MXPA06009682A

MXPA06009682A - DIBENZO CHROMENE DERIVATIVES AND THEIR USE AS ERbeta SELECTIVE LIGANDS

Info

Publication number: MXPA06009682A
Application number: MXPA/A/2006/009682A
Authority: MX
Inventors: E Mewshaw Richard; James Edsall Richard Jr
Original assignee: James Edsall Richard Jr; E Mewshaw Richard; Wyeth
Priority date: 2004-02-26
Filing date: 2006-08-24
Publication date: 2007-04-10

Abstract

This invention provides estrogen receptor modulators of fomula(I), having the structure where R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in the specification.

Description

DERIVATIVES OF DIBENZOCROMENO AND ITS USE AS SELECTIVE LIGANDS OF E BETA Field of the Invention This invention relates to novel substituted 5H-dibenzo [c, g] chromene derivatives, their uses as estrogenic agents, and methods for their preparation. Background of the Invention The pleiotropic effects of estrogens in mammalian tissues have been well documented, and it is now appreciated that estrogens affect many organ systems [Mendelsohn and Aras, New England Journal of Medicine 340: 1801-1811 (1999), Epperson, et al., Psychsomatic Medicine 61: 676-697 (1999), Crandall, Journal of omens Health & Gender Based Medicine 8: 1155-1166 (1999), Mon and Brodaty, Dementia & Geriatric Cognitive Disorders 11: 1-10 (2000), Hurn and Macrae, Journal of Cerebral Blood Flow & Metabolism 20: 631-652 (2000), Calvin, Maturitas 34: 195-210 (2000), Finking, et al., Zeitschrift fur Kardiologie 89: 442-453 (2000), Brincat, Maturitas 35: 10-117 (2000), Al-Azzawi, Postgraduate Medical Journal 77: 292-304 (2001)]. Estrogens can exert effects on tissues in several ways. Probably, the most well-characterized mechanism of action is its interaction with estrogen receptors that lead to alterations in gene transcription. The .estrogen receptors are REF: i75298 activated ligand transcription factors and belong to the nuclear hormone receptor superfamily. Other members of this family include the progesterone, androgen, glucocorticoid and mineralocorticoid receptors. By binding the ligand, these receptors are dimerized and can activate genetic transcription by either directly linking to specific sequences in DNA (known as response elements) or by interacting with other transcription factors (such as APIs), which at their they bind directly to specific DNA sequences [Moggs and Orphanides, EMBO Reports 2: 775-781 (2001), may, et al., Journal of Biological Chemistry 276: 36869-36872 (2001), McDonnell, Principles of Molecular Regulation, p351-361 (2000)]. A class of "corregulatory" proteins can also interact with the ligand bound receptor and further modulate their transcriptional activity [McKenna, et al., Endocrine Reviews '20: 321-344 (1999)]. It has also been shown that estrogen receptors can suppress transcription mediated by NFKB in both a ligand-independent and dependent manner [Quaedackers, et al., Endocrinology 142: 1156-1166 (2001), Bhat, et al., Journal of Steroid Biochemistry & Molecular Biology 67: 233-240 (1998), Pelzer et al., Biochemical & Biophysical Research Communications 286: 1153-7 (2001)]. Estrogenps receptors can also be activated by phosphorylation. This phosphorylation is mediated by growth factors such as EGF and causes changes in gene transcription in the absence of the ligand [Moggs and Orphanides, EMBO Reports 2: 775-781 (2001), Hall, et al., Journal of Biological Chemistry 276 : 36869-36872 (2001)]. A less well characterized means by which estrogens can affect cells is through the so-called membrane receptor. The existence of such a receptor is controversial, but it has been well documented that estrogens can produce very rapid non-genomic responses from cells. The molecular entity responsible for transducing these effects has not been definitively isolated, but there is evidence to suggest that it is at least related to the nuclear forms of estrogen receptors [Levin, Journal of Applied Physiology 91: 1860-1867 (2001), Levin, Trends in Endocrinology & Metabolism 10: 374-377 (1999)]. Two estrogen receptors have been discovered to date. The first estrogen receptor was cloned approximately 15 years ago and is now referred to ERa [Green, et al., Nature 320: 134-9 (1986)]. The second was comparatively recently discovered and is called ERß [Kuiper, et al., Proceedings of the National Academy of Sciences of the United States of America 93: 5925-5930 (1996)]. Early development in ERβ focused on defining its affinity for a variety of ligands and, in effect, some differences with ERa was observed. The tissue distribution of ERβ has been mapped well in the rodent and is not coincident with ERa. Tissues such as mouse uterus and rat predominantly express ERa, while mouse and rat lung predominantly express ERβ [Couse, et al., Endocrinology 138: 4613-4621 (1997), Kuiper, et al., Endocrinology 138 : 863-870]. - _ Even within the same organ, the distribution of ERa and Erß can be shared. For example, in the mouse ovary, ERß. it is highly expressed in granulosa cells and ERa is restricted to fecal and stromal cells [Sar and Welsch, Endocrynology 140: 963-971 (199-9), Fitzpatrick, et al., Endocrynology 140: 2581-2591 (1999) ] However, there are examples where the receptors are co-expressed and there is evidence from in vitro studies that ERa and ERß can form heterodimers [Cowley, et al. , Journal of Biological Chemistry 272: 19858-19862 (1997)]. The most potent endogenous estrogen is 17β-estradiol. A large number of compounds have been described that either mimic or block the activity of 17β-estradiol. Compounds that have approximately the same biological effects as 17β-estradiol are referred to as "estrogen receptor agonists". Those which block the effects of 17β-estradiol, when given in combination with it, are called "estrogen receptor antagonists". Actually there is a continuum between the activity of the estrogen receptor agonist and the estrogen receptor antagonist and indeed some compounds behave as estrogen receptor agonists in some tissues but estrogen receptor antagonists in others. These compounds with mixed activity are called selective estrogen receptor modulators (SERMS) and are therapeutically useful agents (eg EVISTA) [McDonnell, Journal of the Society for cologic Investigation 7: S10-S15 (2000), Goldstein, et al., Human Reproduction Update 6: 212-224. (2000)]. The precise reason why the same compound may have the specific effects on cells has not been elucidated, but differences in conformation of the receptor and / or coregulatory protein environment have been suggested. It has been known for some time that estrogen receptors adopt different conformations when they bind ligands. However, the consequence and delicacy of these changes has only recently been revealed. The three-dimensional structures of ERa and ERβ have been solved by co-crystallization with several ligands and clearly show the repositioning of helix 12 in the presence of an estrogen receptor antagonist, which sterically hinders the protein sequences required for coregulatory protein interaction of the receptor [Pike, et al., E bo 18: 4608-4618 (1999), Shiau et al., Cell 95: 927-937 (1998)]. In addition, the phage display technique has been used to identify peptides that interact with estrogen receptors in the presence of different ligands [Paige, et al., Proceedings of the National Academy of Sciences of the United States of America 96: 3999- 4004 (1999)]. For example, a peptide distinguishing between ERa linked to the total estrogen receptor agonists 17β-estradiol and diethylstilbesterol is identified. A different peptide is shown to distinguish between clomiphene linked to ERa and ERβ. These data indicate that each ligand potentially places the receptor in a unique and non-predictable conformation that has a probability to have two distinct biological activities. As mentioned above, estrogens affect a collection of biological processes. In addition, where gender differences have been described (eg frequencies of the disease, responses to the challenge, etc.), the explanation may imply the difference in estrogen levels between males and females. Summary of the Invention The present invention relates to compounds of the formula: R1, R2, R3, R5, R6, R7 and R8 are each, independently, selected from hydrogen, hydroxyl, C? -C6 alkyl, C? -C6 alkoxy, or halogen; R 4 is hydrogen, Ci-Cß alkyl, halogen, Ci-Ce alkoxy, -CN, C2-C8 ienyl, -CHO, aryl, furyl, thienyl, pyrimidinyl or pyridinyl; With the proviso that at least one of R1-R8 is different from H; Or a pharmaceutically acceptable salt thereof. In another aspect, the invention is directed to a pharmaceutical composition which comprises at least one of the above compounds. In still other aspects, the invention is directed to the use of the above compounds in the treatment or prevention of diseases. DETAILED DESCRIPTION OF THE INVENTION This invention provides compounds of the formula I R1, R2, R3, R5, R6, R7 and R8 are each, independently, selected from hydrogen, hydroxyl, C? -C6 alkyl, C? -C6 alkoxy, or halogen; R4 is hydrogen, Ci-Cg alkyl, halogen, C1-C6 alkoxy, -CN, C2-C8 alkenyl, -CHO, aryl, furyl, thienyl, pyrimidinyl or pyridinyl; With the proviso that at least one of R1-R8 is different from H; In some embodiments, the aryl group is an optionally substituted phenyl or naphthyl. In other embodiments, it is preferred that R5, R7 and R8 are "each, independently, hydrogen or halogen, and R4 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, alkenyl of 2-8 carbon atoms, -CN, furyl, thienyl or pyridinyl In still other preferred embodiments, R5, R7 and R8 are each, independently, hydrogen or halogen, R4 is a hydrogen, alkyl of 1-6 carbon atoms , alkoxy of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, -CN, furyl, thienyl and pyridinyl, and R1, R2, R3 and R6 are each, independently, hydrogen, halogen, or hydroxyl It is more preferred, in still other embodiments, that R5, R7 and R8 are each, independently, hydrogen or halogen: R4 is hydrogen, alkoyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, -CN, furyl, thienyl and pyridinyl; R1, R2, R3 and R6 are each, independently, hydrogen, halogen, or hydroxyl; and at least one of R1, R2, R3 and R6 is hydroxyl. Pharmaceutically acceptable salts can be formed from organic or inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and acceptable auxiliaries similarly known when a compound of this invention contains a basic portion. The salts can also be formed from organic and inorganic bases, such as alkali metal salts (eg, sodium, lithium or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms. carbon or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when a compound of this invention contains an acid portion. The term "alkyl", as used herein, whether used alone or as part of another group, for example, alkoxy, arylalkyl, alkoxycarbonyl, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, is limited to linear and branched chains containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, unless explicitly specified otherwise. