BENZOFURAN COMPOUNDS, COMPOSITIONS, AND METHODS

Abstract: The present invention provides novel benzofuran compound, pharmaceutical formulations and processes for preparation thereof, and methods of using such compounds for alleviating the symtoms of post-menopausal syndrome, and inhibiting endometriosis, uterine fibrosis, and aortal smoother muscle cell proliferation.

Description: TITLE BENZOFURAN COMPOUNDS, COMPOSITIONS, AND METHODS Field of the Invention This invention relates to the fields of pharmaceutical and organic chemistry and provides novel benzofuran compounds which are useful for the treatment of the various medical indications associated with post¬ menopausal syndrome, and uterine fibroid disease, endometriosis, and aortal smooth muscle cell proliferation. The present invention further relates to intermediate compounds useful for preparing the pharmaceutically active compounds of the present invention, and pharmaceutical compositions. Furthermore, the present invention relates to a novel process for preparing the pharmaceutically active compounds of the present invention. Background of the Invention "Post-menopausal syndrome" is a term used to describe various pathological conditions which frequently affect women who have entered into or completed the physiological metamorphosis known as menopause. Although numerous pathologies are contemplated by the use of this term, three major effects of post-menopausal syndrome are the source of the greatest long-term medical concern: osteoporosis, cardiovascular effects such as hyperlipidemia, and e .rogen-dependent cancer, particularly breast and uterine cancer. Osteoporosis describes a group of diseases which arise from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and 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 m the trabecular compartment of the bone within 3 to 6 years after the cessation ot menses. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among post¬ menopausal women. There are an estimated 25 million women m the United States, alone, who are afflicted with this disease. The results of osteoporosis are personally harmful and also account for a large economic loss due its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is not generally thought of as a life threatening condition, a 20% to 30% mortality rate is related with hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with post¬ menopausal osteoporosis. The most vulnerable tissue in the bone to the effects of post-menopausal osteoporosis is the trabecular bone. This tissue is often referred to as spongy or cancellous bone and is particularly concentrated near the ends of the bone (near the oints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which mter-connect with each other, as well as the more solid and dense cortical tissue which makes up the outer surface and central shaft of the bone. This inter-connected network of trabeculae gives lateral support to the outer cortical structure and is critical to the bio- mechanical strength of the overall structure. In post¬ menopausal osteoporosis, it is, primarily, the net resorption and loss of the trabeculae which leads to the failure and fracture of bone. In light of the loss of the trabeculae in post-menopausal women, it is net surprising that the most common fractures are those associated with bones which are highly dependent on trabecular support, e.g., the vertebrae, the neck of the weight bearing bones such as the femur and the fore-arm. Indeed, hip fracture, colles fractures, and vertebral crush fractures are hall-marks of post-menopausal osteoporosis. At this time, the only generally accepted method for treatment of post-menopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low primarily because estrogen treatment frequently produces undesirable side effects. Throughout premenopausal time, most women have less incidence of cardiovascular disease than age-matched men. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match 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 the levels of serum lipids. The nature of estrogen's ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can upregulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health. It has been reported in the literature that post¬ menopausal women having estrogen replacement therapy have a return of serum lipid levels to concentrations to those of the pre-menopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side-effects of estrogen replacement therapy are not acceptable to many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent which would regulate the serum lipid level as does estrogen, but would be devoid of the side-effects and risks associated with estrogen therapy. The third major pathology associated with post¬ menopausal 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 solely limited to a post-menopausal women, they are more prevalent in the older, post-menopausal population. Current chemotherapy of these cancers have relied heavily on the use of anti-estrogen compounds such as, for example, Tamoxifen. Although such mixed agonist-antagonists have beneficial effects in the treatment of these cancers, and the estrogenic side-effects are tolerable in acute life-threatening situations, they are not ideal. For example, these agents may have stimulatory effects on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and they may, therefore, be contraproductive in some cases. A better therapy for the treatment of these cancers would be an agent which is an anti-estrogen compound having 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, inter al ia , post-menopausal syndrome, the present invention provides new benzofuran compounds, pharmaceutical compositions thereof, and methods of using such compounds for the treatment of post-menopausal syndrome and other estrogen-related pathological conditions such as those mentioned below. Uterine fibrosis (uterine fibroid disease) is an old and ever present clinical problem which goes under a variety of names, including uterine hypertrophy, uterine lieomyomata, myometrial hypertrophy, fibrosis uteri, and fibrotic metritis. Essentially, uterine fibrosis is a condition where there is an inappropriate deposition of fibroid tissue on 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 evidence suggests that it is an inappropriate response of fibroid tissue to estrogen. Such a condition has been produced m 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. Further, in rats, estrogen causes similar hypertrophy. The most common treatment of uterine fibrosis involves surgical procedures both costly and sometimes a source of complications such as the formation of abdominal adhesions and infections. In some patients, initial surgery is only a temporary treatment and the fibroids regrow. In those cases a hysterectomy is performed which effectively ends the fibroids but also the reproductive life of the patient. Also, gonadotropm releasing hormone antagonists may be administered, yet their use is tempered by the fact they can lead to osteoporosis. Thus, there exists a need for new methods for treating uterine fibrosis, and the methods of the present invention satisfy that need. Endometriosis is a condition of severe dysmenorrhea, which is accompanied by severe pain, bleeding into the endometrial masses or peritoneal cavity and often leads to infertility. The cause of the symptoms of this condition appear to be ectopic endometrial growths which respond inappropriately to normal hormonal control and are located in inappropriate tissues. Because of the inappropriate locations for endometrial growth, the tissue seems to initiate local inflammatory-like responses causing macrophage infiltration and a cascade of events leading to initiation of the painful response. The exact etiology of this disease is not well understood and its treatment by hormonal therapy is diverse, poorly defined, and marked by numerous unwanted and perhaps dangerous side effects. One of the treatments for this disease s the use of low dose estrogen to suppress endometrial growth through a negative feedback effect on central gonadotropin release and subsequent ovarian production of estrogen; however, it is sometimes necessary to use continuous estrogen to control the symptoms. This use of estrogen can often lead to undesirable side effects and even the risk of endometrial cancer. Another treatment consists of continuous administration of progestins which induces amenorrhea and by suppressing ovarian estrogen production can cause regressions of the endometrial growths. The use of chronic progestin therapy is often accompanied by the unpleasant CNS side effects of progestins and often leads to infertility due to suppression of ovarian function. A third treatment consists of the administration of weak androgens, which are effective in controlling the endometriosis; however, they induce severe masculinizing effects. Several of these treatments for endometriosis have also been implicated in causing a mild degree of bone loss with continued therapy. Therefore, new methods of treating endometriosis are desirable. Smooth aortal muscle cell proliferation plays an important role in diseases such as atherosclerosis and restenosis. Vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA) has been shown to be a tissue response characterized by an early and late phase. The early phase occurring hours to days after PTCA is due to thrombosis with some vasospaεms while the late phase appears to be dominated by excessive proliferation and migration of aortal smooth muscle cells. In this disease, the increased cell motility and colonization by such muscle cells and macrophages contribute significantly to the pathogenesis of the disease. The excessive proliferation and migration of vascular aortal smooth muscle cells may be the primary mechanism to the reocclusion of coronary arteries following PTCA, atherecto y, 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 (Aug. 1985) . Vascular restenosis remains a major long term complication following surgical intervention of blocked arteries by percutaneous transluminal coronary angioplasty (PTCA) , atherectomy, laser angioplasty and arterial bypass graft surgery. In about 35% of the patients who undergo PTCA, reocclusion occurs within three to six months after the procedure. The current strategies for treating vascular restenosis include mechanical intervention by devices such as stents or pharmacologic therapies including h-^parin, low molecular weight heparin, coumarin, aspirin, fish oil, calcium antagonist, steroids, and prostacyclin. These strategies have failed to curb the reocclusion rate and have been ineffective for 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 excessive cell proliferation and migration occurs as a result of growth factors produced by cellular constituents in the blood and the damaged arterial vessel wall which mediate the proliferation of smooth muscle cells in vascular restenosis. Agents that inhibit the proliferation and/or migration of smooth aortal muscle cells are useful in the tree ιent and prevention of restenosis. The present invention provides for the use of compounds as smooth aortal muscle cell proliferation inhibitors and, thus inhibitors of restenosis. Summary of the Invention The present invention relates to compounds of formula I I wherein R is -H, -OH, -0(Cι-C alkyl) , -O-CO- (Cι-C 6 alkyl), -O-CO-Ar in which Ar is optionally substituted phenyl, or -0- S0 2 - (C 4 -C6 alkyl) ; R 1 is -H, -OH, -0(Cι-C alkyl) , -O-CO- (Cι-C 6 alkyl) , -O-CO-Ar in which Ar is optionally substituted phenyl, -O- SO 2 - (C 4 -C 6 alkyl), chloro or bromo; R 2 and R 3 each are independently C 1 -C 4 alkyl, or combine to form 1-pιperιdιnyl, 1-pyrrolιdmyl, methyl-1- piperidmyl, dιmethyl-1-pιperιdιnyl, 4-morpholmo, or 1- hexamethyleneimino; or a pharmaceutically acceptable salt thereof. Also provided are compounds of formula IX which are useful for preparing compounds of formula I. The present invention also relates to pharmaceutical compositions containing compounds of formula I, optionally containing estrogen or progestm, and the use of such compounds, alone, or in combination with estrogen or progestm, for alleviating the symptoms of post-menopausal symptoms, particularly osteoporosis, cardiovascular related pathological conditions, and estrogen-dependent cancer. As used herein, the term "progestm" includes compounds having progeεtational activity such as, for example, progesterone, norethynodrel, norgestrel, megestrol acetate, norethindrone, and the like. The present invention further relates to