WO2004091488A2 - Estrogen receptor modulators - Google Patents

Abstract

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, and cancer, in particular of the breast, uterus and prostate.

Description

TΓΓLE OF THE INVENTION ESTROGEN RECEPTOR MODULATORS

BACKGROUND OF THE INVENTION Naturally occurring and synthetic estrogens have broad therapeutic utility, including: relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, treatment of osteoporosis, treatment of hirsutism, treatment of prostatic cancer, treatment of hot flashes and prevention of cardiovascular disease. Because estrogen is very therapeutically valuable, there has been great interest in discovering compounds that mimic estrogen-like behavior in estrogen responsive tissues.

For example, estrogen-like compounds would be beneficial in the treatment and prevention of bone loss. Bone loss occurs in a wide range of subjects, including women that are post- menopausal or have had a hysterectomy, patients who were or are currently being treated with corticosteroids, and patients having gonadal dysgenesis. The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopema, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone lesorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.

In the U.S., there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis. In addition, there are about 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% ofthe patients require nursing home care after the fracture.

Osteoporosis affects approximately 20 to 25 million post-menopausal women in the U.S. alone. It has been theorized that the rapid loss of bone mass in these women is due to the cessation of estrogen production of the ovaries. Since studies have shown that estrogen slows the reduction of bone mass due to osteoporosis, estrogen replacement therapy is a recognized treatment for post-menopausal osteoporosis.

In addition to bone mass, estrogen appears to have an effect on the biosynthesis of cholesterol and cardiovascular health. Statistically, the rate of occurrence of cardiovascular disease is roughly equal in po stmenopausal women and men; however, prønenopausal women have a much lower incidence of cardiovascular disease than men. Because postmenopausal women are estrogen deficient, it is believed that estrogen plays a beneficial role in preventing cardiovascular disease. The mechanism is not well understood, but evidence indicates that estrogen can upregulate the low density lipid (LDL) cholesterol receptors in the liver to remove excess cholesterol. Postmenopausal women given estrogen replacement therapy experience a return of lipid levels to concentrations comparable to levels associated with the premenopausal state. Thus, estrogen replacement therapy could be an effective treatment for such disease. However, the side effects associated with long term estrogen use limit the use of this alternative.

Other disease states that affect postmenopausal women include estrogen-dependent breast cancer and uterine cancer. Anti-estrogen compounds, such as tamoxifen, have commonly been used as chemotherapy to treat breast cancer patients. Tamoxifen, a dual antagonist and agonist of estrogen receptors, is beneficial in treating estrogen-dependent breast cancer. However, treatment with tamoxifen is less than ideal because tamoxifen' s agonist behavior enhances its unwanted estrogenic side effects. For example, tamoxifen and other compounds that agonize estrogen receptors tend to increase cancer cell production in the uterus. A better therapy for such cancers would be an anti-estrogen compound that has negligible or nonexistent agonist properties.

Although estrogen can be beneficial for treating pathologies such as bone loss, increased lipid levels, and cancer, long-term estrogen therapy has been implicated in a variety of disorders, including an increase in the risk of uterine and endometrial cancers. These and other side effects of estrogen replacement therapy are not acceptable to many women, thus limiting its use.

Alternative regimens, such as a combined progestogen and estrogen dose, have been suggested in an attempt to lessen the risk of cancer. However, such regimens cause the patient to experience withdrawal bleeding, which is unacceptable to many older women. Furthermore, combining estrogen with progestogen reduces the beneficial cholesterol-lowering effect of estrogen therapy. In addition, the long term effects of progestogen treatment are unknown.

In addition to post-menopausal women, men suffering from prostatic cancer can also benefit from anti-estrogen compounds. Prostatic cancer is often endocrine-sensitive; androgen stimulation fosters tumor growth, while androgen suppression retards tumor growth. The administration of estrogen is helpful in the treatment and control of prostatic cancer because estrogen administration lowers the level of gonadotropin and, consequently, androgen levels.

The estrogen receptor has been found to have two forms: ER and ERβ. Ligands bind differently to these two forms, and each form has a different tissue specificity to binding ligands. Thus, it is possible to have compounds that are selective for ERα or ERβ, and therefore confer a degree of tissue specificity to a particular ligand. What is needed in the art are compounds that can produce the same positive responses as estrogen replacement therapy without the negative side effects. Also needed are estrogen-like compounds that exert selective effects on different tissues of the body.

The compounds ofthe instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, glucocorticoid induced osteoporosis, bone pain, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma, cartilage degeneration, endometriosis, uterine fibroid disease, cancer of the breast, uterus or prostate, hot flashes, cardiovascular disease, impairment of cognitive function, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity and incontinence.

SUMMARY OF THE INVENTION The present invention relates to compounds that are capable of treating and/or preventing a variety of conditions related to estrogen functioning. One embodiment of the present invention is illustrated by a compound of Formula I , and the pharmaceutically acceptable salts and stereoisomers thereof:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds useful as estrogen receptor modulators. Compounds ofthe present invention are described by the following chemical formula:

wherein Rl is hydrogen, C1-.5 alkyl or halogen;

R2 is hydrogen or hydroxy;

R3 is hydrogen or hydroxy; R4 is hydrogen, C1-.5 alkyl or halogen;

R5 is hydrogen, C1-.5 alkyl or halogen;

R6 is hydrogen, C1-.5 alkyl or halogen;

R7 is hydrogen, hydroxy, halogen, C1-.5 alkyl, CF3 or 0(Cι_5 alkyl);

R°> is hydrogen, hydroxy, halogen, C1-.5 alkyl, CF3 or 0(Cι_5 alkyl); R9 is hydrogen, C1-.5 alkyl or halogen;

RlO is hydrogen, C1.5 alkyl or halogen; each RU is independently hydrogen, C1-.5 alkyl or halogen; or two Rl 1 , when on separate carbons, can be taken together to form a three membered ring; n is an integer from one to four; m is an integer from one to two; or a pharmaceutically acceptable salt or stereoisomer thereof. hi one class of compounds of the present invention, compounds of the present invention are described by the following chemical formula:

wherein n is an integer from one to three; or a pharmaceutically acceptable salt or stereoisomer thereof. hi another class of compounds ofthe present invention, Rl is hydrogen, fluoro, chloro or C1-3 alkyl. In another class of compounds of the present invention, R4 is hydrogen, fluoro, chloro or

C1-3 alkyl.

In another class of compounds ofthe present invention, 5 is hydrogen, Cl-3 alkyl or fluoro.

In another class of compounds of the present invention, 6 is hydrogen, Cl-3 alkyl or fluoro.

In another class of compounds of the present invention, R? is hydrogen, hydroxy, fluoro, Cl-3 alkyl, CF3 or 0(Ci-3 alkyl).

In another class of compounds of the present invention, R^§ is hydrogen, hydroxy, fluoro, C1-3 alkyl, CF3 or 0(Ci-3 alkyl). In another class of compounds of the present invention, R9 is hydrogen, Cl-3 alkyl or fluoro.

In another class of compounds ofthe present invention, RlO is hydrogen, Cι_3 alkyl or fluoro. hi another class of compounds ofthe present invention, each Rl 1 is independently hydrogen, Cl-3 alkyl or fluoro.

In another class of compounds of the present invention, n is one. In another class of compounds ofthe present invention, n is two.

Non-limiting examples of the present invention include:

((+)-cis)-3-(4-hydroxyphenyl)-4,4-dimethyl-2-[4-(2-piperid-l-ylethoxy)phenyl]chroman-6-ol;

((+-)cis)-3-(4-hydroxyphenyl)-4,4-dimethyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)chroman-6-ol;

((+-)cis)-3-(4-hydroxyphenyl)-4,4-dimethyl-2-[4-(2-pyrrolidin-l-ylethoxy)phenyl]chroman-6-ol;

5-fluoro-3-(4-hydroxyphenyl)-4-methyl-2-[4-(2-piperidin-l-ylethoxy)phenyl]chroman-6-ol;

(2R,3R,4S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-(2-piperidin-l-ylethoxy)phenyl]chroman-7-ol;

(2R,3R,4S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-(2-piperidin-l-ylethoxy)phenyl]chroman-6-ol;

(2R,3R,4S)-3-(4-hydroxyphenyl)-4-methyl-2'[4-(2-pyrrolidin-l-ylethoxy)phenyl]chro an-6-ol;

(2R,3R,4S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3S)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)chroman-6-ol;

(2R,3R,4S)-2-[4-({(2S)-2-[(3R,4S)-3,4-dimethylpyrrolidin-l-yl]propyl}oxy)phenyl]-3-(4- hydroxyphenyl)-4-methylchroman-6-ol;

(2R,3R,4S)-2-(4-{(lR)-2-[(3R,4S)-3,4-dimethylpyrrolidin-l-yl]-l-methylethoxy}phenyl)-3-(4- hydroxyphenyl)-4-methylchroman-6-ol;

(2R,3R,4S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-({(2S)-2-[(3R)-3-methylpyrrolidin-l- yl]propyl}oxy)phenyl]chroman-6-ol;

(2R,3R,4S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-(2-pyrrolidin-l-ylethoxy)phenyl]chroman-6-ol;

(2R,3R,4S)-5-fluoro-3-(4-hydroxyphenyl)-4-methyl-2-(4-{[(2S)-2-pyrrolidin-l- ylpropyl]oxy}phenyl)chroman-6-ol;

(2R,3R,4S)-3-(4-hydroxyphenyl)-4-methyl-2-{4-[(lR)-l-methyl-2-pyrrolidin-l- ylethoxy]phenyl}chroman-6-ol;

(2R,3R,4S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{(lR)-l-methyl-2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)chroman-6-ol;

(2R,3R,4S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{[(2S)-2-piperidin-l-ylpropyl]oxy}phenyl)chroman-6-ol;

(2R,3R,4S)-3-(4-hydroxyphenyl)-4-methyl-2-{4-[(lR)-l-methyl-2-piperidin-l-ylethoxy]phenyl}chroman- 6-ol;

5-fluoro-3-(3-hydroxyphenyl)-4-methyl-2-[4-(2-piperidin-l-ylethoxy)phenyl]chroman-6-ol;

4-ethyl-3-(4-hydroxyphenyl)-2-[4-(2-pyrrolidin-lⁱylethoxy)phenyl]chroman-6-ol;

4-ethyl-3-(4-hydroxyphenyl)-2-[4-(2-pyrrolidin-l-ylethoxy)phenyl]chroman-6-ol;

4-ethyl-3-(4-hydroxyphenyl)-2-(4-{2-[3-methylpyrrolidin-l-yl]ethoxy}phenyl)chroman-6-ol;

4-ethyl-3-(4-hydroxyphenyl)-2-[4-(2-piperidin-l-ylethoxy)phenyl]chroman-6-ol;

4-ethyl-3-(4-hydroxyphenyl)-2-(4-{2-[3-methylpyrrolidin-l-yl]ethoxy}phenyl)chroman-6-ol; and the pharmaceutically acceptable salts and stereoisomers thereof.

Also included within the scope of the present invention is a pharmaceutical composition which is comprised of a compound of Formula I as described above and a pharmaceutically acceptable carrier. The invention is also contemplated to encompass a pharmaceutical composition which is comprised of a pharmaceutically acceptable carrier and any ofthe compounds specifically disclosed in the present application. The present invention also relates to methods for making the pharmaceutical compositions ofthe present invention. The present invention is also related to processes and intermediates useful for making the compounds and pharmaceutical compositions ofthe present invention. These and other aspects of the invention will be apparent from the teachings contained herein. Utilities

The compounds of the present invention are selective modulators of estrogen receptors and are therefore useful to treat or prevent a variety of diseases and conditions related to estrogen receptor functioning in mammals, preferably humans. "A variety of diseases and conditions related to estrogen receptor functioning" includes, but is not limited to, bone loss, bone fractures, osteoporosis, glucocorticoid induced osteoporosis, bone pain, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma, cartilage degeneration, endometriosis, uterine fibroid disease, cancer of the breast, uterus or prostate, hot flashes, cardiovascular disease, impairment of cognitive function, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity and incontinence. In treating such conditions with the instantly claimed compounds, the required therapeutic amount will vary according to the specific disease and is readily ascertainable by those skilled in the art. Although both treatment and prevention are contemplated by the scope of the invention, the treatment of these conditions is the preferred use.

The present invention also relates to methods for eliciting an estrogen receptor modulating effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions ofthe present invention.

The present invention also relates to methods for eliciting an estrogen receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The estrogen receptor antagonizing effect can be either an ERα antagonizing effect, an ERβ antagonizing effect or a mixed ERα and ERβ antagonizing effect.

The present invention also relates to methods for eliciting an estrogen receptor agonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. The estrogen receptor agonizing effect can be either an ERα agonizing effect, an ERβ agonizing effect or a mixed ERα and ERβ agonizing effect.

The present invention also relates to methods for treating or preventing disorders related to estrogen functioning, bone loss, bone fractures, osteoporosis, glucocorticoid induced osteoporosis, bone pain, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma, cartilage degeneration, endometriosis, uterine fibroid disease, cancer ofthe breast, uterus or prostate, hot flashes, cardiovascular disease, impairment of cognitive function, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity and incontinence in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention. Exemplifying the invention is a method of treating or preventing osteoporosis. Exemplifying the invention is a method of treating or preventing bone loss. Exemplifying the invention is a method of treating or preventing metastatic bone disease. Exemplifying the invention is a method of treating or preventing cancer. Exemplifying the invention is a method of treating or preventing cardiovascular disease. An embodiment of the invention is a method for treating or preventing cancer, especially ofthe breast, uterus or prostate, in a mammal in need thereof by administering the compounds and pharmaceutical compositions ofthe present invention. The utility of SERMs for the treatment of breast, uterine or prostate cancer is known in the literature, see TJ. Powles, "Breast cancer prevention," Oncologist 2002; 7(l):60-4; Park, W.C. and Jordan, V.C., "Selective estrogen receptor modulators (SERMS) and their roles in breast cancer prevention." Trends Mol Med. 2002 Feb;8(2):82-8; Wolff, A.C. et al, "Use of SERMs for the adjuvant therapy of early-stage breast cancer," Ann N Y Acad Sci. 2001 Dec;949:80-8; Steiner, M.S. et al, "Selective estrogen receptor modulators for the chemoprevention of prostate cancer," Urology 2001 Apr; 57(4 Suppl l):68-72.

Another embodiment ofthe invention is a method of treating or preventing metastatic bone disease in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of SERMs in the treatment of metastatic bone disease is known in the literature, see, Campisi, C. et al, "Complete resoultion of breast cancer bone metastasis through the use of beta-interferon and tamoxifen," Eur J Gynaecol Oncol 1993;14(6):479-83. Another embodiment of the invention is a method of treating or preventing gynecomastia in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of SERMs in the treatment of gynecomastia is known in the literature, see, Ribeiro, G. and Swindell R., "Adjuvant tamoxifen for male breast cancer." Br J Cancer 1992;65:252-254; Donegan, W., "Cancer ofthe Male Breast," JGSM Vol. 3, Issue 4, 2000.

Another embodiment of the invention is a method of treating or preventing postmenopausal osteoporosis, glucocorticoid osteoporosis, hypercalcemia of malignancy, bone loss and bone fractures in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of SERMs to treat or prevent osteoporosis, hypercalcemia of malignancy, bone loss or bone fractures is known in the literature, see Jordan, V.C. et al, "Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis and coronary heart disease," Natl Cancer Inst 2001 Oct; 93(19): 1449- 57; Bjarnason, NH et al, "Six and twelve month changes in bone turnover are realted to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postemenopausal osteoporosis," Osteoporosis hit 2001; 12(11):922-3; Fentiman I.S., "Tamoxifen protects against steroid-induced bone loss," Eur J Cancer 28:684-685 (1992); Rodan, G.A. et al, "Therapeutic Approaches to Bone Diseases,"

Science Vol 289, 1 Sept. 2000.

Another embodiment ofthe invention is a method of treating or preventing periodontal disease or tooth loss in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of

SERMs to treat periodontal disease or tooth loss in a mammal is known in the literature, see Rodan, G.A. et al, "Therapeutic Approaches to Bone Diseases," Science Vol 289, 1 Sept. 2000 pp. 1508-14.

Another embodiment ofthe invention is a method of treating or preventing Paget's disease in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMs to treat

Paget's disease in a mammal is known in the literature, see Rodan, G.A. et al, "Therapeutic Approaches to Bone Diseases," Science Vol 289, 1 Sept. 2000 pp. 1508-14.

Another embodiment ofthe invention is a method of treating or preventing uterine fibroid disease in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMS to treat uterine fibroids, or uterine leiomyomas, is known in the literature, see Palomba, S., et al, "Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women," Fertil Steril. 2001

Jul;76(l):38-43.

Another embodiment ofthe invention is a method of treating or preventing obesity in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMs to treat obesity is known in the literature, see Picard, F. et al, "Effects of the estrogen antagonist EM-652.HC1 on energy balance and lipid metabolism in ovariectomized rats," t J Obes Relat Metab Disord. 2000

Jul;24(7):830-40. Another embodiment of the invention is a method of treating or preventing cartilage degeneration, rheumatoid arthritis or osteoarthritis in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any ofthe compounds or pharmaceutical compositions described above. The use of SERMs to treat cartilage degeneration, rheumatoid arthritis or osteoarthritis is known in the literature, see Badger, A.M. et al, "Idoxifene, a novel selective estrogen receptor modulator, is effective in a rat model of adjuvant-induced arthritis." J Pharmacol Exp Ther. 1999

Dec;291(3): 1380-6.

Another embodiment ofthe invention is a method of treating or preventing endometriosis in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMs to treat endometriosis is known in the art, see Steven R. Goldstein, "The Effect of SERMs on the Endometrium," Annals ofthe New York Academy of Sciences 949:237-242 (2001).

Another embodiment of the invention is a method of treating or preventing urinary incontinence in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The use of SERMs to treat urinary incontinence is known in the art, see, Goldstein, S.R., "Raloxifene effect on frequency of surgery for pelvic floor relaxation," Obstet Gynecol. 2001, Jul; 98(l):91-6.

Another embodiment of the invention is a method of treating or preventing cardiovascular disease, restenosis, lowering levels of LDL cholesterol and inhibiting vascular smooth muscle cell proliferation in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of SERMs in treating or preventing cardiovascular disease, restenosis, lowering levels of LDL cholesterol and inhibiting vascular smooth muscle cell proliferation is known in the art, see Nuttall, ME et al., "Idoxifene: a novel selective estrogen receptor modulator prevents bone loss and lowers cholesterol levels in ovariectomized rats and decreases uterine weight in intact rats," Endocrinology 1998 Dec; 139(12):5224-34; Jordan, V.C. et al, "Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis and coronary heart disease," Natl Cancer hist 2001 Oct; 93(19): 1449-57; Guzzo JA., "Selective estrogen receptor modulators—a new age of estrogens in cardiovascular disease?," Clin Cardiol 2000 Jan;23(l):15-7; Simoncini T, Genazzani AR., "Direct- vascular effects of estrogens and selective estrogen receptor modulators," Curr Opin Obstet Gynecol 2000 Jun;12(3): 181-7.

