MXPA97006741A - Novedous pharmaceutical compounds of naft - Google Patents

Abstract

The present invention provides a compound of formula (I) in which R1 is H, OH, halo, OCO (C1-C6 alkyl), OCO (aryl), OSO2 (C4-C6 alkyl), OCOO (C1 alkyl) -C6), OCOO (aryl), OCONH (C 1 -C 6 alkyl) or OCON (C 1 -C 6 alkyl) 2; R 2 is aryl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-cyclohexanol; R 3 is O (CH2) 2 or O (CH2) 3; R4 and R5 are optionally CO (CH2) 2CH3, CO (CH2) 3CH3, C1-C6 alkyl or R4 and R5 combine to form, together with the nitrogen to which they are attached; bound, piperidine, morpholine, pyrrolidine, 3-methylpyrrolidine, 3,3-dimethylpyrrolidine, 3,4-dimethylpyrrolidine, acepine or pipecoline; R6 is = C = CH2, = CH (C1-C5 alkyl), = CH (alkenyl) C2-C5), = C = CH (C1-C5 alkyl), = CH (aryl), = C (OH) (C1-C5 alkyl), = C (OH) (C2-C5 alkenyl), = C (OH) aryl, and pharmaceutically acceptable salts thereof. The present invention additionally provides pharmaceutical compositions containing compounds of formula (I) which optionally contains estrogen or progestin, and the use of such compounds alone or in combination with estrogen or progestin, to alleviate the symptoms of post-menopausal syndrome, particularly osteoporosis, cardiovascular related pathological conditions and estrogen-dependent cancer. As used herein, the term "progestin" includes compounds that have progestational activity such as, for example, progesterone, norethylnodrel, megestrol acetate, norethindrone, and the like. The compounds of the present invention are also useful for inhibiting uterine fibroid disease and endometrosis in women and the proliferation of smooth muscle cells in the aorta, particularly human restenosis.