the use of the compounds of the present invention for inhibiting uterine fibroid disease and endometriosis in women and aortal smooth muscle cell proliferation, particularly restenosis, in humans. Furthermore, the present invention relates to a process for preparing a compound of formula la la wherein R a and R la each are -OH or -0(Cι-C 4 alkyl); R 2 and R 3 each are independently C 1 -C 4 alkyl, or combine to form C4-C6 polymethylene, -CH 2 CH(CH 3 )CH 2 CH 2 -, -CH 2 C(CH3) 2 CH 2 CH 2 -, or -CH 2 CH 2 θCH 2 CH 2 -; and n is 2 or 3 ; or a pharmaceutically acceptable salt thereof, which comprises a) optionally dealkylating a compound of formula II - II wherein R a , R la , R 2 , R 3 , and n are as defined above; b) reacting said formula II compound with a reducing agent in the presence of a solvent having a boiling point in the range from about 150° C to about 200° C, and heating the mixture to reflux; and c) optionally salifying the reaction product form step b) . Detailed Description of the Invention One aspect of the present invention includes compounds of formula I wherein R is -H, -OH, -CXC1-C4 alkyl) , -O-CO- (Cι-C 6 alkylϊ , -O-CO-Ar which Ar is optionally substituted phenyl, or -O- SO2- (C4-C6 alkyl) ; R 1 is -H, -OH, -CXC1-C4 alkyl) , -O-CO- (Cι-C 6 alkyl) , -O-CO-Ar in which Ar is optionally substituted phenyl, -O- SO 2 - (C 4 -C 6 alkyl) , chloro or bromo; R 2 and R 3 each are independently C 1 -C 4 alky] , or combine to form 1-pιperιdmyl, 1-pyrrolιdιnyl, methyl-1- piperidmyl, dιmethyl-1-pyrrolιdmyl, 4-morpholmo, or 1- hexamethyleneimino; or a pharmaceutically acceptable salt thereof. General terms used in the description of compounds herein described bear their usual meanings. For example, "C 1 -C 4 alkyl" refers to straight or branched aliphatic chains of 1 to 4 carbon atoms including methyl, ethyl, propyl, isopropyl, butyl, n-butyl, and the like; and "Ci-Cβ alkyl" encompasses the groups included in the definition of "C 1 -C 4 alkyl" in addition to groups such as pentyl, isopentyl, hexyl, lsohexyl, and the like. The term "substituted phenyl" refers to a phenyl group having one or more substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 5 alkoxy, hydroxy, nitro, chloro, fluoro, or tri (chloro or fluoro)methyl. "C 1 -C 5 alkoxy" represents a C 1 -C 5 alkyl group attached through an oxygen bridge such as, for example, methoxy, ethoxy, n- propoxy, isopropoxy, and the like. The compounds of the present invention are derivatives of benzo[b] furan which is named and numbered according to the Ring Index, The American Chemical Society, as follows ■ ι; The starting materials of the present invention, compounds of formula II below, are made essentially as described in United States Pat. Nos. 4,133,814, issued January 9, 1979, 4,418,068, issued November 29, 1983, and 4,380,635, issued April 19, 1983, each of which is herein incorporated by reference. This process provides a convenient process which acylates a methylated starting compound and then optionally dealkylates it to obtain the desired dihydroxy product. The acylation and dealkylation may be performed successive steps in a single reaction mixture or the intermediate may be isolated and the dealkylation step be performed a separate reaction. R- II wherein R a , R la , R 2 , R 3 , and n are as defined above, or a salt thereof . In the preparation of a formula II compound, an alkyl-protected compound of formula III III is most easily obtained by reacting a 3-(Cι~C alkyl)phenol, preferably 3-methoxyphenol, and a-bromo-4- 'C 1 -C 4 alkyl)acetophenone, preferably 4-methoxyacetophenone, the presence of a strong base at a relatively low temperature, to form a- (3-methoxyphenoxy) -4-methoxyacetophenone, which is then ring clcsed with an agent such as polyphosphoric acid at a high temperature to obtain the intermediate compound of formula III. The acylation of this invention is a Friedel-Crafts acylation, and is carried out in the usual way, using a Lewis acid such as aluminum chloride or bromide, preferably the chloride, as the acylation catalyst. The acylation is ordinarily carried out in a solvent, and any inert organic solvent which is not significantly attacked by the conditions may be used. For example, halogenated solvents such as dichloromethane, 1,2- dichloroethane, chloroform, and the like may be used, as can aromatics such as benzene, chlorobenzene, and the like. It is preferred to use a halogenated solvent, especially dichloromethane. It has been found that toluene is rather easily acylated under the conditions used in the Friedel-Crafts acylation. Therefore, it is important, when toluene is used in an earlier step of the process, to remove it as completely as possible from the protected starting compound. Furthermore, if toluene remains following preparation of a compound of formula IV below, it should be removed to avoid wasting the acylating agent and contaminating the product. The acylations may be carried out at temperatures from about -30° C to about 100° C, preferably at about ambient temperature, in the range of from about 15° C to about 30° C. The acylating agent is an active form of the appropriate benzoic acid of formula IV IV wherein R a is chloro or bromo, and R 2 and R 3 are as defined above. The preferred acylating agents are those wherein R a is chloro. Thus, using this reaction scheme, the most highly preferred individual acylating agents are 4- [2- (pιperιdm-1- yl) ethoxy]benzoyl chloride, 4- [2- (hexamethyleneιmm-1- yl) ethoxy] benzoyl chloride, and 4- [2- (pyrrolιdm-1- yl) ethoxy]benzoyl chloride. The acyl chloride used as an acylating agent may be prepared from the corresponding carboxylic acid by reaction with a typical chlorinating agent such as thionyl chloride. Care must be taken to remove any excess chlorinating agent from the acyl chloride. Most conveniently, the acyl chloride is formed m si tu , and the excess chlorinating agent is removed under vacuum. It is generally preferred that an equimolar amount of the compounds of formulae III and IV are reacted together. If desired, a small excess of either reactant may be added to assure the other is fully consumed. It is generally preferred to use a large excess of the acylation catalyst, such as about 2-12 moles per mole of product, preferably about 5-10 moles of catalyst per mole of product. The acylation is rapid. Economically brief reaction times, such as from about 15 minutes to a few hours provide high yields of the acylated intermediate. Longer reaction times may be used if desired, but are not usually advantageous. As usual, the use of lower reaction temperatures call for relatively longer reaction times. The acylation step is ended and the optional dealkylation step is begun by the addition of a sulfur compound selected from the group consisting of methionme and compounds of the formula X-S-Y wherein X is hydrogen or unbranched C 1 -C 4 alkyl, and Y is C 1 -C 4 alkyl or phenyl. The sulfur compounds are, preferably, the alkylthiols, such as methanethiol, ethanethiol, isopropanethiol, butanethiol, and the like; dialkyl sulfides, such as diethyl sulfide, ethyl propyl sulfide, butyl isopropyl sulfide, dimethyl sulfide, methyl ethyl sulfide, and the like; benzenethiol; methionme; and alkyl phenyl εulfides, such as methyl phenyl sulfide, ethyl phenyl sulfide, butyl phenyl sulfide, and the like. It has been found that dealkylation is most efficient when a substantial excess of the sulfur compound is used, in the range of about 4 to about 10 moles per mole of the starting benzofuran. The process may be carried out, although less efficiently, with a smaller amount of the sulfur compound (in the range of about 2 to 3 moles per mole of the starting compound) . It is also possible to use a small amount of the sulfur compound, and to improve the yield by the addition of about 1 to 3 moles of an alkali metal halide, such as sodium, potassium, or lithium chloride, bromide, or iodide. The dealkylation reaction goes well at about ambient temperature, in the range of from about 15° C to about 30° C, and such operation is preferred. The dealkylation may be carried out, however, at temperatures in the range of from about -30° C to about 50° C if it is desired to do so. Short reaction times, in the range of about one hour, have been found to be sufficient. After the product has been dealkylated, it is recovered and isolated by conventional means. It is customary to add water to decompose the complex of the acylation catalyst. Addition of dilute aqueous acid is often advantageous. The product precipitates in many instances, or may be extracted with an organic solvent according to conventional methods. The examples below further illustrate the isolation. In an alternative, preferred process, an intermediate compound of formula V V wherein R a and R 1 are as defined above, is prepared by the reaction of 2-hydroxy-4-methoxybenzaldehyde and l-(4-(Cι-C4 alkoxy)phenyl) -2- (4- (C 3. -C4 alkoxy)phenyl) ethanone, essentially as described in Preparation 3, infra. This reaction usually employs equimolar amounts of the two reactants although other ratios are operable. The reaction is performed in a non- reactive solvent such as ethyl acetate, chloroform, and the like, in the presence of an acid. Hydrochloric acid, particularly in the form of anhydrous hydrogen chloride, is an especially preferred acid. Lower alkyl alcohols are usually added to the non-polar solvent so as to retain more of the hydrochloric acid created in si t u , with ethanol and methanol being especially preferred. The reaction is performed at temperatures ranging from ambient temperature up to the reflux temperature of the mixture. This reaction results in the preparation of the compound of formula VI OCH- (or an equivalent anion if hydrochloric acid is not used) , which is then oxidized to the compound of formula V by the action of hydrogen peroxide. The intermediate of formula VI may be isolated or may preferably be converted to the compound of Formula V in the same reaction vessel. The compound of formula V is then selectively dealkylated essentially as described in Preparation 4, infra, to yield the compound of formula VII VII wherein R a and R la are as defined above. The ether form of compounds of formula II is then produced by the substitution of the hydrogen on the hydroxy group by an alkyl group. The last step in preparing starting materials of formula II via the present process involves alkylating the selectively dealkylated compound of formula VII with an appropriate alkylation agent of formula VIII below, essentially as described in Preparation 5B, infra. R~ Z-(CH ) ~ -N \ R J VIII wherein Z is a leaving group such as chloro or bromo, and n, R 2 , and R 3 are as defined above. This reaction usually employs equimolar to a slight excess of a formula VIII compound relative to the formula VII substrate. The reaction is performed in a non-reactive solvent such as N,N-dιmethylformamide and the like, in the presence of a base such as, for example, potassium carbonate. The reaction is performed at temperatures from about 80° C to about 120° C and allowed to run until compounds of formula II are prepared. The reaction typically takes about 1 hour when run at 100° C. However, the progress of the reaction may be monitored by using standard chromatographic techniques. Preferred formula II starting materials are those which n is 2, and R 2 and R 3 are methyl or ethyl, or P 2 and P J are combined to form a pyrrolid o moiety or a piperidino moiety. Of these, combining P 2 and P 3 to form a piperidino moiety is especially preferred. Compounds of formula IX generally are prepared by adding a formula II compound, or, preferably, the hydrochloride salt thereof, to an appropriate solvent, and reacting the resulting mixture with a reducing agent such as, for example, lithium aluminum hydride (LAH) , under an inert gas such as nitrogen. The amount of reducing agent used this reaction is an amount sufficient to reduce the carbonyl group of a formula II compound to form a carb ol of formula IX below. Generally, a liberal excess of the reducing agent per equivalent of the substrate is used. IX wherein R a , R la , R 2 , R 3 ' and n of formula IX are as defined above, or a salt thereof. Appropriate solvents include any solvent or mixture of solvents which will remain inert under reducing conditionε. Suitable solvents include ether, dioxane, and tetrahydrofuran (THF) . The temperature employed in this step is that which is sufficient to effect completion of the reduction reaction. Ambient temperature, in the range from about 17° C to about 25° C, generally is adequate. The