Another embodiment of the invention is a method of treating or preventing the impairment of cognitive functioning or cerebral degenerative disorders in a mammal in need thereof by administering to the mammal a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. The utility of SERMs to prevent the impairment of cognitive functioning is known in the art, see Yaffe, K., K. Krueger, S. Sarkar, et al. 2001, "Cognitive function in postmenopausal women treated with raloxifene," N. Eng. J. Med. 344: 1207-1213.

Exemplifying the invention is the use of any ofthe compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal in need thereof. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of: bone loss, bone resorption, bone fractures, metastatic bone disease and/or disorders related to estrogen functioning.

The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. For oral use of a therapeutic compound according to this invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. For oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH ofthe solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Compounds ofthe present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds ofthe present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds ofthe present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polyactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

The instant compounds are also useful in combination with known agents useful for treating or preventing bone loss, bone fractures, osteoporosis, glucocorticoid induced osteoporosis, bone pain, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma, cartilage degeneration, endometriosis, uterine fibroid disease, cancer ofthe breast, uterus or prostate, hot flashes, cardiovascular disease, impairment of cognitive function, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity and incontinence. Combinations ofthe presently disclosed compounds with other agents useful in treating or preventing osteoporosis or other bone disorders are within the scope of the invention. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics ofthe drugs and the disease involved. Such agents include the following: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen or an estrogen receptor modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; a cholesterol ester transfer protein inhibitor; an integrin receptor antagonist; an osteoblast anabolic agent, such as PTH; calcitonin; Vitamin D or a synthetic Vitamin D analogue; selective serotonin reuptake inhibitors (SSRIs); a NK-1 receptor antagonist; and the pharmaceutically acceptable salts and mixtures thereof. A preferred combination is a compound of the present invention and an organic bisphosphonate. Another preferred combination is a compound of the present invention and a cathepsin K inhibitor. Another preferred combination is a compound ofthe present invention and an estrogen. Another preferred combination is a compound ofthe present invention and an androgen receptor modulator. Another preferred combination is a compound of the present invention and an osteoblast anabolic agent.

"Organic bisphosphonate" includes, but is not limited to, compounds ofthe chemical formula

P0₃H₂

A-(CH₂)_n-C-X

PQ₃H₂ wherein n is an integer from 0 to 7 and wherein A and X are independently selected from the group consisting of H, OH, halogen, NH2, SH, phenyl, C1-C30 alkyl, C3-C30 branched or cycloalkyl, bicyclic ring structure containing two or three N, C1-C30 substituted alkyl, C1-C10 alkyl substituted NH2, C3- C10 branched or cycloalkyl substituted NH2, C1-C10 dialkyl substituted NH2, C1-C10 alkoxy, C1-C10 alkyl substituted thio, thiophenyl, halophenylthio, C1-C10 alkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl, imidazopyridinyl, and benzyl, such that both A and X are not selected from H or OH when n is 0; or A and X are taken together with the carbon atom or atoms to which they are attached to form a C3-C10 ring.

In the foregoing chemical formula, the alkyl groups can be straight, branched, or cyclic, provided sufficient atoms are selected for the chemical formula. The C1-C30 substituted alkyl can include a wide variety of substituents, nonlimiting examples which include those selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH2. C1-C10 alkyl or dialkyl substituted NH2, OH, SH, and C1-C10 alkoxy. .

The foregoing chemical formula is also intended to encompass complex carbocyclic, aromatic and hetero atom structures for the A and/or X substituents, nonlimiting examples of which include naphthyl, quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.

Pharmaceutically acceptable salts and derivatives ofthe bisphosphonates are also useful herein. Non-limiting examples of salts include those selected from the group consisting alkali metal, alkaline metal, ammonium, and mono-, di-, tri-, or tetra-Cl-C30-alkyl-substituted ammonium. Preferred salts are those selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts. More preferred are sodium salts. Non-limiting examples of derivatives include those selected from the group consisting of esters, hydrates, and amides.

It should be noted that the terms "bisphosphonate" and "bisphosphonates", as used herein in referring to the therapeutic agents ofthe present invention are meant to also encompass diphosphonates, biphosphonic acids, and diphosphonic acids, as well as salts and derivatives of these materials. The use of a specific nomenclature in referring to the bisphosphonate or bisphosphonates is not meant to limit the scope of the present invention, unless specifically indicated. Because ofthe mixed nomenclature currently in use by those of ordinary skill in the art, reference to a specific weight or percentage of a bisphosphonate compound in the present invention is on an acid active weight basis, unless indicated otherwise herein. For example, the phrase "about 5 mg of a bone resorption inhibiting bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof, on an alendronic acid active weight basis" means that the amount ofthe bisphosphonate compound selected is calculated based on 5 mg of alendronic acid.

Non-limiting examples of bisphosphonates useful herein include the following: Alendronate, which is also known as alendronic acid, 4-amino-l-hydroxybutylidene-l,l- bisphosphonic acid, alendronate sodium or alendronate monosodium trihydrate, 4-amino-l- hydroxybutylidene-l,l-bisphosphonic acid monosodium trihydrate.

Alendronate is described in U.S. Patents 4,922,007, to Kieczykowski et al, issued May 1, 1990; 5,019,651, to Kieczykowski et al, issued May 28, 1991; 5,510,517, to Dauer et al, issued April 23, 1996; 5,648,491, to Dauer et al, issued July 15, 1997, all of which are incorporated by reference herein in their entirety.

Cycloheptylaminomethylene-l,l-bisphosphonic acid, YM 175, Yamanouchi (incadronate, formerly known as cimadronate), as described in U.S. Patent 4,970,335, to Isomura et al, issued November 13, 1990, which is incorporated by reference herein in its entirety.

1,1-dichloromethylene- 1,1 -diphosphonic acid (clodronic acid), and the disodium salt (clodronate, Procter and Gamble), are described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of which are incorporated by reference herein in their entirety. l-hydroxy-3-(l-pyrrolidinyl)-propylidene-l,l-bisphosphonic acid (EB-1053). 1 -hydroxy ethane- 1,1 -diphosphonic acid (etidronic acid). l-hydroxy-3-(N-methyl-N-pentylamino)propylidene-l,l-bisphosphonic acid, also known as BM-210955, Boehringer-Mannheim (ibandronate), is described in U.S. Patent No. 4,927,814, issued May 22, 1 90, which is incorporated by reference herein in its entirety.

1 -hydroxy-2-imidazo-( 1 ,2-a)pyridin-3-yethylidene (minodronate). 6-amino-l-hydroxyhexylidene-l,l-bisphosphonic acid (neridronate).

3-(dimethylamino)-l-hydroxypropylidene-l,l-bisphosphonic acid (olpadronate). 3-amino-l-hydroxypropylidene-l,l-bisphosphonic acid (pamidronate). [2-(2-pyridinyl)ethylidene]-l,l-bisphosphonic acid (piridronate) is described in U.S. Patent No. 4,761,406, which is incorporated by reference in its entirety. l-hydroxy-2-(3-pyridinyl)-ethylidene-l,l-bisphosphonic acid (risedronate).

(4-chlorophenyl)thiomethane-l,l-disphosphonic acid (tiludronate) as described in U.S. Patent 4,876,248, to Breliere et al, October 24, 1989, which is incorporated by reference herein in its entirety. l-hydroxy-2-(lH-imidazol-l-yl)ethylidene-l,l-bisphosphonic acid (zoledronate). Nonlimiting examples of bisphosphonates include alendronate, cimadronate, clodronate, etidronate, ibandronate, incadronate, minodronate, neridronate, olpadronate, pamidronate, piridronate, risedronate, tiludronate, and zolendronate, and pharmaceutically acceptable salts and esters thereof. A particularly preferred bisphosphonate is alendronate, especially a sodium, potassium, calcium, magnesium or ammonium salt of alendronic acid. Exemplifying the preferred bisphosphonate is a sodium salt of alendronic acid, especially a hydrated sodium salt of alendronic acid. The salt can be hydrated with a whole number of moles of water or non whole numbers of moles of water. Further exemplifying the preferred bisphosphonate is a hydrated sodium salt of alendronic acid, especially when the hydrated salt is alendronate monosodium trihydrate.

It is recognized that mixtures of two or more ofthe bisphosphonate actives can be utilized.

The precise dosage ofthe organic bisphosphonate will vary with the dosing schedule, the particular bisphosphonate chosen, the age, size, sex and condition ofthe mammal or human, the nature and severity ofthe disorder to be treated, and other relevant medical and physical factors. Thus, a precise pharmaceutically effective amount cannot be specified in advance and can be readily determined by the caregiver or clinician. Appropriate amounts can be determined by routine experimentation from animal models and human clinical studies. Generally, an appropriate amount of bisphosphonate is chosen to obtain a bone resorption inhibiting effect, i.e. a bone resorption inhibiting amount ofthe bisphosphonate is administered. For humans, an effective oral dose of bisphosphonate is typically from about 1.5 to about 6000 μg/kg body weight and preferably about 10 to about 2000 μg/kg of body weight. For alendronate monosodium trihydrate, common human doses which are administered are generally in the range of about 2 mg/day to about 40 mg/day, preferably about 5 mg/day to about 40 mg/day. In the U.S. presently approved dosages for alendronate monosodium trihydrate are 5 mg/day for preventing osteoporosis, 10 mg/day for treating osteoporosis, and 40 mg/day for treating Paget's disease.

In alternative dosing regimens, the bisphosphonate can be administered at intervals other than daily, for example once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing. In a once weekly dosing regimen, alendronate monosodium trihydrate would be administered at dosages of 35 mg/week or 70 mg/week. The bisphosphonates may also be administered monthly, ever six months, yearly or even less frequently, see WO 01/97788 (published December 27, 2001) and WO 01/89494 (published November 29, 2001). "Estrogen" includes, but is not limited to naturally occurring estrogens [7-estradiol (E₂), estrone(Eι), and estriol (E₃)], synthetic conjugated estrogens, oral contraceptives and sulfated estrogens. See, Gruber CJ, Tschugguel W, Schneeberger C, Huber JC, "Production and actions of estrogens" N Engl J Med 2002 Jan 31;346(5): 340-52.

"Selective estrogen receptor modulators" refers to compounds which interfere or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, estrogen, progestogen, estradiol, droloxifene, raloxifene, lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2- dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(l-piperidinyl)ethoxy]phenyl]-2H-l-benzopyran-3-yl]-phenyl- 2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646. An "estrogen receptor beta modulator" is a compound that selectively agonizes or antagonizes estrogen receptor beta (ERβ). Agonizing ERβ increases transcription of the tryptophan hydroxylase gene (TPH, the key enzyme in serotonin synthesis) via an ERβ mediated event. Examples of estrogen receptor beta agonists can be found in PCT International publication WO 01/82923, which published on Novembwer 08, 2001, and WO 02/41835, which published on May 20, 2002, both of which are hereby incorporated by reference in their entirety.

"Cathepsin K inhibitors" refers to compounds which interfere with the activity ofthe cysteine protease cathepsin K. Nonlimiting examples of cathepsin K inhibitors can be found in PCT publications WO 00/55126 to Axys Pharmaceuticals and WO 01/49288 to Merck Frosst Canada & Co. and Axys Pharmaceuticals.

"Androgen receptor modulators" refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate. "An inhibitor of osteoclast proton ATPase" refers to an inhibitor of the proton ATPase, which is found on the apical membrane of the osteoclast, and has been reported to play a significant role in the bone resorption process. This proton pump represents an attractive target for the design of inhibitors of bone resorption which are potentially useful for the treatment and prevention of osteoporosis and related metabolic diseases. See C. Farina et al., "Selective inhibitors ofthe osteoclast vacuolar proton ATPase as novel bone antiresoφtive agents," DDT, 4: 163-172 (1999)), which is hereby incoφorated by reference in its entirety.

"HMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy- 3-methylglutaryl-CoA reductase. Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Patent 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33. The terms "HMG-CoA reductase inhibitor" and "inhibitor of HMG-CoA reductase" have the same meaning when used herein.

Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR®; see U.S. Patent Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Patent Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S. Patent Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®; see U.S. Patent Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896), atorvastatin (LMTOR®; see U.S. Patent Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; see US Patent No. 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patent Nos. 4,782,084 and 4,885,314. The term HMG- CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention. An illustration ofthe lactone portion and its corresponding open-acid form is shown below as structures I and H

Lactone Open-Acid

I II

In HMG-CoA reductase inhibitors where an open-acid form can exist, salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein. Preferably, the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin. Herein, the term "pharmaceutically acceptable salts" with respect to the HMG-CoA reductase inhibitor shall mean non- toxic salts ofthe compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, l-prchlorobenzyl-2-pyrrolidine-l '-yl-methylbenz-imidazole, diethylamine, piperazine, and tris(hydroxymethyl) aminomethane. Further examples of salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, sahcylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.

As used herein, "cholesterol ester transfer protein inhibitor" refers to an inhibitor of cholesterol ester transfer protein (CETP), a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglycerides in very low density lipoprotein (VLDL). A non- limiting example of a CETP inhibitor is torcetrapib. As used above, "integrin receptor antagonists" refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the α_vβ3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αvβ5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the α_vβ3 integrin and the α_vβ5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the α_vβ6_. o._vβ8, αiβi, α2βl, sβi, αgβi and ββ4 integrins. The term also refers to antagonists of any combination of α_vβ3, α_vβs, α_vβ6. o-vβδ. ociβl. cc2βl> 0C5βl. «6βl and α6β4 integrins. H.N. Lode and coworkers in PNAS USA 96: 1591-1596 (1999) have observed synergistic effects between an antiangiogenic αv integrin antagonist and a tumor-specific antibody-cytokine (interleukin-2) fusion protein in the eradication of spontaneous tumor metastases. Their results suggested this combination as having potential for the treatment of cancer and metastatic tumor growth. θyβ₃ integrin receptor antagonists inhibit bone resoφtion through a new mechanism distinct from that of all currently available drugs. Integrins are heterodimeric transmembrane adhesion receptors that mediate cell-cell and cell- matrix interactions. The α and β integrin subunits interact non-covalently and bind extracellular matrix ligands in a divalent cation-dependent manner. The most abundant integrin on osteoclasts is θyβ₃

(>10⁷/osteoclast), which appears to play a rate-limiting role in cytoskeletal organization important for cell migration and polarization. The θ_vβ₃ antagonizing effect is selected from inhibition of bone resoφtion, inhibition of restenosis, inhibition of macular degeneration, inhibition of arthritis, and inhibition of cancer and metastatic growth. "An osteoblast anabolic agent" refers to agents that build bone, such as PTH. The intermittent administration of parathyroid hormone (PTH) or its amino-terminal fragments and analogues have been shown to prevent, arrest, partially reverse bone loss and stimulate bone formation in animals and humans. For a discussion refer to D.W. Dempster et al. , "Anabolic actions of parathyroid hormone on bone," Endocr Rev 14: 690-709 (1993). Studies have demonstrated the clinical benefits of parathyroid hormone in stimulating bone formation and thereby increasing bone mass and strength. Results were reported by RM Neer et al., in New Eng J Med 344 1434-1441 (2001).

In addition, parathyroid hormone-related protein fragments or analogues, such as PTHrP- (1-36) have demonstrated potent anticalciuric effects [see M.A. Syed et al, "Parathyroid hormone- related protein-(l-36) stimulates renal tubular calcium reabsoφtion in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy," JCEM 86: 1525-1531 (2001)] and may also have potential as anabolic agents for treating osteoporosis.

Calcitonin is a 32 amino acid pepetide produced primarily by the thyroid which is known to participate in calcium and phosphorus metabolism. Calcitonin suppresses resoφtion of bone by inhibiting the activity of osteoclasts. Thus, calcitomn can allow osteoblasts to work more effectively and build bone.

"Vitamin D" includes, but is not limited to, vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol), which are naturally occurring, biologically inactive precursors of the hydroxylated biologically active metabolites of vitamin D: lα-hydroxy vitamin D; 25-hydroxy vitamin D, and l ,25- dihydroxy vitamin D. Vitamin D₂ and vitamin D₃ have the same biological efficacy in humans. When either vitamin D₂ or D₃ enters the circulation, it is hydroxylated by cytochrome P₄₅₀-vitamin D-25- hydroxylase to give 25-hydroxy vitamin D. The 25-hydroxy vitamin D metabolite is biologically inert and is further hydroxylated in the_kidney by cytochrome P450-monooxygenase, 25 (OH) D-lα - hydroxylase to give 1,25-dihydroxy vitamin D. When serum calcium decreases, there is an increase in the production of parathyroid hormone (PTH), which regulates calcium homeostasis and increases plasma calcium levels by increasing the conversion of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D.

1,25-dihydroxy vitamin D is thought to be reponsible for the effects of vitamin D on calcium and bone metabolism. The 1,25-dihydroxy metabolite is the active hormone required to maintain calcium absoφtion and skeletal integrity. Calcium homeostasis is maintained by 1,25 dihydroxy vitamin D by inducing monocytic stem cells to differentiate into osteoclasts and by maintaining calcium in the normal range, which results in bone mineralization by the deposition of calcium hydroxyapatite onto the bone surface, see Holick, MF, Vitamin D photobiology, metabolism, and clinical applications, In: DeGroot L, Besser H, Burger HG, eg al.,_eds. Endocrinology, 3^rd ed., 990- 1013 (1995). However, elevated levels of lα,25-dihydroxy vitamin D₃ can result in an increase of calcium concentration in the blood and in the abnormal control of calcium concentration by bone metabolism, resulting in hypercalcemia. lα,25-dihydroxy vitamin D₃ also indirectly regulates osteoclastic activity in bone metabolism and elevated levels may be expected to increase excessive bone resoφtion in osteoporosis. "Synthetic vitamin D analogues" includes non-naturally occurring compounds that act like vitamin D.

