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  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
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  • A61K38/08—Peptides having 5 to 11 amino acids
  • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
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  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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  • A61P25/00—Drugs for disorders of the nervous system
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  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
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  • A61P5/00—Drugs for disorders of the endocrine system
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  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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• • A—HUMAN NECESSITIES
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  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• Arzoxifene is a nonsteroidal mixed estrogen antagonist/agonist , useful for, inter alia, lowering serum cholesterol and for inhibiting hyperlipidemia, osteoporosis, estrogen dependent cancers including breast and uterine cancer, endo etriosis, CNS disorders including Alzheimer's disease, aortal smooth muscle cell proliferation, and restenosis.
• arzoxifene is useful for, and is being clinically evaluated for the treatment of receptor positive metastatic breast cancer; the adjuvent treatment of receptor positive patients following appropriate systemic or local therapy; the reduction of recurrence of invasive and noninvasive breast cancer; and the reduction of the incidence of invasive breast cancer and ductal carcinoma in si tu (DCIS) .
• Arzoxifene is also useful in combination with radiotherapy, aromatase inhibitors, LHRH analogues, and acetyl choline esterase (AChE) inhibitors.
• arzoxifene prepared by the procedures taught in ⁇ 474 could be used as a pharmaceutical, it would be highly desired and advantageous to find a more crystalline form of arzoxifene that did not contain an organic solvent within its crystal lattice which could be reproducibly and efficiently prepared on a commercial scale.
• the present invention is related to a novel non- stoichiometric hydrated crystalline form of 6-hydroxy-3- (4- [2- (piperidin-1-yl) ethoxy]phenoxy) -2- (4- methoxyphenyl) benzo [b] thiophene hydrochloride (F-I) having an X-ray diffraction pattern which comprises the following peaks: 7.9 ⁇ 0.2 , 10.7 ⁇ 0.2, 14.9 ⁇ 0.2, 15.9 ⁇ 0.2, 18.3 ⁇ 0.2, and 20.6 ⁇ 0.2° in 2 ⁇ ; when obtained from a copper radiation source .
• the present invention relates to a pharmaceutical formulation
• a pharmaceutical formulation comprising F-I; one or more pharmaceutical carriers, diluents, or excipients; and optionally estrogen, optionally progestin, optionally an aromatase inhibitor, optionally an LHRH analogue and optionally an acetyl choline esterase (AChE) inhibitor.
• the present invention is related to methods for using F-I to inhibit pathological conditions such as: uterine fibrosis, endometriosis, aortal smooth muscle cell proliferation, restenosis, breast cancer, uterine cancer, prostatic cancer, benign prostatic hyperplasia, bone loss, osteoporosis, cardiovascular disease, hyperlipidemia, CNS disorders, and Alzheimer's disease and for using F-I for the manufacture of a medicament for inhibiting same.
• pathological conditions such as: uterine fibrosis, endometriosis, aortal smooth muscle cell proliferation, restenosis, breast cancer, uterine cancer, prostatic cancer, benign prostatic hyperplasia, bone loss, osteoporosis, cardiovascular disease, hyperlipidemia, CNS disorders, and Alzheimer's disease
• the present invention is further related to methods for using F-I to up-regulate choline acetyltransferase (ChAT) and for using F-I for the manufacture of a medicament for up-regulating same.
• ChAT choline acetyltransferase
• Figure 1 is a representative differential scanning calorimetry (DSC) /TGA trace of S-II.
• Figure 2 is a representative DSC/TGA trace of F-I.
• Figure 3 is a representative DSC/TGA trace of F-III.
• Figure 4 depicts moisture sorption isotherms for F-I and F-III.
• Figure 5 depicts desolvation of S-II as a function of drying time and temperature.
• F-I may be prepared by removing the ethyl acetate from S-II's crystal lattice by vacuum drying/annealing S-II at elevated temperatures .
• the time and temperature required to anneal S-II in order to prepare F-I will vary from lot to lot but is typically on the order of 5 days at around 100°C. High temperatures are needed to effect the conversion of S- II to F-I via this procedure, since slurrying S-II in water at ambient temperature or storing a sample at 98% RH for 3 weeks afforded no conversion to F-I.
• F-I is readily prepared and isolated at ambient temperature by crystallization of arzoxifene (or any polymorph/solvate thereof) from tetrahydrofuran.
• This crystallization is preferably performed by initially dissolving arzoxifene in wet tetrahydrofuran (1-10% water by volume, preferably 2.5-7.5% and most preferably 4.5 to 5.5%) followed by removal of said water via atmospheric distillation.
• An example of this crystallization is detailed below in Example 2.
• Suitable arzoxifene starting material for this crystallization includes, but is not limited to, S-II, F- III, arzoxifene prepared by the procedures taught in ⁇ 474, or any mixture thereof. It is not important which form of arzoxifene one starts with because crystallization from tetrahydrofuran, according to the procedures described herein, results in F-I crystals. For commercial scale synthesis of F-I, it may be advantageous to seed the crystallization with F-I.