Description

COMPOSITES PHARMACEUTICALS NOVEDOS OF HAFTILO DESCRIPTION OF THE INVENTION This invention relates to the fields of pharmaceutical and organic chemistry and provides novel naphthyl compounds which are useful for the treatment of various indications or medical disorders associated with postmenopausal syndrome and uterine fibroid disease, endometriosis and proliferation of smooth muscle cells. in the aorta. The "postmenopausal syndrome" is a term used to describe various pathological conditions which often affect women who have entered or are completely in a physiological metamorphosis known as menopause. Although numerous pathologies are contemplated by the use of this term, the three main effects of postmenopausal syndrome are the source of long-term medical concern: osteoporosis, cardiovascular effects such as hyperlipidemia and estrogen-dependent cancer, particularly breast and uterine cancer. Osteoporosis describes a group of diseases that arise from different etiologies, but which are characterized by a net loss of bone mass by REF: 25331 unit volume. The consequence of this loss of bone mass and the resulting bone fracture is the failure of the skeleton to provide adequate structural support for the body. One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone in the next 3 to 6 years after they stop menstruating. This rapid loss is generally associated with an increase in bone resorption and information. 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. An estimate of 25 million women in the United States, only, who are affected with this disease. The results of osteoporosis are personally harmful and are also considered a large economic loss due to their chronicity and the need for extensive and long-term support (hospitalization and home care by nurses) from the aftermath of the disease. This is especially true in older patients. Additionally, although osteoporosis is not generally considered a life-threatening condition, a mortality rate of 20% to 30% is related to hip fractures in older women.A large percentage of this mortality rate can be associated directly with postmenopausal osteoporosis The most vulnerable tissue in bone that affects postmenopausal osteoporosis is trabecular bone.This tissue is often referred to as cancellous or cancerous bone and is particularly concentrated near the ends of the bone (near the 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 a more solid and dense cortical tissue which constitutes the outer surface and the central axis of the bone. of trabeculae provides lateral support to the outer cortical structure and is critical for the Biomechanics of the total structure. In postmenopausal osteoporosis, it is mainly the net resorption and loss of trabeculae which leads to bone failure and fracture. Based on the loss of trabeculae in postmenopausal women, it is not surprising that the most common fractures are those associated with bones which depend to a large extent on trabecular support, for example vertebrae, the neck of bones that support weight such as the femur and the forearm. In fact, hip fracture, coccis fractures, and pressure fractures of the vertebrae are instinctive for postmenopausal osteoporosis. At this time, the only 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. During the premenopausal period, most women do not have a lower incidence of cardiovascular disease compared to men of the same age. However, after menopause, the rate of cardiovascular disease in women increases slowly until it is identical to the rate seen 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 has not been well understood, but evidence to date indicates that estrogen can upregulate low-density lipid (LDL) receptors in the liver to eliminate excess of cholesterol. Additionally, estrogen seems to have some effect on cholesterol biosynthesis, and other beneficial effects on cardiovascular health. It has been reported in the literature that postmenopausal women who have estrogen replacement therapy have a return to serum lipid levels at concentrations similar to those in the premenopausal state. Therefore, estrogen seems to be a reasonable treatment for this condition, however, the side effects of estrogen replacement therapy are not acceptable for many women, so the use of this therapy is limited. An ideal therapy for this condition would be an agent which will regulate the level of serum lipids as estrogen does, but which lacks the side effects and risks associated with estrogen therapy. The third major pathology associated with postmenopausal syndrome is estrogen-dependent breast cancer and, to a lesser extent, estrogen-dependent cancers of other organs, particularly the uterus. Although such "neoplasms are not only limited to a postmenopausal woman, they are more prevalent in the older, menopausal population." Current chemotherapy of these cancers is based primarily on the use of antiestrogen compounds such as, for example, tamoxifen. such mixed agonist-antagonists have beneficial effects in the treatment of these cancers, and the estrogenic side effects are tolerable in acute situations where life is in danger, are not ideal.For example, these agents can have stimulatory effects on certain populations of cancer cells In the uterus due to its estrogenic properties (agonists) and therefore may be counterproductive in certain cases.A better therapy for the treatment of these cancers would be an agent which was an antiestrogenic agent that had negligible or no estrogen agonist properties on reproductive tissues. In response to the clear need for new pharmaceutical agents which are capable of alleviating the symptoms of, for example, postmenopausal syndrome, the present invention provides novel naphthyl compounds, pharmaceutical compositions thereof and methods for using such compounds for the treatment of postmenopausal syndrome and other pathological conditions related to estrogen such as those mentioned below. Uterine fibrosis (uterine fibroid disease) is an old and always present clinical problem which is known under various names, including uterine fibroid disease, uterine hypertrophy, uterine leiomyomata, myometrial hypertrophy, fibrosis of the uterus and fibrotic metritis. Essentially, uterine fibrosis is a condition in which there is an inappropriate deposition of fibroid tissue in the wall of the uterus. This condition is a cause of dysmenorrhea and infertility in women. The exact cause of this condition is poorly understood, but the evidence suggests that there is an inappropriate response of fibroid tissue to estrogen. Such a condition has occurred in rabbits by daily administrations of estrogen for 3 months. In guinea pigs, the condition has been produced by daily administration of estrogen for four months. In addition, in rats, estrogen produces similar hypertrophy. The most common treatment of uterine fibrosis involves both costly surgical procedures and is sometimes a source of complications such as the formation of abdominal adhesions and infections. In some patients, the initial surgery is only a temporary treatment and the fibroids grow back. In some cases a hysterectomy is performed which ends effectively with the fibroids, but also with the patient's reproductive life. In addition, antagonists of the gonadotropin-releasing hormone can be administered although their use is limited by the fact that they can produce osteoporosis. Therefore, there is a need for new methods to treat uterine fibrosis and the methods of the present invention meet that need. Endometriosis is a condition of severe dysmenorrhea, which is accompanied by severe pain, bleeding into the endometrial mass or peritoneal cavity and often leads to infertility. The cause of symptoms of this condition seems to be ectopic endometrial growths which respond inappropriately to normal hormonal control and are located in inappropriate tissues. Due to the inappropriate positions of the endometrial growth, the tissue seems to initiate local responses similar to the inflammatory ones that cause macrophage infiltration and a cascade of phenomena that lead to the onset of a pain response. The exact phylogeny of this disease is not well understood and its treatment by hormonal therapy is diverse, has been little defined and is marked by unwanted and perhaps dangerous side effects. One of the treatments for this disease is the use of estrogen at low doses to suppress the growth of the endometrium through a negative feedback effect on the release of central gonadotropin and the subsequent production of estrogen in the ovaries, - however, some Sometimes it is necessary to use continuous estrogen to control the symptoms. This use of estrogen often leads to unwanted side effects and even the risk of endometrial cancer. Another treatment consists of the continuous administration of progestins which induces amenorrhea and by suppression of the production of estrogen in the ovary can cause regressions of growth of the endometrium. The use of chronic progestin therapy is often accompanied by unpleasant side effects in the CNS of progestins and often leads to infertility due to suppression of ovarian function. A third treatment consists in the administration of weak androgens, which are effective in controlling endometriosis, - however, they induce serious masculinizing effects. Several of these treatments for endometriosis have also been implicated in the cause of a moderate degree of bone loss with continuous therapy. Therefore, new methods for treating endometriosis are desirable. The proliferation of smooth muscle cells in the aorta plays an important role in diseases such as atherosclerosis and restenosis. It has been shown that vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA) "is a tissue response characterized by an early and a delayed phase.The early phase occurs from a few hours to days after the PTCA and is due to the thrombosis with certain vasospasms while the late phase appears to be dominated by excessive proliferation and migration of smooth muscle cells from the aorta.In this disease, increased cell motility and colonization by muscle cells and macrophages contribute significantly to pathogenesis of the disease Excessive proliferation and migration of vascular smooth muscle cells of the aorta may be the main mechanism for reocclusion of coronary arteries after PCTA, atherectomy, laser angioplasty and arterial bypass graft surgery. See "Intimal Proliferation of Smooth Muscle Cells as an Explanation for Recurrent Coronary Artery Stenosis after Percutaneous Transluminal Coronary Angioplasty," Austin et al. , Journal of the American College of Cardiology. £, 369-375 (August 1985). Vascular restenosis remains the main long-term complication after surgical intervention of arteries blocked by percutaneous transluminal coronary angioplasty (PCTA), atherectomy, laser angioplasty and arterial bypass graft surgery. In approximately 35% of patients who undergo PTCA, reocclusion occurs in the following three to six months after the procedure. Current strategies for treating vascular restenosis include mechanical intervention by devices such as stents or pharmacological therapies including heparin, low molecular weight heparin, coumarin, aspirin, fish oil, calcium antagonists, steroids and prostacyclin. These strategies have failed to prevent the speed of reocclusion and have been ineffective in the treatment and prevention of vascular restenosis. See "Prevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty: The Search for a 'Magic Bullet'," Hermans et al., American Heart Journal, 122: 171-187 (July 1991). In the pathogenesis of restenosis there is an excessive proliferation and migration of cells as a result of growth factors produced by cellular substituents in the blood and the wall of the damaged arterial vessels which mediate the proliferation of smooth muscle cells in vascular restenosis. Agents that inhibit the proliferation and / or migration of smooth muscle cells of the aorta are useful in the treatment and prevention of restenosis. The present invention provides the use of compounds as inhibitors of the proliferation of smooth muscle cells of the aorta and therefore as inhibitors of restenosis. The present invention relates to compounds of formula I wherein Rj is H, OH, halo, OCO (Cx-C6 alkyl), OCO (aryl), OS02 (C4-C6 alkyl), OCOO (CX-C6 alkyl), OCOO (aryl), OCONH (C ^ C alkyl or OCON (alkyl) Ca-C6) R2 is aryl, C3-C6 cycloalkyl alkyl or 4-cyclohexanol; R3 is 0 (CH2) 2 or 0 (CH2) 3; R4 and Rs are optionally C0 (CH2) 2CH3, C0 (CH2) 3CH3, CJ-CJ alkyl, or R4 and R5 combine to form, with the nitrogen to which piperidine, morpholine, pyrrolidine, 3-methylpyrrolidine, are attached. , 3-dimethylpyrrolidine, 3,4-dimethylpyrrolidine, azepine or pipecoline; R6 is ^ C = CH2, CH (C? -C5 alkyl), CH (C2-C5 alkenyl), "C = CH- (C1-C5 alkyl), xCH (aryl), C (OH) (C 1-C 3) C (OH) (ßlqußollo dβ C a-C3) r ^ cfOH ^ ßlilO- and pharmaceutically acceptable salts thereof. The present invention is further related to pharmaceutical compositions containing compounds of formula I, and optionally containing estrogen or progestin, and with the use of such compounds, alone or in combination with estrogen or progestin to alleviate the symptoms of postmenopausal syndrome, particularly osteoporosis, cardiovascular related pathological conditions and estrogen-dependent cancer. As used herein, the term "estrogen" includes steroidal compounds that contain estrogenic activity such as, for example, 173-estradiol, estrone, conjugated estrogen (Premarin ™), equine estrogen, 17 / S-ethinylestradiol, and the like. As used herein, the term "progestin" includes compounds that have progestational activity such as, for example, progesterone, norethylnodrel, nongestrel, megestrol acetate, norethindrone, and the like. The compounds of the present invention are also useful for inhibiting uterine fibroid disease and endometriosis in women and proliferation of smooth muscle cells of the aorta, particularly restenosis, in humans. Another aspect of the present invention includes compounds of the formula I where R *. is H, OH, halo, OCO (C-C6 alkyl), OCO (aryl), 0S02 (C4-C6 alkyl), 0C00 (Cx-C6 alkyl), OCOO (aryl), OCONH (C-alkyl) ^ C or OCON (alkyl of R2 is aryl, C3-C6 cycloalkyl alkyl or 4-cyclohexanol; R 3 is 0 (CH 2) 2 O 0 (CH 2) 3; R4 and Rs are optionally CO (CH2) 2CH3, C0 (CH2) 3CH3, alkyl of -Cj, or R4 and R5 combine to form, with the nitrogen to which they are attached piperidine, morpholine, pyrrolidine, 3-methylpyrrolidine, 3, 3-dimethylpyrrolidine, 3, 4-dimethylpyrrolidine, azepine or pipecoline; is C = CH2, "CH (C? -C5 alkyl), CH (C2-C5 alkenyl), C = CH - (C 1 -C 5 alkyl), CH (aryl), / XC (OH) (ßlflilo d? C 1-C3), X / C (OH) (ßlfJßn ± lo d? C a-C3), N ^ VoWHl Bß-riillnU, -and pharmaceutically acceptable salts thereof. The general terms used in the description of the compounds described herein have their usual meaning. For example, "alkyl" refers to aliphatic or branched chains of 2 to 6 carbon atoms including ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like. Similarly, the term "C2-C6 alkene" represents linear or branched alkenes having 2 to 6 carbons and including propylene, ethylene, isopropylene, butylene, n-butylene, hexylene, pentylene and the like. The term "aryl" includes phenyl optionally substituted 1 to 3 times with haloalkoxy alkyl, amino, nitro or hydroxy.