Selective Serotonin Reuptake Inhibitors act by increasing the amount of serotonin in the brain. SSRIs have been used successfully for a decade in the United States to treat depression. Non- limiting examples of SSRIs include fluoxetine, paroxetine, sertraline, citalopram, and fluvoxamine. SSRIs are also being used to treat disoreders realted to estrogen functioning, suchs as premenstrual syndrome and premenstrual dysmoφhic disorder. See Sundstrom-Poromaa I, Bixo M, Bjorn I, Nordh O., "Compliance to antidepressant drug therapy for treatment of premenstrual syndrome," J Psychosom Obstet Gynaecol 2000 Dec;21(4):205-ll. Neurokinin 1 (NK-1, Substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess of or imbalance of tachykinins, and I particular, substance P. NK-1 receptor antagonist can be useful in the treatmetn of abnormal bone resoφtion, see International Patent Publication WO 00/07598, which is hereby incoφorated by reference in its entirety. Neurokinin-1 receptor antagonists of use in the present invention are fully described, for example, in U.S. Patent Nos. 5, 162,339, 5,232,929, 5,242,930,

5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,889,042, 5,962,505, 6,011,006, 6,107,331, 6,245,812; European Patent Publication Nos. EP 0309473, 0360 390, 0 394989, 0428434, 0429366, 0430771, 0436334, 0443 132, 0482539, 0498 069, 0499 313, 0512901, 0512902, 0514273, 0514 274, 0514275, 0514276, 0515 681, 0517 589, 0520555, 0522 808, 0 528495, 0532456, 0533 280, 0536 817, 0545 478, 0558 156, 0577 394, 0585 913,0590 152, 0 599 538, 0 610793, 0634402, 0686629, 0693489, 0694535, 0699 655, 0699 674, 0707 006, 0708 101, 0709 375, 0709 376, 0714 891, 0723 959, 0733 632, 0776 893, and 0943 329; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942, 97/21702, 97/49710, 00/12087, 98/34608, 99/03880, 99/44627 andOO/63228, 00/07598, 01/07037; and in British Patent Publication Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2271 774, 2292 144, 2293 168, 2293 169, and 2302689.

Specific neurokinin-1 receptor antagonists of use in the present invention include:

(±)-(2R3R, 2S3S)-N-{ [2-cyclopropoxy-5-(trifluoromethoxy)- phenyl]methyl } -2-phenylpiperidin-3-amine;

2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-lH,4H- 1 ,2,4-triazolo)methyl)moφholine;

2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-lH,4H-l,2,4- triazolo)methyl)-3-(S)-phenyl-moφholine; 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methyl)-3-

(S)-phenyl-moφholine;

2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5- oxo-lH,4H-l,2,4-triazolo)methyl)moφholine;

2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl- l,2,3-triazol-4-yl)methyl-3-(S)-phenylmoφholine;

2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl- l,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)moφholine;

(3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-aza- spiro[4.5]decane; (3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-aza- spiro[4.5]decane;

2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmoφholine;

2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4- monophosphoryl-5-oxo-lH-l,2,4-triazolo)methyl)moφholine;

2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(l- monophosphoryl-5-oxo-lH-l,2,4-triazolo)methyl)moφholine;

2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2- monophosphoryl-5-oxo-lH-l,2,4-triazolo)methyl)moφholine; 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5- oxyphosphoryl-lH-l,2,4-triazolo)methyl)moφholine;

2-(S)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(l- monophosphoryl-5-oxo-4H-l,2,4-triazolo)methyl)moφholine;

2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn- yl)-3-(S)-(4-fluorophenyl)moφholine; or a pharmaceutically acceptable salt thereof. The preparation of such compounds is fully described in the aforementioned patents and publications.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.

The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound ofthe invention means introducing the compound or a prodrug of the compound into the system ofthe animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a bisphosphonate, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents. The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is incoφorated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.

The present invention also encompasses a pharmaceutical composition useful in the treatment of osteoporosis or other bone disorders, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's bloodstream by local bolus injection.

When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.

In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment. Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.

The compounds of the present invention can be used in combination with other agents useful for treating estrogen-mediated conditions. The individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be inteφreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating cathepsin-mediated conditions includes in principle any combination with any pharmaceutical composition useful for treating disorders related to estrogen functioning. The scope of the invetion therefore encompasses the use of the instantly claimed compounds in combination with a second agent selected from: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen; an estrogen receptor modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; an integrin receptor antagonist; an osteoblast anabolic agent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; a selective serotonin reuptake inhibitor; a NK-1 receptor antagonist; and the pharmaceutically acceptable salts and mixtures thereof.

These and other aspects of the invention will be apparent from the teachings contained herein.

Definitions

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

The terms "treating" or "treatment" of a disease as used herein includes: preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop in a mammal that may be exposed to or predisposed tothe disease but does not yet experience or display symptoms ofthe disease; inhibiting the disease, i.e., arresting or reducing the development ofthe disease or its clinical symptoms; or relieving the disease, i.e., causing regression ofthe disease or its clinical symptoms.

The term "bone resoφtion," as used herein, refers to the process by which osteoclasts degrade bone.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, Ci-Cio, as in "Ci-Cio alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement. For example, "Ci-Cio alkyl" specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on. "Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.

As appreciated by those of skill in the art, "halo" or "halogen" as used herein is intended to include chloro, fluoro, bromo and iodo.

The present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula I. For example, when compounds of Formula I contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods well known in the art. Also when compounds of Formula I contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, hie. 1981, the disclosure of which is incoφorated herein by reference in its entirety. The protected derivatives of compounds of Formula I can be prepared by methods well known in the art.

The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more ofthe disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention. In addition, the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted. For example, any claim to compound A below is understood to include tautomeric structure B, and vice versa, as well as mixtures thereof.

A B

When any variable (e.g. R , R2, R3 etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms. If the ring system is polycyclic, it is intended that the bond be attached to any ofthe suitable carbon atoms on the proximal ring only. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase "optionally substituted with one or more substituents" should be taken to be equivalent to the phrase "optionally substituted with at least one substituent" and in such cases the preferred embodiment will have from zero to three substituents.

Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a Ci-5 alkylcarbonylamino Cι_6 alkyl substituent is equivalent to

O

II - C₁-₆alkyl-NH-C-C₁-₅alkyl

In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹ , n and m are to be chosen in conformity with well-known principles of chemical structure connectivity. Representative compounds ofthe present invention typically display submicromolar affinity for alpha and/or beta estrogen receptors. Compounds of this invention are therefore useful in treating mammals suffering from disorders related to estrogen functioning.

The compounds of the present invention are available in racemic form or as individual enantiomers. For convenience, some structures are graphically represented as a single enantiomer but, unless otherwise indicated, is meant to include both racemic and enantiomerically pure forms. Where cis and trans sterochemistry is indicated for a compound ofthe present invention, it should be noted that the stereochemistry should be construed as relative, unless indicated otherwise. For example, a (+) or (-) designation should be construed to represent the indicated compound with the absolute stereochemistry as shown.

Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include, but are not limited to, chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts. Deracemization procedures may also be employed, such as enantiomeric protonation of a pro-chiral intermediate anion, and the like.

The compounds ofthe present invention can be used in combination with other agents useful for treating estrogen-mediated conditions. The individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be inteφreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating estrogen-mediated conditions includes in principle any combination with any pharmaceutical composition useful for treating disorders related to estrogen functioning.

The pharmaceutically acceptable salts ofthe compounds of this invention include the conventional non-toxic salts ofthe compounds of this invention as formed inorganic or organic acids. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared • from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. The preparation ofthe pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al, "Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1-19, hereby incoφorated by reference. The pharmaceutically acceptable salts ofthe compounds of this invention can be synthesized from the compounds of this invention which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of the basic compounds are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.

ASSAYS

The utility of the compounds of the instant invention can be readily determined by methods well known to one of ordinary skill in the art. These methods may include, but are not limited to, the assays described in detail below. The compounds of the instant invention were tested in the following assays and found to have the relevant activity.

Estrogen Receptor Binding Assay

The estrogen receptor ligand binding assays are designed as scintillation proximity assays employing the use of tritiated estradiol and recombinant expressed estrogen receptors. The full length recombmant human ER-α and ER-β proteins are produced in a bacculoviral expression system. ER-α or ER-β extracts are diluted 1:400 in phosphate buffered saline containing 6 mM α- monothiolglycerol. 200 μL aliquots of the diluted receptor preparation are added to each well of a 96- well Flashplate. Plates are covered with Saran Wrap and incubated at 4 ° C overnight. The following morning, a 20 ul aliquot of phosphate buffered saline containing 10% bovine serum albumin is added to each well of the 96 well plate and allowed to incubate at 4° C for 2 hours. Then the plates are washed with 200 ul of buffer containing 20 mM Tris (pH 7.2), 1 mM EDTA, 10% Glycerol, 50 mM KC1, and 6 mM α-monothiolglycerol. To set up the assay in these receptor coated plates, add 178 ul of the same buffer to each well of the 96 well plate. Then add 20 ul of a 10 nM solution of ³H-estradiol to each well of the plate.

Test compounds are evaluated over a range of concentrations from 0.01 nM to 1000 nM. The test compound stock solutions should be made in 100% DMSO at 100X the final concentration desired for testing in the assay. The amount of DMSO in the test wells of the 96 well plate should not exceed 1%. The final addition to the assay plate is a 2 ul aliquot ofthe test compound which has been made up in 100% DMSO. Seal the plates and allow them to equilibrate at room temperature for 3 hours. Count the plates in a scintillation counter equipped for counting 96 well plates.

Ovariectomized Rat Assay hi the ovariectomized (OVX) Rat Assay, estrogen-deficiency is used to induce

2 cancellous osteopenia (e.g. low bone mineral density [BMD; mg/cm ]), associated with accelerated bone resoφtion and formation. Both the BMD and bone resoφtion/f ormation outcomes are used to model the changes in bone that occur as women pass through menopause. The OVX Rat Assay is the principal in vivo assay used by all major academic and industrial laboratories studying the efficacy of new chemical entities in preventing estrogen-deficiency bone loss. Sprague-Dawley female rats aged 6-8 months are OVXd and, within 24 hours, started on treatment for 42 days with vehicle or multiple doses of test compound. Untreated sham-OVX and alendronate-treated (.003 mg/kg s.c, q.d.) or 17-β-estradiol-treated (.004 mg/kg s.c, q.d.) groups are included as positive controls. Test compounds may be administered orally, subcutaneously, or by infusion through subcutaneously-implanted minipump. Before necropsy, in vivo dual labeling with calcein (8 mg/kg by subcutaneous injection), a bone seeking fluorochrome, is completed. At necropsy, blood, femurs, a vertebral body segment, and the uterus, are obtained.

The routine endpoints for the OVX Rat Assay include assessments of bone mass, bone resoφtion, and bone formation. For bone mass, the endpoint is BMD ofthe distal femoral metaphysis, a region that contains about 20% cancellous bone. The vertebral segment, a region with -25% cancellous bone may also be used for BMD determination. The BMD measurement is made by dual energy x-ray absoφtiometry (DXA, Hologic 4500A; Waltham, MA). For bone resoφtion, the endpoint is urinary deoxypyridinoline crosslinks, a bone collagen breakdown product (uDPD; expressed as nM DPD/ nM creatinine). This measurement is made with a commercially available kit (Pyrilinks; Metra Biosystems, Mountain View, CA). For bone formation, the endpoints are mineralizing surface and mineral apposition rate, histomoφhometric measures of osteoblast number and activity. This measurement is done on 5μm sections ofthe non-decalcified proximal tibial metaphysis, using a semi-automated system (Bioquant; R&M Biometrics; Nashville, TN). Similar endpoints and measuring techniques for each endpoint are commonly used in postmenopausal women.

Rat Cholesterol Lowering Assay

Sprague-Dawley rats (5 per group) weighing about 250g were subcutaneously dosed with compounds of the present invention dissolved in propylene glycol for 4 days. A group of 5 rats was dosed with vehicle only. On the fifth day, rats were euthanized with carbon dioxide and their blood samples were obtained. Plasma levels of cholesterol were assayed from these samples with commercially available cholesterol determination kits from Sigma.

MCF-7 Estrogen Dependent Proliferation Assay

MCF-7 cells (ATCC #HTB-22) are human mammary gland adenocarcinoma cells that require estrogen for growth. The growth media (GM) for the MCF-7 cells is Minimum Essential Media (without phenol red) supplemented with fetal bovine serum (FBS) to 10%. The FBS serves as the sole source of estrogen and this GM supports the full growth of the cells and is used for the routine growth of the cell cultures. When MCF-7 cells are placed in a media in which 10% Charcoal-Dextran treated fetal bovine serum (CD-FBS) is substituted for FBS, the cells will cease to divide but will remain viable. The CD-FBS does not contain detectable levels of estrogen and the media containing this sera is referred to as Estrogen Depleted Media (EDM). The addition of estradiol to EDM stimulates the growth of the MCF-7 cells in a dose dependent manner with an EC₅₀ of 2pM.

Growing MCF-7 cells are washed several times with EDM and the cultures then maintained in EDM for a minimum of 6 days in order to deplete the cells of endogenous estrogen. On day 0 (at the startof the assay), these estrogen depleted cells are plated into 96-well cell culture plates at a density of 1000 cells/well in EDM in a volume of 180ul/well. On day 1 test compounds are diluted in a 10-fold dilution series in EDM and 20ul of these dilutions added to the 180ul of media in the appropriate well ofthe cell plate resulting in a further 1:10 dilution ofthe test compounds. On days 4 and 7 ofthe assay, the culture supernatant is aspirated and replaced with fresh EDM and test compound dilutions as above. The assay is terminated at day 8-10 when the appropriate controls reach 80-90% confluency. At this point, the culture supernatants are aspirated, the cells washed 2X with PBS, the wash solution aspirated and the protein content of each well determined. Each drug dilution is evaluated on a minimum of 5 wells and the range of dilution of the test compounds in the assay is O.OOlnM to lOOOnM. The assay in the above format is employed to determine the estradiol agonist potential of a test compound.

In order to evaluate the antagonist activity of a test compound, the MCF-7 cells are maintained in EDM for a minimum of 6 days. Then on day 0 (at the start of the assay), these estrogen depleted cells are plated into 96-well cell culture plates at a density of 1000 cells/well in EDM in a volume of 180ul/well. On day 1 the test compounds in fresh media containing 3 pM estradiol are applied to the cells. On days 4 and 7 ofthe assay, the culture supernatant is aspirated and replaced with fresh EDM containing 3 pM estradiol and the test compound. The assay is terminated at day 8-10 when the appropriate controls reach 80-90% confluency and the protein content of each well is determined as above.

Rat endometriosis model Animals: Species: Rattus norvegicus Strain: Sprague-Dawley CD Supplier: Charles River Laboratories, Raleigh, NC Sex: Female Weight : 200 - 240 gram Rats are single-housed in polycarbonate cages and are provided Teklad Global Diet 2016 (Madison, WI) and bottled reverse osmosis purified H20 ad libitum. They are maintained on al2/12 light/dark cycle. Rats are anesthetized with Telazol™ (20 mg/kg, ip) and oxymoφhone (0.2 mg/kg sc) and positioned dorsoventrally on a sterile drape. Body temperature is maintained using a underlying circulating water blanket. The surgical sites are shaved with clippers and cleaned using tliree cycles of betadine/ isopropyl alcohol or Duraprep® (3M). The incisional area is covered with a sterile drape.

Using aseptic technique, a 5 cm midline lower abdominal incision is made through the skin, subcutaneous and muscle layers. A bilateral ovariectomy is performed. The left uterine blood vessels are ligated and a 7 mm segment ofthe left uterine horn is excised. The uterus is closed with 4-0 gut suture. The myometrium is aseptically separated from the endometrium and trimmed to 5X5 mm. The trimmed section ofthe endometrium is transplanted to the ventral peritoneal wall with the epithelial lining ofthe segment opposed to the peritoneal wall. The explanted endometrial tissue is sutured at its four corners to the body wall using sterile 6-0 silk. The abdominal muscular layer is closed using sterile 4-0 chromic gut. The skin incision is closed using sterile stainless surgical clips. A sterile 90-day sustained release estrogen pellet (Innovative Research of America, 0.72 ng/pellet; circulating estrogen equivalent of 200-250 pg/mL) is implanted subcutaneously in the dorsal lateral scapular area. A sterile implantable programmable temperature transponder (IPTT) (BMDS, Seaford, DE) is injected subcutaneously in the dorsoscapular region. The rats are observed until fully ambulatory, and allowed to recover from surgery undisturbed for 3 weeks. Three weeks after transplantation of the endometrial tissue, the animals undergo a repeat laparotomy using aseptic surgical site preparation and technique. The explant is evaluated for graft acceptance, and the area is measured with calipers and recorded. The animals with rejected grafts are removed from the study. Animals are sorted to create similar average explant volume per group.

Drug or vehicle (control) treatment is initiated one day after the second laparotomy and continued for 14 days. Body temperature is recorded every other day at 10:00 am using the BMDS scanner.

At the end ofthe 14 day treatment period, the animals are euthanized by C0₂ overdose. Blood is collected by cardiocentesis for circulating estrogen levels. The abdomen is opened, the explant is examined, measured, excised, and wet weight is recorded. The right uterine horn is excised, and wet and dry weights are recorded.

The novel compounds ofthe present invention can be prepared according to the following schemes, using appropriate materials, and are further exemplified by the subsequent specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. Those skilled in the art will readily understand that known variations ofthe conditions and processes ofthe following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted. hi words relative to Scheme I, the lactone intermediate I was prepared according to the procedure described in Nicolas, M. G.; Yuan, Chong-Sheng; Borchardt, R. T. J.Org.Chem., 1996, 61, 8636 - 8641. The methyl ether groups were then transformed into triisopropylsilyl ( TIPS ) ether groups by sequential removal with a reagent, such as pyridine hydrochloride, or one that is well documented in the literature which are incoφorated in standard textbooks, such as Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, Third Ed., Wiley, New York (1999), followed by silylation with triisopropylchlorosilane (TIPSCl) in the presence of a base such as triethylamine, diisopropylethylamine, sodium hydride, cesium carbonate, or the like, in a solvent such as dimethylformamide ( DMF ), formamide, acetonitrile, dimethylsulfoxide ( DMSO ), tetrahyrdrofuran ( THF ), dichloromethane, or the like. The lactone intermediate II was converted into the vinyl-triflate intermediate III, by treatment with a base, such as sodium hydride or the like, and a triflating agent, such as N-phenyl- bis(trifluoromethanesulfonimide), triflic anhydride, or the like, in the appropriate solvent and at the appropriate temperature. Intermediate III was arylated via a Suzuki coupling reaction, as reviewed in Suzuki, A. Pure Appl. Chem. 1994, 66, 213, and references therein, with the use of an appropriately functionalized phenylboronic acid reagent to provide intermediate IV. Catalytic reduction ofthe double bond using hydrogen gas and a catalyst such as 10% Pd C provided the cis stereochemistry present in intermediate V along with concommitant removal ofthe benzyl protecting group. Installation of the basic side chain was accomplished by alkylation with either the appropriate 2-chloroethylamine hydrochloride salt and a base, such as potassium or cesium carbonate, or in a Mitsunobu process, as reviewed in Hughes, D.L. Org. React. 1992, 42, 335, utilizing the analogous aminoethanol reagent. Finally, deprotection of the TIPS-protecting group, using tetrabutylammonium fluoride or reagents readily found in Greene and Wuts, Protective Groups in Organic Synthesis, yielded the bis-phenol product VI.