length of time for this step is that amount necessary for the reaction to occur. Typically, this reaction takes from about 1 to about 20 hours. The optimal time can be determined by monitoring the progress of the reaction via conventional chromatographic techniques. Optionally, the C 1 -C 4 alkoxy moieties of a formula IX compound may be dealkylated, via standard procedures, prior to further reduction as described below. The resulting diphenolic compounds of formula IXa are considered to be part of the present invention IXa wherein R 2 , R 3 , and n are as defined above. The carbinol products from this reaction are extracted essentially via the method described in Example 1, infra, are novel, and are useful intermediates for the preparation of formula I compounds of the present invention by further reduction. In formula IX, the carbon atom designated "*" is an asymmetric center. Thus, these compounds can have an R- or S-configuration, or a mixture thereof. Both enantiomers are considered to be part of the present invention. Once a carbinol of the present invention is prepared, one option is to further reduce such a carbmol via standard procedures, to give a compound of formula I. Typically a carbmol of formula IX is suspended in an appropriate solvent and cooled under an inert gaε such as nitrogen. To this suspension is added a suitable trialkyl silane reducing agent, preferably triethyi silane, and a reasonably strong protic acid such as hydrochloric acid, trifluoracetic acid, and the like. Appropriate solvents can be any solvent or mixture of solvents which remain inert under the reaction conditions employed in the process. For example, halogenated alkane solvents such as dichloromethane and 1, 2-dιchloroethane, as well as haloaromaticε such as chlorobenzene and the like may be used. Of these, dichloromethane is preferred. The temperature employed in this step is that which is sufficient to effect completion of the present reduction process. Typically, the reaction is cooled to about 0° C and the reaction solution is kept on ice until the reaction is complete; however, ambient temperature also is satisfactory. In general, this reaction is completed in less than three hours, and the progress of the reaction can be mo tored via standard techniques. In particular cases, when phenolic hydroxys are present in the compounds of formula IXa, the use of triethylsilyl as a reducing agent can lead to the formation of the silyl adduct of the phenol. On occasion, this adduct can be isolated as seen in Example 2. In other cases, traces of such silylated phenols can be seen as minor impurities. The intermediate methylene free bases which contain such impurities are cleaved to the free phenol when the compounds are converted to their hydrochloride salts, as seen in Example 3, infra. Alternatively, a novel proceεs may be used to prepare compounds of formula la of the present invention by reducing a ketone of formula II above. This process is shown below in Scheme I . Scheme I II la wherein R e ila R 2 , R 3 , and n are as defined above, or a pharmaceutically acceptable salt thereof. In this process, a formula II compound, or a salt thereof, is optionally dealkylated and then reacted with a reducing agent such as lithium aluminum hydride in the presence of a solvent having a boiling point in the range from about 150° C to about 200° C. The reaction product of this reduction step can then optionally be salified via standard procedures. Alternatively, the reduction εtep of the preεent proceεs may first be carried out, followed by the optional dealkylation step. Preferably, each step of this novel process is carried out in separate vesεels, but it is possible to carry out each step of the present process in the same vessel. The amount of reducing agent used this reaction is an amount sufficient to reduce the carbonyl group of a formula II compound to form a compound of formula I. Generally, a generous excesε of the reducing agent per equivalent of the εubεtrate lε uεed. The εolvent uεed m the preεent process is required to have a relatively high boiling point, the range from about 150° C to about 200° C, as represented by solvents such as, for example n-propylbenzene, diglyme (1, 1 ' -oxybis [2- methoxyethane] ) , and anisole, and Red-Al® {[sodium bis (2- methoxyethoxylalummum hydride) ] } which also is used as the reducing agent. Of these, n-propylbenzene is the preferred εolvent with formula II compoundε as shown above. The alkoxy substituents of compounds of formula II may first be dealkylated, to form a diphenol compound via standard procedures herein described, which can then be reduced via the present, novel process to provide formula I compounds. In this instance, Red-Al is the preferred reducing agent. The temperature used in this reaction is that which is sufficient to complete the reduction reaction. Preferably, the reaction mixture is heated to reflux for about 15 minutes to about 6 hours, and allowed to cool to ambient temperature. A εmall amount of deionized water lε added to the mixture followed by the addition of a εmall aliquot of 15% εodium hydroxide: deionized water (w/w) . The mixture is stirred until the reaction is complete. The optimal amount of time for this reaction to run, typically from about 10 minutes to about 1 hour, can be determined by monitoring the progress of the reaction via standard techniques. The formula I products from this reduction reaction are extracted essentially as described m Example 7, infra. Formula I compounds in which R and R 1 are -OH and/or -0(Cι~C 4 alkyl) are novel and can be used as pharmaceutically active agents for the methods herein described, or can be derivalitized to provide other novel compounds of formula I which alεo are uεeful for the present methods . For example, when R and/or R 1 are -0{Cι~C 4 alkyl), (thus, not having been dealkylated as one above option provides), such groupε can be removed via standard dealkylation techniques to prepare an especially preferred compound of formula I . Other formula I compounds are prepared by replacing the newly formed R and P. 1 hydroxy groupε with a moiety of the formula -O-CO- (Ci-Cg alkyl) , -O-CO-Ar in which Ar is optionally substituted phenyl, or -O-SO 2 - (C 4 -C 6 alky) via well known procedures. See, e.g., U.S. Pat. No. 4,358,593, supra. For example, when a -0-CO(Cι-C δ alkyl) or -O-CO-Ar group is desired, the dihydroxy compound of formula I is reacted with an agent such as acyl chloride, bromide, cyanide, or azide, or with an appropriate anhydride or mixed with anhydride. The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such aε triethylamine, tributylamine, methylpiperidine, and the like. The reaction also may be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, 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, has been added. if desired, acylation catalysts such as 4-dimethylaminepyridine or 4-pyrrolidinopyridine may be used. See, e.g., Haslam, et al . , Tetrahedron. 3_6_:2409-2433 (1980) . The acylation reactions which provide the aforementioned R and R 1 groupε are carried out at moderate temperatures in the range from about -25° C to about 100° C, frequently under an inert atmosphere such as nitrogen gas. However, ambient temperature is usually adequate for the reaction to run. Such acylations of the hydroxy group also may be performed by acid-catalyzed reactions of the appropriate carboxylic acids in inert organic solvents or heat. Acid catalystε εuch as sulfuric acid, polyphosphoric acid, methanesulfonic acid, and the like are uεed. The aforementioned R and R 1 groupε alεo may be provided by forming an active eεter of the appropriate acid, such as the esterε formed by εuch known reagents such as dicyclohexylcarbodiimide, acylimidazoleε, nitrophenolε, pentachlorophenol, N-hydroxysuccinimide, and 1- hydroxybenzotriazole. See, e.g., Bull. Chem. Soc . Japan. 3_£:1979 (1965; , and Chem. Ber.. 788 and 2024 (1970) . Each of the above techniques which provide -O-CO- (Ci-Cg alkyl) and -O-CO-Ar groups are carried out in solventε as discussed above. These techniques which do not produce an acid product the courεe of the reaction, of course, do not call for the use of an acid scavenger in the reaction mixture. When a formula I compound is deεired in which R and R 1 is -O-SO 2 - (C 4 -C 6 alkyl), the formula I dihydroxy compound is reacted with, for example, a derivative of the appropriate sulfonic acid εuch as a sulfonyl chloride, bromide, or sulfonyl ammonium salt, as taught by King and Monoir, j. Am. Chem. Soc.. « :2566-2567 (1975) . The dihydroxy compound alεo can be reacted with the appropriate εulfonic anhydride. Such reactionε are carried out under conditionε εuch aε were explained above m the discuεεion of reaction with acid halideε and the like. Compounds of formula I can be prepared so that R and R 1 bear different biological protecting groups or, preferably, are prepared so that R and R 1 each bear the εame biological protecting group. Preferred protecting groupε include -OCH 3 , -O-CO-C (CH 3 ) 3 , -0-CO-C 6 H 5 , and -0-S0 2 - (CH 2 ) 3 - CH 3 . The term "biological protecting groups" refers to those R and R 1 subεtituentε which delay, reεiεt, or prohibit removal of εuch groups in a biological system such as, for example, following administration of a formula I compound containing the above-described R and R 1 groups to a human. Such compounds of formula I also are useful for the methods herein described. Although the free-base form of formula I compounds can be used in the methods of the present invention, it is preferred to prepare and use a pharmaceutically acceptable εalt form. Thus, 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 often 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, phoεphoric, hypophoεphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acidε, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, ma} also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, ethylbenzoate, o- acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β-hydroxybutyrate, butyne-1,4- dioate, hexyne-1, 4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, meεylate, nicotinate, iεonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, εuccinate, εuberate, εulfate, bisulfate, pyrosulfate, εulfite, biεulfite, εulfonate, benzeneεulfonate, p-bromophenylεulfonate, chlorobenzeneεulfonate, ethaneεulfonate, 2- hydroxyethanesulfonate, methanesulfonate, naphthalene-1- εulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt. The pharmaceutically acceptable acid addition saltε are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual εolvent εuch aε diethyl ether or ethyl acetate. The salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional meanε. Likewiεe, εaltε of formula IX also can be prepared by the procedures discusεed above. The pharmaceutically acceptable εaltε generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions. The following examples are preεented to further illustrate the preparation of compounds of the present invention. It is not intended that the invention be limited m scope by reason of any of the following examples. The terms "NMR", "IR" or "MS" following a synthesis protocol indicates that the nuclear magnetic resonance spectrum, infrared spectrum, or the mass spectrometry was performed and was consistent with the title product. Preparation 1 2- ( 3-methoxyphenoxy) -1- (4-methoxyphenyl ) ethanone . In a one liter round-bottom flask, fitted with a condenser and nitrogen inlet, were added 3-methoxyphenol (12.4 g, 0.1 mole) , 4-methoxyphenacyl bromide (22.9 g, 0.1 mole), potasεium carbonate (17.3 g, 0.125 mole) in 100 ml of 2-butanone. Thiε mixture was heated to 80° C and was maintained at this temperature for about four hours. The progreεε of the reaction waε monitored by thin layer chromatography (silica gel, 9:1 toluene:ethyl acetate) . After the four hours at 80° C the reaction mixture was cooled and the reaction mixture waε partitioned by the addition of water. The organic phaεe was removed and the aqueous layer was washed with 2-butanone. The organic layers were then combined, dried over magnesium εulfate, and the solvents were removed in vacuo to yield 31.1 grams of a yellow oil. The yellow oil was further purified by chromatography, the fractions containing the desired product were then crystallized. All of the crystalline fractionε were combined and then diεεolved in 80 ml of hot ethanol. Fifteen milliliters of hot water was then added, the product was cryεtallized, and subsequently washed with an ethanol/water mixture to yield 19.1 g (70%) of the desired title product. mp 52.5°-53.5° C. Analysiε for the title compound: Theory: C, 68.08; H, 5.71; N, 2.84. Found: C, 67.86; H, 5.51; N, 2.88. Preparation 2 2-4 ' -met oxyphenyl-6-methoxybenzofuran. The cyclization-rearrangement of the product of Preparation 1 waε performed essentially as described in C. Goldenberg, et al . , Chimie Therapeuticπi . 