Preparation of Naphthyl The starting material for a preparation pathway of compounds of the present invention occurs essentially as produced in U.S. Patent No. 4,230,862 filed October 28, 1980, which is incorporated herein by reference.

In general, a tetralone readily available or a salt thereof, of the formula wherein R7 is a hydroxy protecting group, it is reacted with an acylating agent such as phenyl benzoate of the formula wherein R3, R4 and R5 are as defined above. The reaction is generally carried out in the presence of a moderately strong base such as sodium amide and is carried out at room temperature or a lower temperature. The preferred hydroxy protecting group is C 1 -C 1 alkyl and methyl is especially preferred. See, for example, the US patents incorporated above, J. W. Barton, "Protective Groups in Organic Chemistry," J. G.. McOmie (ed.), Plenum Press, New York / NY, 1973, Chapter 2, and TW Green, "Protective Groups in Organic Synthesis," John Wiley and Sons, New York, NY, 1981, Chapter 7. For the next stage , the product is converted to an enolophosphate derivative generated in itself with reaction of the enol with a phosphonate precursor such as C1P (0) (OPh) 2 and the appropriate base. Subsequent reaction with a Grignard reagent (R2MgBr) or cuprate reagent (R2CuLi) or another species of nucleophilic carbon provides compounds of formula III below, some of which are known in the art (see, for example, U.S. Patent No. 4,230,862, supra): III wherein R2, R3, R4, Rs and R7 are as defined above, or a pharmaceutically acceptable salt thereof.

Subsequently, compound III is subjected to selective dehydrogenation of the 3,4-dihydro group. This can be carried out by treatment with 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (DDQ) at a temperature of about 50 * C to about 100 * C. This results in a compound of formula II.

II The compounds of formula II represent the starting material for a process for preparing the pharmaceutically active compounds of formula I. The a (carboxy) carbon can then be modified to the groups defined by R6, when R6 is C (OH) (Ci-Cs alkyl), C (OH) (C2-C5 alkenyl), aryl A group such as RLi, RMgX or another nucleophilic species at the carbon where R is C2-C5 alkenyl alkyl or aryl, is added to a compound of formula II in a suitable solvent as previously defined, at a temperature from 0 to -85 * C. After a sufficient amount of time has been supplied (15 minutes to 20 hours) to allow completion of the reaction, saturated aqueous sodium bicarbonate is added and the mixture is extracted, and the combined extracts are washed, dried, filtered, concentrate and purify to produce a compound of formula la. For the groups in which R6 is CH (to <? Uilo of C i-Cg), CH (alkynil d? C to-C5), or XCH (aryl), the a-hydroxy group is reduced from the above compound with a reducing agent, such as triethylsilane, followed by the addition of an acid such as trifluoroacetic acid. After a sufficient period (15 minutes to 24 hours), the reaction is suspended for example by the use of a mixture of ethyl acetate / saturated aqueous sodium bicarbonate. The mixture is extracted and the organic fractions are dried, dried, filtered and concentrated and purified to yield the compound of formula Ib. Alternative methods for accomplishing this include: (a) trialkylsilane with a Lewis acid such as Et 2 AlCl 2 or BF 3 * Et 20 (boron trifluoride etherate); (b) hydrogenolysis (H2) with a catalyst such as palladium on carbon. In addition, dichlorodimethylsilane followed by sodium iodide is effective. When Rs is a group of the formula (C1-C5 alkyl), an appropriate compound of formula la in an appropriate solvent if it cools from 10 * C to -25 * C. Subsequently, the hydroxy group is eliminated. Such elimination can be carried out by adding a base such as dimethylaminopyridine (DMAP) followed by the addition of methanesulfonyl chloride, followed again by DMAP. Alternatively, the desired alkenes can be prepared by reacting the carbonyl compound with a phosphonium hulide such as R2 + P-CH (alkyl) Other organophosphorus compounds such as Ar2P (0) CHR can also be used or (RO) 2P (0) CHR, (Boutagy et al., Chem Reviews, 74, 87 (1974)). Other compounds are prepared by substituting the hydroxyl groups Rx and R2 with a portion of the formula -O-CO- (Ci-Cg alkyl), -O-CO-Ar in which Ar is optionally substituted phenyl, or -0 -S02- (C4-C6 alkyl), via a well-known process. See, for example, U.S. Patent No. 4,358,593, supra. For example, when a group is desired -0-C0 (alkyl of o -0-CO-Ar, the dihydroxy compound of formula I is reacted with an agent such as an acyl chloride, bromide, cyanide or azide, or with a suitable anhydride or is mixed with an Anhydride The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline 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, such as a tertiary amine, have been added. it can use acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine, see, for example, Haslam, et al., Tetrahedron, 3_6_: 2409-2433 (1980). The Rx and R2 groups mentioned above are carried out at moderate temperatures in the range from about -25 ° C to about 100 ° C, often under an inert atmosphere such as nitrogen gas. However, the room temperature is usually adequate for the reaction to be carried out. Such acylations of the hydroxy group can also be carried out by reactions catalyzed by acid of the appropriate carboxylic acids in inert organic solvents or with heat. Acid catalysts such as sulfuric acid, phosphoric acid, methanesulfonic acid and the like are those which are used. The Rx and R2 groups mentioned above can also be provided by forming an active ester of the appropriate acid such as the esters formed by known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide and 1-hydroxybenzotriazole. See, for example, Bull. Chem. Soc. Japan. 3_8_: 1979 (1965), and Chem. Ber .. 788 and 2024 (1970). Each of the above techniques which provide -O-CO- (C1-C6 alkyl) and -O-CO-Ar groups are carried out in solvents as described above. These techniques, which do not produce an acid product in the course of the reaction, of course, do not require the use of an acid scavenger in the reaction mixture.