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl, and t-butyl are understood by the term "alkyl". Specifically included within the definition of "alkyl" are those aliphatic hydrocarbon chains that are optionally substituted. The carbon number as used in the definitions herein refers to the main structure of carbon and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. The term "alkenyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight or branched chains that they have 2 to 8 carbon atoms and contain at least one double bond. Preferably, the alkenyl portion has 1 or 2 double bonds. Such alkenyl portions may exist in the E or Z conformations and the compounds of this invention include both conformations. Specifically included within the definition of "alkenyl" are those aliphatic hydrocarbon chains that are optionally substituted. The heteroatoms, such as O, S or N-Ri, attached to an alkenyl should not be attached to a carbon atom that is linked to a double bond. "Aryl" as used herein as a group or part of a group, refers to an optionally substituted 5 to 13 membered mono or bicarbomethyl ring such as phenyl or naphthyl. Preferably, the groups containing the aryl portions are monocyclic having 5 to 7 carbon atoms in the ring. Phenyl is a preferred aryl. In some embodiments, the phenyl portions are optionally substituted with C? -C6 alkenyl, C2-C7 alkenyl, halogen, hydroxyl, Ci-Ce alkoxy, -CN, -N02, amino, C? -C6 alkylamino, dialkylamino from 1-6 carbon atoms per alkyl, thio, Cilt-C6 alkylthio group, Ci-Cß alkylsulfunyl, C 1 -C 6 alkylsulfonyl, C 2 -C 7 alkoxycarbonyl, 2-7 carbon atoms, 2- alkylcarbonyl 7 carbon atoms, trifluoroalkoxy, benzylnitrile or benzoyl. Heteroaryl as a group or part of a group means a mono- or bicyclic ring containing 5-13 members of an aromatic atom having one to five heteroatoms which independently may be nitrogen, oxygen or sulfur. Preferably, the groups containing the heteroaryl moieties are monocyclic having 5 to 7 members in the ring where one to two of the ring members are independently selected from nitrogen, oxygen or sulfur. Groups containing portions of aryl or heteroaryl may optionally be substituted as subsequently defined or unsubstituted. Examples of heteroaryls include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl. , quinoxalinyl or quinazolinyl. The term halogen includes bromine, chlorine, fluorine and iodine. An optionally substituted substituent described herein, such as alkyl, alkenyl, aryl, or heteroaryl, may be substituted with one or more substituents, for example 1-5 or 1-3. The substituents Optionally suitable may be independently selected from nitro, cyano, -N (RU) (R 2), halo, hydroxy, carboxy, alkyl, alkenyl, alkynyl, (for example from 2-7 carbon atoms), cycloalkyl (from example of 5-8 carbon atoms), aryl, heteroaryl, alkoxy, aryloxy, Heteroaryloxy, alkylalkoxy, alkoxycarbonyl, alkoxyalkoxy, perfluoroalkyl, perfluoroalkoxy, arylalkyl, alkylaryl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, -S (0) 2 -N (Ru) (Ru), -C (= 0) -N (Ru) (Ri2), (Rn) (R12) N-alkyl, (R11) (Ri2) N-alkyl, (R11) (R? 2) N- 25. alkoxyalkyl, (Rn) (R? 2) N-alkylaryloxyalkyl, -S (0 ) s-aryl (where s = 0-2), or -S (0) s-heteroaryl (where s = 0-2); wherein Ru and Ri2 are each, independently, hydrogen, unsubstituted alkenyl groups (Ci-Cß), unsubstituted (C3-C7) cycloalkyl, aryl, aryl (C1-C3) alkyl, aryloxy-alkyl (Ci- C3) ), arylthio-alkyl (C? _C3), heteroaryl, heteroaryl (C1-C3) alkyl, heteroaryloxy-(C? -C3) alkyl, or heteroarylthio- (C? -C3) alkyl; or if they are optionally taken together they can be linked as an alkylene group to form a ring, for example, of 3-8 ring members. In certain embodiments of the invention, preferred substituents for alkyl, alkenyl, alkynyl, and cycloalkyl include nitro, cyano-N (Rn) (R12), halo, hydroxyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl. In certain embodiments of the invention, preferred substituents for aryl and heteroaryl include -N (Rn) (R 2), alkyl, halo, perfluoroalkyl, perfluoroalkoxy, arylalkyl and alkylaryl. Examples of substituted alkyl and alkenyl portions include 1-bromovinyl, 1-fluorovinyl, 1,2-difluoro-2,2-difluorovinyl, 1,2,2-trifluorovinyl, 1,2-dibromoethane, 1,2-difluoroethane, 1-fluorocarbon, 2-bromoethane, CF2CF3, CF2CF2CF3, and the like. The term "lower alkyl" refers to an alkyl group which has 1 to 6 carbon atoms, in some embodiments 1 to 3 carbon atoms are preferred. "Alkoxy", as used herein, refers to the group R-O- where R is an alkyl group as defined above. The term "lower alkoxy" as used herein, refers to the group R-0 where R is an alkyl group of 1 to 6 carbon atoms. In some embodiments, an R having 1 to 3 carbon atoms is preferred. As used in accordance with this invention, the term "provide" with respect to providing a compound or substance covered by this invention, means either directly administering such a compound or substance, or administering a prodrug, derivative, or analogue which will form the effective amount of the compound or substance within the body. The compounds of this invention can be used as estrogen receptor modulators useful in the treatment or inhibition of conditions, disorders, or disease states that are at least partially mediated by a deficiency or excess of estrogen, or which can be treated or inhibited through the use of an estrogenic agent. The compounds of this invention are particularly useful for treating a perimenopausal, menopausal or postmenopausal patient in which the levels of endogenous estrogens produced are greatly reduced. Menopause is generally defined as the natural menstrual period and is characterized by the cessation of ovarian function, leading to the substantial decrease of circulating estrogen in the bloodstream. As used herein, menopause also includes conditions of decreased estrogen production that can be surgically, chemically, or caused by a disease state which leads to a premature decline or cessation of ovarian function. Therefore, the compounds of this invention can be used to treat or inhibit osteoporosis and in the inhibition of bone demineralization, which can result from an imbalance in the formation of new bone tissues and the reabsorption of older tissues of the individual, leading to a net loss of bone. Such bone depletion results in a range of individuals, particularly in postmenopausal women who have undergone bilateral oophorectomy, those who receive or who have received extended corticosteroid therapies, those who experience gonadal dysgenesis, and those who suffer from Cushing's syndrome. The special needs for bone, including teeth and oral bone, replacement can also be managed using these compounds in individuals with bone fractures, defective bone structures, and those receiving bone-related surgeries and / or prosthetic implantation. In addition to those problems described above, these compounds can be used in treatment or inhibition for osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalistresis, multiple myeloma and other forms of cancer that have harmful effects on bone tissues. The compounds of this invention are also useful for treating or inhibiting the growth of abnormal benign or malignant tissue, including prostatic hypertrophy, uterine leiomyomas, breast cancer, endometriosis, endometrial cancer, polycystic ovary syndrome, endometrial polyps, benign breast disease, Ovarian cancer, melanoma, prostate cancer, colon cancers, CNS cancers, such as glioma or astioblastomy. The compounds of this invention are cardioprotective and are useful for lowering cholesterol, triglycerides, Lp (a), and LDL levels; inhibit or treat hypercholesterolemia; hyperlipidemia; cardiovascular disease, atherosclerosis, peripheral vascular disease; restenosis and vasospasm and inhibit vascular wall damage from cellular events that lead to vascular damage mediated by immunity. These protective cardiovascular properties are of great importance when treating postmenopausal patients with estrogen to inhibit osteoporosis and in the male when estrogen therapy is indicated. The compounds of this invention are also antioxidants, and are therefore useful for treating or inhibiting disease states induced by free radicals. The specific situations in which the antioxidant therapy is indicated to be guaranteed are with cancers, disorders of the central nervous system, Alzheimer's disease, bone disease, aging, inflammatory disorders, peripheral vascular disease, rheumatoid arthritis, autoimmune diseases, respiratory dysfunction, emphysema, prevention of reperfusion damage, viral hepatitis, chronic active hepatitis, tuberculosis, psoriasis, systemic lupus erythematosus, adult respiratory dysfunction syndrome, central nervous system trauma and infarction. The compounds of this invention are also useful for providing increased cognition, and for treating or inhibiting senile dementias, Alzheimer's disease, cognitive decline, neurodegenerative disorders, providing neuroprotection or increased cognition. The compounds of this invention are also useful for treating or inhibiting inflammatory bowel disease, ulcerative proctitis, Crohn's disease, and colitis; menopausal related conditions, such as vasomotor symptoms including hot flashes, vaginal or vulvar atrophy, atrophic vaginitis, vaginal dryness, prutitus, dyspareunia, dysuria, frequent urination, urinary incontinence, urinary tract infections, vasomotor symptoms, including hot flashes, myalgia, arthralgia, insomnia , irritability and the like; male pattern baldness; skin atrophy; acne; type II diabetes; dysfunctional uterine bleeding and infertility. The compounds of this invention are useful in disease states where amenorrhea is advantageous, such as leukemia, endometrial ablations, chronic kidney or liver disease or diseases or coagulation disorders. The compounds of this invention can be used as a contraceptive agent, particularly when combined with progestin. When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that the effective dose may vary depending on the particular compound used, the mode of administration, the condition, and severity thereof, of the condition that is treated, as well as the various physical factors related to the individual being treated. The effective administration of the compounds of this invention can be given in an oral dose of about 0.1 mg / day to about 1,000 mg / day. Preferably, the administration will be from about 10 mg / day to about 600 mg / day, more preferably from about 50 mg / day to about 600 mg / day, in a single dose or in two or more divided doses. The projected daily doses are exposed to vary the route of administration.

Such doses may be administered in some useful way to direct the active compounds of the present to the bloodstream of the recipient, including orally, by means of implants, parentally (including intravenous, intraperitoneal and subcutaneous injections), rectally, intranasally, vaginally and transdermally . Oral formulations containing the active compounds of this invention may comprise any oral forms conventionally used, including tablets, capsules, buccal forms, troches, lozenges, and liquids, suspensions or oral solutions. The capsules may contain mixtures of the active compounds with inert fillers and / or diluents such as pharmaceutically acceptable starches (for example corn starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses, such as celluloses. crystalline and microcrystalline, flours, jellies, gums, etc. Useful tablet formulations can be made by conventional compression methods, wet granulation or dry granulation and use pharmaceutically acceptable diluents, bonding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talcum, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate , glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, ketostearyl alcohol, cetomacrogol emulsification wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate. , magnesium aluminum silicate, and triethanolamine. Oral formulations herein may utilize time-release formulations or standard delay to alter the absorption of the active compound. The oral formulation may also consist of administering the active ingredient in water or a fruit juice, which contains the appropriate solubilizers or emulsifiers as necessary. In some cases it may be desirable to administer the compounds directly to the respiratory tract in the form of an aerosol. The compounds of this invention may also be administered parentally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, this preparation contains a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must flow to the extent that syringe handling capacity exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures and vegetable oils. For the purposes of this disclosure, transdermal administrations are understood to include all administrations throughout the body surface and the internal linings of body passages including epithelial and mucosal tissues. Such administrations can be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). Transdermal administration can be accomplished through the use of a transdermal path containing the active compound and a carrier that is inert to the active compound, is not toxic to the skin, and allows the delivery of the agent for systemic absorption into the bloodstream. by means of the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels and occlusive devices. The creams and ointments can be liquid or semi-solid viscous emulsions of either the oil in water or water in oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices can be used to release the active ingredient into the bloodstream such as a semipermeable membrane that covers a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient.