• F-III another non-stoichiometric hydrate of arzoxifene, is readily prepared and isolated at ambient temperature by crystallization of arzoxifene (or any polymorph/solvate thereof) from a mixture of isopropyl alcohol (IPA) and water.
• IPA isopropyl alcohol
• the ratio of water to IPA (v:v) is generally about 1:1 to 9:1. More preferably, the ratio is between 2.5 and 5.6:1. Most preferably, the ratio is between 3 to 5.6:1.
• the ratio of IPA to water is not critical to effect crystallization of F-III but does affect the yield. For commercial scale synthesis of F-III, it may be advantageous to seed the crystallization with F-III.
• Suitable arzoxifene starting material for the above crystallization include, but are not limited to, S-II, F-I, arzoxifene prepared by the procedures taught in '474, or any mixture thereof.
• DSC/TGA and XRD methods were used to characterize S-II, F-I and F-III.
• TGA is often very useful for distinguishing between different solid forms of a material because the temperature (s) at which a physical change in a material occurs is usually characteristic of the polymorph or solvate.
• DSC is a technique that is often used to screen compounds for polymorphism and solvate formation.
• XRD is a technique that detects long-range order in a crystalline material .
• the DSC trace of F-I shows a broad endotherm beginning at about 75°C, followed by a second endotherm beginning at about 155°C corresponding to a melt.
• the TGA trace of F-I shows a gradual weight loss of 0.3% followed by a sharp loss of 1.5%, which together represent dehydration of the lattice.
• the onset of the first DSC transition and the corresponding TGA weight loss are offset slightly due to the difference in heating rates.
• the initial weight loss represents weakly held waters of hydration while the second weight loss is consistent with approximately 0.5 mole of water present in the lattice at very low relative humidities (below 5% - see moisture sorption data) .
• the DSC trace of F-III features a broad, low temperature endotherm at about 30°C, followed by a second broad and relatively weak endotherm beginning at about 70°C, and a final transition beginning at about 146°C corresponding to a melt.
• the sharp 1.5% (-0.5 mole) weight loss in the TGA coincident with the first endotherm corresponds to loss of weakly held water molecules, while the additional -1.6% weight loss above 60°C represents loss of more tightly held water molecules, i.e., those which are present at very low relative humidities.
• the weight loss observed after 170°C corresponds to decomposition of F-III.
• the XRD patterns of F-I and F-III feature sharp peaks and a flat baseline, indicative of highly crystalline materials.
• F-I may be identified by the presence of peaks at 7.9 ⁇ 0.2 , 10.7 ⁇ 0.2, 14.9 ⁇ 0.2 , 15.9 ⁇ 0.2, 18.3
• the difference in the moisture uptake of the two forms likely reflects the amount of water that can be incorporated into the two lattices (i.e., the amount of available space in the lattice that can accommodate water molecules) .
• Lack of hysteresis in the sorption-desorption isotherms of F-I and F-III indicates that the crystal forms rapidly equilibrate at any given humidity.
• F-I and F-III The moisture sorption profiles for F-I and F-III reveal that these forms are essentially non-stoichiometric hydrates.
• F-I contains approximately 1.7% water, corresponding to 0.5 moles of water, while F-III has sorbed about 3.0% water which corresponds to about 0.85 moles of water.
• the bulk forms of F-I and F-III rapidly equilibrate with the atmosphere, so that the water content observed by analytical techniques is a reflection of the relative humidity at the time of data collection. Lot-to-lot differences observed in the DSC data likely results from the samples being hydrated to different extents due to different ambient storage conditions.
• F-I and F-III have several advantages over the prior art form of arzoxifene described above. Relative to the arzoxifene produced by the procedures taught in v 474, F-I and F-III are more stable at ambient temperature and are, therefore, more amenable to pharmaceutical development, i.e., development of a dosage formulation. In addition, F-I and F-III are much more crystalline than the form disclosed in ⁇ 474. Crystalline materials are generally less hygroscopic and more stable ( e . g. , less prone to chemical degradation, maintains consistent potency) than amorphous materials and are, therefore, more desirable for formulation processing. Furthermore, unlike the form of arzoxifene produced by the procedures taught in '474, which contained ethyl acetate and water in its lattice, F-I and F-III contain only water.
• DSC measurements were performed on a TA Instruments 2920 Modulated DSC attached to a Thermal Analyst 3100 and equipped with a refrigerated cooling system. Samples (3-5 mg) were heated in crimped aluminum pans from 10 to 240°C at a heating rate of 2°C/min.
• TGA analyses were performed on a TA Instruments 2050 Thermogravimetric Analyzer attached to a Thermal Analyst 3100. Samples (5-10 mg) were heated in open pans from 25°C to 250°C at a heating rate of 5°C/min.