3_9_δ_:-411 (1973) . In a 500 ml 3-neck round bottom flaεk polyphoεphoric acid (30 g) waε added to 200 ml of xylene. The mixture was then heated to about 120° C. To this heated mixture was then added 2- (3-methoxyphenoxy) -1- (4-methoxyphenyl) ethanone (10 g, 0.037 mole), prepared as described supra, and the temperature was raised to about 170° C, and maintained at that temperature for about eight hourε . The reaction mixture waε then cooled and water waε added. The dark aqueouε layer waε separated from the yellow organic phase. The organics were washed with water and by aqueous sodium carbonate, and then dried over anhydrous magnesium sulfate. The solvents were removed m vacuo , resulting in a yellow-orange solid. The product was recrystallized from a minimum of hot acetone, followed by the addition of ethanol and water. The residual acetone waε removed by boiling. Cooling to room temperature yielded white cryεtalε (2.09 g, 22% yield) . mp 158° C. Analyεis for the title compound: Theory: C, 75.58; H, 5.55; 0, 18.88. Found: C, 75.33; H, 5.67; 0, 18.62. Preparation 3 [2- ( 4 -methoxyphenyl ) -6-methoxybenzofuran-3 -yl] [4- methoxyphenyl] methanone In a 250 ml 3-neck round bottom flask were added 2- hydroxy-4-methoxybenzaldehyde (10 g, 65.7 mmoles), 1- (4- methoxyphenyl) -2- (4-methoxyphenyl) ethanone (16 g, 62.6 mmoles), ethyl acetate (100 ml) and ethanol (25 ml) . The reaction mixture was then warmed to about 45° C unt L1 all the starting materialε were dissolved. Hydrogen chloride gas was then bubbled in for about 30 minutes, resulting in the formation of a bright red coloration. The reaction was then allowed to stand at room temperature for about two hours at which time the εolventε were removed in vacuo to leave a bright red oil. The red oil was disεolved in 180 ml of methanol and 30 ml of 20% sulfuric acid was added with stirring and cooling. Hydrogen peroxide (30 ml) was added dropwise and the mixture waε allowed to stir for about 30 minutes. A saturated sodium chloride solution (500 ml) and ethyl acetate (300 ml) were added to the reaction mixture and the organic fraction was removed. The organic layer was washed with a saturated sodium chloride solution, dried, and the solventε were removed in vacuo to provide 25 g of a reddiεh brown oil which was further purified by chromatography to yield the title product (1.25 g) as a yellow oil. mp 106-109° C. Analyεiε for the title compound: Theory: C, 74.21; H, 5.19; 0, 20.60. Found: C, 74.07; H, 5.22; O, 20.38. Preparation 4 [2- ( 4 -methoxyphenyl ) -6- ethoxybenzof ran-3 -yl] [4 - hydroxyphenyl]methanone In a three-neck round bottom flask under a nitrogen atmosphere and cooled in an ice bath, ethanethiol (0.95 ml, 1.288 mmoles) was dissolved in 10 ml of anhydrous N,N- dimethylformamide. To this solution was added n-butyllithium (0.60 ml of a 1.6 M in hexane solution, 0.966 mmole) followed by the addition of [2- (4-methoxyphenyl) -6-methoxybenzofuran- 3-yl] [4-hydroxyphenyl]methanone (250 mg, 0.644 mmole) , prepared aε described in Preparation 3, supra. The reaction mixture was then heated to 80° C and allowed to remain at that temperature for about 16 hours. The reaction mixture was then poured into 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was then washed with a saturated sodium chloride solution, dried over magnesium εulfate, filtered and the solventε were removed in vacuo . The desired product was further purified by column chromatography. The product was then crystallized from methanol yielding 130 mg (81%) of the desired product. mp 148-149° C. Analysiε for the title compound: Theory: C, 73.79; H, 4.85; 0, 21.37. Found: C, 73.68; H, 5.12; 0, 21.17. Preparation 5 [2- ( 4-methoxyphenyl ) -6-methoxybenzofuran-3 -yl ] [4- ( 2 ( 1-piperidinyl ) ethoxy] phenyl]methanone H Method A: Acylation of 2-4 ' -methoxyphenyl-6- methoxybenzofuran 4- [2- (Piperidin-1-yl) ethoxy]benzoyl chloride (0.562 g, 1.96 mmoleε) was added to ethylene chloride (20 ml), followed by the addition of 2-4 ' -methoxyphenyl-6- methoxybenzofuran (0.500 g, 1.96 mmoles) , prepared as described in Preparation 2, supra. This mixture was stirred at room temperature as aluminum trichloride (1.96 g, 14.7 mmoles) was added. This reaction mixture was then stirred overnight . The reaction mixture was then poured over ice, and extracted with warm chloroform (3 x 50 ml) . The chloroform was removed by evaporation. Sodium carbonate, water and ethyl acetate were then added and the organic layer was removed, dried over magneεium sulfate, and the solvents were removed in vacuo to provide a yellow oil. The desired product was further purified by chromatography of the yellow oil to yield the desired title product. Analysis for the title compound: Theory: C, 74.21; H, 6.44; N, 2.88; 0, 16.47. Found: C, 74.11; H, 6.71; N, 2.75; 0, 16.57. Method B: Alkylation of [2- (4-methoxyphenyl) -6- methoxybenzofuran-3-yl] [4-hydroxyphenyl]methanone In 100 ml of anhydrous N,N-dimethylformamide in a 500 ml round bottom flask were added [2- (4-methoxyphenyl) -6- methoxybenzofuran-3-yl] [4-hydroxyphenyl]methanone (10.50 g, 28 mmoles) , prepared as described in Preparation 4, supra. and potassium carbonate (6.20 g, 34 mmoles) . This mixture waε heated to 100° C and then N-2-chloroethyl piperidine (6.20 g, 34 mmoles) was added gradually. The reaction mixture was kept at 100° C for about one hour. The N, -dimethylformamide was removed under reduced pressure and the residue was dissolved in ethyl acetate and water. The ethyl acetate layer was removed and the aqueous layer was washed with more ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, and the solventε were removed in vacuo, yielding 13.3 g of a yellow oil which crystallized upon standing. The product was recrystallized from methanol which waε cooled to -30° C prior to filtration, yielding 11.4 g (84%) of the deεired product as pale yellow crystals, mp 87-89° C. Analysiε for the title compound: Theory: C, 74.21; H, 6.44; N, 2.88; 0, 16.47 Found: C, 74.31; H, 6.34; N, 2.63; 0, 16.47 Preparation 6 [2- (4-hydroxyphenyl ) -6-hydroxybenzof ran-3 -yl] [4- [2 ( 1-piperidinyl ) ethoxy]phenyl]methanone The title product was prepared by the demethylation of the product of preparation 5, supra. In a 250 ml three- neck round bottom flask were combined 1,2-dichloroethane (50 ml) and aluminum trichloride (9.60 g, 72 mmoles) and ethanethiol (6.39 g, 103 mmoles) to provide a pale yellow solution. To this liquid was then added the product of Example 1 (5.00 g, 10.3 mmoles) in a gradual fashion. A red oil precipitated and the mixture was stirred for about 20 minutes. After cooling the reaction mixture in an ice bath, 100 ml of tetrahydrofuran was added and the mixture was allowed to stir until all of the oil had gone into solution. The reaction mixture was then poured over ice (200 ml) and water (500 ml) and concentrated hydrochloric acid (10 ml) were added. The oil which precipitated was εeparated from the liquid by decantation. The liquid waε extracted with chloroform (warm, 2 x 300 ml) . The oil waε dissolved by mixing with ethyl acetate, chloroform, sodium bicarbonate, and a εmall amount of εodium hydroxide. The chloroform extract and the ethyl acetate-chloroform εolution containing the dissolved oil were combined and transferred to a separatory funnel. The organic phase was washed with sodium bicarbonate, dried over magnesium sulfate, and the εolvents were removed under reduced preεεure to yield a yellow foam, which was further purified by high performance liquid chromatography. Example 1 [2- ( 4-Hydroxyphenyl ) -6-hydroxybenzof ran-3-yl] [4- [2 ( 1-piperidinyl ) ethoxy] phenyl ]methanol 4.57 g (0.01 mol) of [2- (4-hydroxyphenyl) -6- hydroxybenzofuran-3-yl] [4- [2- (1-piperidiny1) ethoxy]phenyl] methanone was dissolved in 250 mL of THF and 2 g (0.053 mol) of iAlH 4 was slowly added over a period of twenty minutes to the stirring εolution. The reaction mixture waε stirred and kept under a nitrogen atmosphere and the reaction was allowed to proceed for eighteen hours at room temperature and then it waε concentrated to dryness in vacuo . 500 mL of EtOAc was slowly added along with 2mL of water. After stirring for 10 minutes, 500 mL of water was added and the EtOAc layer was removed. The EtOAc layer was washed with an additional 500 mL of water and the layers were separated. The EtOAc layer was dried with anhydrous Na 2 S0 4 and concentrated to dryness to yield 2.66 g of the title compound as tan amorphous powder. -HNMR: Consiεtent with the propoεed structure. MS: m/e=460 (M+l) FD C 28 H 29 O 5 Examp l e 2 [2- (4-Triethylsilyloxyphenyl ) -6-hydroxybenzofuran-3- yl ] [4- [2- ( 1-piperidinyl ) ethoxy] phenyl ] methane 1.69 g (0.0036 mol) of 2- (4-hydroxyphenyl) -6- hydroxybenzofuran-3-yl] [4- [2- (1-piperidinyl) ethoxy]phenyl] methanol was dissolved in 25 mL of CH 2 CI 2 and 470 mg (0.004 mol) of triethyl silane was added. The reaction mixture was stirred under a nitrogen atmosphere. 25 mL of trifluoroacetic acid was added. The reaction was allowed to proceed at room temperature for six hours. The reaction waε terminated by evaporating the volatiles in vacuo . 200mL of saturated aCθ 3 solution was added and extracted (3x) with 100 mL portions of EtOAc. The combined EtOAc extracts were washed with water and dried by filtration through anhydrous Na 2 Sθ 4 and the reaction mixture waε evaporated to dryness. This yielded 690 mg of the title compound as a tan amorphous powder. PMR: Consistent with the proposed structure (one -SiEt3 ) MS: m/e= 558 (M+l) and 444 (M-Et3Si) FD Example 3 [2- ( 4-Hydroxyphenyl ) -6-hydroxybenzofuran-3 -yl ] [4- [2 ( 1-piperidinyl ) ethoxy] phenyl]methane hydrochloride 650 mg of [2- (4-triethylsilyloxyphenyl) -6- hydroxybenzofuran-3-yl] [4- [2- (1-piperidinyl) ethoxy]phenyl] methane waε diεεolved in 50 mL of methylene chloride and 5 mL of methanol. 25 mL of a εaturated εolution of ethyl ether- hydrochlo lc acid waε added. The reaction mixture waε evaporated to dryneεε . This yielded 550 mg of the title compound as a light pink amorphous powder. PMR: Consiεtent with the proposed structure (no Et 3 Si- group) Analysiε for the title compound: Theory: C, 70.06; H, 6.30; N, 2.92. Found: C, 69.86: H, 6.48; N, 2.66. C 28 H 29 O 4 • HC1 MS m/e = 444(M-HC1)FD Exampl e 4 [2- ( 4-Methoxyphenyl ) -6-methoxybenzofuran-3 -yl] [4- [2 ( 1-piperidinyl ) ethoxy] phenyl]methanol Thiε compound was prepared in a manner similar to that in Example 1, starting with 2 g (4.13 mmol) of [2- (4- methoxyphenyl) -6-methoxybenzofuran-3-yl] [4- [2- tl- piperidinyl) ethoxy]phenyl] methanone and obtaining 1.66 g of the title compound as a tan amorphous powder. 1 HNMR: Consistent with the proposed structure. MS: m/e=487 (M+) FD Analysis for the title compound: Theory: C, 73.90; H, 6.82; N, 2.87. Found: C, 73.66; H, 6.88; N, 3.06 Example ≥ [2- ( 4-Methoxyphenyl ) -6-methoxybenzofuran-3 -yl] [4- [2 ( 1-piperidinyl ) ethoxy] phenyl] methane H^CO Thiε compound waε prepared in a manner similar to that in Example 2, starting with 1.64 g (3.36 mmol) of the carbinol from Example 4 and obtaining 680 mg of the title compound as a tan amorphous powder. 1 HNMR: Consiεtent with the proposed structure. MS: m/e=471 (M+) FD C 3 oH 33 Nθ4 Example 6 [2- (4-Methoxyphenyl) -6-methoxybenzofuran-3-yl] [4- [2- ( 1-piperidinyl ) ethoxy] phenyl] ethane hydrochloride This compound was prepared in the same manner as Example 3, the final product was crystallized from ethyl acetate-methanol . 