When a compound of formula I is desired in which Rx and R2 are -0-S02- (C4-C6 alkyl), the dihydroxy compound of formula I is reacted with, for example, an appropriate sulfonic acid derivative such as sulfonyl chloride, bromide or the ammonium sulfonyl salt, as described by King and Monoir, J. Am. Chem. Soc. 97: 2566-2567 (1975). The dihydroxy compound can also react with the appropriate sulfonic anhydride. Such reactions are carried out under conditions such as those explained above in the discussion of reaction with acid halides and the like. The compounds of formula I can be prepared so that Rx and R2 have different biological protecting groups or, preferably, are prepared according to each of R? and R2 has the same biological protective group. Preferred protecting groups include -0CH3, -0-C0-C (CH3) 3, -0-C0-C6H5 and -0-S02- (CH2) 3-CH3. Although the compounds of formula I can be used in free base form in the methods of the present invention, it is preferred to prepare and use the pharmaceutically acceptable salt form. Therefore, 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 physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts also form part of this invention. Typical inorganic acids used to form the salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like. Salts derived from organic acids such as mono- and dicarboxylic aliphatic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxy-aldoic acid, aliphatic and aromatic sulfonic acids can also be used. Such pharmaceutically acceptable salts include, therefore, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β- hydroxybutyrate, butyne-l, 4-dioate, hexane-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxyalate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethane-sulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensu lphonate, xylene sulfonate, tartrate and the like. A preferred salt is the hydrochloride salt. The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess acid amount. The reagents are generally combined in a mutual solvent such as diethyl ether or ethyl acetate. The salt is usually separated by precipitation from the solution in about one hour to 10 days and can be isolated by filtration or the solvent can be removed by distillation by conventional means. The pharmaceutically acceptable salts generally have characteristics of increased solubility as compared to the compound from which they are derived, and are often more susceptible to formulation as liquids or emulsions. The following examples are presented to further illustrate the preparation of compounds of the present invention. It is not desired that the invention be limited in scope by reason of any of the following examples.

XH NMR and 13C NMR are measured as indicated at 300 and 75, respectively. The chemical shifts of XH NMR are reported as d values in ppm, relative to the NMR of the solvent used. The coupling constants of 1 H NMR are reported in Hz (Hz) and are mentioned as apparent multiplicities. The multiplicity is indicated as follows, s (singlet); d (doublet), t (triplet), c (quartet); m (multiplet); com (complex), a (broad) and ap (apparent) Column chromatography is carried out according to the method of Stil (Still, C., Kahn, M., Mitra, AJ Org. Chem. 1978, 43, 2923) unless indicated otherwise by gel EM Science silica (230-400 mesh ASTM). Radial chromatography is carried out on a Chromatotron using 1, 2 or 4 mm plates. All air and / or moisture sensitive reactions are carried out under argon or under a nitrogen atmosphere in carefully dried glassware. In all cases, the concentrations are carried out under reduced pressure with a rotary evaporator. Preparation 1 II To a solution of compound II (R2 = ArOH) with the unprotected 4 'and 6-hydroxy groups (1.00 g), stirred in THF (20 ml) at room temperature, add N, N-dimethylaminopyridine (1.00 g) followed by t-butyldimethylsilyl chloride (0.90 g). After 12 hours, the reaction is diluted with water and extracted with chloroform. The combined organic extracts are dried (sodium sulfate) and concentrated. The oil is treated in ethyl acetate and the resulting precipitate is filtered off. The filtrate is concentrated and purified by flash chromatography (silica gel, ethyl acetate) to provide the desired product. g-jftmplr) 1 To a solution of the product of Preparation 1, (2.04 g) stirring at -78 ° C in THF (10 mL) is added MeLi (4.16 mL of a 1.4 M solution in diethyl ether) dropwise. After 15 minutes, the reaction is stopped with an excess of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO 4), filtered and concentrated. The resulting material is purified by radial chromatography (silica gel, 4 mm 2.5: 2.5: 0.1: 0.1 exanos: ethyl acetate: triethylamine: MeOH) to provide the desired product.

Example 2 To a solution of the product of Example 1 (0.50 g) stirred in THF (5 ml) at O'C is added tetrabutylammonium fluoride (1.74 ml of a 1.0 M solution in THF).

After 15 minutes, saturated aqueous sodium bicarbonate is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO 4), filtered and concentrated. The resulting material is purified by radial chromatography (silica gel, 2 mm, 2.5: 2.5: 0.1: 0.1 hexanes: ethyl acetate: MeOH: triethylamine) to provide the desired product.

Example .

To a solution of the product of Example l (1.77 g) stirred in CH2C12 (50 ml) at 0 * C added triethylsilane (2.36 ml), followed by trifluoroacetic acid (4.72 ml). After 15 minutes, the reaction is stopped by carefully pouring the reaction mixture into a mixture of ethyl acetate / saturated aqueous sodium bicarbonate. The biphasic mixture is extracted with ethyl acetate and the combined organic extracts are washed with brine, dried (MgSO), filtered and concentrated.The resulting material is purified by radial chromatography (silica gel, 2 mm, 2.5: 2.5: 0.1: 0.1 hexanes: ethyl acetate: triethylamine: eOH) to provide the desired product.

Example 4 To a solution of the product of Example 3 (0.50 g) stirred in THF (5 ml) at 0 * C is added tetrabutylammonium fluoride (1.78 ml of a 1.0 M solution in THF). After 15 minutes, the reaction is stopped by the addition of saturated aqueous sodium bicarbonate. The resulting mixture is extracted with ethyl acetate and the combined organic extracts are subsequently washed with brine, dried (MgSO 4), filtered and concentrated. The resulting material is purified by radial chromatography (silica gel, 2 mm, 2.5: 2.5: 0.75: 0.25 hexanes: ethyl acetate.-MeOH: triethylamine) to provide the desired product.

± SSRl? _5_ To a solution of the product of Example 1 (1.70 g) stirred in CH2C12 (20 mL) at 0 * C added N, N-dimethylaminopyridine (461 mg), followed by methanesulfonyl chloride (0.27 mL). After half an hour, a second portion of N, N-dimethylaminopyridine (461 mg) is added and the solution allowed to warm to room temperature. After 20 hours, the reaction mixture is poured into brine and subsequently extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO 4), filtered and concentrated. Purification by radial chromatography (silica gel, 2 mm, 2.5: 2.5: 0.1: 0.1 hexanes: ethyl acetate: triethylamine: MeOH) gives the desired product. * 1fflitT? F To a solution of the product of Example 5 (0.42 g) stirred with THF (5 ml) at 0 * C was added tetrabutylammonium fluoride (1.51 ml of a 1.0 M solution, in THF). After 15 minutes, saturated aqueous sodium bicarbonate is added to the reaction and the mixture is subsequently extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO 4), filtered and concentrated. The resulting material is purified by radial chromatography (silica gel, 2 mm, 2.5: 2.5: 0.70: 0.30 g of ethyl hexamethyl ester: MeOH: triethylamine) to provide the desired product.