• a 1L, 3-necked round bottom flask equipped with a reflux condenser and an overhead agitator is charged with 25.0 g of arzoxifene, 475 ml of tetrahydrofuran and 25 ml of water.
• the reaction vessel is then equipped for simple distillation.
• the reaction mixture is heated to reflux and 250 ml of distillate are removed. Heat is briefly removed and 250 ml of fresh anhydrous tetrahydrofuran is added to the vessel. Atmospheric distillation is continued with removal of an additional 250 ml of distillate. Heat is briefly removed, 250 ml of fresh tetrahydrofuran added, and an additional 250 ml of distillate are removed.
• the term “effective amount” means an amount of F-I that is capable of inhibiting conditions, or detrimental effects thereof, described herein.
• F-I is co-administered with estrogen, progestin, an aromatase inhibitor, an LHRH analogue, or an AChE inhibitor
• the term “effective amount” also means an amount of such an agent capable of producing its intended effect.
• inhibitors include their generally accepted meaning, i.e., preventing, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, or reversing the progression or severity of a pathological condition, or sequela thereof, described herein.
• estrogen deprived and “estrogen deprivation” refer to a condition, either naturally occurring or clinically induced, where a woman can not produce sufficient endogenous estrogenic hormones to maintain estrogen dependent functions, e . g. , menses, homeostasis of bone mass, neuronal function, cardiovascular condition, etc.
• estrogen deprived situations arise from, but are not limited to, menopause and surgical or chemical ovarectomy, including its functional equivalent, e . g.
• Disease states associated with an estrogen deprived state include, but are not limited to: bone loss, osteoporosis, cardiovascular disease and hyperlipidemia .
• estrogen includes steroidal compounds having estrogenic activity such as, for example,
• a preferred estrogen-based compound is Premarin®, and norethylnodrel .
• progestin includes compounds having progestational activity such as, for example, progesterone, norethylnodrel, nongestrel, megestrol acetate, norethindrone, and the like. Norethindrone is a preferred progestin-based agent.
• aromatase inhibitor includes compounds capable of inhibiting aromatase, for example commercially available inhibitors such as aminoglutemide
• LHRH analogue refers to an analogue of lutenizing hormone releasing hormone that inhibits estrogen production in a premenopausal women including for example, goserlin (ZOLADEX ), leuprolide
• the term "AChE inhibitor” includes compounds that inhibit acetyl choline esterase, for example, physostigmine salicylate, tacrine hydrochloride, donepezil hydrochloride and the like.
• up-regulate ChAT refers to increasing the enzymatic activity of ChAT, i.e., promoting the conversion of choline to acetyl choline. This promotion would include an increase in the efficiency and/or rate of reaction of ChAT and choline and/or an increase in the amount of ChAT present at the site of action. This increase in the amount of enzyme present may be due to gene regulation or other synthetic step of the enzyme's formation and/or a decrease in the enzyme's de-activation and metabolism.
• mice Seventy-five day old (unless otherwise indicated) female Sprague Dawley rats (weight range of 200 to 225g) are obtained from Charles River Laboratories (Portage, MI) . The animals are either bilaterally ovariecto ized (OVX) or exposed to a Sham surgical procedure at Charles River Laboratories, and then shipped after one week. Upon arrival, they are housed in metal hanging cages in groups of 3 or 4 per cage and have ad libi tum access to food (calcium content approximately 0.5%) and water for one week. Room temperature is maintained at
• Dosing Regimen Tissue Collection After a one week acclimation period (therefore, two weeks post-OVX) daily dosing with F-I is initiated. 170-ethynyl estradiol or F-I is given orally, unless otherwise stated, as a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. Animals are dosed daily for 4 days. Following the dosing regimen, animals are weighed and anesthetized with a ketamine: Xylazine (2:1, v:v) mixture and a blood sample is collected by cardiac puncture.
• Cardiovascular Disease/Hyperlipidemia The blood samples from above are allowed to clot at room temperature for 2 hours, and serum is obtained following centrifugation for 10 minutes at 3000 rpm. Serum cholesterol is determined using a Boehringer Mannheim Diagnostics high performance cholesterol assay. Briefly the cholesterol is oxidized to cholest-4-en-3-one and hydrogen peroxide. The hydrogen peroxide is then reacted with phenol and 4-aminophenazone in the presence of peroxidase to produce a p-quinone imine dye, which is read spectrophotemetrically at 500 run. Cholesterol concentration is then calculated against a standard curve. The entire assay is automated using a Biomek Automated Workstation.
• EPO Eosinophil Peroxidase
• the uteri from above are kept at 4°C until time of enzymatic analysis.
• the uteri are then homogenized in 50 volumes of 50 mM Tris buffer (pH - 8.0) containing 0.005% Triton X-100.
• Tris buffer pH - 8.0
• the presence of eosonophils in the uterus is an indication of estrogenic activity of a compound.
• the maximal velocity of a 15 second interval is determined over the initial, linear portion of the reaction curve.