680 mg of the starting free base yielded 320 mg of the final salt. X HNMR: Consistent with the proposed structure. Analysis for the title compound: Theory: C, 70.92; H, 6.74; N, 2.76. Found: C, 70.76; H, 6.79; N, 2.75 Exa ple 7 [2- { 4-Me hoxyphenyl ) -6-methoxybenzofuran-3 -yl] [4 - [2- ( 1-piperidinyl ) ethoxy]phenyl] methane hydrochloride 500 mg (12.52) mmol) of 95% lithium aluminum hydride and 500 mg (1.03 mmol) [2- (4-methoxyphenyl) -6- methoxybenzofuran-3-yl] [4- [2- (1-piperidinyl) ethoxy]phenyl] methanone in 20 mL of n-propyl benzene were heated to reflux one hour and then allowed to cool to room temperature. To the mixture waε carefully added 1 mL of deionized water followed by 3 mL of 15% (w/w) εodiu hydroxide/deionized water and then another 1 mL deionized water. The mixture waε stirred for 15 minutes at ambient temperature and the resulting precipitate was removed by vacuum filter. The mother liquor was then diluted with methylene chloride (100 mL) , washed once with brine, dried on sodium εulfate, and then retovaped to dryneεs. The clear gum was purified by radial chromatography on a 4 mm plate and 19:1 methylene chloride:methanol as eluent. The clear gum was taken up in a minimal amount of methanol and then a saturated solution of methanol/hydrochloric acid (g) was added. Product crystallized from methanol to yield 230 mg of off-white amorphous material (47% yield) . Analysis for title compound: Theory: C, 70.92; H, 6.75; N, 2.76. Found: C, 70.69; H, 6.53; N, 2.88. Example 8 [2- ( 4-Hydroxyphenyl ) -6-hydroxybenzof ran-3 -yl ] [4- [2 ( 1-hexamethyleneimine) ethoxy] phenyl] methanol 1.524 g (3mmol) of [2- (4-hydroxyphenyl) -6- hydroxybenzofuran-3-yl] [4- [2- (1-hexamethyleneimine) ethoxy] p " yl] methanone hydrochloride salt was converted to 830 mg c he title compound through the procesε deεcribed in Example 1. -HNMR: Conεistent with the proposed structure MS: m/e=474 IM+I) FD C 29 H 31 N0 5 Example 9 t2- ( 4-Hydroxyphenyl) -6-hydroxybenzof ran-3-yl] [4- [2- ( 1-hexamethyleneimine ) ethoxy] phenyl ] methane 800 g (1.7 mmol) of the product of Example 8 was converted to 700 mg of the title compound by the process described in Example 2. MS: m/e=458 (M+l) FD C 29 H 31 NO 4 Exampl e 10 [2- ( 4-Hydroxyphenyl) -6-hydroxybenzofuran-3 -yl ] [4 - [2 ( 1-hexamethyleneimine ) ethoxy] phenyl ] methane hydrochloride 700 mg of the compound from Example 9 was converted to its hydrochloride by the method described in Example 3. This yielded 300 mg of the title compound as a white amorphous powder. 1 HNMR: Consiεtent with the propoεed εtructure. MS: m/e=457 (M-HCl) FD Analyεis for the title compound: Theory: C, 70.51; H, 6.53; N, 2.84. Found: C, 70.23; H, 6.53; N, 2.95. Example 11 [2- ( 4-Hydroxyphenyl ) -6-hydroxybenzofuran-3 -yl ] [4- [2 ( 1-pyrrolidinyl ) ethoxy] phenyl ] methanol 1.38 g (3 mmol) of [2- (4-hydroxyphenyl) -6- hydroxybenzofuran-3-yl] [4- [2- (1-pyrrolidenyl) ethoxy]phenyl] methanone was reduced to the carbinol by the method described in Example 1. This yielded 550 mg of the title compound as an amorphous powder. 1 HNMR: Consistent with the proposed structure. MS: m/e= 462 (M+l) FD C 27 H 27 O 5 Example 12 [2- ( 4-Hydroxyphenyl ) -6-hydroxybenzofuran-3 -yl ] [4- [2- ( 1-pyrrolidinyl ) ethoxy] phenyl ] methane 550 mg (1.2 mmol) of the product of Example 11 was reduced to the methane by the method described in Example 2. This yielded 270 mg of the title compound as an amorphous powder. 1 HNMR: Conεiεtent with the propoεed structure. MS: m/e= 446 (M+l) FD C27H27NO4 Example 13 [2 -Phenyl -6 -hydroxybenzof uran -3 -yl] [4- [2 - ( 1 piperi inyl ) ethoxy] phenyl ] methanol 0-CH--CH -N O 2000 mg (4.1 mmol) of [2-phenyl-6- hydroxybenzofuran-3-yl] [4- [2- (1-pιperιdmyl) ethoxy]phenyl] methanone hydrochloride was reduced by the method described in Example 1. This yielded 1.31 g of the title compound as an amorphous powder. 1 HNMR: Consistent with the propoεed εtructure. MS: m e=443 (M) FD Analyεis for the title compound: Theory: C, 75.82; H, 6.59; N, 3.16. Found: C, 75.14; H, 6.88; N, 3.03. Example 14 [2-Phenyl-6-hydroxybenzofuran-3-yl] [4- [2-(l- piperidinyl ) ethoxy]phenyl] methane 1.3 g (2.9 mmol) of the carb ol from Example 13 was reduced in the manner described in Example 2. This yielded 1.23 g of the title compound as an amorphous powder, 1 HNMR: Consistent with the proposed structure. MS: m/e=428 (M+l) and small peak of 542 indicating a small amount of the 6-trιethylsιlyloxy derivative. C2 3 H2 9 NO4 Example 15 [2 -Phenyl-6-hydroxybenzofuran-3-yl] [4- [2 - ( 1- piperidinyl ) ethoxy] phenyl] methane hydrochloride 1.23 g of the free base derived in Example 14 was converted to its hydrochloride salt in the manner exemplified in Example 3. This yielded 720 mg of the title compound as a white amorphous powder. ^-HNMR: Conεiεtent with the proposed structure. MS: m/e=429 (M-HCl) FD Analysis for the title compound: Theory: C, 72.48; H, 6.52; N, 3.02. Found: C, 72.18; H, 6.73; N, 2.78. Example 16 [2- ( 4-Hydroxyphenyl ) -benzofuran-3-yl] [4 - [2- ( 1 piperidinyl ) ethoxy]phenyl ] methanol 2.0 g (4.23 mmol) of [2- (4-hydroxyphenyl) - benzofuran-3-yl] [4- [2- (1-piperidinyl) ethoxy]phenyl] methanone hydrochloride was reduced to the carbinol using the method deεcribed in Example 1. This yielded 1.59 g of the title compound as an amorphous powder. 1 HNMR: Consistent with the proposed structure. MS: m/e=444 (M+l) FD Analyεiε for the title compound: Theory: C, 75.82; H, 6.59; N, 3.16. Found: C, 75.34; H, 6.93; N, 3.02. Example 17 [ 2 - ( 4 -Hydroxyphenyl ) -benzof uran- 3-yl] [ 4 - [ 2 - ( 1 - piperidinyl ) ethoxy] phenyl ] methanol 1.5 g (3.38 mmol)of the carbinol in Example 16 was further reduced to the methane derivative aε deεcribed in Example 2. This yielded 1.29 g of the title compound as an amorphous solid. i HNMR: Conεiεtent with the proposed structure. MS: m/e=428 (M+l) and a small peak at 542 which is the triethylsilyloxy derivative on the phenol. C 28 H 29 NO 3 Example 18 [2- ( 4-Hydroxyphenyl ) -benzofuran-3-yl] [4 - [2- ( 1- piperidinyl ) ethoxy] phenyl] methane hydrochloride 1.2 g of the free base εyntheεized in Example 17 waε converted to the hydrochloride εalt in a manner described in Example 3. This yielded 810 mg of the title compound as an amorphous solid. 1 HNMR: Consistent with the proposed structure. MS: m/e=428 (M-HCl) FD Analysis for the title compound: Theory: C, 72.48; H, 6.52; N, 3.02. Found: C, 71.95; H, 6.67; N, 2.78. Example 19 [2- { 4-Methoxyphenyl ) -6-methoxybenzofuran-3 -yl] [4- [2- dimethylaminoethoxy] phenyl ] methanol H^ 1.335 g (3 mmol) of [2- (4-methoxyphenyl) -6- methoxybenzofuran-3-yl] [4- [2-dimethylaminoethoxy]phenyl] methanone was reduced to the carbinol by the method described in Example 1. This yielded 920 mg of the title compound as an oil. 1 HNMR: Conεiεtent with the proposed structure. MS: m/e=448 (M+l) FD C27H29NO5 Example 20 [2- ( 4-Methoxyphenyl ) -6-methoxybenzofuran-3 -yl ] [4- [2 dimethylaminoethoxy] phenyl] methane 890 mg (2 mmol) of the carbinol in Example 19 was reduced in the manner described in Example 2. This yielded 640 mg of the title compound as an oil. MS: m/e=432 (M+l) FD C27H29NO4 Example 21 [2 - ( 4 -Methoxyphenyl ) -6 -methoxybenzof uran -3 -yl ] [ 4 - [2 dimethylaminoethoxy] henyl ] methane hydrochloride 800 mg of the free base in Example 20 was converted to its hydrochloride salt in the manner described in Example 3. This yielded 570 mg of the title compound as an amorphous solid. 1 HNMR: Consistent with the proposed structure. MS: m/e=431 (M-HCl) FD Analysiε for the title compound: Theory: C, 69.29; H, 6.46; N, 2.99 Found: C, 68.83; H, 6.77; N, 3.47 Example 22 [2- ( 4-Methoxyphenyl ) -6-methoxybenzofuran-3 -yl ] [4- [2 diethylaminoethoxy] phenyl ] methanol 1.420 g (3 mmol) of [2- (4 -methoxyphenyl ) -6- methoxybenzofuran-3 -yl ] [ 4- [2-diethylaminoethoxy ] phenyl] methanone waε reduced to the carbinol by the method deεcribed in Example 1. Thiε yielded 1.07 g of the title compound aε an oil. i -HNMR: Consistent with the proposed structure. MS: m/e=475 (M) FD C29H33NO5 Example 23 [2- ( 4 -Methoxyphenyl ) - 6 -methoxybenzof ran -3 -yl ] [ 4 - [2 diethylaminoethoxy ] phenyl ] methane 1.070 g (2.25 mmol) of the carbinol from Example 22 was reduced by the method described in Example 2. This yielded 800 mg of the title compound aε an oil. 1 HNMR : Consi stent with the proposed structure . MS : m/ e= 459 (M ) FD C2 9 H3 3 NO4 Example 24 [2- ( 4-Methoxyphenyl ) -6-methoxybenzofuran-3 -yl ] [4 - [2 diethylaminoethoxy] phenyl ] methane hydrochloride 900 mg of the free base in Example 23 was converted to its hydrochloride salt in the manner described in Example 3. This yielded 370 mg of the title compound as an amorphous solid. -HNMR: Consistent with the proposed εtructure. MS: m/e=459 (M-HCl) FD Analysis for the title compound: Theory: C, 70.22; H, 6.93; N, 2.82. Found: C, 69.97; H, 6.90; N, 2.75. Example 25. [2- ( 4-Methoxyphenyl ) -6-methoxybenzof ran-3-yl ] [4- [2- diisopropylaminoethoxy] phenyl ] methanol 1.5 g (3 mmol) of [2- (4-methoxyphenyl) -6- methoxybenzofuran-3-yl] [4- f2-diisopropylaminoethoxy]phenyl] methanone was reduced to the carbinol by the method described in Example 1. This yielded 830 mg of the title compound as an oily solid 1 HNMR: Consistent with the proposed structure. MS: m/e=503 (M) FD Analysis for the title compound: Theory: C, 73.93; H, 7.40; N, 2.78. Found: C, 73.64; H, 7.21; N, 2.49. Example 26 [2- ( 4-Methoxyphenyl ) -6-methoxybenzof ran-3 -yl] [4- [2- diisopropylaminoethoxy] phenyl] methane 800 mg (1.6 mmol) of the carbinol from Example 25 waε reduced by the method of Example 2. This yielded 630 mg of the title compound as an oil. 1 HNMR: Consistent with the proposed structure. MS: m/e=488 (M+l) FD C 31 H37NO4 Example 27 [2- ( 4-Methoxyphenyl ) -6-methoxybenzofuran-3-yl] [4- [2- diisopropylaminoethoxy] phenyl] methane hydrochloride 700 mg of the free base in Example 26 was converted to its hydrochloride salt by the method described in Example 3. The product was crystallized from ethyl acetate-ethanol, which yielded 110 mg of the title compound. -HNMR: Consistent with the proposed structure. MS: m/e=487 (M-HCl) FD Analysiε for the title compound: Theory: C, 71.04; H, 7.31; N, 2.68. Found: C, 70.84; H, 7.35; N, 2.63. Example 28 [2 -Phenyl-6-methoxybenzofuran-3-yl] [4- [2 - ( 1■ piperidinyl ) ethoxy]phenyl ] methanol 1.47 g (3 mmol) of [2-phenyl-6-methoxybenzofuran-3- yl] [4- [2- (1-piperidinyl) ethoxy]phenyl] methanone hydrochloride was reduced by the method described in Example 1. This yielded 1.08 g of the title compound as an oil. 1 HNMR: Consistent with the proposed structure. MS: m/e=457 (M) FD C29H31NO4 Example 29 [2 -Phenyl- 6 -methoxybenzof ran -3 -yl] [4 - [2 - ( 1 piperidinyl ) ethoxy] phenyl ] methane 1.08 g (2.4 mmol) of the carbinol from Example 2i was reduced by the method described in Example 2. This yielded 940 mg of the title compound as an oil. 1 HNMR: Consistent with the proposed structure. MS: m/e=441 (M) FD C 31 H 31 NO 3 Example 30 [2 -Phenyl-6-methoxybenzofuran-3 -yl] [4- [2 - ( 1- piperidinyl ) ethoxy] phenyl] methane hydrochloride 1.0 g of the free base in Example 29 was converted to its hydrochloride salt by the method of Example 3. The product crystallized from the ether-hydrochloric acid solution and was filtered and washed with ether, then dried. This yielded 630 mg of the title compound. X HNMR: Consistent with the proposed structure. MS: m/e=441 (M-HCl) FD Analyεis for the title compound: Theory: C, 72.86; H, 6.75; N, 2.93. Found: C, 72.74; H, 6.78; N, 2.94. Example 31 [2 - ( 4-Met oxyphenyl )benzofuran-3-yl] [4- [2- ( 1- piperidinyl ) ethoxy] phenyl ] methanol 1.47 g (3 mmol) of [2- (4-methoxyphenyl)benzofuran- 3-yl] [4- [2- (1-piperidinyl) ethoxy]phenyl] methanone hydrochloride was reduced by the method described in Example 1. This yielded 880 mg of the title compound as an oil. 1 HNMR: Consiεtent with the propoεed εtructure. MS: m/e=457 (M) FD C 29 H 31 NO 4 Example 32 [2 - ( 4-Methoxyphenyl)benzofuran-3 -yl] [4- [2-(l piperidinyl ) ethoxy] phenyl] methane 880 mg (1.75 mmol) of the carbinol from Example 31 was reduced by the method described in Example 2. This yielded 650 mg of the title compound as an oil . 1 HNMR: Consistent with the proposed structure. MS: m/e=441 (M) FD C29H31NO3 Example 33 [2 - ( 4 -Methoxyphenyl )benzofuran-3-yl] [4- [2- ( 1- piperidinyl ) ethoxy ] phenyl ] methane hydrochloride 600 mg of the free base in Example 32 was converted to its hydrochloride salt in the manner described in Example 3. The compound crystallized from the ether-hydrochloric acid solution. The compound was filtered, washed with ether, and dried. This yielded 380 mg of the title compound. 1 HNMR: Consistent with the proposed structure. Analysiε for the title compound: Theory: C, 72.86; H, 6.75; N, 2.93. Found: C, 72.66; H, 6.88; N, 3.11. Example 34 [2- ( 4-Methoxyphenyl ) -6-methoxybenzof ran-3 -yl ] [4- [2 ( 1-hexamethyleneimine ) ethoxy] phenyl ] methanol H ^ C 1.5 g (3 mmol) of [2- (4-methoxyphenyl) -6- methoxybenzofuran-3-yl] [4- [2- (1-hexamethyleneimine) ethoxy] phenyl] methanone waε reduced to the carbinol by the method deεcribed in Example 1. This yielded 1.15 g of the title compound as an oil. 1 HNMR: Consistent with the proposed structure. MS: m/e=501 (M) FD C 3 iH 35 N0 5 Example 35 [2- ( 4-Methoxyphenyl ) -6-methoxybenzofuran-3 -yl ] [4- [2 ( 1-hexamethyleneimine ) ethoxy]phenyl ] methane 1.15 g (2.3 mmol) of the carbinol from Example 34 was reduced by the method described in Example 2. This yielded 900 mg of the title compound aε an oil. ^ ■ HNMR: Consistent with the proposed structure. MS: m/e=485 (M) FD C31H35NO4 Example 3 6 [2- ( 4-Methoxyphenyl ) -6-methoxybenzofuran-3 -yl ] [4- [2 ( 1-hexamethyleneimine ) ethoxy] phenyl ] methane hydrochloride 1.05 g of the free base Example 35 was converted to its hydrochloride salt by the method described in Example 3. The product was recrystallized from ethyl acetate-ethanol . This yielded 170 mg of the title compound. 