SCHEME I

In words relative to Scheme π, the coumarin intermediate VII was prepared by well established methods utilizing readily available starting materials, and then after a demethylation and reprotection step, converted to the chromene intermediate VIII by a Grignard reaction with an appropriately functionalized phenyl Grignard reagent followed by acid hydrolysis to effect dehydration. As shown above in Scheme I, conversion of intermediate VIII to the final product IX followed analogously.

SCHEME II

P

M

X

m n = as e ne Similarly in Scheme m, the readily prepared coumarin X was reacted with a reducing agent, such as diisobutylaluminum hydride or the like, to afford the lactol intermediate XI. Activation of the lactol XI as the phenyl ether was achieved by reaction with phenol in the presence of a dehydrating agent, such as anhydrous sodium sulfate or the like, which in turn was converted to intermediate XII by reaction with an appropriately functionalized phenyl Grignard reagent. Hydroboration of the 3,4-chromene bouble bond with borane-THF complex followed by oxidation with sodium perborate, or the like, gave the 2,3- cz^'s-substituted chromanol intermediate XIII. Stereospecific introduction ofthe methyl group was achieved by the reaction ofthe "Me₂TiCl₂" reagent, formed in situ from dimethylzinc and titanium tetrachloride, with XIII to provide intermediate XIV. After the selective removal ofthe protecting group P in intermediate XIV, the resulting phenol is alkylated with the basic side chain and the TIPS protecting group removed as previously described in Scheme I to provide product XV.

SCHEME IH

m n = as e ne

In words relative to Scheme IV, the chromanone starting materials were readily prepared utilizing the methods described in Saeed, A etal J. Med. Chem., 1990, 33, 3210, and Donnelly, D.M.X. etal, Tetrahedron, 1993, 49, 7967. Sequential reductions with lithium triethylborohydride or the like, and triethylsilane-trifluoroacetic acid, or the like, and deprotection of P, gave the final C-4 unsubstituted chromanes XVI. SCHEME IV

= protecting group m & n = as defined In words relative to Scheme V, the chromanol intermediate XIII, prepared in Scheme HI, was converted to the corresponding iodide XVI, upon exposure to a mixture of potassium iodide and tetra- butylammonium iodide in the presence of boron trifluoride-etherate. In turn, treatment of iodide XVI with methyllithium at -78°C in THF provided intermediate XIV which then processed as previously described in Scheme JH.

SCHEME V

TIPS = triisopropylsilyl Me = methyl P = protecting group m & n = as defined EXAMPLE 1 Preparation of 3

A stirred mixture of 1 g (4.55 mmol ) of 1 ( prepared according to: Raap, R. etal. Can. J. Chem. 1971, 49, 2143-2151), 677 mg of 4-methoxyphenol (2), and 0.8 mL MeS0₃H was heated at 40°C to 70°C for over 2 days and then quenched by the addition of aqueous NaHC0₃ solution. Extractive workup with EtOAc- hexane and purification by silica gel flash chromatography (hexane:EtOAc-9:l ) gave 3.

H NMR (CDC1₃, δ, ppm) 7.07 (d, IH), 6.99 (d, 2H), 6.79 (m, 4H), 3.81 (s, 3H), 3.77 (s, 3H), 3.71 (s, IH), 1.30 (s, 3H), 1.21 (s, 3H).

EXAMPLE 2 Preparation of 4

A stirred mixture of 2 g ( 6.41 mmol ) of 3, generated according to the procedure in Example 1, and 4.5 g ( 39.1 mmol ) of pyridine hydrochloride was heated at 145-170°C for two days. The reaction was quenched with water and after an organic extractive workup with EtOAc-hexane and drying in vacuo the crude bis-phenol was obtained. It was dissolved in 9 mL of DMF and treated with 3.43 mL of triisopropylsilyl chloride (TIPSC1 ) and 3.14 mL of diisopropylethylamine ( Hunig's base ) overnight. Aqueous quench and organic extractive workup with EtOAc-hexane, followed by a coarse silica gel chromatography ( hexane:EtOAc-96:4 ) afforded the crude bis-silylated lactone. This was further treated with 4.23 g of N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf₂₎ and 14 mL of a 1M solution of sodium hexamethyldisilazide (NaHMDS) in THF at 0°C in 30 mL THF over a period of 5h. Aqueous quench, organic extractive workup with EtOAc-hexane, trituration with hexanes, to partially remove PhNTf₂, and silica gel flash chromatography ( hexane:EtOAc-97.3:2.7 ) gave 4.

Η NMR (CDC1₃, 6, ppm) 7.11 (d, 2H), 6.93 (d, 2H), 6.85 (m, 2H), 6.75 (dd, IH), 1.39 (s, 6H), 1.28 (m, 6H), 1.14 (d, 36H).

EXAMPLE 3 Preparation of 5

A mixture of 850 mg ( 1.09 mmol ) pf 4, generated in Example 2, 2.493 g of 4-benzyloxy-phenylboronic acid, 253 mg of Pd(PPh₃)₄, 154 mg of Pd(PPh₃)₂Cl₂, 3.83 mL 2M Na₂C0₃ solution, and 834 mg of LiCl in 18 mL of DME was stirred at 80°C for 17 h, and then diluted with 40 mL of hexane. After filtration through sand and a silica pad, purification by silica gel flash chromatography ( hexane:EtOAc-9: 1 ) gave

^XH NMR (CDC1₃, δ, ppm) 7.37 (m, 5H), 7.19 (d, 2H), 7.02 (d, 2H), 6.93 (d, IH), 6.89 (d, IH), 6.80 (d, 2H), 6.74 (dd, IH), 6.72 (d, 2H), 5.00 (s, 2H), 1.39 (s, 6H), 1.28 (m, 6H), 1.15 (d, 18H), 1.11 (d, 18H). EXAMPLE 4 Preparation of 6

TI

A mixture of 660 mg ( 0.87 mmol ) of 5, generated in Example 3, 267 mg of Pd-black and 868 mg of 10%Pd-C in 24 mL of EtOAc-EtOH ( 5:1 ) was stirred under a balloon of hydrogen gas overnight. After filtration and removal of the volatiles, the product 6 was obtained.

*HNMR (CDC1₃, δ, ppm) 6.86 (m, 4H), 6.75 (dd, IH), 6.60 (d, 2H), 5.52 (d, IH), 2.72 (d, IH), 1.63 (s, 3H), 1.23 (m, 6H), 1.13 (dd, 18H), 1.09 (s, 3H), 1.07 (dd, 18H).

EXAMPLE 5 Preparation of 7

To a stirred mixture of 30 mg ( 0.0445 mmol ) of 6, generated in Example 4, and 430 mg of l-(2- chloroethyl)-piperidine monohydrochloride in 0.08 mL of H₂0 and 1.4 mL of acetone was added 630 mg of cesium carbonate portionwise over a period of 20 h. During this time the mixture was heated in a sealed vessel at 40-70°C. Water quench, organic extractive workup with EtOAc, and preparative thin layer chromatography (PLC) gave 30 mg of a crude mixture. Further treatment with 0.1 mL of a 1M solution of tetrabutylammonium fluoride ( TB AF ) in 1 mL of THF for 20 min, followed by aqueous workup, organic extraction with EtOAc, water washing (x2), and PLC, afforded 7

^XH NMR (acetone-d₆, δ, ppm) 7.03 (d, J=8.6Hz, 2H), 6.87 (d, J=2.8Hz, IH), 6.80 (d, J=8.7Hz, IH), 6.73 (d, J=8.7Hz, 2H), 6.70 (dd, IH), 5.54 (d, J=2.3Hz, IH), 4.08 (t, J=6.0Hz, 2H), 2.88 (d, J=2.5Hz, 1H),2.79 (t, J=5.7Hz, 2H), 2.61 (band, 4H), 1.64 (s, 3H), 1.61 ( , 4H), 1.45 (band, 2H), 1.07 (s, 3H)

Utilizing the Mitsunobu reaction procedure, detailed in Example 15, with compound 6 and the appropriate amino alcohols, the following compounds were prepared as TFA salts after purification on a reverse phase YMS-Pack ODS-A HPLC column ( acetonitrile-0.1% aqueous TFA ):

*H NMR (methanol-d₄, δ, ppm)

7.01 (d, 2H), 6.62 (dd, IH), 5.50 (d, IH), 4.21 (t, 2H), 1.60 (s, 3H), 1.03 (s, 3H)

^XH NMR (methanol-d₄, δ, ppm)

7.02 (d, J=8.7Hz, 2H), 6.81- 6.77 (m, 4H), 6.64 (dd, IH), 5.51 (d, J=2.5Hz, IH), 4.24 (t, J=5.0Hz, 2H),

3.60 (t, J=5.0Hz, 2H), 3.60 (t, J=5.7Hz, 2H) EXAMPLE 6 Preparation of 8a and 8b

To a stirred solution of 52.3g ( 393 mmol ) l,4-dimethoxy-2-fluorobenzene in 600 mL of dry THF cooled by a dry ice-acetone bath was slowly added 200 mL of 2.5M BuLi in hexane over a period of lh such that the internal temperature was kept below -70°C. The reaction mixture was then stirred further for 30 min, followed by the slow addition of 24.256 g of acetaldehyde over a period of 30 min such that the internal temperature was kept below -55°C. The reaction mixture was let stir until a thin layer chromotogram ( TLC ) indicated it was complete. The reaction was quenched with MeOH and then saturated NH C1 solution, and allowed to warm up to room temperature. Extractive workup with EtOAc- hexane and purification by silica gel flash chromatography ( 7:1 to 2:l-hexane:EtOAc ) gave 8a.

ΗNMR (CDCI₃, δ, ppm) 6.82 (t, IH), 6.61 (dd, IH), 5.25 (m, IH), 3.87 (s, 3H), 3.85 (s, 3H), 1.57 (d, 3H)

Utilizing the above procedure the following compound 8b was prepared by condensing the aryl lithium with DMF.

*H NMR (CDC1₃, δ, ppm) 10.44 (d, IH), 7.17 (t, IH), 6.70 (dd, IH), 3.90 (s, 3H), 3.88 (s, 3H EXAMPLE 7 Preparation of 9

To a stirred mixture of 55 g ( 311 mmol ) of 8a, generated in Example 6, 43.683 g of N-methyl- moφholine-N-oxide, and 100 g of powdered molecular sieves in 1.52 L of methylene chloride at 0°C was added 5 g of tetra-propylammonium-perruthenate. The reaction was stirred until TLC indicated it was complete. The reaction mixture was passed through a silica gel pad eluted with hexane-EtOAc, then washed with 2N HCl, and evaporated to give 9.

Η NMR (CDC1₃, δ, ppm) 6.94 (t, IH), 6.62 (dd, IH), 3.85 (s, 3H), 3.80 (s, 3H), 2.54 (s, 3H)

EXAMPLE 8 Preparation of 10a and 10b

10a

To a stirred solution of 40 g ( 226 mmol ) of 9, generated in Example 7, in 1.2 L of methylene chloride at 0°C was added 137 g of A1C1₃ in three portions over 30 min. After 10 min, the reaction mixture was poured into a stirred mixture of ice-water, 300 mL concentrated hydrochloric acid, hexane and EtOAc. After 25 min, organic extractive workup with EtOAc-hexane, elution through a silica gel pad, and evaporation gave 10a.

^l NMR (methanol-d₄, δ, ppm) 7.31 (t, IH), 6.69 (dd, IH), 3.84 (s, 3H), 2.66 (d, 3H) Utilizing the above procedure the following 10b was prepared by using 8b from Example 6.

10b

1HNMR (CDC1₃, δ, ppm) 10.92 (s, IH), 10.32 (s, IH), 7.26 (t, IH), 6.72 (dd, IH), 3.90 (s, 3H)

EXAMPLE 9A Preparation of 11, 11a, and lib

11

A stirred mixture of 6.95 g ( 39 mmol ) of 10a, generated in Example 8, 8.40 g of 4-methoxy- phenylacetic acid, 11.76 mL acetic anhydride, and 5.7 mL triethylamine was heated at 135-145°C over night. The crude reaction mixture was allowed to cool to ambient temperature and then added to ice- water. The separated solid was collected by filtration, washed with water and hexane, and dried in vacuo to give 11.

1H NMR (CDC1₃, δ, ppm) 7.24 (d, 2H), 7.20 (t, IH), 7.14 (dd, IH), 7.02 (d, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 2.48 (d, 3H).

Utilizing the above procedure the following compound was prepared by using 10a from Example 8 and 3-methoxy-phenyl acetic acid.

11a

^!H NMR (CDCI₃, δ, ppm) 7.42 (t, IH), 7.23 (t, IH), 7.17 (dd, IH), 6.99 (dd, IH), 6.89 (d, IH), 6.86 (m, IH), 3.98 (s, 3H), 3.87 (s, 3H), 2.47 (d, 3H).

Utilizing the above procedure the following lib was prepared by using 10b from Example 8 and 4- Methoxyphenyl acetic acid.

lib

^XH NMR (CDC1₃, δ, ppm) 8.00(s, IH), 7.72 (d, 2H), 7.18 (t, IH), 7.12 (dd, IH), 7.00 (d, 2H), 3.97 (s, 3H), 3.88 (s, 3H)

EXAMPLE 9B Preparation of lie and lid

lie A stirred mixture of 3.32 g ( 20 mmol ) of 2',5'-dihydroxypropiophenone, 6.11 mL of 4- methoxyphenylacetyl chloride, and 10.5 g of potassium carbonate in 60 mL of acetone was refluxed at 65°C overnight. After the acetone was evaporated, the residue was washed with water and hexane to give lie.

^XH NMR (DMF-d₇, δ, ppm) 7.14 (m, 3H), 7.09 (d, IH), 7.00 (dd, IH), 6.91 (d, 2H), 3.72 (s, 3H), 2.49 (q, 2H), 1.01 (t, 3H).

Utilizing the above procedure, the following compound lid was prepared using 2' ,5'- dihydroxyacetophenone and 3-methoxy-phenylacetyl chloride.

lid

^XH NMR (DMF-d₇, δ, ppm) 7.23 (t, IH), 7.09 (d, IH), 7.04 (d, IH), 6.99 (dd, IH), 6.83 (dd, IH), 6.79 (s, IH), 6.75 (d, IH), 3.66 (s, 3H), 2.08 (s, 3H).

EXAMPLE 10 Preparation of 12, 12a, and 12b

To a stirred solution of 13.1 g ( 41 mmol ) of 11, generated in Example 9A, in 150 mL of methylene chloride at 0°C was added drop wise 123 mL of a IM solution of boron tribromide in methylene chloride. After 0.5 h, the reaction mixture was poured into a mixture of ice-2N HCl and hexane. The separated solid was collected by filtration, washed with water and hexane, and dried in vacuo to give 12.

^XHNMR (methanol-d₄, δ, ppm) 7.09 (d, 2H), 7.15 (t, IH), 7.03 (dd, IH), 6.85 (d, 2H), 2.41 (d, 3H). Utilizing the above procedure the following compound was prepared by using 11a from example 9A.

12a

*H NMR (methanol-d₄, δ, ppm) 7.26 (t, IH), 7.09 (t, IH), 7.06 (dd, IH), 6.82 (dd, IH), 6.71 (d, IH), 6.69 (m, IH), 2.41 (d, 3H).

Utilizing the above procedure the following compound was prepared by using lib from example 9A.

ΗNMR (methanol-d₄, δ, ppm) 7.99(s, IH), 7.57 (d, 2H), 7.12 (t, IH), 7.01 (dd, IH), 6.83 (d, 2H)

EXAMPLE 10A Preparation of 12c, 12d, 12e, and 12f

A stirred mixture of 3 g ( 10 mmol ) of 6-methoxy-3-(4'-methoxyphenyl)-4-methyl-coumarin and 15.7 g pyridine-HCl was heated at 150-180°C overnight. Extraction with EtOAc-EtOH and water wash gave 12c.

Η NMR (methanol-d₄, δ, ppm) 7.21 (d, IH), 7.11 (m, 3H), 7.04 (dd, IH), 6.87 (d, 2H), 2.28 (s, 3H).

Utilizing the above procedure the following compounds were prepared:

12d, by using lid from Example 9B,

Η NMR (methanol-d₄, δ, ppm) 7.25 (t, IH), 7.19 (d, IH), 7.13 (d, IH), 7.06 (dd, IH), 6.80 (d, IH), 6.74 (m, 2H), 2.25 (s, 3H);

12e, by using lie from Example 9B,

Η NMR (methanol-d₄, δ, ppm) 7.20 (d, IH), 7.15 (d, IH), 7.06 (m, 3H), 6.84 (d, 2H), 2.64 (q, 2H), 1.14 (t, 3H); 12f, by using 7-ethoxy-3-(4'-methoxyphenyl)-4-methyl-coumarin.

'HNMR (methanol-d₄, δ, ppm) 7.66 (d, IH), 7.11 (d, 2H), 6.86 (m, 3H), 6.74 (d, IH), 2.29 (s, 3H).

EXAMPLE 11 Preparation of 13a-g

13g To a stirred solution of 10.72 g ( 38.42 mmol ) of 12, generated in Example 10, in 80 mL of anhydrous DMF was added 18.07 mL of Hunig's base and then 19.73 mL TIPSCl. The reaction mixture was stirred overnight and then poured into a mixture of 2N HCl-ice-hexane-EtOAc, and stirred for 5 min. The organic layer was separated, washed with water and brine, and dried to give 13a, which was either used without further purification or purified by silica gel flash chromatography (hexane-methylene chloride, then hexane-EtOAc).

^XH NMR (CDC1₃, δ, ppm) 7.17 (d, 2H), 7.14 (t, IH), 7.06 (dd, IH), 6.98 (d, 2H), 2.44 (d, 3H), 1.31 (m, 6H), 1.15 (m, 36H).

Utilizing the above procedure the following compounds were prepared:

13b, by using 12a from Example 10,

1H NMR (CDC1₃, δ, ppm) 7.33 (t, IH), 7.15 (t, IH), 7.05 (d, IH), 6.94 (dd, IH), 6.87 (d, IH), 6.81 (s, IH), 2.43 (d, 3H), 1.31 (m, 6H), 1.14 (m, 36H);

13g, by using 12b from Example 10,

^XH NMR (CDC1₃, δ, ppm) 7.99(s, IH), 7.65 (d, 2H), 7.12 (t, IH), 7.04 (dd, IH), 6.97 (d, 2H), 1.30 (m, 6H), 1.14 (m, 36H)

13c, by using 12c from Example 10A,

^XH NMR (CDC1₃, δ, ppm) 7.25 (d, IH), 7.18 (d, 2H), 7.12 (d, IH), 7.08 (dd, IH), 6.97 (d, 2H), 2.28 (s, 3H), 1.29 (m, 6H), 1.14 (d, 36H);

13d, by using 12d from Example 10A,

^XH NMR (CDC1₃, δ, ppm) 7.32 (t, IH), 7.26 (d, IH), 7.14 (d, IH), 7.10 (dd, IH), 6.94 (dd, IH), 6.89 (m, IH), 6.84 (t, IH), 2.27 (s, 3H), 1.30 (m, 6H), 1.15 (m, 36H);

13e, by using 12e from Example 10A, ^XH NMR (CDCI₃, δ, ppm) 7.28 (d, IH), 7.16 (d, 2H), 7.14 (d, 2H), 7.09 (dd, IH), 6.98 (d, 2H), 2.63 (q, 2H), 1.31 (m, 6H), 1.19 (t, 3H), 1.15 (d, 36H);

13f, by using 12f from Example 10A,

^XHNMR (CDC1₃, δ, ppm) 7.55 (d, IH), 7.19 (d, 2H), 6.98 (d, 2H), 6.90 (m, 2H), 2.31 (s, 3H), 1.34 (m, 6H), 1.17 (d, 36H).