• the right femurs are excised and digitilized X-rays generated and analyzed by an image analysis program (NIH image) at the distal metaphysis.
• NASH image image analysis program
• the proximal aspect of the tibiae from these animals are also scanned by quantitative computed tomography.
• F-I or ethynyl estradiol (EE2) in 20% hydroxypropyl ⁇ -cyclodextrin are orally administered to test animals.
• F-I is also useful in combination with estrogen or progestin.
• MCF-7 breast adenocarcinoma cells are maintained in MEM (minimal essential medium, phenol red- free, Sigma, St. Louis, MO) supplemented with 10% fetal bovine serum (FBS) (V/V) , L-glutamine (2 mM) , sodium pyruvate (1 mM) , HEPES ⁇ (N- [2-hydroxyethyl]piperazine-N' - [2- ethanesulfonic acid] 10 mM ⁇ , non-essential a ino acids and bovine insulin (1 ug/mL) (maintenance medium) .
• FBS fetal bovine serum
• L-glutamine 2 mM
• sodium pyruvate (1 mM
• HEPES ⁇ N- [2-hydroxyethyl]piperazine-N' - [2- ethanesulfonic acid] 10 mM ⁇
• non-essential a ino acids and bovine insulin (1 ug/mL
• MCF-7 cells are switched to maintenance medium supplemented with 10% dextran coated charcoal stripped fetal bovine serum (DCC-FBS) assay medium) in place of 10% FBS to deplete internal stores of steroids.
• DCC-FBS dextran coated charcoal stripped fetal bovine serum
• MCF-7 cells are removed from maintenance flasks using cell dissociation medium (Ca++/Mg++ free HBSS (phenol red-free) supplemented with 10 mM HEPES and 2 mM EDTA) . Cells are washed twice with assay medium and adjusted to 80,000 cells/mL.
• Approximately 100 mL (8,000 cells) are added to flat-bottom microculture wells (Costar 3596) and incubated at 37°C in a 5% C ⁇ 2 humidified incubator for 48 hours to allow for cell adherence and equilibration after transfer.
• Serial dilutions of drugs or DMSO as a diluent control are prepared in assay medium and 50 mL transferred to triplicate microcultures followed by 50 mL assay medium for a final volume of 200 mL .
• microcultures are pulsed with tritiated thymidine (1 uCi/well) for 4 hours. Cultures are terminated by freezing at -70°C for 24 hours followed by thawing and harvesting of microcultures using a Skatron
• Estrogen-dependent mammary tumors are produced in female Sprague-Dawley rats which are purchased from Harlan Industries, Indianapolis, Indiana. At about 55 days of age, the rats receive a single oral feeding of 20 mg of 7,12- dimethylbenz [a] anthracene (DMBA) . About 6 weeks after DMBA administration, the mammary glands are palpated at weekly intervals for the appearance of tumors. Whenever one or more tumors appear, the longest and shortest diameters of each tumor are measured with a metric caliper, the measurements are recorded, and that animal is selected for experimentation. An attempt is made to uniformly distribute the various sizes of tumors in the treated and control groups such that average-sized tumors are equivalently distributed between test groups. Control groups and test groups for each experiment contain 5 to 9 animals.
• F-I is administered either through intraperitoneal injections in 2% acacia, or orally.
• Orally administered compounds are either dissolved or suspended in 0.2 mL corn oil.
• Each treatment, including acacia and corn oil control treatments, is administered once daily to each test animal.
• tumors are measured each week by the above- mentioned method.
• the treatment and measurements of animals continue for 3 to 5 weeks at which time the final areas of the tumors are determined. For each compound and control treatment, the change in the mean tumor area is determined.
• Test 1 Between 3 and 20 women having uterine fibrosis are administered F-I.
• the amount of compound administered is from 0.1 to 1000 mg/day, and the period of administration is 3 months. The women are observed during the period of administration, and up to 3 months after discontinuance of administration, for effects on uterine fibrosis.
• Test 2 The same procedure is used as in Test 1, except the period of administration is 6 months.
• Test 3 The same procedure is used as in Test 1, except the period of administration is 1 year.
• Test 4 Prolonged estrogen stimulation is used to induce leiomyomata in sexually mature female guinea pigs. Animals are dosed with estradiol 3-5 times per week by injection for 2-4 months or until tumors arise. Treatment consisting of F-I or vehicle is administered daily for 3-16 weeks and then animals are sacrificed and the uteri harvested and analyzed for tumor regression.
• Test 5 Tissue from human leiomyomas are implanted into the peritoneal cavity and/or uterine myometrium of sexually mature, castrated, female, nude mice. Exogenous estrogen is supplied to induce growth of the explanted tissue. In some cases, the harvested tumor cells are cultured in vi tro prior to implantation. Treatment consisting of F-I or vehicle is supplied by gastric lavage on a daily basis for 3-16 weeks and implants are removed and measured for growth or regression. At the time of sacrifice, the uteri are harvested to assess the status of the organ.