1 HNMR: Consistent with the proposed structure. The compounds of formula I of the present invention are uεeful for alleviating the symptoms of post-menopausal syndrome, particularly osteoporosis, asεociated cardiovaεcular diεeases, particularly estrogen-dependent breast and uterine carcinoma. The term "alleviating" is defined to include prophylactically treating a woman from incurring one or more symptomε/pathological conditionε of post-menopausal syndrome, holding in check such symptomε/pathological conditionε, and/or treating exiεting εymptomε/pathological conditionε. As εuch, the present methods include both medical therapeutic and/or prophylactic treatment, as appropriate. Compounds of formula I, also are effective for inhibiting uterine fibroid disease and endometriosis in women, and smooth muscle cell proli eration in humans. The following non-limiting test examples illustrate the methods of the present invention. Test Procedure General Preparation Procedure In the examples illustrating the methods, a post¬ menopausal model was used in which effects of different treatments upon circulating lipids were determined. Seventy-five day old female Sprague Dawley rats (weight range of 200 to 225 g) were obtained from Charles River Laboratories (Portage, MI) . The animals were either bilaterally ovariectomized (OVX) or exposed to a Sham surgical procedure at Charles River Laboratories, and then shipped after one week. Upon arrival, they were housed m metal hanging cages in groups of 3 or 4 per cage and had ad libi tum access to food (calcium content approximately 0.5%) and water for one week. Room temperature was maintained at 22.2° ± 1.7° C with a minimum relative humidity of 40%. The photoperiod m the room was 12 hours light and 12 hours dark, Dosinσ Reσimen Tissue Collection. After a one week acclimation period (therefore, two weeks post-OVX) daily dosing with test compound was initiated. 17α-ethynyl estradiol or the test compound were given orally, unless otherwise stated, aε a suspension in 1% carboxymethyl- celluloεe or dissolved in 20% cyclodextrm. Animals were dosed daily for 4 days. Following the dosing regimen, animals were weighed and anesthetized with a ketamme: Xylazme (2:1, V:V) mixture and a blood sample waε collected by cardiac puncture. The animals were then sacrificed by asphyxiation with CO 2 , the uterus was removed through a midline incision, and a wet uterine weight was determined. Cholesterol Analysis. Blood samples were allowed to clot at room temperature for 2 hours, and serum was obtained following centrifugation for 10 minutes at 3000 rpm. Serum cholesterol waε determined using a Boehrmger Mannheim Diagnostics high performance cholesterol assay. Briefly the cholesterol was oxidized to choleεt-4-en-3-one and hydrogen peroxide. Th<=- hydrogen peroxide was then reacted with phenol and 4-ammoph nazone in the presence of peroxidase to produce a p-qumone nine dye, which waε read spectrophotemetrically at 500 nm. Cholesterol concentration was then calculated against a standard curve. The entire asεay waε automated using a Biomek Automated Workstation. Uterine Eosmophil Peroxidase (EPO^ Assay. Uteri were kept at 4° C until time of enzymatic analysis. The uteri were then homogenized in 50 volumes of 50 mM Tris buffer (pH - 8.0) containing 0.005% Triton X-100. Upon addition of 0.01% hydrogen peroxide and 10 mM o-phenylenediamme (final concentrations) m Tris buffer, increase m absorbance was monitored for one minute at 450 nm. The presence of eosonophils in the uterus is an indication of eεtrogenic activity of a compound. The maximal velocity of a 15 εecond interval was determined over the initial, linear portion of the reaction curve. Source of Compound: 17α-ethynyl eεtradiol waε obtained from Sigma Chemical Co., St. Louis, MO. Influence of Formula I Compounds on Serum Choleεterol and Determination of Aαonist/Non-Aσomst Activity Data presented in Table 1 below show comparative resultε among ovariectomized ratε, ratε treated with 17α- ethynyl eεtradiol (EE ; an orally available form of estrogen) , and ratε treated with certain compoundε of the present invention. Although EE 2 caused a decrease in serum cholesterol when orally administered at 0.1 mg/Kg/day, it also exerted a stimulatory action on the uterus so that EE 2 uterine weight was substantially greater than the uterine weight of ovariectomized test animals. This uterine reεponse to estrogen is well recognized in the art. Not only did the compounds of the present invention generally reduce serum choleεterol compared to the ovariectomized control animals, but uterine weight was only minimally increased to slightly decreased. Compared to estrogenic compounds known in the art, the benefit of serum cholesterol reduction without adversely affecting uterine weight is quite rare and desirable. As lε expressed in the below data, estrogenicity also was assessed by evaluating the adverse responεe of eosmophil infiltration into the uterus. The compounds of the present invention did not cause any increase m the number of eos ophils observed m the stromal layer of ovariectomized rats, while estradiol cauεed a substantial, expected increase m eosmophil infiltration. The data preεented in the following Tableε 1 and 2 reflect the reεponse of 5 to 6 rats per treatment. Table 1 Dose Uterine Weight Uterine EPO Serum Cholesterol C ompound mq/kα (% increase vs OVX) (V max) { decrease vs OV EE2 0.1 172.8 201.9 92.6 Ex-3* 0.1 8.6 4.7 38.9 1.0 26.3 5.8 53.0 10 0 30.1 11.3 73.3 *referε to the compound described m the stated Example, in ra. In addition to the demonstrated benefitε of the compounds of the present invention, especially when compared to estradiol, the above data clearly demonstrate that compounds of Formula I are not estrogen mimetics. Furthermore, no deleterious toxicological effects (survival) were observed with any treatment. Osteoporosis Test Procedure Following the General Preparation Procedure, infra, the rats are treated daily for 35 days (6 rats per treatment group) and sacrificed by decapitation on the 36th day. The 35 day time period is sufficient to allow maximal reduction in bone density, measured aε deεcribed herein. At the time of εacrifice, the uteri are removed, diεεected free of extraneous tisεue, and the fluid contents are expelled before determination of wet weight in order to confirm estrogen deficiency aεεociated with complete ovariectomy. Uterine weight iε routinely reduced about 75% in response to ovariectomy. The uteri are then placed in 10% neutral buffered formalin to allow for subsequent histological analyεiε. The right femurε are exciεed and εcanned at the diεtal metaphysis 1 mm from the patellar groove with εingle photon absorptiometry. Results of the denεitometer meaεurementε represent a calculation of bone density as a function of the bone mineral content and bone width, and demonstrate the activity of tested compounds. MCF-7 Proliferation Aεsav MCF-7 breast adenocarcinoma cells (ATCC HTB 22) are maintained in MEM (minimal eεεential medium, phenol red-free, Sigma, St. Louiε, MO) supplimented with 10% fetal bovine serum (FBS) (V/V) , L-glutamine (2 mM) , sodium pyruvate (1 mM) , HEPES { (N- [2-hydroxyethyl]piperazine-N' - [2- ethaneεulfonic acid]10 mM} , non-essential amino acids and bovine insulin (1 ug/mL) maintenance medium) . Ten days prior to asεay, MCF-7 cells are switched to maintenance medium supplemented with 10% dextrancoated charcoal stripped fetal bovine serum (DCC-FBS) asεay medium in place of 10% FBS to deplete internal εtoreε of steroids. MCF-7 cells are removed from maintenance flasks using cell dissociation medium (Ca++/Mg++ free HBSS (phenol red-free) supplementac with 10 mM HEPES and 2 mM EDTA) . Cells are washed twice wich assay medium and adjusted to 80,000 cells/mL. Approximately 100 μL (8,000 cells) are added to flat-bottom microculture wells (Costar 3596) and incubated at 37° C in a 5% CO 2 humidified incubator for 48 hours to allow for cell adherence and equilibration after transfer. Serial dilutions of drugs or - 60 - DMSO aε a diluent control are prepared in assay medium and 50 μL tranεferred to triplicate microcultures followed by 50 μL asεay medium for a final volume of 200 μL. After an additional 48 hours at 37° C m a 5% CO 2 humidified incubator, microcultures are pulsed with tritiated thymid e (1 uCi/well) , for 4 hours. Cultures are terminated by freezing at -70° C for 24 hours followed by thawing and harvesting of microcultures using a Skatron Semiautomatic Cell Harvester. Samples are counted by liquid scintillation using, for example, a Wallac BetaPlace β counter. DMBA-Induced Mammary Tumor Inhibition Estrogen-dependent mammary tumors are produced in female Sprague-Dawley ratε which are purchaεed from Harlan Industries, Indianapolis, Indiana. At about 55 dayε of age, the ratε receive a single oral feeding of 20 mg of 7,12- dimethylbenz [a]anthracene (DMBA) . About 6 weeks after DMBA administration, the mammary glands are palpated at weekly intervals for the appearance of tumorε. Whenever one or more tumors appear, the longest and shortest diameters of each tumor are measured with a metric caliper, the measurements are recorded, and that animal is selected for experimentation. An attempt is made to uniformly distribute the various sizeε of tumorε m the treated and control groupε εuch that average-sized tumors are equivalently distributed between test groups. Control groupε and teεt groups for each experiment contain 5 to 9 animals. Compounds of Formula I are administered either through mtraperitoneal injections in 2% acacia, or orally. Orally administered compounds are either dissolved or suspended in 0.2 mL corn oil. Each treatment, including acacia and corn oil control treatments, is administered once daily to each test animal. Following the initial tumor measurement and selection of teεt animalε, tumors are measured each week by the above-mentioned method. The treatment and measurements of animals continue for 3 to 5 weeks at which time the final areas of the tumors are determined. For each compound and control treatment, the change in the mean tumor area is determined. Uterine Fibrosis Test Procedures Test 1 Between 3 and 20 women having uterine fibrosis are administered a compound of the present invention. The amount of compound administered is from 0.1 to 1000 mg/day, and the period of adminiεtration iε 3 months. The women are observed during the period of administration, and up to 3 months after discontinuance of administration, for effects on uterine fibrosis. Test 2 The same procedure iε uεed aε in Teεt 1, except the period of adminiεtration iε 6 monthε. Teεt 3 The εame procedure iε used as in Teεt 1, except the period of adminiεtration is 1 year. Test 4 A. Induction of fibroid tumors in guinea pig. Prolonged estrogen stimulation is used to induce leiomyomata in sexually mature female guinea pigs. Animals are doεed with eεtradiol 3-5 times per week by injection for 2-4 months or until tumorε ariεe. Treatmentε consisting of a compound of the invention or vehicle is administered daily for 3-16 weeks and then animalε are sacrificed and the uteri harvested and analyzed for tumor regresεion. B. Implantation of human uterine fibroid tissue in nude mice. Tissue from human leiomyomas are implanted into the peritoneal cavity and or uterine myometriu of sexually mature, castrated, female, nude mice. Exogenous estrogen are supplied to induce growth of the explanted tissue. In some caseε, the harvested tumor cells are cultured m vi tro prior to implantation. Treatment consisting of a compound of the present inver' ion or vehicle lε supplied by gastric lavage on a daily basis for 3-16 weeks and implantε are removed and meaεured for growth or regression. At the time of sacrifice, the uteri are harvested to assess the status of the organ. Test 5 A Tissue from human uterine fibroid tumors is harvested and maintained, m vi tro, as primary nontransformed cultures. Surgical specimens are pushed through a sterile mesh or sieve, or alternately teased apart from surrounding tiεεue to produce a single cell suspension. Cells are maintained meαia containing 