Other occlusive devices are known in the literature. Suppository formulations can be made from traditional materials, including coca butter, with or without the addition of waxes to alter the suppository melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used. The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. The preparation of several representative examples of this invention are described in the following reaction schemes 1-6. Reaction scheme 1 Reaction Scheme 2 Reaction Scheme 3 Reaction Scheme 4 Reaction scheme 5 Reaction Scheme 6 Example 13 X = phenyl Example 23 X = 2-methylphenyl Example 24 X = 3-methylphenyl Example 25 X = 4-methylphenyl Example 26 X = 4-methoxyphenyl Example 27 X = 4-chlorophenyl Example 28 X = 4- fluorophenyl Example 29 X = 2-thiophene Example 30 X = 3-thiophene Example 31 X = 3-fluorophenyl Example 32 X = 3-chlorophenyl Example 33 X = 3-methoxyphenyl Example 34 X = 2-chlorophenyl Example 35 X = 3, -difluorophenyl Example 36 X = 4-pyridyl Example 37 X = 2-fluorophenyl Example 38 X = 3,4-dimethoxyphenyl Example 39 X = 4-cyanophenyl Example 40 X = 3-fluoro-4-methylphenyl Example 41 X = 3,4-dimethoxyphenyl Example 42 X = 3-trifluoromethylphenyl Example 43 X = 3,5-difluorophenyl Example 44 X = 3,5-dichlorophenyl Example 45 X = 3-methyl-4-fluorophenyl Example 46 X = -3-furanyl Example 47 Reaction Scheme 7 The present invention will now be illustrated by reference to the following non-limiting examples: EXAMPLE 1 3-Bromo-5-methoxybenzyl alcohol The title compound is prepared by reacting 3-methoxybenzyl alcohol (13.82 g, 0.1 mole) and NBS (19.58 g. 0.11 mole) of acetonitrile (250 ml) at room temperature for 3 hours The solvent is removed and the resulting mass is suspended in dichloromethane (250 ml) and filtered to remove the insoluble succinimide side product. Unpurified material by chromatography (20% EtOAC-hexanes) to give a white solid (17.69 g, 81%), melting point 57-58 [deg.] C. Example 2 2 - [(2-bromo-5-methoxybenzyl) oxy] ] -7-methoxynaphthalene It is added to a solution of 7-methoxy-2-naphthol (26.92 g, 0.15 mole), 2-bromo-5-methoxybenzyl alcohol (33.58 g, 0.15 mole), and triphenylphosphine (39.3 g, 0.15 mole) ) in anhydrous THF (500 ml) a solution of DEAD (26.10 g, 0.15 mol) in THF (100 ml) in drops of 0.5 The solution is stirred at room temperature overnight and, upon evaporation of half the volume, the product precipitated in good purity. The solid is filtered and rinsed with THF, then dried to yield 32.96 g (59%) of a white solid: melting point 156-157 ° C; X H-NMR (DMSO-d 6): d 3.77 (3 H, s), 3.86 (3 H, s), 5.18 (2 H, s); 6.92 (HH, dd, J = 3.2 Hz, J- 8.7 Hz), 7.00 (1H, dd, Hz, J = 8.9 Hz), 7.22 (1H, d, J = 3.2 Hz), 7.25 (HH, d, J = 2.4 Hz), 7.35 (1H, -d, J = 2.4 Hz), 7.59 (1H, d, J = 8.7 Hz), 7.74 (IH, d, J = 8.7 Hz), 7.76 (IH, d, J = 8.7 Hz); MS m / z 373/375 ([M + H] +). Analysis for C? 9H? 7Br03: Calculated: C: 61.14; H: 4.59. Found: C: 61.29; H: 4.21 Example 3 3, 9-dimethoxy-5H-dibenzo [c, g] chromene A mixture of 2 - [(2-bromo-5-methoxybenzyl) oxy] -7-methoxynaphthalene (9.35 g, 25 mmol) is stirred , dichlorobis (triphenylphosphine) palladium (1.75 g, 2.5 mmol), and sodium acetate (6.15 g, 75 mmol) in anhydrous dimethylacetamide (500 ml) at 130 ° C under nitrogen for two days. After cooling, the catalyst is filtered and the di-ethylacetamide is removed under vacuum. The residue is formed in suspension in methane (200 ml) and the desired product is isolated by filtration to yield 2.9 g (40%) of a dark solid: dot. fusion 190-191 ° C; ^? - NMR (DMSO-de): d 3.81 (3H, s), 3.85 (3H, s), 5.14 (2H, s); 6.92 (1H, d, J = 2.6 Hz), 7.00-7.03 (2H, m), 7.18 (1H, d, "J = 2.4 Hz), 7.29 (1H, s), 7.79 (ÍH, d, J = 9 Hz), 7.92 (1H, d, J = 8.7 Hz), 8.26 (1H, s), MS, m / z 293 ([M + H] +), Analysis for C? 9H? 603: Calculated C: 78.06; H: 5.52 Found: C: 77.95; H: 5.34 The above cyclization also supplies the unwanted regioisomer, which is obtained from the methanol filtrate.The unwanted regioisomer is not obtained pure and is demethylated as explained below for the Example 4 Example 4 5 H -dibenzo [c, g] chromene-3,9-diol Add to pyridinium hydrochloride (30 g, 0.26 mole) at 190 ° C 3, 9-dimethoxy-H-dibenzo [c, g ] chromene (7.0 g, 23.9 mmol). The solution is stirred at 190 ° C for 3.5 hours and the mixture is cooled to almost room temperature. The mixture is poured into water (300 ml) and stirred as a precipitated solid. This solid is filtered, washed well with water and dried. Purification by chromatography (50% ethyl acetate-hexanes) yields 5.0 g (79%) of a white solid: melting point of 231-233 ° C; XH-NMR (DMSO-de): d 5.05 (2H, s), 6.68 (1H, d, J = 2.3 Hz), 6.83 (HH, dd, J = 2.4 Hz, J = 8 Hz), 6.90 (HH, dd, J = 2.3 Hz, J = 8.7 Hz), 6.93 (1H, d, J = 2.3 Hz), 6.96 (lH, d, J = 2.1 Hz), - 7.13 (HH, s), 7.7.1 (HH, d, J = 8.8 Hz), 7.78 (1H, d, J = 8.5 Hz), 9.70 (2H, s); MS m / z 265 ([M + HJ +). Analysis for C? 7H? 203: Calculated: C: 77.26, H: 4.58 Found: C: 77.00; H: 4.32 EXAMPLE 5 5H-dibenzole [c, f] chromene-3, 11-diol 4 The mixture of the other regioisomer and the de-bromine coupled product is subjected to the same demethylation conditions according to Example 2. The product is purified by chromatography (50% ethyl acetate-hexanes) to give a dark solid 0.45 g (1%): mp 199-201 ° C; XH-NMR (DMSO-de): d 4.93 (2H, s), 6.83 (ΔI, d, J = 2.5 Hz), 6.89 (ΔI, dd, J = 2.5 Hz, J = 8.4 Hz), 6.95-6.99 ( 2H,), 7.63 (ÍH, d, J = 8.7 Hz), 7.73-7.81 (3H, m), 9.75 (2H, s); MS m / z 265 ([M + H] +).