• Test 6 Tissue from human uterine fibroid tumors is harvested and maintained, in vi tro, as primary non- transformed cultures. Surgical specimens are pushed through a sterile mesh or sieve, or alternately teased apart from surrounding tissue to produce a single cell suspension. Cells are maintained in media containing 10% serum and antibiotic. Rates of growth in the presence and absence of estrogen are determined. Cells are assayed for their ability to produce complement component C3 and their response to growth factors and growth hormone. In vi tro cultures are assessed for their proliferative response following treatment with progestins, GnRH, F-I, and vehicle. Levels of steroid hormone receptors are assessed weekly to determine whether important cell characteristics are maintained in vi tro . Tissue from 5-25 patients is utilized.
• Test 7 F-I's ability to inhibit estrogen-stimulated proliferation of leiomyoma-derived ELT cell lines is measured substantially as described in Fuchs-Young, et al . , "Inhibition of Estrogen-Stimulated Growth of Uterine Leiomyomas by Selective Estrogen Receptor Modulators", Mol . Car., 17 (3) : 151-159 (1996), the teachings of which are herein incorporated by reference.
• Test 1 Twelve to thirty adult CD strain female rats are used as test animals. They are divided into three groups of equal numbers. The estrous cycle of all animals is monitored. On the day of proestrus, surgery is performed on each female. Females in each group have the left uterine horn removed, sectioned into small squares, and the squares are loosely sutured at various sites adjacent to the mesenteric blood flow. In addition, females in Group 2 have the ovaries removed. On the day following surgery, animals in Groups 1 and 2 receive intraperitoneal injections of water for 14 days whereas animals in Group 3 receive intraperitoneal injections of 1.0 mg of F-I per kilogram of body weight for the same duration. Following 14 days of treatment, each female is sacrificed and the endometrial explants, adrenals, remaining uterus, and ovaries, where applicable, are removed and prepared for histological examination. The ovaries and adrenals are weighed.
• Test 2 Twelve to thirty adult CD strain female rats are used as test animals. They are divided into two equal groups. The estrous cycle of all animals is monitored. On the day of proestrus, surgery is performed on each female. Females in each group have the left uterine horn removed, sectioned into small squares, and the squares are loosely sutured at various sites adjacent to the mesenteric blood flow. Approximately 50 days following surgery, animals assigned to Group 1 receive intraperitoneal injections of water for 21 days whereas animals in Group 2 receive intraperitoneal injections of 1.0 mg of F-I per kilogram of body weight for the same duration. Following 21 days of treatment, each female is sacrificed and the endometrial explants and adrenals are removed and weighed. The explants are measured as an indication of growth. Estrous cycles are monitored.
• Test 3 Autographs of endometrial tissue are used to induce endometriosis in rats and/or rabbits.
• Female animals at reproductive maturity undergo bilateral oophorectomy, and estrogen is supplied exogenously thus providing a specific and constant level of hormone.
• Autologous endometrial tissue is implanted in the peritoneum of 5-150 animals and estrogen supplied to induce growth of the explanted tissue.
• Treatment consisting of a compound of the present invention is supplied by gastric lavage on a daily basis for 3-16 weeks, and implants are removed and measured for growth or regression. At the time of sacrifice, the intact horn of the uterus is harvested to assess status of endometrium.
• Test 4 Tissue from human endometrial lesions is implanted into the peritoneum of sexually mature, castrated, female, nude mice. Exogenous estrogen is supplied to induce growth of the explanted tissue. In some cases, the harvested endometrial cells are cultured in vi tro prior to implantation. Treatment consisting of F-I supplied by gastric lavage on a daily basis for 3-16 weeks, and implants are removed and measured for growth or regression. At the time of sacrifice, the uteri are harvested to assess the status of the intact endometrium.
• Test 5 Tissue from human endometrial lesions is harvested and maintained in vi tro as primary non-transformed cultures.
• Surgical specimens are pushed through a sterile mesh or sieve, or alternately teased apart from surrounding tissue to produce a single cell suspension.
• Cells are maintained in media containing 10% serum and antibiotic. Rates of growth in the presence and absence of estrogen are determined. Cells are assayed for their ability to produce complement component C3 and their response to growth factors and growth hormone.
• vi tro cultures are assessed for their proliferative response following treatment with progestins, GnRH, F-I, and vehicle. Levels of steroid hormone receptors are assessed weekly to determine whether important cell characteristics are maintained in vi tro . Tissue from 5-25 patients is utilized.
• Estrogens such as 17 ⁇ -estradiol , regulate gene transcription by binding to estrogen receptors (ER) which reside in the cytoplasm of certain cell populations. Ligand activation of the ER is a prerequisite for nuclear transport of the complex where binding to a 13 base-pair palindromic DNA consensus sequence (estrogen response element, or ERE) begins assembly of a transcriptional apparatus which culminates in the activation of appropriate target genes.
