of 1 to 4 carbon atoms), -OCOAr where Ar is phenyl or substituted phenyl, -0 (C0) 0Ar where Ar is phenyl or substituted phenyl, -OCO (alkyl of 1 to 6 carbon atoms), -0 (CO) 0 (alkyl of 1 to 6 carbon atoms), or -0S02 (alkyl of 4 to 6 carbon atoms), with the condition that only one of R2a, R3a_ and R4a can be hydrogen; and Q is a leaving group; or a pharmaceutically acceptable salt or solvate thereof.