HPLC shows 98.9% purity @ 254 nm. Analysis for C? H? 20 0.2H2O: Calculated for C: 76.22, H: 4.67 Found: C: 76.43; H: 4.49 Example 6 S-chloro-SH-dibenzocglcrome oS / g-aiol A solution of H-dibenzo [c, g] chromene-3,9-diol (0.20 g, "0.76 moles) and N-chlorosuccinimide ( 0.12 g, 0.91 mmol) in THF (20 ml) at room temperature for 48 hours The reaction solution is concentrated on Florosil and purified by silica chromatography (30% ethyl acetate-hexanes) to yield 0.14 g (62%). %) of a dark solid This material is further purified by preparative reverse phase HPLC to yield the title compound as a cream solid: melting point 212-214 ° C; ^? - NMR (DMSO-de): d 5.12 (2H, s), 6.70 (HH, d, J = 2.37 Hz), 6.85 (HH, dd, J = 2.4 Hz, J = 8.46 Hz), 7.13. (HH, d, J = 9.06 Hz), 7.30 (HH, s), 7.73 (HH, d, J = 8.91 Hz), 7.82 (HH, d, J = 8.53 Hz), 8.24 (lH, s), 9.81 (lH, s), 10.39 (1H, s); MS m / z 297/299 ([MH] -) Analysis for C? 7HnCl03: Calculated for C: 68.35; H: 3.71 Found: C: 68.17; H: 3.65 Example 7 Acetate of 3- (acetyloxy) -5H -dibenzo [c / g] cromen-9-i It is added to a mixture of pyridine (35 ml) and acetic anhydride (35 ml) (H-dibenzo [c, g] chromene-3, 9-diol (.50 g, 18.9 mmol) and the mixture is stirred at room temperature. ambient. After approximately one hour a precipitate forms and stirring is continued for another 5 hours. The mixture is filtered and the product is washed with ethyl acetate. Purify the crude product by chromatography (25% ethyl acetate-hexanes) to give a white solid (5.0 g, 76%): mp 194-195 ° C; XH-NMR (DMSO-d5): d 2.31 (3H, s), 2.33 (3H, s), 5.20 (2H, s); 7.16 (ÍH, d, J = l.9 Hz), 7.19 (lH, dd, J = 2.4 Hz, J = 8.8 Hz), 7.25 (ÍH, dd, J = 2.5 Hz, J = 8.3 Hz), 7.44 (1H, s), 7.54 (1H, d, J = 2.4 Hz), 7.95 (lH, d, J = 9.3 Hz) , 8.09 (ÍH, d, J = 8.3 Hz), 8.50 (ÍH, s); MS m / z 349 ([M + H] +). Analysis for C2? H? 605: Calculated: C: 72.41; H: 4.63 Found: C: 72.06; H-.4.48 Example 8 Acetate of 3- (acetyloxy) -7-bromo-5H-dibenzo [c, g] chromen-9-yl It is added to a mixture of N-bromosuccinimide (3.1 g, 17. 2 mmole) in anhydrous acetonitrile (400 ml) 3- (acetyloxy) -H-dibenzo [c, g] chromen-9-yl acetate (5.0 g, 14.4 mmol). The reaction mixture is stirred at room temperature overnight. The solid is filtered, washed with acetonitrile and dried to give 5.9 g (96%) of light dark solid. A sample of this solid is purified by chromatography (methylene chloride) to give a white solid: mp 224-226 ° C; ^ -NMR (DMSO-de): d 2.32 (3H, s), 2.35 (3H, s), 5.35 (2H, s); 7.92 (HH, d, J = 2.4 Hz), 7.28 (HH, dd, J = 2.4 Hz, .J = 8.3 Hz), 7.31 (HH, dd, J = 2.0 Hz, J = 8.8 Hz), 7.75 (HH) , d, J = 2.4 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.12 (H, d, J = 8.8 Hz), 8.59 (H, s); MS m / z 427/429 ([M + H] +). Analysis for C2? H? 5Br? 5: Calculated for C: 59.04: H: 3.54 Found: C: 58.87; H: 3.34 'EXAMPLE 9 l-Chloro-7-methoxy-2-naphthol It is added to a solution of 7-methoxy-2-naphthol in acetonitrile (100 ml) at ice-bath temperature N-chlorosuccimide (1.61 g, 12.07 mmoles). The reaction mixture is allowed to stir for 2 hours at ice bath temperature and another 0.1 equivalents of N-chlorosuccinimide are added. The reaction is allowed to warm to room temperature in 1 hour and is poured into water (180 ml) and extracted with ethyl acetate (2 x 300 ml). It washes l. organic layer with brine and dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. Ether is added and insoluble impurities are filtered. The mother liquor is concentrated and taken to chromatography (1: 4, ethyl acetate. Hexanes) to yield a light yellow solid: melting point 76-78 ° C. HPLC reveals a product with 98.0% purity (230 nm). Analysis for CnH9Cl02: Calculated: C, 63.32 H, 4.35 Found: C, 63.12 H, 4.25 Example 10 2 - [(2-Bromo-5-methoxy-benzyl) oxy] -l-chloro-7-methoxynaphthalene is added slowly to a solution of Example 7 (3.05 g, 14.6 mmol), 2-bromo-5-methoxybenzyl alcohol (3.49 g, 16.08 mmol) and triphenylphosphine (4.22 g, 16.08 mmol) in dry THF (50 mL) at room temperature DEAD (2.8 g, 16.08 mmol) in 15 minutes. After stirring 40 minutes, the .THF is evaporated and the product is triturated without purification with methanol to yield 5.31 g of white solid product (89%): melting point 126-127 ° C. Analysis for Ci9H? EBrC103: Calculated: C, 55.98 H, 3.96 Found: C, 55.86 H, 4.01 Example 11 7-Chloro-3,9-dimethoxy-5H-dibenzo [c, g] chromene A mixture of Example 8 is heated (3.12 g, 7.66 mmol), sodium acetate (1.88 g, 23.0 mmol) and dichlorobis (triphenylphosphine) palladium (1.61 g, 2.3 mmol) in dimethyacetamide (220 ml) at 130 ° C for 3 hours. The solvent is removed under high vacuum and the catalyst is filtered through florisil using methylene dichloride. The solid is washed with methylene dichloride-methanol (1: 2) to yield 2.59 g of the product. The mother liquor is concentrated and chromatographed (10% ethyl acetate-hexane) and washed with methanol to give another 160 mg of the product as a white solid. Total yield 2.75 g (74.5%): melting point 166-168 ° C. Analysis for C19H15CIO3: Calculated: C, 69.84 H, 4.63 Found: C, 69.59 H, 4.32 Example 12 7-Chloro-5H-dibenzo [c, g] chromene-3,9-diol A mixture of Example 9 is heated (2.25 g, 6.92 mmole), and pyridimium hydrochloride (21.9 g, 162 mmol) at 184 ° C for 2 hours. The reaction mixture is allowed to cool and is poured into water (300 ml) and extracted with ethyl acetate (2 x 200 ml), washed with brine and dried over anhydrous magnesium sulfate. The solvent is removed and the product is chromatographed (40% ethyl acetate-hexane) to yield a white solid which is triturated with methylene chloride (25 ml) to yield 1.2 g (58%); melting point 230-231 ° C. Analysis for Ci6HnCl03: Calculated: C, 68.35 H, 3.71 Found: C, 68.02 H, 3.57 Example 13 7-bromo-5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of sodium acetate and sodium acetate. -bromo-3- (acetyloxy) -H-dibenzo [c, g] chromen-9-yl (427 mg, 1 mmol) in methanol (25 ml) 25% sodium methoxide in methanol (6 ml). The reaction is stirred at room temperature for 0.5 hours, then diluted with ethyl acetate (300 ml) and IN HCl (150 ml). The ethyl acetate portion is washed with water (2 x 100 ml) and brine (150 ml), then dried over anhydrous magnesium sulfate and filtered. The solvent is removed under vacuum and the solid obtained is purified by chromatography (25% ethyl acetate-hexanes) to give a yellow solid (286 mg, 83%); melting point above 260 ° C; ^ - MR (DMSO-de): d 5.19 (2H, s), 6.70 (ÍH, d, J = 2.4 Hz), 6.86 (HH, dd, J = 2.4 Hz, J = 8.5 Hz), 6.99 (HH, dd, J = 2.3 Hz, J = 8.8 Hz), 7.31 (HH, d, J = 2.3 Hz), 7.79 (ÍH, d, J = 6.3 Hz), 7.81 (1H, d, J = 6.0 Hz), 8.22 (1H, s), 9.97 (2H, br s); MS m / z 343/345 ([M + H] +). Analysis for C? 7HnBr03: Calculated for C: 59.50; H: 3.23 Found: C: 59.22; H: 3.29 EXAMPLE 14 3, 9-dihydroxy-SH-dibenzofc, g] chromene-7-carbonitrile It is added to a mixture of 3- (acetyloxy) -7-bromo-H-dibenzo [c, g] chromium acetate. 9-yl (855 mg, 2 mmol) and anhydrous dimethylformamide (20 ml) copper cyanide (1.0 g, 10 mmol). The mixture is heated to 150 ° C and maintained overnight. The mixture is cooled and suspended between ethyl acetate and water. Separate the layers, wash the ethyl acetate portion with water (3 x 50 ml) and brine (50 ml). The ethyl acetate is dried over anhydrous magnesium sulfate, the solvent is removed and the resulting solid is dissolved in methanol (10 ml) and 25% sodium methoxide (3 ml) is added. After stirring for 0.5 hours, ethyl acetate is added (50 ml) and 1N HCl (20 ml), separate the layers and wash the organic portion with water (3 x 30 ml) and brine (30 ml).

After drying in anhydrous magnesium sulfate, the solvent is removed to give a dark yellow solid, which is purified by chromatography (25% ethyl acetate-hexanes) to yield a pale yellow solid (208 mg, 36%). : melting point > 280 ° C; ^? - NMR (DMSO-d6): d 5.32 (2H, s), 6.71 (1H, d, J = 2.4 Hz), 6.87 (lH, dd, J = 2.4 Hz, J = 8.3 Hz), 7.06 (lH , dd, J = 2.4 Hz, J = 8.9 Hz), 7.18 (1H, d, J = 2.4 Hz), 7.84 (1H, d, J = 8.8 Hz), 7.87 (1H, d, J = 8.8 Hz), 8.50 (ÍH, s), 9.90 (1H, br s) 10.32 (ÍH, br s); MS m / z 288 ([M-H] -). HPLC 98.5% @ 254 nm. Analysis for C? 8HnNO3 »0. 5H20: Calculated for C: 72.48; H: 4.05; N: 4.70 Found: C: 72.31; H: 3.96; N: 4.55 Example 15 7-methoxy-5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 3- (acetyloxy) -7-bromo-H-dibenzo acetate [c, g] Chromen-9-yl (427 mg, 1 mmol), CuBr (143 mg, 1 mmol) and anhydrous DMF (6 mL) 25% NaOMe / methanol (3 ml). The mixture is heated at 120 ° C for 1 hour. The reaction mixture is cooled and ethyl acetate (100 ml) and 1 N HCl (50 ml) are added. Separate the layers and wash the organic portion with water (3 x 50 ml) and brine (50 ml) then dry over anhydrous magnesium sulfate. The solvent is evaporated and the product is purified without purification by chromatography (25% ethyl acetate-hexanes) to yield a yellow solid (260 mg, 88%): dec. 240 ° C; aH-NMR (DMSO-de): d 3.88 (3H, s), 5.09 (2H, s) 6.70 (1H, d, J = 2.4 Hz), 6.83 (ÍH, dd, J = 2.4 Hz, J = 8.3 Hz), 6.93 (1H, dd, J = 2.4 Hz, J = 8.8 Hz), 7.19 (1H, d, J = 2.4 Hz), 7.72 (HH, d, J = 8.5 Hz), 7.77 (HH, d, J = 8.8 Hz), 7.92 (HH, s), 9.75 (2H, s); MS m / z 295 ([M + H] +). Analysis for C? SH 404: Calculated for C: 73. 46; H: 4 .79 Found: C: 73. 19; H: 4 Example 16 7-vinyl-5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 3- (acetyloxy) -7-bromo-H-dibenzo [c, g] chromium acetate. 