• ERE estrogen response element
• a variety of genes have been identified which are regulated by estrogen. These include cytoskeletal proteins, neuro- transmitter biosynthetic and metabolic enzymes and receptors, as well as other hormones and neuropeptides . ERE's have been identified in many estrogen-responsive genes including vitellogenin, c-fos, prolactin, and luteinizing hormone .
• ERE-like sequences have been identified in p75 n 9 r and trkA, both of which serve as signaling molecules for the neurotrophins : nerve growth factor (NGF) , brain derived nerve growth factor (BDNGF) , and neurotrophin-3.
• NGF nerve growth factor
• BDNGF brain derived nerve growth factor
• neurotrophin-3 neurotrophin-3
• BDNF as well as NGF have been shown to promote the survival of cholinergic neurons in culture. It is postulated that if the interactions between neurotrophins and estrogens are important for the development and survival of basal forebrain neurons (which degenerate in Alzheimer's disease) then clinical conditions in which an estrogen deficiency exists (as after menopause) may contribute to a loss of these neurons.
• Polymerase chain reactions are carried out in a cocktail consisting of: random 5' oligonucleotides (10 base-pairs in length; total of 150), reaction buffer, Taq polymerase, and a ⁇ p ⁇ TCP.
• the reaction products are size fractionated on a 6% TBE-urea gel, dried and exposed to X-ray film.
• the resulting mRNA display patterns are compared between treatment groups .
• Use of F-I in Conjunction with Estrogen Peri- and post-menopausal women often undergo hormone replacement therapy (HRT) to combat negative consequences associated with the drop in circulating endogenous estrogen, e . g. , to treat hot flashes.
• HRT hormone replacement therapy
• F-I may be employed in conjunction with HRT to inhibit these risks.
• the ovaries of a postmenopausal woman are not functioning.
• Her only source of estrogen is through conversion of adrenal androgens to estrogens by the enzyme aromatase, which is found in peripheral tissues (including fat, muscle and the breast tumor itself) .
• aromatase inhibitors drugs that inhibit aromatase (aromatase inhibitors) deplete the postmenopausal woman of circulating estrogen.
• Estrogen deprivation by means of aromatase inhibition is an important treatment option for patients with metastatic breast cancer.
• lack of circulating estrogen may cause negative, unintended side- effects, for example on serum lipid levels.
• F-I may be employed to inhibit these negative effects.
• LHRH leukinizing hormone releasing hormone
• analogue inhibits estrogen production in the premenopausal women by desensitizing the pituitary gland, which then no longer stimulates the ovaries to produce estrogen.
• the clinical effect is a "medical oophrectomy" which is reversible upon cessation of the LHRH analogue.
• lack of circulating estrogen may cause negative, unintended side- effects, for example on serum lipid levels.
• F-I may be employed to inhibit these negative effects.
• choline acetylcholine The level of acetylcholine in a neuron is basically determined by where the equilibrium between its biosynthesis and bio-degradation lies.
• the enzyme choline acetyltransferase (ChAT) is primarily responsible for its synthesis and acetylcholineesterase (AChE) for its degradation.
• F-I is used in combination with an AChE inhibitor.
• Use of an AChE inhibitor increases levels of acetylcholine by blocking its degradation via inhibition of AChE.
• Benign Prostatic Hyperplasia For background on the link between estrogen action and treatment of BPH and prostate carcinoma, see PCT Application No. WO 98/07274, International Publication Date: October 15, 1998.
• Lysates of the LNCaP, DU-45 and PC-3 human prostatic cancer cell lines are prepared in a TEG medium comprising 50 nM Tris»HCl pH 7.4, 1.5 mM ethylenediamine tetraacetic acid (EDTA) 0.4 M KCl, 10% glycerol, 0.5 mM 2-ME, and 10 mM sodium molybdate further containing the protease inhibitors pepstatin (1 mg/mL) , leupeptin (2 mg/mL) , aprotinin (5 mg/mL) and phenylmethylsulfonyl fluoride (PMSF, 0.1 mM) (TEGP) .
• EDTA ethylenediamine tetraacetic acid
• the cell lysates are centrifuged and the pellets resuspended in cold TEGP (1 mL TEGP/100 mg of pellet) and sonicated for 30 seconds (duty cycle 70%, output 1.8) on a Branson Model 450 Sonifier. Lysates are pelleted by centrifugation at 10,000 x G for 15 minutes at 4°C after which the supernates are withdrawn and either used immediately or stored at -70°C.
• the binding buffer is TEG in which the 0.4 M KCl is replaced by 50 mM NaCl and to which 1 mg/mL of ovalbumin had been further added (TEGO) .
• F-I is diluted to 20 nM in TEGO from which 3-fold serial dilutions are prepared. Assays are performed in round-bottom polyprolylene microplates in triplicate microwells .