10% serum and antibiotic. Rates of growth m the presence and absence of eεtrogen are determined. Ceils are asεayed for their ability to produce complement component C3 and their reεponεe to growth factorε and growth hormone. In l tro cultureε are assessed for their proliferative responεe following treatment with progeεtins, GnRH, a compound of the preεent invention and vehicle. Levelε of εteroid hormone receptorε are asseεsed weekly to determine whether important cell characteristics are maintained in vi tro. Tissue from 5-25 patients are utilized. Activity in at least one of the above testε indicates the compounds of the present invention are of potential in the treatment of uterine fibrosis. Endometriosis Test Procedure In Testε 1 and 2, effectε of 14-day and 21-day adminiεtration of compoundε of the preεent invention on the growth of explanted endometrial tiεεue can be examined. Teεt 1 Twelve to thirty adult CD εtrain female rats are used as test animals. They are divided into three groups of equal numbers. The estrous cycle of all animals is monitored. On the day of proestrus, εurgery is performed on each female. Females m each group have the left uterine horn removed, sectioned into small squares, and the squares are loosely sutured at variouε sites adjacent to the meεenteric blood flow. In addition, females in Group 2 have the ovaries removed. On the day following surgery, animals m Groups 1 and 2 receive mtraperitoneal injections of water for 14 days wnereas animals in Group 3 receive mtraperitoneal injections of 1.0 mg of a compound of the present invention per kilogram of body weight for the same duration. Following 14 days of treatment, each female is sacrificed and the endometrial explants, adrenals, remaining uterus, and ovaries, where applicable, are removed and prepared for histological examination. The ovaries and adrenals are weighed. Test 2 Twelve to thirty adult CD strain female rats are used as test animals. They are divided into two equal groups. The estrous cycle of all animals is monitored. On the day of proestrus, εurgery lε performed on each female. Females m each group have the left uterine horn removed, sectioned into small squareε, and the squares are loosely sutured at various sites adjacent to the mesenteric blood flow. Approximately 50 days following εurgery, animals assigned to Group 1 receive mtraperitoneal injections of water for 21 days whereas animals in Group 2 receive mtraperitoneal injections of 1.0 mg of a compound of the present invention per kilogram of body weight for the same duration. Following 21 days of treatment, each female is εacπficed and the endometrial explantε and adrenalε are removed and weighed. The explants are measured as an indication of growth. Estrous cycles are monitored. Test 3 A. Surgical induction of endometriosis Autographs of endometrial tissue are used to induce endometriosis in rats and/or rabbits. Female animals at reproductive maturity undergo bilateral oophorectomy, and estrogen is εupplied exogenouεly thuε providing a εpecific and constant level of hormone. Autologous endometrial tisεue is implanted in the peritoneum of 5-150 animals and estrogen supplied to induce growth of the explanted tissue. Treatment consisting of a compound of the present invention is supplied by gastric lavage on a daily basis for 3-16 weeks, and implants are removed and measured for growth or regreεεion. At the time of sacrifice, the intact horn of the uterus is harvested to asεess εtatus of endometrium. B. Implantation of human endometrial tissue m nude mice. Tisεue from human endometrial leεions is implanted into the peritoneum of sexually mature, castrated, female, nude mice. Exogenous estrogen is supplied to induce growth of the explanted tisεue. In some cases, the harvested endometrial cells are cultured in vi tro prior to implantation. Treatment consisting of a compound of the present invention supplied by gastric lavage on a daily basis for 3-16 weeks, and implants are removed and measured for growth or regresεion. At the time of εacrifice, the uteri are harvested to asεeεε the status of the intact endometrium. Test 4 A. Tissue from human endometrial lesionε is harvested and maintained m vi tro as primary nontransformed cultureε. Surgical specimens are pushed through a sterile mesh or sieve, or alternately teased apart from surrounding tissue to produce a single cell suεpenεion. Cells are maintained m media containing 10% serum and antibiotic. Rates of growth m the presence and absence of estrogen are determined. Cells are assayed for their ability to produce complement component C3 and their responεe to growth factors and growth hormone. In vi tro cultures are asεeεsed for their proliferative response following treatment with progestins, GnRH, a compound of the invention, and vehicle Levels of steroid hormone receptors are asεeεεed weekly to determine whether important cell characteriεticε are maintained m vi tro . Tiεεue from 5-25 patients is utilized. Activity any of the abo^e asεayε indicates that the compounds of the present invention are useful in the treatment of endometriosis. Inhibition of Aortal Smooth Cell Proliferation/ Pestenosis Test Procedure Compounds of the present invention have capacity to inhibit aortal smooth cell proliferation. This can be demonstrated by using cultured smooth cells derived from rabbit aorta, proliferation being determined by the measurement of DNA synthesis. Cells are obtained by explant method as described Rosε, J. of Cell Bio. 50: 172 (1971) . Cellε are plated in 96 well microtiter plates for five days. The cultures become confluent and growth arrested. The cells are then transferred to Dulbecco' s Modified Eagle's Medium (DMEM) containing 0.5 - 2% platelet poor plasma, 2 mM L- glutamme, 100 U/ml penicillin, 100 mg ml streptomycin, 1 mC/ml 3 H-thymιdme, 20 ng/ml platelet-derived growth factor, and varying concentrations of the present compounds. Stock solution of the compounds is prepared in dimethyl sulphoxide and then diluted to appropriate concentration (0.01 - 30 mM) in the above aεεay medium. Cellε are then incubated at 37° C. for 24 hourε under 5% C0 2 /95% air. At the end of 24 hours, the cells are fixed in methanol. 3 H thymidme incorporation in DNA lε then determined by scintillation counting as described in Bonm, et al . , Exp. Cell Res. 181: 475-482 (1989) . Inhibition of aortal smooth muscle cell proliferation by the compounds of the present invention are further demonstrated by determining their effectε on exponentially growing cells. Smooth muscle cells from rabbit aortae are seeded m 12 well tissue culture plates m DMEK containing 10% fetal bovine serum, 2 mM L-glutamme, 100 U/ml penicillin, and 100 mg/ml streptomycin. After 24 hours, the cells are attached and the medium is replaced with DMEM containing 10% εerum, 2 mM L-glutamme, 100 U/ml penicillin, 100 mg/ml streptomycin, and desired concentrations of the compounds. Cells are allowed to grow for four days. Cells are treated w th trypsm and the number of cells m each culture is determined by counting using a ZM-Coulter counter. Activity m the above tests indicates that the compounds of the present invention are of potential in the treatment of restenosis. The present invention also provides a method of alleviating post-menopausal syndrome m women which comprises he aforementioned method using compounds of Formula I and further comprises administering to a woman an effective amount of eεtrogen or progestm. These treatments are particularly useful for treating osteoporosis and lowering serum cholesterol because the patient will receive the oenefits of each pharmaceutical agent while the compounds of tne present invention would inhibit undesirable side-effects of estrogen and progestm. Activity of these combination treatments in any of the poεt-menopauεal tests, infra, indicates that the combination treatments are useful for alleviating the symptoms of post-menopausal symptoms m women. Various forms of estrogen and progestm are commercially available. Estrogen-based agents include, for example, ethenyl estrogen (0.01 - 0.03 mg/day), mestranol (0.05 - 0.15 mg/day) , and conjugated eεtrogenic hormoneε εuch as Premarm® (Wyeth-Ayerst; 0.3 - 2.5 mg/day) . Progest - baεed agentε include, for example, medroxyprogesterone such as Provera® (Upjohn; 2.5 -10 mg/day), norethylnodrel (1.0 - 10.0 mg/day), and nonethmdrone (0.5 - 2.0 mg/day) . A preferred estrogen-based compound is Premarm, and norethylnodrel and norethindrone are preferred progestin- baεed agentε. The method of adminiεtration of each eεtrogen- and progeεtin-based agent is consistent with that which is known in the art. For the majority of the methods of the present invention, compounds of Formula I are administered continuously, from 1 to 3 times daily. However, cyclical therapy may especially be useful in the treatment of endometriosis or may be used acutely during painful attackε of the diεeaεe. In the case of restenosiε, therapy may be limited to εhort (1-6 months) intervals following medical procedures such as angioplasty. As used herein, the term "effective amount" means an amount of compound of the present invention which is capable of alleviating the symptoms of the various pathological conditions herein described. The specific dose of a compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case including, for example, the compound administered, the route of administration, the state of being of the patient, and the pathological condition being treated. A typical daily dose will contain a nontoxic dosage level of from about 5 mg to about 600 mg/day of a compound of the present invention. Preferred daily doεes generally will be from about 15 mg to about 80 mg/day. The compounds of thiε invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuεcular, and intranasal. These compounds preferably are formulated prior to administration, the selection of which will be decided by the attending physician. Thus, another aspect of the preεent invention iε a pharmaceutical composition compriεing an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally containing an effective amount of eεtrogen or progeεtin, and a pharmaceutically acceptable carrier, diluent, or excipient. The total active ingredients m εuch formulations comprises from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable" it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof . Pharmaceutical formulations of the present invention can be prepared by procedures known in the art using well known and readily available ingredients. For example, the compounds of formula I, with or without an estrogen or progestm compound, can be formulated with common excipients, diluents, or carriers, and formed 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 extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such aε carboxymethyl celluloεe and other cellulose derivatives, alginates, gelatin, and polyvinyl¬ pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding disεolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols. The compoundε alεo can be formulated aε elixirε or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes. Additionally, tne compounds are well suited to formulation as sustained release doεage formε and the like. The formulations can be so constituted that they release the active ingredient only or preferably in a particular physiological location, possibly over a period of time. The coatings, envelopes, and protective matrices may be made, for example, from polymeric subεtanceε or waxeε. Compounds of formula I, alone or in combination with a pharmaceutical agent of the present invention, generally will be administered in a convenient formulation. The following formulation examples only are illustrative and are not intended to limit the scope of the present invention. Formulationε In the formulationε which follow, "active ingredient" means a compound of formula I, or a salt thereof. Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared using the following: Ingredient Quantity (mg/capsule) Active ingredient 0 . 