9-yl (300 mg, 0.7 mmol), anhydrous toluene (2 ml) and tributylvinyltin (254 mg, 0.8 mmol) tetrakis (triphenylphosphine) palladium (160 mg, 0.14 mmol). The mixture is heated under reflux and maintained for 4.5 hours. The reaction mixture is cooled and diluted with water and ethyl acetate and the organic portion is washed with water and brine. After drying in anhydrous magnesium sulfate and removing the solvent, the crude material is treated with methanol (10 ml) and 25% sodium methoxide (2 ml). The mixture is stirred for 0.5 hours, then ethyl acetate (50 ml) and IN HCl (20 ml) are added. The organic portion is separated and washed with water (2 x 20 ml) and brine (25 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent gives a solid which is purified by chromatography (25% ethyl acetate-hexanes) to yield a dark solid (45 mg, 15%): melting point dec 195-197 ° C; XH-NMR (DMSO-d6): d 5.07 (2H, s), 5.66-5.76 (2H,) 6. 69 (1H, d, J = 2.4 Hz), 6.84 (1H, dd, J = 2.5 Hz, J = 845 Hz), 6.91-7.04 (2H, m) 7.34 (lH, d, J = 2.4 Hz), 7.74 (1H, d, J = 8.9 Hz), 7.78 (1H, d, J = 8.6 Hz), 8.10 (1H, s), 9.72 (2H, s); MS m / z 291 ([M + H] +). Analysis for C? 9H14O3 »0.2 H20: Calculated for C: 77.64; H: 4.94 Found: C: 77.63; H: 4.81 Example 17: Acetate of 3- (acetyloxy) -7-methoxy-5H-dibenzo [c, g] chromene-9-yl It is added to a mixture of pyridine (8 ml) and acetic anhydride (8 ml) 7- methoxy-H-dibenzo [c, g] chromen-3,9-diol (1.37 g, 4.7 mmol) and the mixture stirred at room temperature for 2 hours. The insoluble solid is filtered and rinsed with 10% ethyl acetate-hexanes to give a dark solid (1.6 g, 90%). A portion of this solid is purified by chromatography (25% acetonitrile-methylene chloride) to obtain a white solid: melting point: 165-167 ° C; ^ - MR (DMS0-d6): d 2.31 (3H, s), 2.33 (3H, s), 3.95 (3H, s) 5.24 (2H, s), 7.18 (1H, d, J = 2.4 Hz), 7.22 (IH, dd, J = 2.4 Hz, J = 8.8 Hz), 7.25 (1H, dd, J = 2.4 Hz, J = 8.8 Hz), 7.67 (HH, d, J = 2.4 Hz), 7.96 (HH, d, J = 8.8 Hz), 8.08 (HH, d, J = 8.8 Hz), 8.28 (ÍH, s); MS m / z 379 ([M + H] +). An. HPLC of 99. 8% @ 280nm. Analysis for C22H? 806 * 0.3 H20: Calculated for C: 68.85; H: 4.88 Found: C: 68.93; H: 4.72 Example 18 Acetate of 3- (acetyloxy) -12-bromo-7-methoxy-5H-dibenzo [c, g] chromene-9-yl It is added to a mixture of 3- (acetyloxy) -12- acetate. bromo-7-methoxy-H-dibenzo [c, g] chromen-9-yl (750 mg, 1.5 mmol) in anhydrous acetonitrile (100 ml) N-bromosuccimide (350 mg, 1.95 mmol) and the reaction mixture is stirred at room temperature for 1 hour. The solvent is removed and the residue is purified without purification by chromatography (25% ethyl acetate-hexanes) to yield a pale yellow solid (500 mg, 73%): mp 176-177 ° C; XH-NMR (DMSO-de): d 2.33 (3H, s), - 2.35 (3H, s), 3.96 (3H, s), 5.12 (2H, s) 7.30 (H, d, J = 2.9 Hz), 7.31 HH, s) 7.42 (HH, dd, J = 2.4 Hz, J = 9.3 Hz), 7.80 (HH, d, J = 2.4 Hz), 8.35 (HH, d, J = 9.3 Hz), 8.54 (HH, dd, J = 2.0 Hz, J = 7.6 Hz). Analysis for C22H? 7Br? 6: Calculated for C: 57.79; H: 3.75 Found: C: 57.54; H: 3.63 Example 19 12-bromo-7-methoxy-5H-dibenzo [cfg] chromene-3,9-diol It is added to a mixture of 3- (acetyloxy) -12-bromo-7-methoxy-H- acetate dibenzo [c, g] chromen-9-yl (260 mg, 0.57 mmol) in methanol (25 ml) 25% sodium methoxide in methanol (3 ml) and the mixture is stirred for 0.5 hours. The reaction mixture is suspended between ethyl acetate (50 ml) and 1 N HCl (20 ml) and the organic portion is washed with water (3 x 50 ml) then brine (50 ml). Dry the ethyl acetate in anhydrous magnesium sulfate and remove the solvent to produce a dark solid, which is purified by silica gel chromatography (50% ethyl acetate - hexanes) to yield 95 mg (45%). of a dark solid: melting point above 250 ° C; ^ -NMR (DMSO-d6): d 3.89 (3H, s), 4.97 (2H, s), 6.82 (ÍH, d, J = 2.4 Hz), 6.88 (1H, dd, J = 2.7 Hz, J = 8.5 Hz), 7.12 (1H, dd, J = 2.4 Hz, J = 9.3 Hz), 7.29 (IH, d, J = 2.4 Hz), 8.12 (IH, d, J = 9.3 Hz), 8.29 (IH, d, J = 8.3 Hz), 9.93 (HH, s), 10.06 (HH, s); - MS m / z 373/375 ([M + H] +). Analysis for C? 8H? 3Br04: Calculated for C: 57.93; H: 3.51 Found: C: 57.64; H: 3.34 Example 20 12-chloro-7-methoxy-5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 3- (acetyloxy) -7-methoxy-H-dibenzo acetate [ c, g] chromen-9-yl (290 mg, 0.77 mmol) in anhydrous THF (10 ml) N-chlorosuccimide (133 mg, 1.0 mmol). The reaction mixture is stirred at room temperature for 3 hours. The solvent and methanol (10 ml) are removed and 25% sodium methoxide-methanol (3 ml) is added. After stirring at room temperature for 0.5 hours, ethyl acetate (25 ml) and 1 N HCl (10 ml) are added, the mixture is stirred, the layers are separated and the ethyl acetate is washed with water (3 x 10 ml) and brine (10 ml). Dry the mixture in anhydrous magnesium sulfate, remove the solvent and purify the dark solid without purification by silica gel chromatography (25% ethyl acetate-hexanes) to yield 16.6 mg (66%) of a white solid. : melting point dec 240 ° C; ^ -NMR (DMSO-de): d 3.89 (3H, s), 4.99 (2H, s), 6.82 (IH, d, J = 2.4 Hz), 6.88 (IH, dd, J = 2.4 Hz, J = 8.8 Hz), 7.12 (1H, dd, J = 2.4 Hz, J = 8.8 Hz), 7.29 (1H, d, J = 2.4 Hz), 8.11 (1H, d, J = 9.3 Hz), 8.27 (ÍH, d, J = 8.3 Hz), 10.00 (2H, br s); MS m / z 329/331 ([M + H] +), Cl. An HPLC gives a purity of 99.6% @ 280nm Analysis for C? 8H? 3CIO4 * 0.2 H20: Calculated for C: 65.05; H: 4.06 Found: C: 65.21; H: 4.12 Example 21 7-methoxy-5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromen-3, 9-diol ( 343 mg, 1 mmol), anhydrous dimethylformamide (10 ml), and dichlorobis (tri-o-tolylphosphine) palladium (79 mg, 0.1 mmol) tetramethyltin (268 mg, 1.5 mmol). The reaction mixture is heated to 80 ° C and maintained for 3 hours. The TLC and MS analysis show a 1: 1 mixture of starting material to product. The mixture is cooled to room temperature and additional tetramethyltin is added. (268 mg, 1.5 mmol) and catalyst (79 mg, 0.1 mmol). The mixture is heated overnight at 80 ° C. The reaction mixture is cooled and ethyl acetate (50 ml) and water (25 ml) are added. After separating the layers, the organic portion is washed with water (3 x 20 ml), then brine (20 ml) and dried in anhydrous magnesium sulfate. The solvent is removed and the product is purified without purification by chromatography (25% ethyl acetate-hexanes) which gives a pale yellow solid (117 mg, 42%): melting point 224-226 ° C; aH-NMR (DMSO-de): d 2.38 (3H, s), 5.06 (2H, s) 6.69 (HH, d, J = 2.4 Hz), 6.83 (HH, dd, J = 2.5 Hz, J = 8.4 Hz), 6.93 (HH, dd, J = 2.3 Hz, J = 8.7 Hz), 7.08 (HH, d , J = 2.3 Hz), 7.71 (ÍH, d, J = 8.8 Hz), 7.77 (HH, d, J = 8.6 Hz), 8.01 (HH, s), 9.67 (2H, s); MS m / z 279 ([M + H] +). An HPLC gives a purity of 99.5% @ 280 nm. Analysis for C? 8H? 403 «(0.2 H20): Calculated for C: 76.69; H: 5.15 Found: C: 76.61; H-.4.99 Example 22 7- [2- (hydroxymethyl) phenyl] -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 3- (acetyloxy) -7-bromo acetate -H-dibenzo [c, g] chromen-9-yl (2.03 g, 4.8 mmol), (2-hydroxymethylphenyl) boronic acid (1.54 g, 13.3 mmol), potassium carbonate (2.07 g, 15 mmol), dimethoxyethane ( 100 ml), and water (10 ml) tetrakis (triphenylphosphine) palladium (600 mg, 0.4 mmol). The mixture is heated to reflux for 1 hour. The reaction mixture is cooled and suspended between ethyl acetate (200 ml) and water (75 ml). Wash the ethyl acetate with water (2 x 75 ml), followed by brine (75 ml) and dry in anhydrous magnesium sulfate. The solvent is removed and the resulting yellow liquid is dissolved in methanol (100 ml) and 25% sodium methoxide (10 ml) is added.The mixture is stirred at room temperature for 0.5 hours, then diluted with ethyl acetate (200 ml) and 1 N HCl (75 ml) Wash the ethyl acetate with water (3 x 75 ml), then brine (75 ml) and dry in anhydrous magnesium sulfate. dark solid, which is purified by chromatography (35% ethyl acetate-hexanes) to yield a white solid (500 mg, 15%): melting point 171-173 ° C. ^ -NMR (DMSO-de): d 4.08 (ΔI, dd, J = 3.7 Hz, J = 14.3 Hz), 4.26 (ΔI, dd, J = 3.6 Hz, J = 14.3 Hz), 4.92 (2H, s) 4.94-4.99 (1H; s), 6.36 (1H, d, J = 2.0 Hz), 6.63- (1H, d, J = 2.1 Hz), 6.85 (IH, dd, J = 2.3 Hz, J = 8.5 Hz), 6.89 (IH, dd , J = 2.3, J = 8.7 Hz), 7.11 (HH, d, J = 7.4 Hz), 7.36-7.39 (HH, m), 7.45-7.49 (1H, m) 7.67 (HH, d, J = 7.7 Hz 7.78 (1H, d, J = 8.9 Hz), 7.83 (1H, d, J = 8.6 Hz), 8.20 (1H, s) 9.53 (1H, br s), 9.70 (1H, br s); MS m / z 369 ([M-H] -). An HPLC gives a purity of 94.9% @ 280 nm. Analysis for C2 H? 8O4 «0 .3 H20: Calculated for C: 76.71; H: 4.99 Found: C: 76.56; H: 4.95 Example 23 7-phenyl-5H-dibenzo [c, g] chromene-3,9-diol Be added to a mixture of 7-bromo-H-dibenzo [c, -g] chromen-3,9-diol (343 mg, 1 mmol), dimethylacetamide (5 ml), 2 M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) phenylboronic acid (366 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 3 hours. The reaction mixture is cooled and diluted with ethyl acetate (25 ml) and ammonium chloride %. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark liquid is purified by chromatography (5% acetonitrile-dichloromethane) to yield a dark solid (170 mg, 50%): melting point 225-227 ° C; ^ -NMR (DMSO-de): d 4.95 (2H, s), 6.63 ((2H, s) 6.85 (1H, dd, J = 2.2 Hz, J = 8.4 Hz), 6.92 (IH, dd, J = 2.2 Hz, J = 8.7 Hz), 7.33 (2H, d, J = 7.0 Hz), 7.40-7.43 (HH, m), 7.49-7.53 (2H, m) 7.77 (HH, d, J = 8.9 Hz), 7.83 (HH, d, J = 8.6 Hz), 7.19 (1H, s), 9.61 (1H, br s) 9.69 (ÍH, br s); MS m / z 341 ([M + H] +). An HPLC gives a purity of 98.2% 280 280 nm. Analysis for C23H? 5O3 »0 .5 H20: Calculated for C: 79. 