• Each well receives 35 mL of tritiated 17 ⁇ -estradiol (0.5 nM, specific activity 60.1 Ci/mmol, DuPont-New England Nuclear, Boston, MA) and 35 mL of cold competitot test compound (0.1 nM - 5 mM) or TEGO, and following incubation for 5 minutes at 4°C with shaking, 70 mL of MCF-7 cell line lysate .
• This invention also relates to the administration of F- I to a recipient who is at risk of developing de novo breast cancer.
• e novo means the lack of transformation or metamorphosis of normal breast cells to cancerous or malignant cells in the first instance. Such a transformation may occur in stages in the same or daughter cells via an evolutionary process or may occur in a single, pivotal event. This de novo process is in contrast to the metastasis, colonization, or spreading of already transformed or malignant cells from the primary tumor site to new locations.
• a person who is at no particular risk of developing breast cancer is one who may develop de novo breast cancer, has no evidence or suspicion of the potential of the disease above normal risk, and who has never had a diagnosis of having the disease.
• the greatest risk factor contributing to the development of breast carcinoma is a personal history of suffering from the disease, or an earlier occurrence of the disease, even if it is in remission with no evidence of its presence.
• Another risk factor is family history of the disease.
• compositions when used herein as an adjective means substantially non-deleterious to the recipient mammal.
• pharmaceutical formulation it is meant the carrier, diluent, excipients and active ingredient (s) must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof .
• F-I is preferably formulated prior to administration.
• the selection of the formulation should be decided by the attending physician taking into considerations the same factors involved with determining the effective amount.
• the total active ingredients in such formulations comprises from 0.1% to 99.9% by weight of the formulation.
• no more than two active ingredients are contained in said formulation. That is, it is preferred to formulate F-I with a second active ingredient selected from an estrogen, progestin, aromatase inhibitor, LHRH analogue and AChE inhibitor. Most preferred formulations are those where F-I is the sole active ingredient.
• compositions of the present invention are prepared by procedures known in the art using well known and readily available ingredients.
• F-I either alone, or in combination with an estrogen, progestin, aromatase inhibitor, LHRH analogue or an AChE inhibitor compound
• Pharmaceutical compositions of this invention for parenteral administration comprise sterile aqueous or non- aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders which are reconstituted immediately prior to use into sterile solutions or suspensions.
• Suitable sterile aqueous and non- aqueous carriers, diluents, solvents or vehicles include water, physiological saline solution, ethanol, polyols (such as glycerol, propylene glycol, poly (ethylene glycol) , and the like), and suitable mixtures thereof, vegetable oils
• injectable organic esters such as ethyl oleate.
• Proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by the maintenance of proper particle size in the case of dispersions and suspensions, and by the use of surfactants.
• Parenteral compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms is ensured by the inclusion of antibacterial and antifungal agents, for example, paraben, chlorobutanol , phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of injectable formulations may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
• the rate of absorption of the drug depends upon its rate of dissolution.
• Injectable "depot” formulations of F-I are made by forming microencapsulated matrices of the drug in biodegradable polymers such as poly (lactic acid), poly (glycolic acid), copolymers of lactic and glycolic acid, poly (orthoesters) , and poly (anhydrides) these materials which are described in the art. Depending upon the ratio of drug to polymer and the characteristics of the particular polymer employed, the rate of drug release can be controlled.
• Injectable formulations are sterilized, for example, by filtration through bacterial-retaining filters, or by presterilization of the components of the mixture prior to their admixture, either at the time of manufacture or just prior to administration (as in the example of a dual chamber syringe package) .
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• F-I is mixed with at least one inert, pharmaceutical carrier such as sodium citrate, or dicalcium phosphate, and/or (a) fillers or extenders such as starches, sugars including lactose and glucose, mannitol, and silicic acid, (b) binding agents such as carboxymethyl-cellulose and other cellulose derivatives, alginates, gelatin, poly (vinylpyrrolidine) , sucrose and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar- agar, calcium carbonate, sodium bicarbonate, potato or tapioca starch, alginic acid, silicates and sodium carbonate, (e) moisturizing agents such as glycerol; (f) solution retarding agents such as paraffin, (g) absorption accelerating agents such as quaternary ammonium compounds, (h
• Solid compositions of a similar type may also comprise the fill in soft or hard gelatin capsules using excipients such as lactose as well as high molecular weight poly (ethylene glycols) and the like.
• Solid dosage forms such as tablets, dragees, capsules, pills and granules can also be prepared with coatings or shells such as enteric coatings or other coatings well known in the pharmaceutical formulating art.
• the coatings may contain opacifying agents or agents which release the active ingredient ( s) in a particular part of the digestive tract, as for example, acid soluble coatings for release of the active ingredient ( s) in the stomach, or base soluble coatings for release of the active ingredient (s) in the intestinal tract.
• the active ingredient (s) may also be microencapsulated in a sustained-release coating, with the microcapsules being made part of a pill of capsule formulation.
• Liquid dosage forms for oral administration of F-I include solution, emulsions, suspensions, syrups and elixirs.