Example 7 To a solution of the product of Preparation 1 (1.00 g) stirred at -78 * C PhLi (1.6 ml of a 1.8 M solution) is added. After 15 minutes, saturated aqueous sodium bicarbonate is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO 4), filtered and concentrated. Purification of the crude material by radial chromatography (4 mm, silica gel, 2 . 5: 2 5 : . 01:. 005 ethyl acetate: hexane: triethylamine: MeOH) gives the desired product. ^ y ^ r? 1 ^ y To a solution of the product of Example 7 (0.50 g) stirred in THF (5 mL) at 0 ° C is added tetrabutylammonium fluoride (1.60 mL of a 1.0 M solution in THF).

After 15 minutes, saturated aqueous sodium bicarbonate is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO 4), filtered and concentrated. The resulting material is purified by radial chromatography (silica gel, 2 mm, 2.5: 2.5: 0.1: 0.1 hexanes: ethyl acetate: MeOH: triethylamine) to provide the desired product.

PROOF PROCEDURE General Preparation Procedure In the examples that illustrate the methods, a postmenopausal model is used in which the effects of different treatments against circulating lipids are determined. Female 75-day-old Sprague Dawley rats (weight range 200 to 225 g) are obtained from Charles River Laboratories (Portage, MI). The animals were ovariectomized (OVX) bilaterally or were exposed to a false surgical procedure in Charles River Laboratories, and then they were sent after a week.

Upon arrival, they were placed in metal hanging cages in groups of 3 or 4 per cage and had ad libium access to the feed (calcium content of approximately 0.5%) and water for a week. The temperature of the room was maintained at 22.2 * ± 1.7 * C with a minimum relative humidity of 40%. The lighting period in the room is 12 hours of light and 12 hours of darkness.

Fabric Collection of the Dosing Regimen. After a one-week acclimation period (therefore, two weeks after the OVX) daily dosing with the test compound is started. 17ar-ethinylestradiol or the test compound is administered orally, unless otherwise indicated, as a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. The animals were dosed daily for 4 days. After the dosing regimen, the animals were weighed and anesthetized with a mixture of ketamine: Xylazine (2: 1, V: V) and blood samples were collected by cardiac puncture. After the animals are sacrificed by asphyxia with C02, the uterus is removed through incision in the midline and the wet uterine weight is determined.

Cholesterol analysis. The blood samples are allowed to coagulate at room temperature for 2 hours and the serum is obtained after centrifugation for 10 minutes at 3000 rpm. Serum cholesterol is determined using a high resolution cholesterol assay from Boehringer Mannheim Diagnostics. Briefly, cholesterol is oxidized to Colest-4-en-3-one and hydrogen peroxide. The hydrogen peroxide then reacts with phenol and 4-aminophenazone in the presence of peroxidase to produce a p-quinonaimine dye which is read spectrophotometrically at 500 nm. Subsequently, the cholesterol concentration is calculated against a standard curve. The entire assay is automated using a Biomek Automated Workstation.

Uterine Peroxidase Eosinophilic Assay (EPO). The uteri are kept at 4 * C until the moment of the enzymatic analysis. Subsequently the uteri are homogenized in 50 volumes of 50 mM Tris buffer (pH - 8.0) containing Triton X-100 at 0.005%. After the addition of 0.01% hydrogen peroxide and 10 mM O-phenylenediamine (final concentrations) in Tris buffer, the increase in absorbance is verified for one minute at 450 nm. The presence of eosinophils in the uterus is an indication of estrogenic activity of a compound. The maximum velocity of a 15 second interval is determined on the initial linear portion of the reaction curve.

Source of Compound: 17o-ethinylestradiol is obtained from Sigma Chemical Co., St. Louis, MO.

Osteoporosis Test Procedure Following the general preparation procedure, infra, the rats are treated daily for 35 days (6 rats per treatment group) and slaughtered by asphyxiation with carbon dioxide on day 36. The 35-day time period is sufficient to allow maximum reduction in bone density, measured as described herein. At the time of sacrifice, the uteri are removed, dissected free of foreign tissue and the defined contents are expelled before the determination of wet weight in order to confirm the estrogen deficiency associated with complete ovariectomy. The uterine weight is usually reduced by approximately 75% in response to ovariectomy. The uteri are then placed in 10% neutral buffered formalin to allow subsequent histological analysis. The right femurs are extracted and X-rays generated and analyzed by an image analysis program (NIH image) in the distal metaphysis are digitized. The proximal aspect of the tibias of these animals is also examined by quantitative computed tomography.

According to the above procedures, the compounds of the present invention and ethinyl estradiol (EE2) in 20% hydroxypropyl jS-cyclodextrin are orally administered to the test animals. In summary, the ovariectomy of the test animals places a significant reduction in the density of the femur, compared to the intact, vehicle-treated controls. Oral estradiol administered orally (EE2) emits this loss, but the risk of uterine stimulation with this treatment is always present. The compounds of the present invention prevent bone loss in a general dose-dependent manner.

Accordingly, the compounds of the present invention are useful for the treatment of postmenopausal syndrome, particularly osteoporosis.

MCF-7 Proliferation Assay Breast adenocarcinoma cells are maintained MCF-7 (ATCC HTB 22) in MEM (minimal essential medium, free of phenol red, Sigma, St. Louis, MO) supplemented with 10% fetal bovine serum (FBS) (v / v), L-glutamine ( 2 mM), sodium pyruvate (1 mM), HEPES. { (N- [2-hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid] 10 mM.), Non-essential amino acids and bovine insulin (1 μg / ml) (maintenance medium) Ten days before the test, the MCF-7 cells are changed to maintenance media supplemented with assay medium and 10% purified dextran-coated carbon in fetal bovine serum (DCC-FBS) instead of 10% FBS to kill the internal steroid accumulators. MCF-7 are separated from the maintenance flasks using a cell dissociation medium (Ca ++ / Mg ++ free HBSS (free of phenol red) supplemented with 10 mM HEPES and 2 mM EDTA) .The cells are washed twice with medium test and fit 80, 000 cells / ml. Approximately 100 μl (8000 cells) are added to flat bottom microculture plates (Costar 3596) and incubated at 37 ° C in a 5% C02 modified incubator, for 48 hours, to allow cell adhesion and balance after Serial dilutions of the drugs or DMSO are prepared as a diluent control in a test medium and 50 μl are transferred in triplicate to microcultures, followed by 50 μl of assay medium for a final volume of 200 μl. An additional 48 hours at 37 ° C in a humidified incubator with 5% C02, the microcultures are pulsed with tritiated thymidine (1 uCi / well) for 4 hours.The cultures are finished by freezing at -70 ° C for 24 hours and then reheat and harvest the microcultures using a Skatron semiautomatic cell harvester.The samples are counted by liquid scintillation using a Wallac BetaPlace ß counter.