1 - 1000 Starch, NF 0 - 650 Starch flowable powder 0 - 650 Silicone fluid 350 centistokes 0 - 15 The formulation above may be changed in compliance with the reasonable variations provided. A tablet formulation is prepared using the ingredients below: Formulation 2 : Tabletε Inσredient Quantity (mg/tablet! Active ingredient 2.5 1000 Celluloεe, microcrystalline 200 650 Silicon dioxide, fumed 10 650 Stearate acid 5 15 The components are blended and compresεed to form tablets, Alt rnatively, tablets each containing 2.5 - 1000 mg of active ingredient are made up as follows: Formulation 3 : Tablets Ingredient Quantity (mg/tablet^ Active ingredient 25 - 10C0 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone 4 (as 10% solution in water) Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1 The active ingredient, starch, and cellulose are pasεed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone lε mixed with the reεultant powders which are then pasεed through a No. 14 mesh U.S. sieve. The granuleε so produced are dried at 50°-60° C and pasεed through a No. 18 mesh U.S. sieve. The εodium carboxymethyl starch, magnesium stearate, and talc, previously pasεed through a No. 60 U.S. εieve, are then added to the granuleε which, after mixing, are compressed on a tablet machine to yield tablets. Suεpenεionε each containing 0.1 - 1000 mg of medicament per 5 ml dose are made as follows: Formulation 4: Suεpensions Ingredient Quantity (mg/5 ml) Active ingredient 0.1 - 1000 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purified water to 5 mL The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and εyrup to form a εmooth paεte. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume. An aerosol εolution iε prepared containing the following ingredientε: Formulation 5: Aeroεol 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 added to a portion of the propellant 22, cooled to 30° C, and transferred to a filling device. The required amount iε then fed to a εtainleεε εteel container and diluted with the remaining propellant. The valve units are then fitted to the container. Suppositories are prepared as follows: Formulation 6: Suppositories Ingredient Quantity (mg/suppository! Active ingredient 250 Saturated fattv acid glvcerides 2,000 The active ingredient is pasεed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previouεly melted using the minimal necesεary heat. The mixture is then poured into a suppoεitory mold of nominal 2 g capacity and allowed to cool. An intravenous formulation is prepared as follows: Formulation 7: Intravenous Solution Ingredient Quantity Active ingredient 50 mg Isotonic saline 1,000 mL The solution of the above ingredients is intravenously administered to a patient at a rate of about 1 mL per minute. Formulation 8: Combination Capsule I Ingredient Quantity (mg/capsule Active ingredient 50 Premarm 1 Avicel pH 101 50 Starch 1500 117.50 Silicon Oil 2 Tween 80 0.50 Cab-O-Sil 0.25 Formulation 9: Combination Capsule II Ingredient Quantity (mg/capsule Active ingredient 50 Norethylnodrel 5 Avicel pH 101 82.50 Starch 1500 90 Silicon Oil 2 Tween 80 0.50 Formulation 10: Combination Tablet 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

Claims: C l a i ms 1. A compound of formula I I wherein R is -H, -OH, -0(Cι-C 4 alkyl), -O-CO- (Cι-C 6 alkyl) , -O-CO-Ar in which Ar is optionally substituted phenyl, or -O- S0 2 - (C -C 6 alkyl) ; R 1 is -H, -OH, -CXC1-C4 alkyl) , -0-CO-(Cι-C 6 alkyl), -O-CO-Ar in which Ar is optionally substituted phenyl, -0- S0 2 ~(C 4 -C 6 alkyl) chloro or bromo; n is 2 or 3; and R 2 and R 3 each are independently C 1 -C 4 alkyl, or combine to form 1-piperidinyl, 1-pyrrolidinyl, ethyl ^ l- pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, or 1- hexamethylenei ino; or a pharmaceutically acceptable salt thereof. 2. A compound according to Claim 1 wherein n is 2, or a pharmaceutically acceptable salt thereof. 3. A compound according to Claim 2 wherein R 2 and R 3 are combined to form 1-piperidinyl, 1-pyrrolidiny] , or 1- hexamethyleneimino, or a pharmaceutically acceptable salt thereof. 4. A compound according to Claim 3 wherein R 2 and R 3 are combined to form 1-piperidinyl , or a pharmaceutically acceptable salt thereof. 5. A compound according to Claim 4 wherein R and R 1 each are -OH, or a pharmaceutically acceptable salt thereof . 6. A compound according to Claim 4 wherein R and R 1 each are -OCH 3 . 7. A compound aε claimed in any one of Claimε 1 to 6 wherein said salt thereof is the hydrochloride salt. 8. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 6, 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 . 9. A pharmaceutical composition wherein said salt thereof is the hydrochloride salt. 10. A method for alleviating the symptoms of post- menopauεal εyndrome comprising administering to a woman in need of such treatment an effective amount of a compound as claimed in any one of Claimε 1 to 6, or a pharmaceutically acceptable εalt thereof. 11. A method according to Claim 10 wherein the poεt-menopausal εyndrome pathological condition is osteoporosis. 12. A method according to Claim 10 wherein the post-menopausal syndrome pathological condition is related to a cardiovascular disease. 13. A method according to Claim 11 wherein the cardiovascular disease is hyperlipidemia. 14. A method according to Claim 10 wherein the post-menopausal syndrome pathological condition is estrogen- dependent cancer. 15. A method according to Claim 14 wherein the estrogen-dependent cancer is breast or uterine cancer. 16. A method for inhibiting uterine fibroid disease comprising administering to a woman in need of such treatment an effective amount of a compound, as claimed in any one of Claimε 1 to 6, or a pharmaceutically acceptable salt thereof. 17. A method for inhibiting endometrioεiε comprising administering to a woman in need of such treatment an effective amount of a compound, as claimed any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof. 18 A method for inhibiting aortal smooth muscle cell proliferation comprising administering to a human in need of such treatment an effective amount of a compound as claimed in any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof. 19. A method for inhibiting restenoεiε comprising administering to a human in need of such treatment an effective amount of a compound, as claimed in any one of Claimε 1 to 6, or a pharmaceutically acceptable salt thereof. 20. A method for alleviating the symptoms of post- menopausal syndrome comprising the method of Claim 10, and further comprising administering to said woman an effective amount of estrogen. 21. A method for alleviating the εymptomε of post¬ menopausal syndrome comprising the method of Claim 10, and further comprising administering to said woman an effective amount of progestm. 22. A method aε claimed in any one of Claimε 10 to 21 wherein εaid εalt thereof is the hydrochloride salt. 23. A compound as claimed in any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, and, optionally, eεtrogen or progestm, for use as an agent for alleviating the symptomε of post-menopausal syndrome, particularly osteoporosis, cardiovascular diseaεe including hyperlipidemia, and eεtrogen-dependent cancer including breaεt and uterine cancer. 24. A compound according to Claim 23 wherein said salt thereof lε the hydrochloride salt. 25. A compound as claimed in any one of Claims 1 to 6, or a pharmaceutically acceptable εalt thereof, and, optionally, eεtrogen or progestm, for uεe aε an agent for inhibiting uterine fibroid disease, endometriosis, aortal smooth muscle cell proliferation, and restenosiε. 26. A compound according to Claim 25 wherein εaid salt thereof is the hydrochloride salt. 27. A compound of formula IX IX wherein R a is -OH or -0(Cι-C alkyl); P la is -OH or -0(Cι-C 4 alkyl); n is 2 or 3; and R 2 and R 3 each are independently C 1 -C 4 alkyl, or combine to form 1-piperidinyl, 1-pyrrolidinyl, methyl-1- pyrrolidinyl, dimethyl-1-piperidinyl, 4-morpholino, or 1- hexamethyleneimino; or a pharmaceutically acceptable salt thereof. 28. A compound according to Claim 27 wherein R 2 and R 3 are combined to form 1-piperidinyl, and n iε 2, or a pharmaceutically acceptable salt thereof. 29. A compound according to Claims 28 wherein F a and R la each are -OCH 3 , or a pharmaceutically acceptable salt thereof. 30. A compound according to Claim 28 wherein R a and P la each are -OH. 31. A compound aε claimed in any one of Claimε 27 to 30 wherein εaid salt thereof is the hydrochloride salt. 32. A process for preparing a compound of formula la Ia wherein R 1 and R la each are -OH or -0(Cι~C4 alkyl) ; R 2 and R 3 each are independently C1-C4 alkyl, or combine to form 1-piperidinyl , 1-pyrrolidinyl , methyl-1- pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, or 1- hexamethyleneimino; and n iε 2 or 3; or a pharmaceutically acceptable salt thereof, which compriseε optionally dealkylating a compound of formula II II wherein R a , R l , R 2 , R 3 , and n are aε defined above; b) reacting said formula II compound with a reducing agent in the preεence of a εolvent having a boiling point in the range from about 150° C to about 200° C, and heating the mixture to reflux; and c) optionally salifying the reaction product form step b) . 33. A process according to Claim 32 wherein said process is carried out in a single vessel. 34. A process according to Claim 33 wherein the formula la compound is a compound wherein R a and R la each are -OH; R 2 and R 3 are combined to form 1-piperidinyl; and or a pharmaceutically acceptable salt thereof. 35. A process as claimed in any one of Claims 32 to 34 wherein the salt of a compound of formula la is the hydrochloride salt. 36. A process according to Claim 35 './herein said reducing agent is Red-Al. 37. A process according to Claim 36 wherein said solvent having a boiling point from about 150° C to about 200° C is n-propylbenzene. 38. A process for preparing a compound of the formula wherein R is -H, -OH, -0(Cι-C 4 alkyl) , -O-CO- (Cι-C 6 alkyl), -O-CO-Ar in which Ar iε optionally substituted phenyl, or -O- S0 2 - (C4-C6 alkyl) ; R 1 is -H, -OH, -CXC1-C4 alkyl) , -O-CO- (Cι-C 6 alkyl), -O-CO-Ar in which Ar is optionally εubstituted phenyl, -O- SO 2 - (C 4 -C 6 alkyl) chloro or bromo; M is -CH(OH)- or -CH 2 -; n is 2 or 3 ; and R 2 and R 3 each are independently C 1 -C 4 alkyl, or combine to form 1-piperidinyl, 1-pyrrolidino, methyl-1- pyrrolidino, dimethyl-1-pyrrolidino, 4-morpholino or 1- hexamethyleneimino; or a pharmaceutically acceptable salt thereof, which comprises a) optionally dealkylating a compound of formula II R^ II wherein R a , R la , R 2 , R 3 , M and n are as defined above; b) reacting said formula II compound with a reducing agent; c) when R and/or R 1 are -OH, optionally replacing said hydroxy groups with a substituent of the formula -0(Cι-C 4 alkyl) , -OCOC 6 H 5 , -COC(C ! -C 6 alkyl), or -OS0 2 (C 4 -C 6 alkyl) ; and d) optionally salifying the reaction product from εtep b) or c) . 39. A process according to Claim 38 wherein said reaction product is a compound wherein R and R 1 each are -OH, R 2 and P. 3 combine to form 1-piperidinyl, M is -CH 2 -, and n is 2. 40. A process as claimed in any one of Claims 38 to 39 wherein said salt thereof is the hydrochloride salt. 41. A procesε for preparing a compound of formula I R 2 I wherein R is -H, -OH, -0(Cι-C 4 alkyl) , -0-C0-(Cι~C 6 alkyl), -O-CO-Ar in which Ar is optionally subεtituted phenyl, or -0- S0 2 - (C -C 6 alkyl) ; R 1 is -H, -OH, -0(Cι-C 4 alkyl) , -O-CO- (Cι-C 6 alkyl), -O-CO-Ar in which Ar iε optionally substituted phenyl, -O- Sθ 2 -(C 4 -C 6 alkyl) chloro or bromo; n is 2 or 3; and R 2 and R 3 each are independently C 1 -C 4 alkyl, or combine to form 1-piperidinyl, 1-pyrrolidino, methyl-1- pyrrolidino, dimethyl-1-pyrrolidino, 4-morpholino or 1- hexamethyleneimino; or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to any of the examples. 42. A compound of formula I I wherein R is -H, -OH, -0(Cι-C alkyl), -O-CO- (Cι-C 6 alkyl) , -O-CO-Ar in which Ar is optionally substituted phenyl, or -O- S0 2 - (C -C 6 alkyl) ; R 1 is -H, -OH, -0(Cι-C 4 alkyl) , -O-CO- (Cι-C 6 alkyl), -O-CO-Ar in which Ar is optionally substituted phenyl, -O- SO 2 - (C 4 -C 6 alkyl) chloro or bromo; n is 2 or 3; and R 2 and R 3 each are independently C 1 -C 4 alkyl, or combine to form 1-piperidinyl, 1-pyrrolidino, methyl-1- pyrrolidino, dimethyl-1-pyrrolidino, 4-morpholino or 1- hexamethyleneimino; or a pharmaceutically acceptable salt thereof, subεtantially as hereinbefore described with reference to any of the examples .

Inventors: BRYANT HENRY UHLMAN, CULLINAN GEORGE JOSEPH, DODGE JEFFREY ALAN, FAHEY KENNAN JOSEPH, JONES CHARLES DAVID, BRYANT, HENRY, UHLMAN, CULLINAN, GEORGE, JOSEPH, DODGE, JEFFREY, ALAN, FAHEY, KENNAN, JOSEPH, JONES, CHARLES, DAVID
Applicants: BRYANT HENRY UHLMAN, CULLINAN GEORGE JOSEPH, DODGE JEFFREY ALAN, FAHEY KENNAN JOSEPH, JONES CHARLES DAVID, LILLY CO ELI, BRYANT, HENRY, UHLMAN, CULLINAN, GEORGE, JOSEPH, DODGE, JEFFREY, ALAN, ELI LILLY AND COMPANY, FAHEY, KENNAN, JOSEPH, JONES, CHARLES, DAVID
Application year: 1995
Main classification: A61K31
IPC codes: C07D307