EXAMPLE 12 Preparation of 14a-f

To a stirred solution of 21.02 g (35.6 mmol) of 13a, generated in Example 11, in 25 mL anhydrous THF at 0°C was added drop wise 142 mL of 4-(2-tetrahydro-2H-pyranoxy)phenyl-magnesium bromide (0.5 M in THF). When the addition was completed, the ice-water bath was removed and the reaction mixture was allowed to warm to ambient temperature. After 30 min, when TLC indicated the consumption of the starting material, the reaction vessel was cooled to 0°C, and 45 mL of 2N HCl in ether was added drop wise to give a dark red mixture. Upon addition of sat. aq. NaHC0₃ solution and hexane, the red color dissipated. The mixture was stirred for 5 min, and the organic layer was separated, washed with water and brine, dried over anhydrous Na₂S0 , filtered, and concentrated in vacuo. The concentrate was dissolved in 300 mL EtOAc, and stirred with 25 g of 5% Rh-C under a balloon of hydrogen gas for 14 h. The mixture was filtered and the filtrate was concentrated in vacuo. Purification by silica gel flash chromatography gave 14a,

^XHNMR (CDC1₃, δ, ppm) 7.15 (d, 2H), 7.03 (d, 2H), 6.78 (t, IH), 6.77 (d, 2H), 6.68 (dd, IH), 6.61 (d, 2H), 3.98 (q, IH), 1.33 (d, 3H), 1.25 (m, 6H), 1.11 (m, 36H).

Utilizing the above procedure the following compounds were prepared:

14b, by using 13b from Example 11,

^XH NMR (CDCI₃, δ, ppm) 7.32 (2H), 7.14 (IH), 6.91-6.68 (7H), 5.38 (IH), 4.02 (IH), 3.89 (IH), 3.60 (IH), 1.35 (3H), 1.15 (18H), 1.06 (18H);

14c, by using 13c from Example 11,

^XH NMR (CDCI₃, δ, ppm) 7.21 (2H), 7.04 (2H), 6.91 (IH), 6.84 (2H), 6.78 (2H), 6.72 (2H), 5.36 (IH), 3.90 (IH), 3.76 (IH), 3.59 (IH), 1.27 (6H), 1.13 (36H);

14d, by using 13d from Example 11,

^XH NMR (CDCI₃, δ, ppm) 7.19 (d, 2H), 7.11 (t, IH), 6.90 (d, IH), 6.81 (d, IH), 6.72 (m, 3H), 6.64 (d, 2H), 6.68 (m, IH), 3.77 (q, IH), 1.28 (m, 9H), 1.14 (m, 18H), 1.05 (m, 18H);

14e, by using 13e from Example 11, ^XH NMR (CDCI₃, δ, ppm) 7.19 (2H), 7.05 (2H), 6.90 (IH), 6.83 (2H), 6.78 (2H), 6.75 (IH), 6.70 (IH), 5.35 (IH), 3.86 (IH), 3.76 (IH), 3.57 (IH), 1.25 (6H), 1.12 (36H);

14f, by using 13f from Example 11,

^XHNMR (CDCI₃, δ, ppm) 7.21 (2H), 7.03 (3H), 6.85 (2H), 6.79 (2H), 6.64 (IH), 6.59 (IH), 5.37 (IH), 3.76 (IH), 1.26 (6H), 1.14. (36H).

EXAMPLE 13 Preparation of Chiral 15 al-2 and Racemic 15d

A mixture of 10 g (13.16 mmol) of 14a, generated in Example 12, and 2.80 g of 10%Pd-C in 150 mL EtOAc was stirred under a balloon of hydrogen gas for 1 h. The mixture was filtered and the filtrate concentrated in vacuo. Purification by silica gel flash chromatography and subsequent chiral chromatography, using a Chiral AD column ( 2-propanol : heptane - 3:97 ) gave the first eluted chiral entity 15al and then chiral entity 15a2.

^XH NMR (CDC1₃, δ, ppm) 6.86 (m, 3H), 6.65 (m, 3H), 6.58 (d, ZH), 6.49 (d, 2H), 5.25 (d, IH), 3.35 (q, IH), 2.83 (d, IH), 1.60 (d, 3H), 1.31 (m, 3H), 1.21 (m, 3H), 1.16 (m, 18H), 1.08 (m, 18H). Utilizing the above procedure and 14d from Example 12, 15d was prepared in racemic form without chiral resolution:

^XH NMR (CDCI₃, δ, ppm) 6.93 (m, 3H), 6.86 (d, IH), 6.79 (m, 2H), 6.70 (dd, IH), 6.66 (d, 2H), 6.46 (m, IH), 6.25 (d, IH), 5.28 (d, IH), 3.10 (m, IH), 2.94 (t, IH), 1.58 (d, 3H), 1.31 (m, 3H), 1.19 (m, 18H), 1.04 (m, 21H).

EXAMPLE 14 Preparation of 16b, 16cl-3, 16d, 16el-2

racem c

A mixture of 20 g ( 22.99 mmol ) of 14b, generated in Example 12, and 2.437 g of 10%Pd-C in 300 mL EtOAc was stirred under a balloon of hydrogen gas for 2.2 h. The mixture was filtered and the filtrate concentrated in vacuo. The concentrate was stirred in methylene chloride at 0°C and treated with 1 mL of triethylsilane and 1 mL of trifluoroacetic acid ( TFA ) until TLC showed complete removal ofthe THP protecting group. The reaction was quenched with aq. NaHC0₃ solution and after organic extractive workup with EtOAc-hexane the mixture of products was purified by silica gel flash chromatography. Subsequent HPLC, using a Chiral AD column ( 2-propanol : heptane - 3:97 ) afforded 16b. ^XH NMR (CDC1₃, δ, ppm) 6.95 (d, 2H), 6.85 (m, 2H), 6.68 (d, 2H), 6.64 (m, 2H), 6.36 (t, IH), 6.17 (d, IH), 5.27 (d, IH), 3.32 (q, IH), 2.87 (d, IH), 1.60 (d, 3H).

Utilizing the above procedure (with chiral separation where appropriate), the following compounds were prepared:

16cl and 16c2-3 from 14c, of Example 12,

16cl: ^XH NMR (CDC1₃, δ, ppm) 6.88 (d, 2H), 6.84 (m, 2H), 6.76 (dd, IH), 6.61 (m, 6H), 5.39 (d, IH), 3.66 (m, IH), 3.08 (dd, IH), 1.25 (m, 6H);

16c2-3: ^XH NMR (CDC1₃, δ, ppm) 6.81 (m, 4H), 6.76 (dd, IH), 6.63 (d, 2H), 6.60 (d, 2H), 6.54 (d, 2H), 5.22 (d, IH), 3.08 (m, IH), 2.88 (t, IH), 1.53 (d, 3H), 1.25 (m, 6H), 1.15 (18H), 1.08 (18H);

16d, from 14e, of Example 12,

^XH NMR (CDCI₃, δ, ppm) 6.84 (m, 3H), 6.80 (d, IH), 6.77 (dd, IH), 6.60 (m, 4H), 6.56 (d, 2H), 5.21 (d, IH), 3.03 (s, IH), 2.82 (m, IH), 1.93 (m, 2H), 1.25 (m, 6H), 1.15 (18H), 1.08 (18H);

16el-2, from 14f, of Example 12,

^XH NMR (CDCI₃, δ, ppm) 7.08 (d, IH), 6.79 (d, 2H), 6.60 (m, 4H), 6.56 (dd, IH), 6.52 (d, 3H), 5.23 (d, IH), 3.05 (m, IH), 2.88 (t, IH), 1.93 (m, 2H), 1.48 (d, 3H), 1.24 (m, 6H), 1.13 (18H), 1.07 (18H).

EXAMPLE 15 Preparation of 17, 17a-17z, and 17aa-bb.

To a stirred solution of 151 mg ( 0.2 mmol ) of 15al, generated in Example 13, 375 mg of triphenylphosphine and 176 mg of 1-piperidineethanol in 1.5 mL of dry THF was added drop wise 0.32 mL of neat diisopropylazodicarboxylate ( DIAD ). The reaction was stirred further at ambient temperature overnight (about 17 h). Preparative TLC gave a crude mixture which upon treatment with tetrabutylammonium fluoride ( TB AF ) in 2 mL of THF for 30 min gave after aqueous workup, organic extraction, water washing (x3), and PLC the desired product 17.

^XH NMR (methanol-d₄, δ, ppm) 6.94 (d, J=8.6Hz, 2H), 6.78 (t, J=9.2Hz, IH), 6.74 (d, J=8.8Hz, 2H), 6.50 (dd, J=8.9, 1.4Hz, IH), 6.45 (d, J=8.6Hz, 2H), 6.41 (d, J=8.9Hz, 2H), 5.21 (d, J=2.3Hz, IH), 4.04 (t, J=5.6Hz, 2H), 3.19 (dd, IH), 2.86 (t, J=2.3Hz, IH), 2.74 (t, J=5.6Hz, 2H), 2.53 (band, 4H), 1.61 (m, 4H), 1.57 (d, J=7.0Hz, 3H), 1.46 (band, 2H)

Utilizing the above procedure the following compounds were prepared:

17a: ^XH NMR (methanol-d₄, δ, ppm) 7.07 (d, J=8.5Hz, IH), 6.90 (d, J=8.7Hz, 2H), 6.75 (d, J=8.7Hz, 2H), 6.50 (d, J=8.7Hz, 2H), 6.47-6.44 (m, 3H), 6.35 (d, J=2.5Hz, IH), 5.23 (d, J=2.8Hz, IH), 4.08 (t, J=5.7Hz, 2H), 2.96 (m, IH), 2.90 (t, J=2.7Hz, IH), 2.90 (t, J=5.7Hz, 2H), 2.57 (band, 4H), 1.64 (m, 4H), 1.49 (band, 2H), 1.48 (d, J=10.1Hz, 3H);

17b: ^XH NMR (methanol-d₄, δ, ppm) 7.07 (d, J=8.5Hz, IH), 6.90 (d, J=8.7Hz, 2H), 6.75 (d, J=8.7Hz, 2H), 6.50 (d, J=8.7Hz, 2H), 6.47-6.44 (m, 3H), 6.35 (d, J=2.5Hz, IH), 5.23 (d, J=2.8Hz, IH), 4.08 (t, J=5.7Hz, 2H), 2.96 (m, IH), 2.90 (t, J=2.7Hz, IH), 2.90 (t, J=5.7Hz, 2H), 2.57 (band, 4H), 1.64 (m, 4H), 1.49 (band, 2H), 1.48 (d, J=10.1Hz, 3H);

17c: ^XH NMR (methanol-d₄, δ, ppm) 7.07 (d, J=8.5Hz, IH), 6.90 (d, J=8.7Hz, 2H), 6.75 (d, J=8.7Hz, 2H), 6.50 (d, J=8.7Hz, 2H), 6.47-6.44 (m, 3H), 6.35 (d, J=2.5Hz, IH), 5.23 (d, J=2.8Hz, IH), 4.08 (t, J=5.7Hz, 2H), 2.96 (m, IH), 2.90 (t, J=2.7Hz, IH), 2.90 (t, J=5.7Hz, 2H), 2.57 (band, 4H), 1.64 (m, 4H), 1.49 (band, 2H), 1.48 (d, J=10.1Hz, 3H);

17d: ^XH NMR (methanol-d₄, δ, ppm) 6.94 (d, J=8.6Hz, 2H), 6.78 (t, J=9.2Hz, IH), 6.74 (d, J=8.8Hz, 2H), 6.50 (dd, J=8.9, 1.4Hz, IH), 6.45 (d, J=8.6Hz, 2H), 6.41 (d, J=8.9Hz, 2H), 5.21 (d, J=2.3Hz, IH), 4.04 (t, J=5.6Hz, 2H), 3.19 (dd, IH), 2.86 (t, J=2.3Hz, IH), 2.74 (t, J=5.6Hz, 2H), 2.53 (band, 4H), 1.61 (m, 4H), 1.57 (d, J=7.0Hz, 3H), 1.46 (band, 2H);

17e: ^XH NMR (methanol-d₄, δ, ppm) 6.91 (d, J=8.5Hz, 2H), 6.78 (t, J=7.8Hz, IH), 6.74 (d, J=8.6Hz, IH), 6.70-6.66 (m, 3H), 6.24 (t, IH), 6.15 (d, J=7.7Hz, 1H),5.16 (d, J=2.2Hz, IH), 3.98 (m, 2H), 2.96 (dd, IH), 2.87 (broad s, IH), 2.68 (m, 2H), 2.48 (band, 4H), 1.58 (m, 4H), 1.48 (d, J=7.1Hz, 3H), 1.43 (band, 2H);

17f: ^XH NMR (methanol-d₄, δ, ppm) 6.91 (d, J=8.7Hz, 2H), 6.77-6.72 (m, 3H), 6.70 (d, J=3.0Hz, IH), 6.64 (dd, J=8.7, 2.7Hz, IH), 6.50 (d, J=8.7Hz, 2H), 6.44 (d, J=8.7Hz, 2H), 5.18 (d, J=2.7Hz, IH), 4.06 (t, J=5.7Hz, 2H), 2.96 (dd, IH), 2.88 (t, J=2.3Hz, IH), 2.76 (t, J=5.7Hz, 2H), 2.56 (band, 4H), 1.63 (m, 4H), 1.51 (d, J=7.3Hz, 3H), 1.48 (band, 2H);

17g: ^XH NMR (methanol-d₄, δ, ppm) 6.95 (d, J=8.7Hz, 2H), 6.78-6.74 (m, 3H), 6.69 (d, J=2.7Hz, IH),

6.64 (dd, J=8.7, 3.0Hz, IH), 6.51 (d, J=8.7Hz, 2H), 6.43 (d, J=8.7Hz, 2H), 5.16 (d, J=2.5Hz, IH), 4.08 (t, J=5.5Hz, 2H), 3.05 (broad s, IH), 2.80 (t, J=5.5Hz, 2H), 2.69 (m, IH), 2.60 (band, 4H), 1.92 (m, 2H),

1.65 (m, 4H), 1.50 (band, 2H), 1.14 (t, J=7.3Hz, 3H);

17h: ^XH NMR (methanol-d₄, δ, ppm) 6.93 (d, J=8.7Hz, 2H), 6.77 (d, J=8.7Hz, 2H), 6.75 (d, J=8.9Hz, 1H),6.70 (d, J=2.8Hz, IH), 6.64 (dd, J=8.9, 3.0Hz, IH), 6.50 (d, J=8.7Hz, 2H), 6.44 (d, J=8.7Hz, 2H), 5.20 (d, J=2.5Hz, IH), 4.09 (t, J=5.5Hz, 2H), 2.97 (t, J=5.5Hz, 3H), 2.90 (t, J=2.3Hz, 1H),2.75 (band, 4H), 1.92 (m, 2H), 1.86 (m, 4H), 1.53 (d, J=7.1Hz, 3H);

17i: ^XHNMR (methanol-d₄, δ, ppm) 6.91 (d, J=8.7Hz, 2H), 6.77-6.72 (m, 3H), 6.70 (d, J=3.0Hz, IH), 6.64 (dd, J=8.7, 2.7Hz, IH), 6.50 (d, J=8.7Hz, 2H), 6.44 (d, J=8.7Hz, 2H), 5.18 (d, J=2.7Hz, IH), 4.06 (t, J=5.7Hz, 2H), 2.96 (dd, IH), 2.88 (t, J=2.3Hz, IH), 2.76 (t, J=5.7Hz, 2H), 2.56 (band, 4H), 1.63 (m, 4H), 1.51 (d, J=7.3Hz, 3H), 1.48 (band, 2H);

17j: ^XHNMR (methanol-d₄, δ, ppm) 7.09 (d, J=8.5Hz, IH), 7.02 (d, J=8.7Hz, 2H), 6.78 (d, J=8.7Hz, 2H), 6.57 (d, J=8.0Hz, 2H), 6.46-6.41 (m, 3H), 6.36 (d, J=2.3Hz, IH), 5.41 (d, J=2.3Hz, IH), 4.16 (t, J=5.3Hz, 2H), 3.60 (m, IH), 3.26 (t, J=5.3Hz, 2H), 3.21 (dd, IH), 3.02 (band, 4H), 1.08 (d, J=7.1Hz, 3H);

17k: ^XH NMR (methanol-d₄, δ, ppm)

6.93 (d, J=8.7Hz, 2H), 6.77 (d, J=8.7Hz, 2H), 6.75 (d, J=8.9Hz, 1H),6.70 (d, J=2.8Hz, IH), 6.64 (dd, J=8.9, 3.0Hz, IH), 6.50 (d, J=8.7Hz, 2H), 6.44 (d, J=8.7Hz, 2H), 5.20 (d, J=2.5Hz, IH), 4.09 (t, J=5.5Hz, 2H), 2.97 (t, J=5.5Hz, 3H), 2.90 (t, J=2.3Hz, 1H),2.75 (band, 4H), 1.92 (m, 2H), 1.86 (m, 4H), 1.53 (d, J=7.1Hz, 3H);

171: ^XH NMR (methanol-d₄, δ, ppm) 6.91 (d, J=8.7Hz, 2H), 6.77-6.72 (m, 3H), 6.70 (d, J=3.0Hz, IH), 6.64 (dd, J=8.7, 2.7Hz, IH), 6.50 (d, J=8.7Hz, 2H), 6.44 (d, J=8.7Hz, 2H), 5.18 (d, J=2.7Hz, IH), 4.06 (t, J=5.7Hz, 2H), 2.96 (dd, IH), 2.88 (t, J=2.3Hz, IH), 2.76 (t, J=5.7Hz, 2H), 2.56 (band, 4H), 1.63 (m, 4H), 1.51 (d, J=7.3Hz, 3H), 1.48 (band, 2H);