Inhibition of mammary tumor induced by DMBA Estrogen-dependent mammary tumors are produced in female Sprague-Dawley rats which are purchased from Harlan Industries, Indianapolis, Indiana. At approximately 55 days of age, the rats receive a single oral feed of 20 mg of 7,12-dimethylbenz [a] anthracene (DMBA). Approximately 6 weeks after the administration of DMBA, the mammary glands are palpated at weekly intervals to determine the appearance of tumors. Whenever one or more tumors appear, the larger and shorter diameters of each tumor are measured with a metric gauge, the measurements are recorded and that animal is selected for experimentation. An attempt is made to uniformly distribute the various sizes of tumors in the treated and control groups so that tumors of average size are distributed excellently between the test groups. The control groups and the test groups for each experiment contain 5 to 9 animals.

The compounds of formula I are administered either through intraperitoneal injections in 2% acacia, or orally. Orally administered compounds are dissolved or suspended in 0.2 ml of corn oil. Each treatment, which includes control treatments with acacia and corn oil, is administered once daily to each test animal. After the initial tumor measurement in the selection of the test animals, the tumors are measured every week by the method mentioned above. The treatment and measurement of the animals continues for 3 to 5 weeks, time in which the final areas of the tumors are determined. For each compound and control treatment, the change in the mean tumor area is determined.

Test Procedures for Uterine Fibrosis Test 1 Between 3 and 20 women who present uterine fibrosis are administered a compound of the present invention. The amount of the compound administered is between 0.1 and 1000 mg / day and the administration period is 3 months.

Women are observed during the period of administration, and up to 3 months after stopping the administration, to determine effects on uterine fibrosis.

Test 2 The same procedure is used as in test l, except that the administration period is 6 months.

Test 3 The same procedure is used as in test l, except that the administration period is 1 year.

Test 4 A. Induction of fibroid tumors in guinea pigs Prolonged stimulation with estrogen is used to induce leiomyomata in sexually mature female guinea pigs. The animals are dosed with estradiol 3-5 times per week by injection for 2-4 months or until the tumor arises. The treatments consist of a compound of the invention or vehicle that is administered daily for 3-16 weeks and then the animals are sacrificed and the uteri are collected and analyzed for tumor regression.

B. Implantation of human uterine fibroid tissue in atypical mice The tissue of human leiomyomas is implanted in the peritoneal cavity and in the uterine myometrium of female, castrated, sexually mature atlanic mice. Exogenous estrogens are supplied to induce growth of the explanted tissue. In some cases, the collected tumor cells are cultured in vi tro before implantation. The treatment consists of a compound of the present invention or a vehicle that is delivered by gastric tube feeding on a daily basis of 3-16 weeks and the implants are removed and measured for growth or regression. At the time of sacrifice, the uteri are collected to determine the state of the organ.

Test 5 A. Tissue from human uterine fibroid tumors is collected and maintained in vi tro as primary non-transformed cultures. Surgical specimens are pushed through a sterile mesh or sieve, or alternatively cut and they separate from the surrounding tissue to produce a single cell suspension. The cells are maintained in medium containing 10% serum and antibiotic. Growth rates are determined in the presence and absence of estrogen. The ability to produce the complement component C3 by the cells and their response to growth factors and growth hormone is determined. In vitro cultures are carried out to determine their proliferative response after treatment with progestins, GnRH, a compound of the present invention and a vehicle. The levels of steroid hormone receptors are determined weekly to determine if important cell characteristics are maintained in vi tro. Tissue of 5-25 patients is used. The activity of at least one of the above tests indicates that the compounds of the present invention are of potential in the treatment of uterine fibrosis.

Test Procedure for Endometriosis In tests 1 and 2, the eff of 14 days and 21 days of administration of the compounds of the present invention on the growth of explanted endometrial tissue can be examined.

Test 1 Twelve to thirty female rats of the adult CD strain are used as test animals. They are divided into three groups of equal numbers. The estrous cycles of all the animals are verified. On the day of the proestrus, surgery is performed on each female. The females in each group have a left uterine removed, soned into small squares and the boxes are sutured loosely at various sites adjacent to the more enteric blood flow. In addition, the females in group 2 have their ovaries removed. On the day after surgery, animals in groups 1 and 2 receive intraperitoneal injons of water for 14 days, while animals in group 3 receive intraperitoneal injons of 1.0 mg of a compound of the present invention per kilogram of weight body, during the same duration. After 14 days of treatment, each female is sacrificed and the explants of the endometrium, the adrenal glands, the remaining uterus and the ovaries are extracted, when applicable, for histological examination. The ovaries and adrenals are weighed.

Test 2 Twelve to thirty adult female rats of the CD strain were used as test animals. They are divided into two equal groups. The estrus cycle of all the animals is verified. On the day of proestrus, surgery is performed on each female. The females in each group are removed with the left uterine thrombus, cut into small squares and the squares are sutured loosely in various sites adjacent to the mesenteric blood flow. Approximately 50 days after surgery, animals are assigned to group 1 to receive intraperitoneal injons of water for 21 days, while animals in group 2 received intraperitoneal injons of 1.0 mg of a compound of the present invention per kilogram of weight body, during the same duration. After 21 days of treatment, each female is sacrificed and the endometrial and suprarenal explants are weighed and weighed. The explants are measured as an indication of growth. The estrus cycles are verified.

Test 3 A. Surgical induction of endometriosis Autographs of endometrial tissue are used to induce endometriosis in rats and / or rabbits. Female animals in reproductive maturity underwent bilateral cofrmy, and estrogen is delivered exogenously, providing a specific and constant hormone level. Autologous endometrial tissue is implanted in the peritoneum of 5-150 animals and estrogen is supplied to induce the growth of the explanted tissue. The treatment consists of a compound of the present invention which is delivered by gastric tube administration on a daily basis for 3-16 weeks, and the implants are removed and measured to determine growth regression. At the time of sacrifice, the intact uterine tube is colld to determine the state of the endometrium.

B. Implantation of human endometrial tissue in atlanic mice The tissue of human endometrial lesions is implanted in the peritoneum in female, castrated, sexually mature female mice. The exogenous estrogen is supplied to induce the growth of the explanted tissue. In some cases, the colld endometrial cells are cultured in vitro before implantation. The treatment consists of a compound of the present invention delivered by gastric tube administration on a daily basis for 3-16 weeks, and the implants are removed and measured for growth or regression. At the time of sacrifice, the uteri are colld to determine the state of the intact endometrium.

Test 4 A. Tissue from human endometrial lesions is colld and maintained in vi tro as primary untransformed cultures. Surgical specimens are pushed through a mesh or sterile screen, or alternatively they are crushed and stopped from the surrounding tissue to produce a single cell suspension. The cells are maintained in medium containing 10% serum and antibiotic. Growth rates are determined in the presence or absence of estrogen. Tests are conducted to determine the ability of cells to produce the complement C3 component and its response to growth factors and growth hormone. In vitro cultures are determined to determine the proliferative response after treatment with progestins, GnRH, a compound of the invention, and a carrier. The levels of steroid hormone receptors are determined each week to determine if the important characteristics of the cells are maintained in vi tro. The tissue of 5-25 patients is used. The activity in any of the above assays indicates that the compounds of the present invention are useful in the treatment of endometriosis.