• liquid formulations may include inert diluents commonly used in the art such as water or other pharmaceutical solvents, solubilizing agents and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, ground nut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, poly (ethylene glycols), fatty acid esters of sorbitol, and mixtures thereof.
• inert diluents commonly used in the art such as water or other pharmaceutical solvents
• solubilizing agents and emulsifiers such as ethanol, iso
• liquid oral formulations may also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
• Liquid suspension in addition to the active ingredient (s) may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite clay, agar-agar, and tragacanth, and mixtures thereof.
• compositions for rectal or intravaginal administration are prepared by mixing F-I with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or any suppository wax which is a solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active component (s) .
• suitable non-irritating excipients such as cocoa butter, polyethylene glycol or any suppository wax which is a solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active component (s) .
• the compounds are dissolved in the melted wax, formed into the desired shape, and allowed to harden into the finished suppository formulation.
• F-I may also be administered in the form of liposomes.
• liposomes are generally derived from phospholipids or other lipid substances.
• Lipososome formulations are formed by mono- or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, pharmaceutical, and metabolizable lipid capable of forming liposomes can be used.
• the present compositions in liposome form can contain, in addition to F- I, stabilizers, excipients, preservatives, and the like.
• the preferred lipids are phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
• Hard gelatin capsules are Quantity (mg/capsule) prepared using the following: Ingredient
• a tablet formulation is prepared using the ingredients below:
• the components are blended and compressed to form tablets
• Formulation 3 Tablets containing approximately 10 and 50 mgs, respectively, of F-I may be prepared as follows: Ingredient Quantity Quantity
• the components are blended and compressed to form tablets .
• tablets each containing 2.5 - 1000 mg of F-I are made up as follows:
• F-I, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
• the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve.
• the granules so produced are dried at 50°-60°C and passed through a No . 18 mesh U.S. sieve.
• the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
• the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
• the benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
• Aerosol solution is prepared containing the following ingredients: Formulation 6 : Aerosol
• Propellant 22 (Chlorodifluoromethane) 70.00
• F-I is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30°C, and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container .
• Suppositories are prepared as follows:
• F-I is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimal necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
• An intravenous formulation is prepared as follows: Formulation 8 : Intravenous Solution
• the solution of the above ingredients is intravenously administered to a patient at a rate of about 1 mL per minute.
• the specific dose of F-I administered according to this invention is determined by the particular circumstances surrounding each situation. These circumstances include, the route of administration, the prior medical history of the recipient, the pathological condition or symptom being treated, the severity of the condition/symptom being treated, and the age and sex of the recipient. Generally, an effective minimum daily dose of F-I is about 1, 5, 10, 15, or 20 mg. Typically, an effective maximum dose is about 800, 100, 60, 50, or 40 mg. Most typically, the dose ranges between 15 mg and 60 mg. The exact dose may be determined, in accordance with the standard practice in the medical arts of "dose titrating" the recipient; that is, initially administering a low dose of the compound, and gradually increasing the does until the desired therapeutic effect is observed.
• typical doses of active ingredients other than F-III are as follows: ethynyl estrogen (0.01 - 0.03 mg/day), mestranol (0.05 - 0.15 mg/day), conjugated estrogenic hormones (e.g., Premarin®, Wyeth-Ayerst ; 0.3 - 2.5 mg/day), medroxyprogesterone (2.5 -10 mg/day), norethylnodrel (1.0 - 10.0 mg/day), nonethindrone (0.5 - 2.0 mg/day) , aminoglutemide (250-1250 mg/day, preferably 250 mg four times per day), anastrazole (1-5 mg/day, preferably 1 mg once per day), letrozole (2.5-10 mg/day, preferably 2.5 mg once a day) , formestane (250-1250 mg per week, preferably 250 mg twice weekly) , exemestane (25-100 mg/day, preferably
• Route of administration F-I can be administered by a variety of routes including oral, rectal, transdermal, subcutaneus, intravenous, intramuscular, and intranasal .
• the method of administration of each estrogen- and progestin-based agent is consistent with that which is known in the art.
• F-I, alone or in combination with estrogen, progestin, or an AChE inhibitor generally will be administered in a convenient formulation.
• compositions of this invention may be administered to humans and other mammals (e . g. , dogs, cats, horses, swine and the like) orally, rectally, intravaginally, parenterally, topically, bucally or sublingually, or nasally.
• mammals e . g. , dogs, cats, horses, swine and the like
• parenteral administration refers herein to modes of administration which include intravenous, intramuscular, intraperitoneal, instrasternal, subcutaneous, or intraarticular injection or infusion.
• F-I is administered continuously, from 1 to 3 times daily or as often as needed to deliver an effective amount of F-I to the recipient.
• Cyclical therapy may especially be useful in the treatment of endometriosis or may be used acutely during painful attacks of the disease. In the case of restenosis, therapy may be limited to short (1-6 months) intervals following medical procedures such as angioplasty .

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