07; H: 4 90 Found: C: 78.68; H: 4.64 • Example 24 7- (2-tolyl) -5H-dibenzo [c, g] chromene-3,9-diol Added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3 , 9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2 M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 2-tolylboronic acid (400 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 2.5 hours then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate, the solvent is removed and the resulting dark solid is purified by chromatography (5% acetonitrile-dichloromethane or ) to produce a yellow solid (150 mg, 42%): melting point 193-196 ° C; ^? - NMR (DMSO-de): d 1.97 (3H, s), 4.92 (2H, s), 6.36 (ÍH, d, J = 2.3 Hz), 6.62 (1H, dd, J = 2.4 Hz), 6.83-6.92 (2H,), 7. 09-7.13 (ÍH, m), 7.27-7.39 (3H, m) 7.78 (ÍH, d, J = 8.9 Hz), 7. 84 (HH, d, J = 8.6 Hz), 8.20 (HH, s), 9.52 (HH, s), 9.72 (1H, s); MS m / z 355 ([M + H] +). An HPLC. gives a purity of 99. 8% @ 280 nm. Analysis for C2 H? 8? 3 »0. 5 H20: Calculated for C: 79 .32; H: 5 27 Found: C: 79. 04; H: 5 Example 25 7- (3-tolyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-9-diol ( 343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 3-tolylboronic acid (400 mg, 3 mg). mmoles). The reaction mixture is heated at 120 ° C for 2 hours, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark oil is purified by chromatography (5% acetonitrile-dichloromethane) to yield a white solid (264 mg, 75%): mp 219-222 ° C; aH-NMR (DMSO-de): d 2.39 (3H, s), 4.94 (2H, s), 6.61-6.64 (2H, m), 6.84 (ΔH, dd, J = 2.4 Hz, J = 8.5 Hz), 6.90 (lH, dd, J = 2.3 Hz, J = 8.8 Hz), 7.09-7.12 (2H, m), 7.22 (H, d, J = 9.1 Hz), 7.39-7.43 (H, m), 7.77 (H) , d, J = 8.9 Hz), 7.82 (HH, d, J = 8.6 Hz), 8.18 (HH, s), 9.54 (HH, br s), 9.72 (1H, s); MS m / z 355 ([M + H] +). An HPLC gives a purity of 99.3% @ 254 nm. Analysis for C24H? 8O3 * 0. 1 H20: Calculated for C: 80 .93; H: 5 15 Found: C: 80. 81; H: 5 08 Example 26 7- (4-tolyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3,9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 4-tolylboronic acid (400 mg, 3 mmoles). The reaction mixture is heated at 120 ° C for 1 hour. The reaction mixture is cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark oil is purified by chromatography (5% acetonitrile-dichloromethane) to yield a white solid (265 mg, 75%): mp 238-240 ° C; ^ - MR (DMSO-de): d 2.40 (3H, s), 4.93 (2H, s), 6.64 (2H, dd, J = 2.3 Hz, J = 7.0 Hz), 6.84 (1H, dd, J = 2. Hz, J = 8.5 Hz), 6.90 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 7.20 (2H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.76 (IH, d, J = 8.9 Hz), 7.82 (IH, d, J = 8.6 Hz), 8.17 (IH, s) 9.54 (lH, br s), 9.71 (lH, br s); MS m / z 355 ([M + H] +). An HPLC gives a purity of 99.9% @ 280 nm. Analysis for C24H? 8O3 «0. 3 H20: Calculated for C: 80 .16; H: 5 21 Found: C: 79 .99; H.- 5 .12 Example 27 7- (4-methoxyphenyl) -5H-dibenzo [c # g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene -3,9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetraki's (triphenylphosphine) palladium (116 mg, 0.1 mmol) acid 4 -methoxyphenylboronic acid (500 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting brown solid is purified by chromatography (25% ethyl acetate-hexanes) to yield a white solid (215 mg, 58%): melting point 200-203 ° C; ^ - MR (DMSO-de): d 3.85 (3H, s), 4.95 (2H, s), 6.64 (1H, d, J = 2.4 Hz), 6.68 (1H, d, J = 2.4 Hz), 6.85 (1H, dd, J = 2.6 Hz, J = 8.4 Hz), 6.91 (IH, dd, J = 2.2 Hz , J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.77 (IH, d, J = 8.7 Hz), 7.82 (1H, d, J = 8.8 Hz), 8.17 (ÍH, s), 9.50 (lH, s), 9.69 (1H, s); MS m / z 371 ([M + H] +). An HPLC gives a purity of 98.3% @ 254 nm. Analysis for C24H? 8O4 «0.2 H20: Calculated for C: 77.07; H: 4.96 Found: C: 76.81; H: 5.00 Example 28 7- (-chlorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9 -diol (343 mg, 1 mmol), dimethylformamide 5 (5 mL), 2M sodium carbonate (1 mL), water (1 mL), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol), 4-chlorophenylboronic acid (468 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1.5 hours, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark oil is purified by chromatography (25% ethyl acetate-hexanes) to yield a white solid (215 mg, 58%): melting point 239-242 ° C; 5 ^ -NMR (DMS0-d6): d 4.96 (2H, s), 6.60 (ÍH, d, J = 2.3 Hz), 6.64 (ΔI, d, J = 2.4 Hz), 6.84 (ΔI, dd, J = 2.3 Hz, J = 8.8 Hz), 6.92 (1H, dd, J = 2.5 Hz, J = 8.5 Hz), 7.36 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.4 Hz), 7.78 (IH, d, J = 8.9), 7.83 (IH, d, J = 8.6 Hz), 8.21 (1H, s), 9.56 (H, s) 9.72 (1H, s); MS 0 m / z 375/377 ([M + H] +). An HPLC gives a purity of 99. 6% &280 niti. Analysis for C23H? 5CIO3 * 0.2 H20: Calculated for C: 73.00; H-.4.10 Found: C: 72.89; H: 4.01 5 EXAMPLE 29 7- (4-fluorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added "to a mixture of 7-bromo-H-dibenzo [c, g] chromene- 3,9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 4- acid fluorophenylboronic acid (420 mg, 3 mmol) The reaction mixture is heated at 120 ° C for 2 hours, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate, the solvent is removed and the resulting dark solid is purified by chromatography (25% ethyl acetate-hexanes) to give a solid. white (215 mg, 62%): mp 229-232 ° C; ^ -NMR (DMSO-de): d 4.96 (2H, s), 6.62 (2H, dd, J = 2.4 Hz, J = 9.4 Hz), 6.84 (HH, dd, J = 2.5 Hz, J = 8.5 Hz), 6.92 (HH, dd, J = 2.4 Hz, J = 8.8 Hz), 7.33-7.43 (4H, m) 7.78 (ÍH, d, J = 8.8 Hz), 7.83 (HH, d, J = 8.5 Hz), 8.20 (HH, s), 9.56 (1H, s), 9.72 (ÍH, s); MS m / z 359 ([M + H] +). An HPLC gives a purity of 98.1% © 280 nm. Analysis for C23H? 5FO3 «0 .3 H20: Calculated for C: 75.94; H: 4.32 Found: C: 76. 02; H: 4 Example 30 7-Thien-2-yl-5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9- diol (343 mg, 1 mmol), dimethylformamide (5 ml), water (1 ml), 2 N sodium carbonate (1 ml), and tetrakis (triphenylphosphine) paládium (116 mg, 0.1 mmol) 2-thiopheneboronic acid (260 mg) mg, 2 mmol). The reaction mixture is heated to 120 ° C and maintained overnight. The mixture is cooled, and ethyl acetate (50 ml) and 5% ammonium chloride (25 ml) are added. Wash the ethyl acetate with water (2 x 20 ml) and brine (20 ml) and dry in anhydrous magnesium sulfate. After removing the solvent, the solid is purified without purification by chromatography (25% ethyl acetate-hexanes) to yield a pale yellow solid (84 mg, 24%); melting point 233-236 ° C; ^ -H-NMR (DMS0-d6): d 5.01 (2H, s), 6.65 (H, d, J = 2.5 Hz), 6.83-6.88 (2H, m), 6.93 (lH, dd, J = 2.3 Hz , J = 8.8 Hz), 7.09 (HH, dd, J = 1.0 Hz, J = 3.4 Hz), 7.24 (lH, dd, J = 3.5 Hz, J = 5.1 Hz), 7.70 (HH, dd, J = l .0 Hz, J = 5.1 Hz), 7.78 (1H, d, J = 8.8 Hz), 7.83 (H, d, J = 8.7 Hz), 8.24 (1H, s) 9.67 (lH, s), 9.75 (H) , s); MS m / z 347 ([M + H] +). An HPLC gives a purity of 96. 8% @ 300 nm. Analysis for C2? H? 4O3S «0. 2 H20: Calculated for C: 72. 06; H: 4 15 Found: C: 71.82; H: 4.01. Example 31 7-thien-3-yl-5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3,9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 3-thiopheneboronic acid (300 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour. The reaction mixture is cooled and diluted with ethyl acetate (25 ml) and ammonium chloride %. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark liquid is purified by chromatography (5% acetonitrile-dichloromethane) to yield a yellow solid (188 mg, 54%): melting point 159-161 ° C; ^? - NMR (DMSO -de): d 4.98 (2H, s), 6.65 (ÍH, d, J = 2.5 Hz), 6.83-6.86 (2H,) 6.92 (ÍH, dd, J = 2.4 Hz, J = 8.7 Hz), 7.18 (1H, dd, J = 1.2 Hz, J = 4.9 Hz), 7.50 (ΔH, dd, J = 1.2 Hz, J = 4.9 Hz), 7.68 (1H, dd, J = 2.9 Hz, J = 4.9 Hz), 7.76 (IH, d, J = 8.8 Hz), 7.82 (1H, d, J = 8.6 Hz), 8.17 (IH, s) , 9.57 (ÍH, s) 9.70 (ÍH, s); MS m / z 345 ([M-H] -). An HPLC gives a purity of 99. 8% @ 280 nm. Analysis for C2? H? 4O3S «0. 5 H20: Calculated for C: 70. 97; H: 4 25 Found: C: 71.06; H: 3.98 Example 32 7- (3-fluorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9-yl (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 3-fluorophenylboronic acid ( 420 'mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark liquid is purified by chromatography (25% ethyl acetate-hexanes) to yield a white solid (196 mg, 55%): melting point 225-227 ° C; XH-NMR (DMSO-de): d 4.98 (2H, s), 6.62-6.64 (2H,), 6.84 (OH, dd, J = 2.4 Hz, J = 8.5 Hz), 6.92 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 7.16-7.29 (3H, m), 7.52-7.59 (1H,), 7.77-7.85 (2H, m), 8.22 (ÍH, s), 9.59 (lH, s), 9.72 (lH, s); MS m / z 359 ([M + H] +). An HPLC gives a purity of 99.2% @ 210 nm. Analysis for C23H? 5FO3 * 0. 2 H20: Calculated for C: 76 .32; H -. Four . 29 Found: C: 76. twenty-one; H: 4 Example 33 7- (3-chlorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3,9- diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 'mmoles) 3-chlorophenylboronic acid ( 468 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark liquid is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (138.6 mg, 37%): mp 243-246 ° C; ^ - MR (DMSO-d6): d 4.98 (2H, s), 6.59 (ÍH, d, J = 2.3 Hz), 6.64 (HH, d, J = 2 Hz), 6.84 (HH, dd, J = 2.5 Hz, J = 8.4.