Inhibition of Proliferation of Aortic Smooth Cells / Restenosis Test Procedure The compounds of the present invention have the ability to inhibit the proliferation of smooth cells of the aorta. This can be demonstrated by the use of cultured smooth cells derived from rabbit aorta, the proliferation is determined by the measurement of DNA synthesis. The cells are obtained by the explant method as described in Ross, J. of Cell Bio. 50: 172 (1971). The cells are seeded in plates, in 96-well microtiter plates, for five days. The cells become cofluents and growth is suspended. The cells are then transferred to Dulbecco's modified Eagle's medium (DMEM) containing 0.5-2% platelet-poor plasma, 2 mM L-glutamine, 100 U / ml penicillin, 100 mg / ml streptomycin, 1 mC / ml of 3H-thymidine, 20 ng / ml of platelet-derived growth factor and variable concentrations of the present compounds. The concentrated solution of the compounds is prepared in dimethyl sulfoxide and then diluted to the appropriate concentration (0.01-30 mM) in the above assay medium. The cells are then incubated at 37 ° C for 24 hours under 5% CO 2/95% air. At the end of 24 hours, the cells are fixed in methanol. Subsequently, the incorporation of 3H-thymidine into DNA is determined by scintillation counting, as described in Bonin, et al. , Exp. Cell Res. 181: 475-482 (1989). The inhibition of the proliferation of smooth muscle cells of the aorta by the compounds of the present invention is further demonstrated by determining their effects on cells that grow exponentially. The smooth muscle cells of the rabbit aortas are seeded in 12-well tissue culture plates in DMEM containing 10% fetal bovine serum, 2 mM L-glutamine, 100 U / ml penicillin and 100 mg / ml streptomycin. After 24 hours, the cells are bound and the medium is replaced with DMEM containing 10% serum, 2 mM L-glutamine, 100 U / ml penicillin, 100 mg / ml streptomycin and the desired concentrations of the compounds. The cells are allowed to grow for 4 days. The cells are treated with trypsin and the number of cells in each culture is determined by counting using a ZM-Coulter counter. The activity of the above tests indicates that the compounds of the present invention are of potential use in the treatment of restenosis. The present invention also provides a method for alleviating postmenopausal syndrome in women, which comprises the method mentioned in the foregoing using compounds of formula I and which additionally comprises administering to a woman an effective amount of estrogen or progestin. These treatments are particularly useful for treating osteoporosis and lowering serum cholesterol because the patient will receive the benefits of each pharmaceutical agent and at the same time the compounds of the present inhibition will inhibit the undesirable side effects of estrogen and progestin. The activity of these combination treatments, in any of the postmenopausal tests, infra, indicates that the combination treatments are useful for alleviating postmenopausal symptoms in women. Various forms of estrogen and progestin are commercially available. Estrogen-based agents include, for example, ethinylestrogen (0.01-0.03 mg / day), mestranol (0.05-0.15 mg / day) and conjugated estrogenic hormones such as Premarin ™ (Wyeth-Ayerst; 0.3 2.5 mg / day). Progestin-based agents include, for example, medroxyprogesterone such as Provera ™ (Upjohn, 2.5-10 mg / day), norethylnortrel (1.0-10.0 mg / day) and nonentidrone (0.5-2.0 mg / day). A preferred estrogen-based compound is Premarin, and norethynodrel and norethindrone are the preferred progestin-based agents. The method of administration of each agent based on estrogen and progestin is consistent with those known in the art. For most of the methods of the present invention, the compounds of formula I are administered continuously, 1 to 3 times a day. However, cyclic therapy can be especially useful in the treatment of endometriosis or it can be used acutely during painful attacks of the disease. In the case of restenosis, therapy may be limited to brief intervals (1-6 months) subsequent to medical procedures such as angioplasty.

As used herein, the term "effective amount" means an amount of the compound of the present invention which is capable of alleviating the symptoms of various pathological conditions described herein. The specific dose of a compound administered according to this invention, of course, will be determined by the particular circumstances surrounding the case and including, for example, the compound administered, the route of administration, the patient's status, and the pathological condition in question. A typical daily dose will contain a non-toxic dosage level from about 5 mg to about 600 mg / day of a compound of the present invention. Preferred daily doses will generally be between about 15 mg and about 80 mg / day. The compounds of this invention can be administered by various routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal routes. Preferably, these compounds are formulated before their administration, the selection of which will be defined by the method that they serve. Therefore, another aspect of the present invention is a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, which optionally contains an effective amount of estrogen or progestin, and a carrier, diluent or pharmaceutically acceptable excipient. The total active ingredients in such formulations constitute from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable" is meant that the carrier, diluent, excipients and salt must be compatible among the other ingredients of the formulation, and must not be harmful to the recipient thereof. The pharmaceutical formulations of the present invention can be prepared by methods known in the art using well known and readily available ingredients. For example, compounds of formula I, with or without an estrogen or progestin compound, can be formulated with common excipients, diluents or carriers, and made into tablets, capsules, suspensions, powders and the like. Examples of excipients, diluents and carriers that are suitable for such formulations include the following: fillers and diluents 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 calcium carbonate and sodium bicarbonate; agents for delaying dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surfactants such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethylglycols. The compounds may also be formulated as * elixirs or solutions for convenient oral administration or as solutions suitable for parenteral administration, for example, intramuscularly, subcutaneously or intravenously. Additionally, the compounds are suitable for formulation as sustained release dosage forms and the like. The formulations can be constituted so as to release the single active ingredient or preferably in a particular physiological position, possibly over a period of time. The coatings, envelopes and protective matrices can be manufactured, for example, from polymeric substances or waxes. The compounds of formula I, alone or in combination with a pharmaceutical agent of the present invention, will generally be administered in a convenient formulation. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention.

Formulations In the formulations that follow, "active ingredient" means a compound of formula I, or a salt or solvate thereof.

Formulation 1: Gelatin capsules Gelatin capsules are prepared using the following: Ingredient Quantity (mg / capsule Active Ingredient 0.1 - 1000 Starch, NF 0 - 650 Flowable Starch Powder 0 - 650 Fluid Silicone, 350 centistokes 0 - 15 The above formulation can be changed to comply with the reasonable variations provided. A formulation for tablets is prepared using the following ingredients: Formulation 2: Tablets Ingredient 'Amount (mg / tablet) Active ingredient 2.5 - 1000 Microcrystalline cellulose 200 - 650 Smoked silicon dioxide 10 - 650 Stearic acid 5 - 15 The components are mixed and compressed to form tablets. Alternatively, tablets are made as follows, each containing 2.5-1000 mg of active ingredient.

Formulation 3: Tablets Ingredient Quantity (mg / tablet) Active ingredient 25 - 1000 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 (as a 10% solution in water) Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredient, starch and cellulose are passed through a 45 mesh North American sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders which are then passed through a North American sieve mesh number 14. The granules produced in this way are dried at 50 * -60 * C and passed through a North American sieve number 18 mesh. Sodium carboxymethylstarch, magnesium stearate and talc, which are briefly passed through a 60th American sieve, are then added to the granules which, after mixing, are compressed in a tabletting machine to produce tablets.