17m: ^XHNMR (methanol-d₄, δ, ppm) 6.98 (d, J=8.7Hz, IH), 6.75 (m, 2H), 6.74 (d, J=8.7Hz, 2H), 6.63 (dd, 2H), 6.58 (d, J=8.2Hz, 2H),6.44 (d, J=8.9Hz, 2H), 5.34 (d, J=2.1Hz, IH), 4.09 (t, J=5.7Hz, 2H), 3.64 (m, IH), 3.12 (dd, IH), 2.87 (t, J=5.5Hz, 2H), 2.67 (band, 4H), 1.67 (m, 4H), 1.52 (band, 2H), 1.09 (d, J=7.1Hz, 3H);

17n: ^XH NMR (methanol-d₄, δ, ppm) 7.04 (d, J=8.7Hz, IH), 6.81 (d, J=8.7Hz, 2H), 6.75 (m, 3H), 6.64 (dd, 2H), 6.58 (d, J=8.2Hz, 2H), 6.43 (d, J=8.7Hz, 2H), 5.37 (d, J=2.3Hz, IH), 4.21 (t, J=5.5Hz, 2H), 1.10 (d, J=6.9Hz, 3H);

17o: ^XH NMR (methanol-d₄, δ, ppm) 6.99 (d, 2H), 6.77-6.70 (m, 4H), 6.61 (dd, IH), 6.56 (d, 2H), 6.41 (d, 2H), 5.34 (d, IH), 4.11 (t, 2H);

17p: ^XH NMR (methanol-d₄, δ, ppm) 6.91 (d, J=8.7Hz, 2H), 6.77-6.72 (m, 3H), 6.70 (d, J=3.0Hz, IH), 6.64 (dd, J=8.7, 3.0Hz, IH), 6.50 (d, J=8.7Hz, 2H), 6.44 (d, J=8.7Hz, 2H), 5.18 (d, J=2.7Hz, IH), 4.03 (t, J=5.7Hz, 2H), 2.97(m, 2H), 2.86 (m, 4H), 2.61 (m, IH), 2.27 (m, IH), 2.14(m, IH), 2.05(m, IH), 1.51 (d, J=7.3Hz, 3H), 1.38 (m, IH), 1.05 (d, J=6.6Hz, 3H);

17q: ^XH NMR (methanol-d₄, δ, ppm) 6.90 (d, J=8.5Hz, 2H), 6.75-6.71 (m, 3H), 6.68 (d, J=2.7Hz, IH), 6.62 (dd, IH), 6.49 (d, J=8.6Hz, 2H), 6.43 (d, J=8.6Hz, 2H), 5.17 (d, J=2.7Hz, IH), 3.97 (dd, IH), 3.86 (dd, lH),3.21(m, 2H), 2.95 (m, IH), 2.87 (m, IH), 2.77 (m, lH),2.28(m, 2H), 2.19(m, 2H), 1.50 (d, J=7.1Hz, 3H), 1.23 (d, J=6.6Hz, 3H), 0.92 (m, 6H);

17r: ^XH NMR (methanol-d₄, δ, ppm) 6.92 (d, J=8.7Hz, 2H), 6.79-6.73 (m, 3H), 6.70 (d, J=2.8Hz, IH), 6.64 (dd, IH), 6.51 (d, J=8.7Hz, 2H), 6.44 (d, J=8.7Hz, 2H), 5.20 (d, J=2.8Hz, IH), 4.55 (m, IH), 3.17(m, 2H), 2.97 (m, IH), 2.89 (m, IH), 2.79 (dd, lH),2.69(dd, IH), 2.28(m, 2H), 2.16 (t, 2H), 1.53 (d, J=7.1Hz, 3H), 1.23 (d, J=6.2Hz, 3H), 0.92 (d, J=6.6Hz, 6H);

17s: ^XH NMR (methanol-d₄, δ, ppm) 6.93 (d, J=8.7Hz, 2H), 6.79-6.73 (m, 3H), 6.70 (d, J=2.8Hz, IH), 6.64 (dd, IH), 6.51 (d, J=8.7Hz, 2H), 6.44 (d, J=8.7Hz, 2H), 5.20 (d, J=2.5Hz, IH), 4.02 (dd, IH), 3.96 (dd, IH) 3.16(m, IH), 3.07-2.78 (m, 5H), 2.38-2.26 (m, 2H), 2.08 (m, IH), 2.43 (m, IH), 1.52 (d, J=7.3Hz, 3H), 1.29 (d, J=6.6Hz, 3H), 1.07 (d, J=6.6Hz, 3H);

17t: ^XH NMR (methanol-d₄, δ, ppm) 6.92 (d, J=8.7Hz, 2H), 6.77-6.73 (m, 3H), 6.70 (d, J=3.0Hz, IH), 6.64 (dd, J=8.7, 3.0Hz, IH), 6.50 (d, J=8.7Hz, 2H), 6.44 (d, J=8.7Hz, 2H), 5.19 (d, J=2.8Hz, IH), 4.05 (t, J=5.5Hz, 2H), 2.99(m, 2H), 2.88 (m, 4H), 2.64 (m, IH), 2.28 (m, IH), 2.17 (m, IH), 2.06 (m, IH), 1.52 (d, J=7.1Hz, 3H), 1.40 (m, IH), 1.05 (d, J=6.9Hz, 3H);

17u: ^XH NMR (methanol-d₄, δ, ppm) 6.92 (d, J=8.8Hz, 2H), 6.76 (d, J=8.6Hz, 2H), 6.73 (d, J=8.8Hz, 1H),6.68 (d, J=2.5Hz, IH), 6.62 (dd, J=8.7, 2.9 Hz, IH), 6.49 (d, J=8.6Hz, 2H), 6.42 (d, J=8.6Hz, 2H), 5.18 (d, J=2.6Hz, IH), 4.02 (dd, IH), 3.96 (dd, IH), 1.51 (d, J=7.2 Hz, 3H), 1.30 (d, J=6.6Hz, 3H);

17v: ^XH NMR (methanol-d₄, δ, ppm) 6.93 (d, J=8.7Hz, 2H), 6.78 (d, J=8.7Hz, 2H), 6.75 (d, J=8.7Hz, 1H),6.70 (d, J=2.8Hz, IH), 6.64 (dd, J=8.7, 3.0 Hz, IH), 6.49 (d, J=8.6Hz, 2H), 6.42 (d, J=8.6Hz, 2H), 5.20 (d, J=2.8Hz, IH), 4.60 (m, IH), 3.17(m, 2H), 2.97 (m, IH), 2.90 (m, IH), 2.87 (m, IH), 2.81-2.69 (m, 5H), 1.85 (m, 4H), 1.53 (d, J=7.3Hz, 3H), 1.25 (d, J=6.2Hz, 3H);

17w: H NMR (methanol-d₄, δ, ppm) 6.95 (d, J=8.7Hz, 2H), 6.80 (d, J=8.7Hz, 2H), 6.75 (d, J=8.7Hz, 1H),6.70 (d, J=2.8Hz, IH), 6.64 (dd, J=8.7, 2.9 Hz, IH), 6.51 (d, J=8.7Hz, 2H), 6.43 (d, J=8.7Hz, 2H), 5.20 (d, J=2.8Hz, IH), 4.63 (m, IH), 3.20(m, IH), 3.11-2.87 (m, 6H), 2.43 (m, IH), 2.33 (m, lH),2.10(m, IH), 1.53 (d, J=7.2Hz, 3H), 1.25 (d, J=6.2Hz, 3H), 1.08 (d, J=6.6Hz, 3H);

17x: ^XH NMR (methanol-d₄, δ, ppm) 7.08 (d, IH), 7.06 (d, 2H), 6.83 (d, 2H), 6.57 (d, 2H), 6.44 (dd, IH), 6.42 (d, 2H), 6.36 (d, IH), 5.43 (d, IH), 4.25 (t, 2H),1.16 (d, 3H);

17y: ^XH NMR (methanol-d₄, δ, ppm) 7.08 (d, J=8.2Hz, IH), 7.01 (d, J=8.7Hz, 2H), 6.76 (d, J=8.7Hz, 2H),6.57 (d, J=8.2Hz, 2H), 6.46-6.41 (m, 3H), 6.36 (d, J=2.5Hz, IH), 5.41 (d, J=2.3Hz, IH), 4.14 (t, J=5.3Hz, 2H), 3.60 (m, IH), 2.80 (band, 4H), 1.71 (m, 4H), 1.56 (m, 2H), 1.08 (d, J=7.0Hz, 3H);

17z: ^XH NMR (methanol-d₄, δ, ppm) 6.70 (d, IH), 6.44 (dd, IH), 6.50 (d, 2H), 6.44 (d, 2H), 5.20 (d, IH), 1.53 (d, 3H),1.09 (d, 3H);

17aa: ^XH NMR (methanol-d₄, δ, ppm) 6.88 (d, J=8.6Hz, 2H), 6.74-6.69 (m, 3H), 6.68 (d, J=2.7Hz, IH), 6.62 (dd, J=8.6, 2.9 Hz, IH), 6.48 (d, J=8.6Hz, 2H), 6.43 (d, J=8.6Hz, 2H), 5.16 (d, J=2.6Hz, IH), 4.00 (dd, IH), 3.83 (dd, IH), 2.94 (m, 2H), 2.86(m, IH), 2.60 (m, 4H), 1.58 (m, 4H), 1.45 (m, 2H), 1.49 (d, J=7.1Hz, 3H), 1.15 (d, J=6.7Hz, 3H);

17ab: ^XH NMR (methanol-d₄, δ, ppm) 6.88 (d, J=8.7Hz, 2H), 6.75-6.71 (m, 3H), 6.68 (d, J=2.8Hz, IH), 6.62 (dd, J=8.6, 3.0 Hz, IH), 6.48 (d, J=8.6Hz, 2H), 6.42 (d, J=8.6Hz, 2H), 5.17 (d, J=2.6Hz, IH), 4.58 (m, IH), 2.95 (m, IH), 2.87 (t, d=2.4Hz, IH), 2.65 (dd, IH), 2.50 (band, 4H), 2.44 (dd, IH), 1.57 (m, 4H), 1.50 (d, J=7.1Hz, 3H), 1.43 (m, 2H), 1.19 (d, J=6.2Hz, 3H);

17ac: ^XHNMR (methanol-d₄, δ, ppm) 1.59 (d, J=7Hz, 3H), 1.62 (m, 5H), 2.55 (m, 4H), 2.75 (t, 2H), 2.89 (d, J=2.6Hz, IH), 3.21 (dd, IH), 4.06 (t, 2H), 5.23 (d, J=2.6Hz, IH), 6.13 (d, J=7.7Hz, IH), 6.20 (t, IH), 6.48 (dd, IH), 6.62 (dd, IH), 6.74 (d, J=8.8Hz, 2H), 6.79 (m, 2H), 6.98 (d, J=8.8Hz, 2H); MS m/z 478.1 [M+H]⁺;

17ad: ^XHNMR (methanol-d₄, δ, ppm) 0.89 (t, 3H), 1.81 (band, 4H), 2.05 (m, IH), 2.64 (band, 4H), 2.86 (t, 2H), 4.04 (t, 2H), 5.27 (d, J=1.6Hz, IH), 6.41 (d, J=8.6Hz, 2H), 6.51 (d, J=8.2Hz, 2H), 6.61 (dd, IH), 6.71 (m, 3H), 6.82 (d, J=2.3Hz, IH), 6.89 (d, J=8.6Hz, 2H); MS m/z 460.2 [M+H]⁺;

17ae: ^XHNMR (methanol-d₄, δ, ppm) 1.13, (t, 3H), 1.82 (m, 4H), 2.66 (m, 4H), 2.88 (t, 2H), 3.03 (s, broad, IH), 4.06 (t, 2H), 5.15 (d, J=2.7Hz, IH), 6.40 (d, J=8.6Hz, 2H), 6.48 (d, J=8.6Hz, 2H), 6.62 (dd, IH), 6.67 (d, J=2.9Hz, IH), 6.73 (s, IH), 6.75 (m, 2H), 6.93 (d, J=8.6Hz, 2H); MS m/z 460.2 [M+H]⁺;

17af: ^XHNMR (methanol-d₄, δ, ppm) 1.04 (d, J=6.7Hz, 3H), 2.98 (m, IH), 4.03 (t, 2H), 5.26 (d, J=2.2Hz, IH), 6.41 (d, J=8.8Hz, IH), 6.51 (d, J=8.1Hz, 2H), 6.61 (dd, IH), 6.71 (dd, 4H), 6.82 (d, J=1.9Hz, IH), 6.89 (d, J=8.6Hz, 2H); MS m/z 474.2 [M+H]⁺;

17ag: HNMR (methanol-d₄, δ, ppm) 1.04 (d, J=6.7Hz, 3H), 1.13 (t, 3H), 2.99 (m, IH), 3.03 (s, broad, IH), 4.04 (t, 2H), 5.15 (d, J=2.5Hz, IH), 6.40 (d_> J=8.6Hz, 2H), 6.49 (d, J=8.6Hz, 2H), 6.62 (dd, IH), 6.67 (d, J=2.9Hz, IH), 6.73 (s, IH), 6.75 (d, J=8.8Hz, 2H), 6.93 (d, J=8.6Hz, 2H); MS m/z 474.2 [M+H]⁺.

17ah: ^XH NMR (methanol-d₄, δ, ppm) 6.94 (d, 2H), 6.78 (t, IH), 6.75 (d, 2H), 6.59 (d, IH), 6.45 (d, 2H), 6.41 (d, 2H), 5.21 (d, IH), 4.04 (t, 2H), 3.18 (m, IH), 2.89 (t, 2H), 2.86 (d, IH), 2.67 (band, 4H), 1.81 (m, 4H), 1.57 (d, 3H);

17ai: ^XH NMR (HCl salt, methanol-d₄, δ, ppm) 7.06 (d, 2H), 6.82 (t, IH), 6.87 (d, 2H), 6.63 (d, IH), 6.50 (d, 2H), 6.42 (d, 2H), 5.28 (d, IH), 4.28 (t, 2H), 2.92 (d, IH), 1.61 (d, 3H),1.17 (d, 3H);

17aj: ^XH NMR (methanol-d₄, δ, ppm) 6.95 (d, 2H), 6.77 (m, 3H), 6.59 (dd, IH), 6.45 (d, 2H), 6.41 (d, 2H), 5.22 (d, IH), 4.04 (t, 2H), 3.19 (q, IH), 2.99 (dd, IH), 2.62 (m, IH), 2.27 (m, IH), 2.15 (dd, IH), 2.05(m, IH), 1.58 (d, 3H), 1.04 (d, 3H);

17ak: ^XH NMR (methanol-d₄, δ, ppm) 6.97 (d, 2H), 6.80 (t, IH), 6.76 (d, 2H), 6.62 (d, IH), 6.48 (d, 2H), 6.43 (d, 2H), 5.23 (d, IH), 3.98 (dd, IH), 3.87 (dd, IH), 3.21(q, IH), 3.05 (t, IH), 2.91 (m, 2H), 2.76 (m, 2H), 2.67 (m, IH), 1.59 (d, 3H), 1.23 (d, 3H), 1.05 (d, 3H);

17al: ^XH NMR (methanol-d₄, δ, ppm) 6.97 (d, 2H), 6.79 (m, 3H), 6.61 (dd, IH), 6.48 (d, 2H), 6.43 (d, 2H), 5.24 (d, IH), 4.01 (dd, IH), 3.89 (dd, IH), 3.20 (q, IH), 2.89 (d, IH), 2.72 (m, 5H), 1.83 (m, 4H), 1.59 (d, 3H), 1.26 (d, 3H);

17am: ^XH NMR (methanol-d₄, δ, ppm) 7.01 (d, 2H), 6.82 (m, 3H), 6.62 (dd, IH), 6.48 (d, 2H), 6.42 (d, 2H), 5.26 (d, 1H),1.61 (d, 3H), 1.26 (d, 3H);

17an: ^XH NMR (methanol-d₄, δ, ppm) 6.99 (d, 2H), 6.80 (m, 3H), 6.62 (d, IH), 6.48 (d, 2H), 6.42 (d, 2H), 5.25 (d, 1H),4.59 (m, IH), 3.21(m, IH), 3.07 (m, IH), 2.99-2.66 (m, 5H), 1.60 (d, 3H), 1.24 (d, 3H), 1.05 (d, 3H);

17ao: ^XH NMR (methanol-d₄, δ, ppm) 7.01 (d, 2H), 6.79 (t, IH), 6.83 (d, 2H), 6.60 (dd, IH), 6.47 (d, 2H), 6.41 (d, 2H), 5.24 (d, IH), 4.14 (dd, IH), 4.06 (dd, IH), 2.89(d, IH), 2.69 (t, IH), 2.41 (m, IH), 2.17 (m, IH), 1.58 (d, 3H), 1.41 (d, 3H), 1.10 (d, 3H);

17ap: ^XH NMR (methanol-d₄, δ, ppm) 6.97 (d, 2H), 6.80 (t, IH), 6.77 (d, 2H), 6.61 (dd, IH), 6.47 (d, 2H), 6.42 (d, 2H), 5.23 (d, IH), 4.07 (t, 2H), 3.21 (q, IH), 2.97 (t, 2H), 2.88 (d, IH), 2.85 (m, 4H), 1.71 (m, 4H), 1.64 (m, 4H), 1.59 (d, 3H);

17aq: ^XH NMR (methanol-d₄, δ, ppm) 6.98 (d, 2H), 6.79 (m, 3H), 6.62 (dd, IH), 6.47 (d, 2H), 6.42 (d, 2H), 5.24 (d, IH), 4.07 (t, 2H), 3.21 (q, IH), 2.96 (m, 4H), 2.89 (d, IH), 2.48 (t, 2H), 1.77 (m, 2H), 1.60 (d, 3H), 1.06 (d, 6H);

17ar: ^XH NMR (methanol-d₄, δ, ppm) 6.98 (d, 2H), 6.79 (m, 3H), 6.61 (dd, IH), 6.48 (d, 2H), 6.43 (d, 2H), 5.24 (d, IH), 4.00 (dd, IH), 3.86 (dd, IH), 3.21 (q, IH), 3.07 (dd, 2H), 2.85 (m, IH), 2.89 (d, IH), 2.48 (t, 2H), 1.72 (m, 2H), 1.60 (d, 3H), 1.26 (d, 3H), 1.05 (d, 6H);

17as: ^XH NMR (methanol-d₄, δ, ppm) 6.98 (d, 2H), 6.79 (m, 3H), 6.62 (dd, IH), 6.47 (d, 2H), 6.42 (d, 2H), 5.24 (d, IH), 4.03 (dd, IH), 3.93 (dd, IH), 3.21 (q, IH), 3.01 (q, IH), 2.96 (q, IH), 2.95 (m, IH), 2.89 (d, IH), 2.77 (m, IH), 1.99 (m, IH), 1.79 (m, 2H), 1.48 (m, IH), 1.60 (d, 3H), 1.16 (d, 3H), 1.14 (d, 3H);