Hz), 6.93 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 7.297.32 (ÍH, m), 7. 38-7.41 (HH, m), 7.45-7.58 (2H, m), 7.77-7.85 (2H, m), 8.22 (1H, s), 9.61 (HH, s) 9.73 (HH, s); MS m / z 375/377, 1 Cl, ([M + H] +) .. An HPLC gives a purity of 97.5% 280 280 nm. Analysis for C23H? 5CI03: Calculated for C: 73.70; H-.4.03 Found: C: 73.84; H: 4.15 Example 34 7- (3-methoxyphenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9-diol (343 mg, 1 mmol), dimethylformamide (5 mL), 2M sodium carbonate (1 mL), water (1 mL), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 3-methoxyphenylboronic acid ( 456 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and then diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x.10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark solid is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (248.3 mg, 67%): mp 220-223 ° C; XH-NMR (DMSO-de): d 3.79 (3H, s), 4.96 (2H, s), 6.64 (2H, dd, J = 2.3 Hz, J = 7.0 Hz), 6.82-6.92 (4H, m), 6.98 (1H, dd, J = 1.5 Hz, J = 6.7 Hz), 7.40-7.45 (HH, m), 7.75-7.84 (2H, m), 8.19 (HH, s), 9.54 (HH, s), 9.70 (ÍH, s); MS m / z 371 ([M + H] +). An HPLC gives a purity of 98.5% Analysis for C24H? 8O4 * 0.3 H20: Calculated for C: 76.71; H: 4.99 Found: C: 76.88; H: 4.80 Example 35 7- (2-chlorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 2-chlorophenylboronic acid ( 468 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark liquid is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (85.1 mg, 22%): mp 220-222 ° C; ^ - MR (DMSO-de): d 4.98 (2H, s), 6.37 (1H, d, J = 2.3 Hz), 6.63 (IH, d, J = 2.4 Hz), 6.85 (IH, dd, J = 2.5 Hz, J = 8.5 Hz), 6.92 (1H, dd, J = 2.4 Hz, J = 8.8 Hz), 7.33-7.38 (ÍH,),. 7.43-7.53 (2H, m), 7.61-7.67 (HH, m), 7.78-7.85 (2H, m), 8.24 (1H, s) 9.58 (1H, s), 9.72 (HH, s); MS m / z 375/377, 1 Cl, ([M + H] +) .An. HPLC of 97. 6% © 280 nm. Analysis for C23H? 5CIO3 * 0. 3 H20: Calculated for C: 72. 65; H: 4 .14 Found: C: 72. 63; H: 3. Example 36 7- (3,4-difluorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9-diol (343 mg, 1 mmol), dimethylformamide (5 mL), 2M sodium carbonate (1 mL), water (1 mL), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) acid 3,4-difluorophenylboronic acid (474 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 2 hours, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark solid is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (162.1 mg, 43%): melting point 235-237 ° C; ^? - NMR (DMSO-de): d 4.99 (2H, s), 6.63 (2H, dd, J = 2.4 Hz, J = 8.8 Hz), 6.84 (1H, dd, J = 2.5 Hz, J = 8.4 Hz), 6.93 (lH, dd, J = 2.3 Hz, J = 8.8 Hz), 7.16-7.21 (lH, m ), 7.42-7.49 (1H,), 7. 53-7.62 (HH, m), 7.77-7.84 (2H, m), 8.23 (HH, s) 9.60 (lH, s), 9.73 (HH, s); MS m / z 377 ([M + H] +). An HPLC gives a purity of 97.6% © 280 nm. Analysis for C23H? F2O3 * 0.1 H20: Calculated for C: 73.05; H: 3.78 Found: C: 72.98; H: 3.63 Example 37 7- (4-pyridyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-9- ilo (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 4-pyridylboronic acid (370 mg , 3 mmol). The reaction mixture is heated at 120 ° C for 2 hours, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The insoluble dark solid is filtered and dried, then dissolved in dichloromethane-methanol and filtered through the filter aid to remove the catalyst. The solvent is removed to yield a dark solid (60 mg, 18%); melting point > 250 ° C; ^ H- MR (DMSO-de): d 4.99 (2H, s), 6.60 (1H, d, J = 2.2 Hz), 6.64 (ÍH, d, J = 2.4 Hz), 6.85 (lH, dd, J = 2.4 Hz, J = 8.5 Hz), 6.94 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 7.40 (2H, dd, J = 1.5 Hz, J = 4.4 Hz), 7.79-7.85 (2H,), 8.26 (ÍH, s), 8.71 (2H, dd, J = 1.5 Hz, J = 4.4 Hz), 9.65 (1H, s), 9.76 (ÍH, s); MS m / z 342 ([M + H] +). An HPLC gives a purity of 99.7% © 280 nm. Analysis for C22H? 5N03 «HCI: Calculated for C: 69.94; H -.4. 27; N-.3 .71 Found: C: 70. 27; H: 4 08; N: 3 .58 Example 38 7- (2-fluorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene- 3,9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 2- acid fluorophenylboronic (420 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 2 hours, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark residue is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (120 mg, 30%): mp 240-242 ° C; ^? - NMR (DMSO-de): d 4.97 (2H, d, J = 2.7 Hz), 6.55 (lH, s), 6.64 (H, d, J = 2.4 Hz), 6.85 (1H, dd, J = 2.5 Hz, J = 8.5 Hz), 6.93 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 7.33-7.43 (3H, m), 7.45-754 (1H, m), 7.78-7.85 (2H, m), 8.25 (1H, s) 9.62 (H, s), 9.72 (H, s) MS m / z 359 ([M + H] +). An HPLC gives a purity of 99.2% © 280 nm. Analysis for C23H? 5FO3 »0.5 H20: Calculated for C: 75.20; H-.4.39 Found: C: 75.09; H: 4.22 EXAMPLE 39 7- (3,4-dimethylphenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene- 3,9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) acid 3, 4-dimethylphenylboronic acid (450 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark solid is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (95 mg, 26%): mp 218-221 ° C; ^? - NMR (DMSO-de): d 2.29 (3H, s), 2.31 (3H, s), 4.92 (2H, s), 6.62-6.65 (2H, m), 6.82-6.91 (2H, m), 7.01-7.05 (1H, m), 7.08 (HH, s), 7.25 (lH, d, J = 7.7 Hz), 7.77-7.83 (2H, m), 8.16 (HH, s), 9.48 (1H, s) 9.70 (ÍH, s); MS m / z 369 ([M + H] +). An HPLC gives a purity of 97.3% © 280 nm. Analysis for C23H2oO3 * 0. 2 H20: Calculated for C: 80. 71; H: 5 .53 Found: C: 80. 61; H: 5 Example 40 7- (4-cyanophenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9- ilo (400 mg, 1.2 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) aladium (140 mg, 0.12 mmol) 4-cyanophenylboronic acid (514 mg , 3.5 mmoles). The reaction mixture is heated at 120 ° C for 2 hours, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark liquid is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (282.3 mg, 66%): melting point 250 ° C: ^ - MR (DMSO-de): d 4.98 (2H, s), 6.55 (H, d, J = 2.2 Hz), 6.64 (1H, d, J = 2.4 Hz), 6.85 (ÍH, dd, J = 2.5 Hz, J = 8.5 Hz), 6.94 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.79-7.85 (2H, m), 7.98 (1H, d, J = 7.8 Hz), 8.25 (HH, s) 9.62 (1H, s), 9.74 (HH, s); MS m / z 364 ([M-H] -). An HPLC gives a purity of 96.5% © 280 nm. Analysis for C2 H? 5NO3 * 0.3 H20: Calculated for C: 77.74; H: 4.24; N: 3.78 Found: C: 77.91; H: 4.07; N: 3.53 Example 41 7- (3-fluoro-4-methylphenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9-yl (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) acid 3-Fluoro-4-methylphenylboronic acid (462 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark solid is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (226 mg, 61%): melting point 238-240 ° C; 2 H-NMR (DMSO-de): d 4.97 (2H, s), 6.63-6.65 (2H, M), 6.84 (ΔH, dd, J = 2.5 Hz, J = 8.5 Hz), 6.91 (1H, dd, J = 2.4 Hz, J = 8.8 Hz), 7.04-7.13 (2H, m), 7.38-7.43 (lH, mj, 7.76-7.84 (2H, m), 8.20 (lH, s), 9.55 (lH, s), 9.72 (1H, s); MS m / z 373 ([M + H] +). An HPLC gives a purity of 98.2%. © 280 nm. Analysis for C24H? O3 »0. 3 H20: Calculated for C: 76. 30; H: 4 70 Found: C: 76. 04; H: 4 Example 42 7- (3,4-dimethoxyphenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 3-fluoro- 4-methylphenylboronic acid (546 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark liquid is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (261.1 mg, 65%): mp 245-248 ° C; XH-NMR (DMSO-de): d 3.75 (3H, s), 3.84 (3H, s), 3.84 (3H, s), 4.96 (2H, s), 6.64 (ΔH, d, J = 2.4 Hz), 6.75 (HH, dd, J = 2.3 Hz), 6.83-6.92 (4H, m), 7.09 (HH, d, J = 8.2 Hz), 7.74-7.83 (2H, m), 8.17 (HH, s) 9.51 ( 1H, s), 9.70 (lH, s); MS m / z 401 ([M + H] +). An HPLC gives a purity of 99.4% © 280 nm. Analysis for C25H2o? 5 * 0. 