It is manufactured as follows suspensions, each containing 0.1 - 1000 mg of medication per 5 ml of dose: Formulation 4: Suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.1 - 1000 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Flavor c.v. Color c.v. Purified water up to 5 mi _______ The medicament is passed through a No. 45 mesh American sieve and mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. The benzoic acid solution, the flavor and the color are diluted with a little water and added, with agitation. Subsequently, enough water is added to produce the required volume. An aerosol solution is prepared containing the following ingredients: Formulation 5: Aerosol Ingredient Quantity (% by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 70.00 The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 * C and transferred to a refilling device. The required quantity is then supplied to a stainless steel vessel and diluted with the remaining propellant. Valve units are subsequently fitted to the container. Prepares as follows suppositories: Formulation 6: Suppositories Ingredient Quantity (mg / suppositories) Active ingredient 250 Saturated fatty acid glycerides 2,000 The active ingredient is passed through a No. 60 mesh American sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. An intravenous formulation is prepared as follows: Formulation 7: Intravenous Solution Ingredient Amount Active ingredient 50 mg Isotonic saline 1000 ml The solution of the above ingredients are administered intravenously to a patient at a rate of about 1 ml per minute.

Formulation 8: Combination of Capsule I Ingredient Quantity (mg / capsule) Active ingredient 50 Premarin 1 Avicel pH 101 50 Starch 1500 117.50 Silicone Oil 2 Tween 80 0.50 Cab-O-Sil 0.25 Formulation 9: Combination of Capsule II Ingredient Quantity (mg / capsule) Active ingredient 50 Norethylnodrel 5 Avicel pH 101 82.50 Starch 1500 90 Silicone Oil 2 Tween 80 0.50 Formulation 10: Tablet combination Ingredient Quantity (mg / capsule) Active Ingredient 50 Premarin 1 Corn Starch NF 50 Povidone, K29-32 6 Avicel pH 101 41.50 Avicel pH 102 136.50 Crospovidone XL10 2.50 Magnesium Stearate 0.50 Cab-O-Sil 0.50 • 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. Having described the invention as above, property is claimed as contained in the following:

Claims (17)

1. CLAIMS A compound of formula I characterized in that R1 is H, OH, halo, OCO (alkyl, OCO (aryl), OS02 (C4-C6 alkyl), OCOO (OCON) alkyl (C1-C6 alkyl) 2; R2 is aryl, Ci-Cg, C3-C6 cycloalkyl or 4-cyclohexanol, R3 is 0 (CH2) 2 O 0 (CH2) 3, R4 and Rs are optionally CO (CH2) 2CH3, C0 (CH2) 3CH3, alkyl or R4 and Rs combine to form, with the nitrogen to which piperidine, morpholine, pyrrolidine, 3-methylpyrrolidine, 3, 3-dimethylpyrrolidine, 3,4-dimethylpyrrolidine, azepine or pipecoline are attached; R is \ C- = CH2, SCH (C? -C5 alkyl), CH (C2C5 alkenyl) (aril), and pharmaceutically acceptable salts thereof.
2. 2. The compound according to claim 1, characterized in that R3 is -0 (CH2) 23.
3. The compound according to claim 2, characterized in that R4 and Rs form piperidino.
4. 4. The compound according to claim 3, characterized in that Rx is -OH and R2 is 4-hydroxyphenyl.
5. 5. The compound according to claim 4, characterized in that R6 is c < OH) methyl, ^ C = CH2, ^ C (OH) phenyl, CHphenyl, or
6. 6. A pharmaceutical composition characterized in that it comprises a compound according to claim 1, or a pharmaceutically acceptable salt thereof and, optionally, an effective amount of estrogen or progestin, in combination with a pharmaceutically acceptable carrier, diluent or excipient.
7. 7. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to alleviate the symptoms of the post-encephalic syndrome by administering to a woman in need of such treatment, an effective amount of said compound.
8. 8. The use according to claim 7, characterized in that the pathological condition in the postmenopausal syndrome is osteoporosis.
9. 9. The use according to claim 7, characterized in that the pathological condition in the postmenopausal syndrome is related to a cardiovascular disease.
10. 10. The use according to claim 9, characterized in that the cardiovascular disease is hyperlipidemia.
11. 11. The use according to claim 7, characterized in that the pathological condition in the postmenopausal syndrome is estrogen-dependent cancer.
12. 12. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof to inhibit uterine fibroid disease by administering to a woman in need of such treatment an effective amount of said compound.
13. 13. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to inhibit endometriosis when administering to a woman in need of such treatment an effective amount of said compound.
14. 14. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to inhibit the proliferation of smooth muscle cells of aorta by administering to a human in need of such treatment an effective amount of said compound.
15. 15. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof when administering to a human in need of such treatment an effective amount of said compound.
16. 16. Use of estrogen to relieve symptoms of postmenopausal syndrome in a woman.
17. 17. Use according to claim 7 for alleviating the symptoms of postmenopausal syndrome, which additionally comprises administering to the woman an effective amount of progestin. SUMMARY OF THE INVENTION The present invention provides a compound of formula (I) wherein R x is H, OH, halo, OCO (C 1 -C 6 alkyl), OCO (aryl), 0 SO 2 (C 4 -C 6 alkyl), OCOO (alkyl, OCOO (aryl), OCONH (alkyl of OCON (C1-C6 alkyl) 2; R2 is aryl, Cj-Cj alkyl, Cj-Cg cycloalkyl or 4-cyclohexanol; R3 is 0 (CH2) 2 or 0 ( CH2) 3; R4 and R5 are optionally CO (CH2) 2CH3, CO (CH2) 3CH3, Ci-Cg alkyl or R4 and R5 combine to form, together with the nitrogen to which they are attached, piperidine, morpholine, pyrrolidine, 3-methylpyrrolidine, 3, 3-dimethylpyrrolidine, 3,4-dimethylpyrrolidine, acepine or pipecoline, - R6 is = C = CH2, = CH (Ci-Cg alkyl), = CH (C2-C3 alkenyl), = C = CH (alkyl) Ci-Cg), = CH (aryl), = C (OH) (Cg alkyl), = C (OH) (C2-C3 alkenyl), = C (OH) aryl; and pharmaceutically acceptable salts thereof. The present invention additionally provides pharmaceutical compositions containing compounds of formula (I) that optionally contain estrogen or progestin, and the use of such compounds alone or in combination with estrogen or progestin, to alleviate the symptoms of postmenopausal syndrome, particularly osteoporosis, Related cardiovascular pathological conditions and estrogen-dependent cancer. As used herein, the term "progestin" includes compounds that have progestational activity such as, for example, progesterone, norethylnodrel, nongestrel, megestrol acetate, norethindrone, and the like. The compounds of the present invention are also useful for inhibiting uterine fibroid disease and endometrosis in women and the proliferation of smooth muscle cells in the aorta, particularly restenosis in humans.