17at: ^XH NMR (methanol-d₄, δ, ppm) 6.99 (d, 2H), 6.81 (m, 3H), 6.62 (d, IH), 6.48 (d, 2H), 6.43 (d, 2H), 5.25 (d, IH), 4.11 (t, 2H), 3.20 (q, IH), 3.07 (t, 2H), 2.89 (d, IH), 2.37 (band, 4H), 1.60 (d, 3H), 0.97 (d, 6H);

17au: ^XH NMR (methanol-d₄, δ, ppm) 6.97 (d, 2H), 6.79 (m, 3H), 6.62 (dd, IH), 6.48 (d, 2H), 6.43 (d, 2H), 5.24 (d, IH), 4.06 (t, 2H), 3.20 (q, IH), 2.96 (m, 4H), 2.89 (d, IH), 2.49 (t, 2H), 1.76 (m, 2H), 1.59 (d, 3H), 1.05 (d, 6H);

17av: ^XH NMR (methanol-d₄, δ, ppm) 7.00 (d, ZH), 6.81 (m, 3H), 6.62 (dd, IH), 6.48 (d, 2H), 6.43 (d, 2H), 5.25 (d, IH), 4.11 (dd, IH), 4.02 (dd, IH), 3.20 (q, IH), 2.90 (d, IH), 1.60 (d, 3H), 1.36 (d, 3H);

17aw: H NMR (HCl salt, methanol-d₄, δ, ppm) 7.06 (d, 2H), 6.87 (d, 2H), 6.81 (t, IH), 6.63 (dd, IH), 6.49 (d, 2H), 6.42 (d, 2H), 5.27 (d, IH), 2.91 (d, IH), 1.61 (d, 3H), 1.46 (d, 3H);

17ax: ^XH NMR (methanol-d₄, δ, ppm) 6.97 (d, 2H), 6.81 (m, 3H), 6.62 (dd, IH), 6.47 (d, ZH), 6.42 (d, 2H), 5.24 (d, IH), 4.59 (m, IH), 3.22 (m, ZH), 3.11 (dd, IH), 2.51 (m, IH), 2.37 (m, ZH), Z.89 (d, IH), 1.99 (m, IH), 1.77 (m, 2H), 1.48 (m, IH), 1.60 (d, 3H), 1.24 (d, 3H), 1.16 (d, 3H);

17ay: ^XH NMR (methanol-d₄, δ, ppm) 7.06 (d, ZH), 6.89 (d, ZH), 6.81 (t, IH), 6.63 (dd, IH), 6.49 (d, ZH), 6.4Z (d, ZH), 5.Z7 (d, IH), 4.79 (m, IH), 2.92 (d, IH), 1.60 (d, 3H), 1.27 (d, 3H), 1.11 (d, 6H);

17az: ^XH NMR (methanol-d₄, δ, ppm) 6.99 (d, 2H), 6.81 (m, 3H), 6.63 (dd, IH), 6.49 (d, 2H), 6.45 (d, 2H), 5.25 (d, IH), 4.12 (m, 2H), 3.22 (q, IH), 3.09-2.86 (m, 5H),1.61 (d, 3H), 0.79 (m, IH), 0.26 ( , IH);

17ba: H NMR (methanol-d₄, δ, ppm) 6.97 (d, 2H), 6.80 (m, 3H), 6.62 (dd, IH), 6.47 (d, 2H), 6.43 (d, 2H), 5.23 (d, IH), 4.10 (m, 2H), 3.20 (q, IH), 3.05-2.83 (m, 5H),1.59 (d, 3H), 0.76 (m, IH), 0.25 (m, IH);

17bb: ^XHNMR (methanol-d₄, δ, ppm) 7.01 (d, 2H), 6.81 (m, 3H), 6.62 (dd, IH), 6.48 (d, 2H), 6.42 (d, H), 5.25 (d, IH), 4.11 (t, 2H), 3.71 (s, 4H), 3.35 (t, 2H), 2.89 (d, IH), 1.60 (d, 3H), 1.33 (s, 6H).

EXAMPLE 18 Preparation of 18

To a stirred solution of the 2,3-trøn-f-diphenyl-bis-t-butyldimethylsilyl protected chromanone

( 75mg, 0.109 mmol ), prepared according to the method described in: Saeed, A; etal J. Med. Chem., 1990, 33, 3210, in 1 mL of anhydrous THF at 0°C, was added a l.OM solution of LiEt₃BH ( 163 uL, 0.163 mmol ) in THF and the solution was let warm to ambient temperature. After 1 h, 1 mL of methanol was added and the solution was stirred for 10 min. The solution was diluted with EtOAc and sequentially washed with sat. aq. NH₄CI solution, water, saturated aq. NaHC0₃ solution and brine. The organic layer was dried over anhydrous Na₂S0₄, filtered, and evaporated in vacuo. The residue was purified by PLC, with hexanes-EtOAc-methanol ( 7:2: 1 ) to give 57 mg of pure carbinol 18.

^XH NMR (CDC1₃) δ: 0.15 (S, 6H), 0.21 (s, 6H), 0.95 (s, 9H), 0.99 (s, 9H), 1.47 (m, 2H), 1.65 (bs, 4H), 2.55 (bs, 4H), 2.79 (bs, ZH), 3.10 (t, J= 10.4 Hz, IH), 4.07 (m, ZH), 5.09 (d, J= 10.8 Hz, IH). 5.15 (dd, J= 4.6 Hz, IH ), 6.42 (d, J=2.3 Hz, IH), 6,52 (dd, J= 2.4 Hz, IH), 6.68 (m, 4H), 6.89 (d, J=8.6 Hz, 2 H), 7.06 (d, J= 8.6 Hz, ZH), 7.41 (d, J= 8.6 Hz, IH). EXAMPLE 19 Preparation of 19

To a stirred solution of 18 ( 40 mg, 0.0579 mmol ), prepared in Example 18, in 1.5 mL of anhydrous methylene chloride at -78°C was sequentially added neat Et₃SiH ( 0.046 mL, 0.289 mmol ) and trifluoroacetic acid (TFA) ( 0.005 mL, 0.0637 mmol ). The solution was then warmed to ambient temperature. After lh, the solution was diluted with methylene chloride and washed with water, sat. aq. NaHC0₃ solution, and brine. The organic layer was dried over anhydrous Na₂S0₄, filtered and evaporated in vacuo. The crude residue was purified by PLC with hexanes-EtOAc-methanol ( 7:2:1 ) to give 25 mg of 19.

^XH NMR (CDC1₃) δ: 0.15(s, 6H), 0.22(s, 6H), 0.95 (s, 9H), 0.99 (s, 9H), 1.44 (m, 2H), 1. 65 (bs, 4H), 2.57 (bs, 4H), 2.79 (bs, 2H), 2.94- 3.24 (m, 3H), 4.02 (bs, 2H), 4.91 (d, J= 10.8 Hz, IH), 6.43-6.49 (m, 2H), 6.65 (d, J= 8.6 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 6.83 (d, J= 8.6 Hz, 2H) 6.97 (d, J=8.6 Hz, IH), 7.05 (d, J=8.6 Hz, 2H). EXAMPLE 20 Preparation of 20

To a stirred solution of 19 ( 25 mg, 0.0371 mmol ) in 1 mL of anhydrous THF at 0°C, was added glacial acetic acid ( 0.008 mL, 0.148 mmol ) followed by a l.OM solution of tetrabutyammonium fluoride (TBAF) ( 0.111 mL, 0.111 mmol ) in THF. After 2 h, the solution was diluted with EtOAc and sequentially washed with water, saturated aq. sodium bicarbonate solution and brine. The organic layer was dried over anhydrous Na₂S0 , filtered and evaporated in vacuo. The crude residue was purified by PLC, with hexanes-EtOAc- methanol ( 45:45: 10 ) to give 8.3 mg of 20.

^XH NMR (d₆-acetone) δ: 1.40 (m , 2H), 1.51 (m, 4H), 2.48 (bs, 4H), 2.66 (t, J=5.9 Hz, ZH), Z.83-3.Z8 (m, ZH), 4.01 (m, ZH), 5.0Z (d, J=9.6 Hz, IH), 6.31 (d, J=Z.3 Hz, IH), 6.31 (dd, J= Z.6 Hz, IH), 6.63 (d, J= 8.6 Hz, ZH), 6.74 (d, J=8.7 Hz, ZH), 6.9Z (d, J=8.7 Hz, IH), 6.96 (d, J= 8.6 Hz, ZH), 7.14 (d, J=8.6 Hz, ZH). EXAMPLE 21 Preparation of 21

Utilizing the procedure of Example 18, the corresponding 2,3-cfs-bis-t-butyldimethylsilyl protected chromanone was converted to the corresponding chromanol 21.

^XH NMR (CDC1₃) δ: 0.15 ( S, 6H), 0.24 (s, 6H), 0.95 (S, 9H), 1.01 (s, 9H), 1.45 (m, 2H), 1.58 (m, 4H), 2.49 (m, 4H), 2.7 (t, J=6.0 Hz, 2H), 3.45 (dd, J= 2.3 Hz, IH), 4.02 (t, J=6.3 Hz, 2H), 5.38 (bs, IH), 5.45 (d, J=2.2 Hz, 1 H), 6.47 (d, J=2.3 Hz, IH), 6.55 (dd, J= 2.3 Hz, IH ), 6.60 (d, J=8.6 Hz, 2H), 6.71 (d, J= 8.6 Hz, 2H) 6.73 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.4 Hz, IH).

EXAMPLE 22 Preparation of 22

Utilizing the procedure of Example 19, the corresponding 2,3-cώ-bis-t-butyldimethylsilyl protected chromanol 21, from example 21, was converted to the corresponding chromane derivative 22.

EXAMPLE 23 Preparation of 23

Utilizing the procedure of Example 20, the corresponding 2,3-cz^'s-bis-t-butyldimethylsilyl protected chromane 22, from Example 22, was converted to the corresponding product 23.

^XH NMR (d₆-acetone) δ: 1.40 (m, 2H), 1.51( m, 4H), 2.48 (bs, 4H), 2.66 (t, J=6.1 Hz, 2H), 2.83-3.34 (q, 2H), 3.41 (m, IH), 4.01 (m, 2H), 5.35 (d, J=3.1 Hz, IH), 6.41 (d, J= 2.3 Hz, IH), 6.45 (dd, J=2.6 Hz, IH), 6.57 (d, J= 8.6 Hz, 2H), 6.72 (m, 4H), 6.88 (d, J= 8.6 Hz, 2H), 6.95 (d, J=8.0 Hz, IH). EXAMPLE Z4 Preparation of R = Propyl

Step A: To a stirred suspension of 3,5-dimethoxybenzonitrile (1.6301 g, 10 mmol) in 10 mL of anhydrous ether was added 6.7 mL ( Z0 mmol ) of a 3 M solution of ethyl magnesium bromide in ether at ambient temperature under nitrogen. The mixture became homogeneous with time. After Z hours and Z0 ' min., an additional 3.5 mL of ethyl magnesium bromide was added and the reaction was sti-tred for 15 min. The reaction was poured into ice/sat. ammonium chloride and the resulting mixture was extracted with ether. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by plate chromatography ( PLC ) with 10% ethyl acetate/hexane as the eluant afforded 1.8543 g of a 3:1 mixture of l-(l-ethylvinyl)~3,5-dimethoxybenzene and the starting material.

Step B: A stirred mixture of l-(l-ethylvinyl)-3,5-dimethoxybenzene ( 1.8543 g, 9.5 mmol ), obtained from Step A, hydrazine monohydrate ( 1.0 g, 20 mmol ), and KOH ( 2.32 g, 41 mmol ) in 15 mL of ethylene glycol was heated to 190°C for 3 hours under nitrogen. The reaction was partitioned between ether and ice/brine/2 N HCl. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was suspended in methylene chloride and the undissolved white solid removed by filtration. The filtrate was concentrated in vacuo and purified by silica gel chromatography with 10% ethyl acetate/hexane as the eluant. The desired product was obtained as a colorless oil (1.0695 g, 62%).

EXAMPLE 25 Preparation of R = Ethyl

l-Ethyl-3,5-dimethoxybenzene was obtained in quantitative yield from commercially available 3',5'- dimethoxyacetophenone ( 1.9038 g, 10.6 mmol ) using the procedure outlined in Example 24, Step B. EXAMPLE 26 Preparation of R = Pentyl

To a stirred mixture of NaH ( 0.5666 g, 14.1 mmol ) in 15 mL anhydrous DMF at 0°C under nitrogen was added a solution of olivetol ( 1.0174 g, 5.6 mmol ) in 5 mL of DMF. After 5 min., Mel ( 1.05 mL, 16.9 mmol ) was added to the reaction. The ice bath was removed and the reaction was warmed to ambient temperature. After 20 min., the reaction was partitioned between ethyl acetate and ice/2 N HCl water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography with 10% ethyl acetate/hexane as the eluant afforded 1.3286 g of l-pentyl-3,5-dimethoxybenzene, as a pale yellow oil.

EXAMPLE 27 Preparation of R=Propyl

Step A: To a stirred solution of l,3-dimethoxy-5-propylbenzene ( 0.8806 g, 4.9 mmol), from

Example 24, and (phenylthio)acetyl chloride ( 0.72 mL, 4.9 mmol ) in 9 mL of anhydrous methylene chloride at 0°C was added dropwise a 1 M solution of SnCl in methylene chloride under nitrogen. After the addition, the ice bath was removed and the reaction was stirred at ambient temperature for 2 hours and 40 min. The reaction was quenched with ice/2 N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 1.5047 g of an inseparable mixture ( 1:1 ) of the desired product and its isomer.

Step B: To a stirred solution of the bismethoxy ketone ( 1.5047 g, 4.9 mmol ), from Step A above, in 20 mL of methylene chloride at 0°C was added dropwise 14.7 mL ( 14.7 mmol ) of a 1 M solution of BBr₃ in methylene chloride under nitrogen. After addition, the reaction was allowed to warm to ambient temperature and stirred for 2 hours and 50 min. At this time, the reaction was heated to 60°C for 1 hour before adding another 5 mL of BBr₃ to the reaction. The reaction was stirred at ambient temperature for 25 min. then reheated to 60°C for another Z5 min. The reaction was partitioned between ethyl acetate and ice/Z N HCl/brine. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by PLC with methylene chloride-ethyl acetate ( Z0:1 ) as the eluant yielded 0.7848 g ( 53% ) of desired product.

Utilizing the foregoing experimental procedure the following compounds were prepared: R=Ethyl and R=Pentyl.

EXAMPLE 28

To a stirred solution of 4-hydroxybenzaldehyde ( 14.08 g, 115 mmol ), triethylamine ( 24 mL, 173 mmol ), and 4-N,N-dimethylaminopyridine (DMAP) ( 1.42 g, 12 mmol ) in 150 mL of methylene chloride at 0°C under nitrogen was added chloro-t-butyldiphenylsilane (TBDPSC1) ( 42 mL, 161 mmol ) via a cannula. After the addition, the reaction was allowed to warm to ambient temperature. After 35 min., the reaction was poured into an ethyl acetate and ice/2 N HCl/water mixture. The organic layer was collected, washed with saturated sodium bicarbonate, 5 N NaOH, and brine; dried over sodium sulfate and concentrated in vacuo. The resulting white solid was triturated with hexane to give 17.30 g product.

EXAMPLE 29 Preparation of 24 ( R=Propyl )

Step A: The ketone ( 0.9017 g, 3.0 mmol ) prepared in Example 27, the benzaldehyde derivative

( 1.2923 g, 3.6 mmol ) from Example 28, and piperidine ( 89 μL, 0.89 mmol ) in 9mL of toluene was stirred and heated to 120°C under nitrogen with removal of water via a Dean-Stark trap for 15 hours. The reaction was partitioned between ethyl acetate and ice/2 N HCl/brine.The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a brown oil. The crude material was purified by silica gel chromatography with 25% ethyl acetate/hexane as the eluant to give the desired product (0.9208 g, 47%) as a 1: 1 mixture of cis and trans isomers.

Step B: To a stirred solution ofthe chromanone ( 0.9208 g, 1.4 mmol ), from Step A, in 9 mL of anhydrous DMF at -8°C (ice/brine bath) was added Hunig's base ( 0.74 mL, 4.3 mmol ) followed by the dropwise addition of chloromethylmethyl ether (MOMC1) ( 0.22 mL, 2.9 mmol ) over 10 min. under nitrogen. The reaction was stirred for a total of 1.5 hours, then worked up by partitioning between ice/2 N HCl and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography with 10% ethyl acetate/hexane as the eluant gave 24 ( R = propyl ) as a yellow oil ( 0.4795 g, 50% ).

Utilizing the foregoing experimental procedure the following compounds were prepared: 24 ( R=Ethyl ) and 24 ( R=Pentyl ).

EXAMPLE 30 Preparation of 25 ( R=Propyl )

Step A: To a stirred solution of 24 ( R = propyl ) ( 0.4795 g, 0.70 mmol ), from Example 29,

Step B, in 8 mL of chloroform was added tris(acetyloxy)[4-(methoxymethoxy)phenyl]plumbane ( 0.7908 g, 1.4 mmol ) and pyridine ( 0.17 mL, 2.1 mmol ). The reaction was heated to 60°C under nitrogen for 20 hours. The reaction was allowed to cool to ambient temperature then filtered through celite. The filtrate was partitioned between ethyl acetate and ice/2 N HCl. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 0.9281 g of residue which was used without further purification. Step B: To a stirred solution of the crude, TBDPS-protected chromanone ( 0.70 mmol ), from

Step A, in 6 mL of anhydrous THF was added AcOH ( 52 μL, 0.90 mmol ) at 0°C under nitrogen, followed by 0.77 mL (0.77 mmol) of a 1 M solution of TBAF in THF. After stirring for 20 min., the reaction was partitioned between ethyl acetate and ice/sat. sodium bicarbonate/brine. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by silica gel chromatography with 25% ethyl acetate/hexane as the eluant to give 25 ( R = propyl ) (0.2628 g, 64%).

Utilizing the foregoing experimental procedure the following compounds were prepared: 25 ( R=Ethyl ) and 25 ( R=Pentyl ).

EXAMPLE 31 Preparation of 26 ( R=Propyl )

To a stirred solution of 0.1834 g ( 0.31 mmol) of 25 ( R = propyl ), generated in Example 30, Step B, in 2.2 mL of acetone/water ( 10: 1 ) was added cesium carbonate ( 1.2028 g, 3.6 mmol ) and chloroethylpiperidine-HCl salt ( 0.3173 g, 1.6 mmol ). The stirred reaction mixture was heated to 60°C under nitrogen for 2.5 hours. The reaction was filtered and the filtrate was partitioned between ethyl acetate and ice/ 2 N HCl/brine.The organic layer was collected and washed thoroughly with 2 N HCl until the chloroethylpiperidine was absent in the TLC (10% MeOH/methylene chloride, iodine stain). The organic layer was then washed with sat. sodium bicarbonate and brine; dried over sodium sulfate, and concentrated in vacuo. Purification by PLC with 10% MeOH in methylene chloride as the eluant gave 26 ( R = propyl ) (0.1911 g, 87%).

Utilizing the foregoing experimental procedure the following compounds were prepared: 26 ( R=Ethyl ) and 26 ( R=Pentyl ). EXAMPLE 32 Preparation of 27 ( R=Propyl )

To a stirred solution of 26 ( R = propyl ) ( 0.0566 g, 0.082 mmol ), from Example 31, in 1 mL of absolute EtOH was added a suspension of Raney nickel (RaNi) in water ( Aldrich, 0.74 g ) and the resulting mixture was stirred vigorously at ambient temperature under nitrogen. After 10 min., an additional 0.48 g of RaNi was added to the mixture. The reaction was complete after stirring for another 10 min. and saturated sodium bicarbonate was added. The resulting mixture was filtered through a celite pad and the solids were rinsed thoroughly with EtOH-ethyl acetate ( 1:1 ). The filtrate was partitioned between ethyl acetate and brine. The organic layer was collected, dried over sodium sulfate, and concentrated in vacuo to give the cis isomer 27 ( R = propyl ) as a pale yellow oil (0.0430 g, 90%).

Utilizing the foregoing experimental procedure the following compounds were prepared: 27 ( R=Ethyl ) and 27 ( R=Pentyl ).

EXAMPLE 33 Preparation of 28 ( R=Propyl )

To a stirred solution of crude 27 ( R = propyl ) ( 0.0430 g, 0.073 mmol ), from Example 32, in 1 mL distilled of THF was added 80 μL, ( 0.080 mmol ) of a 1 M solution of lithium tri-ethyl borohydride in THF at 0°C under nitrogen. After 5 min., another 20 μL of lithium tri-ethyl borohydride was added. The completion ofthe reaction was confirmed by ^XH NMR. The reaction was quenched with 2 N HCl and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by PLC with 10% methanol in methylene chloride as the eluant afforded 28 (R = propyl ) (0.0287 g, 67%).

Utilizing the foregoing experimental procedure the following compounds were prepared: 28 ( R=Ethyl ) and 28 ( R=Pentyl ).

EXAMPLE 34 Preparation of 29 ( R=Propyl )

Step A: To a solution of 28 (R = propyl ) ( 0.0287 g, 0.049 mmol ), from Example 33, in methylene chloride at 0°C was added TFA ( 19 μL, 0.24 mmol ) followed by triethylsilane ( 77 μL, 0.49 mmol ) under an atmosphere of nitrogen. After 25 min., the reaction was allowed to warm to ambient temperature and stirred for another 1.5 hours. The reaction was carefully monitored by ^XH NMR. The reaction was partitioned between ethyl acetate and ice/saturated sodium bicarbonate. The organic layer was collected, washed further with brine, dried over sodium sulfate, and concentrated in vacuo. The crude material was used as is in the next reaction.

Step B: To a solution of the crude bis-MOM-protected chromane ( 0.049 mmol ), prepared above in Step A, in 1 mL of EtOH was added 2 N HCl ( 0.24 mL, 0.049 mmol ). The reaction was heated at 80°C under nitrogen for 2 hours. After completion, the reaction was cooled to ambient temperature and partitioned between ethyl acetate and ice/saturated sodium bicarbonate/brine. The organic layer was collected, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a red oil. The sample was dissolved in a minimal amount of 1:2:2 DMSO/water/acetonitrile and purified by reverse- phase HPLC [λ = 210 nM, YMC-ODSA semi-prep column, flow = 25 mL/min, gradient = acetonitrile/water/water ( 10:80:10 )+1.0%TFA to acetonitrile/water/water ( 60:30:10 ) +1.0%TFA over 45 min.] to give 29 ( R = propyl ) as a pink foam (0.0134 g, 55%).

^XH NMR (400 MHz, d₅-acetone) δ (ppm): 0.96 (t, 3H), 1.40 (m, ZH), 1.52-1.59 (m, 6H), 2.44-Z.51 (m, 5 6H), Z.66 (t, 2H), 2.81 (dd, IH), 3.19 (dd, IH), 3.45 (m, IH), 4.03 (t, 2H), 5.31(d, J=3.2Hz, IH), 6.28 (d, IH), 6.38 (d, IH), 6.58 (d, ZH), 6.71 (d, ZH), 6.75 (d, ZH), 6.89 (d, ZH).

Utilizing the foregoing experimental procedure the following compounds were prepared: Z9 ( R=Ethyl ):

10

^XH NMR (400 MHz, d₆-acetone) δ (ppm): 1.16 (t, 3H), 1.42 (m, 2H), 1.54 (m, 4H), 2.52-2.60 (m, 6H), 2.71-2.83 (m, 3H), 3.19 (dd, IH), 3.47 (m, IH), 4.05 (t, ZH), 5.3 l(d, J=Z.9Hz, IH), 6.Z8 (d, IH), 6.39 (d, IH), 6.59 (d, ZH), 6.71 (d, ZH), 6.76 (d, ZH), 6.89 (d, ZH). Z9 ( R=Pentyl ):

15

^XH NMR (400 MHz, d₆-acetone) δ (ppm): 0.96-2.2 (m, 21H), 2.66 (t, ZH), Z.81 (dd, IH), 3.19 (dd, IH), 3.45 (m, IH), 4.03 (t, 2H), 5.31(d, J=3.2Hz, IH), 6.28 (d, IH), 6.38 (d, IH), 6.58 (d, ZH), 6.71 (d, ZH), 6.79 (d, ZH), 6.89 (d, ZH); MS m/z 516.4 (M⁺+l).

Z0 EXAMPLE 35 Preparation of 30

To a stirred solution of crude 13g ( about 3Z mmol ), prepared in Example 11, in 300 mL of methylene chloride at -78°C was added 39 mL of a 1.5 M solution of diisobutylaluminum hydride ( DIBAL-H ) in toluene. The reaction mixture was stirred further for 2h. The reaction was terminated by the addition of 6

Z5 mL of 2-propanol, 2N HCl, and then a mixture of hexane and EtOAc. The organic phase was separated, washed with 2N HCl, water, and brine, and the solvent removed to give crude 30. ^XH NMR (CDC1₃, δ, ppm) 7.53 (d, 2H), 7.18 (s, IH), 6.94 (d, ZH), 6.84 (t, IH), 6.73 (dd, IH), 6.26 (d, IH), 3.07 (d, IH), 1.29 (m, 6H), 1.13 (m, 36H).

EXAMPLE 36 Preparation of 31 To a stirred solution of crude 30 (about 32 mmol), prepared in Example 35, in 250 mL of methylene

TI

chloride was added 17 g of phenol and 18 g of sodium sulfate. The resulting mixture was stirred for 22h and the solid was filtered off. The methylene chloride was removed under reduced pressure and the reaction mixture was dissolved in hexane, and washed several times with aq. sodium carbonate, water, and brine to give after removal of the solvent crude 31.

^XH NMR (methylene chloride-d₂, δ, ppm) 7.49 (d, ZH), 7.20 (s, IH), 6.64 (s, IH), 1.31 (m, 6H), 1.15 (m, 36H)

EXAMPLE 37 Preparation of 32 PS

Step I: Preparation of 4-Benzyloxyphenylmagnesium Bromide:

A stirred mixture of 50 g ( 190 mmol ) of 4-benzyloxyphenyl bromide, 5.08 g of magnesium powder, and 0.6 mL of 1,2-dibromoethane in 277 mL of THF was heated briefly at 50°C to initiate the reaction. The reaction mixture was allowed to reflux on its own for 40 min, at which time the reflux subsided. The reaction was heated to reflux in a 75°C bath for 1 h, and then allowed to cool overnight. The solution of the Grignard reagent was used as is. Step II: A ylation:

To a stirred solution of crude 31 ( about 30 mmol ), prepared in Example 36, in 100 mL of toluene was added 200 mL ofthe 4-benzyloxyphenylmagnesium bromide solution prepared in Step I above. The mixture was heated at 50°C for 2.25h. The reaction mixture was poured into 2N HCl, ice, hexane and EtOAc. The organic phase was separated, washed with aq. Rochelle's salt, water, and brine, and the solvent removed. Purification ofthe residue by silica gel flash chromatography gave 32.

^XHNMR (CDC1₃, δ, ppm) 6.88 (d, ZH), 6.83 (d, 2H), 6.64 (t, IH), 6.40 (dd, IH), 6.14 (s, IH), 5.01 (s, 2H), 1.27 (m, 6H), 1.11 (m, 36H)

EXAMPLE 38 Preparation of 33

TI

A mixture of 8.1 g ( 11 mmol ) of 32, prepared in Example 37, and 200 mL of a 1 M solution of borane- THF complex in THF was stirred at ambient temperature for 15h. The solvent was stripped by evaporation twice with MeOH. The residue was redissolved in 140 mL of THF-water ( 1:1 ), and treated with 15 g of Na₂B0₃'4H₂0 for 1.5h. The reaction mixture was diluted with ca. 500 mL of EtOAc, and the excess reagent was filtered off. The liquid was extracted twice with EtOAc. The combined organic layers were washed with aq. sodium thiosulfate and brine, and the solvent removed to give 33.

^XH NMR (CDC1₃, δ, ppm) 7.36 (m, 5H), 6.98 (m, 3H), 6.81 (d, 2H), 6.72 (dd, IH), 6.58 (d, 2H), 6.50 (d, 2H), 5.41 (d, IH), 5.05 (d, IH), 5.01 (s, 2H), 3.22 (s, IH), 2.56 (d, IH), 1.33-1.15 (m, 6H), 1.13 (m, 18H), 1.15 (m, 18H) EXAMPLE 39 Alternate Preparation of 15al

To a stirred solution of a mixture of 6.26 g ( 8.1 mmol ) 33, prepared in Example 38, in 80 mL of methylene chloride and 32.5 mL of a IM solution of dimethylzinc in heptane at -78°C, was added dropwise, simultaneously 16 mL of a IM solution of dimethylzinc in heptane and 12 mL of a IM solution of titanium tetrachloride in toluene over a 15 minute period. After 4h, the cold reaction mixture was poured into a vigorously stirred slurry of 50 mL of acetone, 20mL of triethylamine, 20 mL of MeOH, 30 mL of EtOAc, 20 mL of hexane, and dry ice. Additional hexane and EtOAc was added, and the reaction mixture was filtered through a glass funnel to remove the insoluble matter. The filtrate was extracted twice with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Purification via a coarse silica gel flash chromatography gave the crude benzyl-protected form of racemic 15al. This material in 100 mL of EtOAc with 2.5 g of 10%Pd on carbon was hydrogenated with a balloon filled with hydrogen gas at ambient temperature for 5h. The insolubles were removed by filtration and the filtrate was concentrated in vacuo. Purification by silica gel flash chromatography and HPLC using a Chiral AD column, with 2-propanol-heptane as the eluent, gave chiral 15al.

EXAMPLE 40 Preparation of 34

To a mixture of 2.5 g ( 3.25 mmol ) of 33, prepared in Example 38, 1.62 g KI, 3.59 g Bi I, and 30 mL methylene chloride at 0°C was added 1.03 mL BF₃-etherate in portions over a period of lh, during which a red color developed. The reaction mixture was stirred with aqueous solution of NaHC0₃ and Na₂S₂0₃ until the red color dissipated, and then diluted with hexanes and washed by water and brine. Purification by silica gel chromatography with methylene chloride/hexane then ethyl acetate/hexane as the eluant gave 34 as a white solid ( 2.1 g, 74 %).

^XH NMR (CDC1₃, δ, ppm) 7.40 (m, 5H), 6.98 (m, 3H), 6.83 (d, ZH), 6.62 (m, 3H), 6.53 (d, ZH), 6.17 (d, IH), 5.84 (s, IH), 3.62 (s, IH), 1.35-1.15 (m, 6H), 1.15 (m, 18H), 1.08 (m, 18H)

EXAMPLE 41 Alternate Preparation of 15al

To a stirred solution of 1.5 g ( 1.71 mmol ) 34, prepared in Example 40, in Z0 mL THF at -78°C, was added dropwise Z.Z mL 1.4 M MeLi in ether. After Z5 min, the reaction mixture was quenched by ZN HCl in ether followed by aqueous solution of NaHC0_3ι diluted with hexanes, and washed by brine. Removal of solvent in vacuo gave the crude benzyl-protected form of racemic 15al. This material in 30 mL of EtOAc with 0.54Z g of 10%Pd on carbon was hydrogenated with a balloon filled with hydrogen gas at ambient temperature for 6 h. The insolubles were removed by filtration and the filtrate was concentrated in vacuo. Purification by silica gel flash chromatography and HPLC using a Chiral AD column, with Z-propanol-heptane as the eluent, gave 380 mg of chiral 15al.

Pharmaceutical Composition

As a specific embodiment of this invention, Z5 mg ofthe compound 17, from Example 15, is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.

Claims

WHAT IS CLAIMED IS:

A compound ofthe formula:

wherein R is hydrogen, Ci-5 alkyl or halogen;

R2 is hydrogen or hydroxy;

R3 is hydrogen or hydroxy;

R4 is hydrogen, Cχ-5 alkyl or halogen;

R5 is hydrogen, Cχ-5 alkyl or halogen;

R6 is hydrogen, Cχ-5 alkyl or halogen;

R7 is hydrogen, hydroxy, halogen, Cχ_5 alkyl, CF3 or 0(Cχ-5 alkyl);

R8 is hydrogen, hydroxy, halogen, Cχ_5 alkyl, CF3 or 0(Cι_5 alkyl);

R9 is hydrogen, Cχ-5 alkyl or halogen;

RlO is hydrogen, C1.5 alkyl or halogen; each RU is independently hydrogen, Cχ-5 alkyl or halogen; or two RU , when on separate carbons, can be taken together to form a three membered ring; n is an integer from one to four; m is an integer from one to two; or a pharmaceutically acceptable salt or stereoisomer thereof.

The compound of Claim 1 ofthe formula:

wherein n is an integer from one to three; or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 2 wherein

Rl is hydrogen, fluoro, chloro or Cχ_3 alkyl;

R4 is hydrogen, fluoro, chloro or Cχ_3 alkyl;

R5 is hydrogen, C _3 alkyl or fluoro; R6 is hydrogen, Cχ-3 alkyl or fluoro;

R7 is hydrogen, hydroxy, fluoro, C1-.3 alkyl, CF3 or 0(Cχ_3 alkyl);

R8 is hydrogen, hydroxy, fluoro, Cχ_3 alkyl, CF3 or 0(Cχ_3 alkyl);

R9 is hydrogen, C1-.3 alkyl or fluoro;

R O is hydrogen, Cχ_3 alkyl or fluoro; each R 1 is independently hydrogen, C1-.3 alkyl or fluoro; or a pharmaceutically acceptable salt thereof.

4. The compound of Claim 3 wherein n is one, or a pharmaceutically acceptable salt thereof.

5. The compound of Claim 3 wherein n is two, or a pharmaceutically acceptable salt thereof. The compound of Claim 1 selected from

or a pharmaceutically acceptable salt thereof.

The compound of Claim 6 which is:

or a pharmaceutically acceptable salt thereof.

The compound of Claim 6 which is:

or a pharmaceutically acceptable salt thereof.

The compound of Claim 6 which is:

or a pharmaceutically acceptable salt thereof.

10. The compound of Claim 6 which is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

11. The compound of Claim 6 which is:

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition made by combining a compound according to Claim 1 and a pharmaceutically acceptable carrier.

14. A process for making a pharmaceutical composition comprising combining a compound according to Claim 1 and a pharmaceutically acceptable carrier.

15. A method of eliciting an estrogen receptor modulating effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to Claim 1.

16. The method according to Claim 15 wherein the estrogen receptor modulation effect is an estrogen receptor agonizing effect.

17. The method according to Claim 16 wherein the estrogen receptor agonizing effect is an ERα receptor agonizing effect.

18. The method according to Claim 15 wherein the estrogen receptor modulation effect is an estrogen receptor antagonizing effect.

19. The method according to Claim 16 wherein the estrogen receptor agonizing effect is an ERα receptor antagonizing effect.

20. A method of treating or preventing a disease in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to Claim 1, wherein said disease is selected from: bone loss, bone fractures, osteoporosis, glucocorticoid induced osteoporosis, bone pain, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, cartilage degeneration, endometriosis, uterine fibroid disease, breast cancer, uterine cancer, prostate cancer, hot flashes, cardiovascular disease, impairment of cognitive function, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity or incontinence.

21. The method of Claim 20 wherein the disease is osteoporosis.

22. The method of Claim 20 wherein the disease is metastatic bone disease.

Z3. A method of treating or preventing an estrogen dependent cancer in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to Claim 1.

24. A pharmaceutical composition comprising a compound of Claim 1 and another agent selected from: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen; a selective estrogen receptor modulator; an estrogen receptor beta modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; a cholesterol ester transfer protein inhibitor; an integrin receptor antagonist; an osteoblast anabolic agent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; or a selective serotonin reuptake inhibitor; a NK-1 receptor antagonist; or a pharmaceutically acceptable salt or mixture thereof.

25. A method of treating osteoporosis comprising administering to a mammal in need thereof a compound of Claim 1 and another agent selected from: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen; a selective estrogen receptor modulator; an estrogen receptor beta modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; a cholesterol ester transfer protein inhibitor; an integrin receptor antagonist; an osteoblast anabolic agent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; or a selective serotonin reuptake inhibitor; a NK-1 receptor antagonist; or a pharmaceutically acceptable salt or mixture thereof.

26. A method of treating bone loss comprising administering to a mammal in need thereof a compound of Claim 1 and another agent selected from: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen; a selective estrogen receptor modulator; an estrogen receptor beta modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; a cholesterol ester transfer protein inhibitor; an integrin receptor antagonist; an osteoblast anabolic agent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; or a selective serotonin reuptake inhibitor; a NK-1 receptor antagonist; or a pharmaceutically acceptable salt or mixture thereof.

27. A method of treating metastatic bone disease comprising administering to a mammal in need thereof a compound of Claim 1 and another agent selected from: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen; a selective estrogen receptor modulator; an estrogen receptor beta modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; a cholesterol ester transfer protein inhibitor; an integrin receptor antagonist; an osteoblast anabolic agent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; or a selective serotonin reuptake inhibitor; a NK-1 receptor antagonist; or a pharmaceutically acceptable salt or mixture thereof.

- Ill -

28. A method of lowering cholesterol comprising administering to a mammal in need thereof a compound of Claim 1 and another agent selected from: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen; a selective estrogen receptor modulator; an estrogen receptor beta modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; a cholesterol ester transfer protein inhibitor; an integrin receptor antagonist; an osteoblast anabolic agent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; or a selective serotonin reuptake inhibitor; a NK-1 receptor antagonist; or a pharmaceutically acceptable salt or mixture thereof.