5 H20: Calculated for C: 73.34; H: 5 17 Found: C: 73 .24; H: 4 Example 43 7_ (3-trifluoromethylphenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3,9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) 3-fluoro-4-methylphenylboronic acid (570 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml). -ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark solid is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (214 mg, 52%): mp 228-231 ° C; XH-NMR (DMSO-de): d 4.99 (2 H, d, J = 2.7 Hz), 6.55 (1 H, d, J = 2.2 Hz), 6.64 (H, d, J = 2.4 Hz), 6.85 (H, dd, J = 2.5 Hz, J = 8.5 Hz), 6.94 (HH, dd, J = 2.3 Hz, J = 8.8 Hz), 7.66-7.86 (6H, m), 8.25 (HH, s), 9.62 (lH, s), 9.73 (1H, s); MS m / z 409 ([M + H] +). An HPLC gives a purity of 100% © 280 nm. Analysis for C24H 5F03: Calculated for C: 70. 59; H -.3 .70 Found: C: 70. 23 H: 3. Example 44 7- (3, 5-difluorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) acid 3, 5- difluoro-phenylboronic acid (475 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1.5 hours, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark liquid is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a white solid (217.4 mg, 58%): melting point 238-240 ° C; XH-NMR (DMSO-de): d 5.01 (2H, s), 6.63 (2H, dd, J = 2.3 Hz, J = 6.4 Hz), 6.84 (ΔI, dd, J = 2.4 Hz, J = 8.5 Hz) , 6.94 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 7.08-7.14 (2H, m), 7.27-7.35 (1H, m), 7.78-7-84 (2H, m), 8.24 (1H , s), 9.65 (1H, s) 9.75 (1H, s); MS m / z 375 ([M + H] +). An HPLC gives a purity of 97.5% © 280 nm. Analysis for C23H? 4F2O3 «0 .3 H20: Calculated for C: 72 .36; H: 3. 85 Found: C: 72 .31; H: 3. Example 45 7- (3,5-dichlorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol It is added to a mixture of 7-bromo-H-dibenzo [c, g] chromene-3, 9-diol (343 mg, 1 mmol), dimethylformamide (5 mL), 2M sodium carbonate (1 mL), water (1 mL), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) acid 3,5-difluoro-phenylboronic acid (573 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent is removed and the resulting dark residue is purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a dark solid (178.9 mg, 44%): mp 252-255 ° C; ^ - MR (DMSO-de): d 5.01 (2H, s), 6.57 (ÍH, d, J = 2.3 Hz), 6.64 (1H, d, J = 2.4 Hz), 6.84 (ÍH, dd, J = 2.5 Hz, J = 8.5 Hz), 6.94 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 7.42 (2H, d, J = l .9 Hz), 7.66-7.70 (HH, m), 7.79-7.85 (2H, m), 8.25 (lH, s) 9.68 (HH, s) 9.76 (HH, s); MS m / z 409/411/413, 2 Cl ([M + H] +). An HPLC gives a purity of 97.6% © 280 nm Analysis for C23H? 4CI203: Calculated for C: 67.50; H: 3.45 Found: C: 67.13; H: 3.63 Example 46 7- (3-methyl-4-fluorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol Added to a mixture of 7-bromo-5H-dibenzo [c, g] chromene-3, 9-diol (343 mg, 1 mmol), dimethylformamide (5 ml), 2M sodium carbonate (1 ml), water (1 ml) and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) acid 3 -methyl-4-fluoro-phenylboronic acid (486 mg, 3 mmol). The reaction mixture is heated at 120 ° C for 1 hour, then cooled and diluted with ethyl acetate (25 ml) and 5% ammonium chloride. The organic layer is washed with water (3 x 10 ml) and brine (10 ml) and dried over anhydrous magnesium sulfate. The solvent was removed and the resulting dark liquid was purified by chromatography (2.5% acetonitrile-dichloromethane) to yield a dark solid (223 mg, 60%); melting point 185-188 ° C; ^ - MR (DMSO-de): d 2.31 (3H, - d, J = 1 .2 Hz), 4.95 (2H, s), 6.62 (2H, dd, J = 2.3 Hz, J = 10.4 Hz), 6.84 (ÍH, dd, J = 2.4 Hz, J = 8.5 Hz), 6.91 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 7.13-7.30 (3H, m), 7.76-7.84 (2H, m), 8.19 (H, s) 9.55 (H, s) 9.73 (ÍH, s) MS m / z 371 ([M-H] -). An HPLC gives a purity of 99.5% © 280 nm. Analysis for C24H? 7F03: Calculated for C: 77.41; H: 4.60 Found: C: 77.17; H: 4.54 EXAMPLE 47 7- (3-fyl) -5H-dibenzo [c, g] chromene-3,9-diol A mixture of 7-bromo-5H-dibenzo [c, g] chromene-3 is heated , 9-diol (342 mg, 1 mmol), furan-3-boronic acid (224 mg, 2 mmol), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) in DMF (20 ml) at 120 ° C with stirring for 4 hours. The mixture is filtered through celite, extracted with ethyl acetate (3 times), washed with brine, dried over sodium sulfate, filtered, the solvent is distilled off and purified by silica column chromatography "( 18% -25% ethyl acetate-hexane) to yield 200 mg (61%) of the title compound as a yellowish solid: mp 216-218 ° C; XH-NMR (DMSO-d6): d 5.00 (2H , s), 6.66 (2H, m), 6.84 (1H, dd, J = 8.45 Hz, J = 2.35 Hz), 6.93 (1H, dd, J = 8.77 Hz, J = 2.35 Hz), 7.04 (HI, d , J = 2.17 Hz), 7.76 (lH, d, J = 8.83 Hz), 7.80-7.85 (3H, m), 8.16 (1H, s), 9.61 (1H, s), 9.71 (1H, s); (ESI) m / z 329 (MH) ~, 331 (M + H) + Analysis for C2? H? 404: Calculated for C: 76.36; H: 4.27 Found: C: 75.81; H: 4.32 Example 48 7- (2-furyl) -5H-dibenzo [c, g] chromene-3,9-diol A mixture of 7-bromo-5H-dibenzo [c, g] chromene-3,9-diol (450 mg, 1.32 g. mmoles), 2- (tributylstannyl) furan (0.622 ml, 1.97 mmol), and tetrakis (triphenylphosphine) palladium (0) (153 mg , 0.132 mmol) in toluene (26 ml) at 110 ° C with stirring for 23 hours. The mixture is filtered through celite, concentrated and purified by reverse phase preparative HPLC to yield 280 mg (64%) of the title compound as a light brown solid. This is further purified by trituration with CH2C12 to produce a gray solid: melting point 158-163 ° C; ^ -NMR (DMSO-de): d 5.04 (2H, s), 6.61 (1H, d, J = 3.11 Hz), 6.67-6.69 (2H, m), 6.85 (H, dd, J = 8.47 Hz, J = 2.33 Hz), 6.95 (HH, dd, J = 8.72 Hz, J = 2.27 Hz), 6.99 (HH, d, J = 1.98 Hz), 7.77 (1H, d, J = 8.77 Hz), 7.82 (1H, d, J = 8.53 Hz), 7.85 (1H, d, J = 1.32 Hz), 8.24 (HH, s) 9.70 (HH, s) 9.75 (1H, s); MS (ESI) m / z 329 (MH) ", 331 (M + H) + Analysis for C2? H? 4O» 0.2CH2CI2: Calculated for C: 72.62; H: 4.06 Found: C: 72.67; H: 4.03 Example 49 7-Butyl-5H-dibenzo [c # g] chromene-3,9-diol A mixture of 7-bromo-5H-dibenzo [c, g] chromene-3,9-diol (420 mg, 1.23 g. mmoles), 2-tributylstanyl thiazole (0.95 ml, 1.15 g, 3.07 mmol), and dichlorobis (tri-O-tolylphosphine) palladium (97 mg, 0.123 mmol) in DMF (12 ml) at 110 ° C with stirring for 18 hours. The mixture is filtered through celite, extracted with ethyl acetate (3 times), washed with brine, dried over sodium sulfate, filtered, the solvent is distilled off and purified by chromatography on a silica column (acetate). ethyl acetate at 25% -hexane) to yield 200 mg (51%) of the title compound as a yellow solid.The analytical sample is further purified by another silica column chromatography (10% ethyl acetate - 20% -hexane) to produce a yellowish solid: melting point 187-187 ° C; hi-NMR (DMSO-de): d 0.94 (3H, t, J = 7.17 Hz), 1.37-1.44 (2H, m), 1.47-1.58 (2H, m), 2.92 (2H, t, J = 7.00 Hz), 5.04 (2H, s), 6.73 (1H, d, J = 2.36 Hz), 6.82 (1H, dd, J = 8.44 Hz, J = 2.48 Hz), 6.92 (lH, dd, J = 8.76 Hz, J = 2.18 Hz), 7.12 (ÍH, d, J = 2.05 Hz), 7.71 (H, d, J = 8.88 Hz), 7.76 (H, d, J = 8.53 Hz), 8.00 (H, s) 9.63 (1 H, s) 9.67 (H, s); MS (ESI) m / z 319 (MH) ", 321 (M + H) + Analysis for C2? H20O3: Calculated for C: 78.73, H: 6.29 Found: C: 78.42; H: 6.27 Example 50 1- ( 3-pyridinyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g] chromene-3,9-diol (686 mg, 2 mmol), and pyridinylboronic acid (737 mg, 6 mmol) as described above in Example 23 to produce a yellow solid (201 mg, 30%): melting point > 250 ° C; XH-NMR (DMSO-de): d 4.99 (2H, s), 6.60 (ΔH, d, J = 2.5 Hz), 6.65 (ÍH, d, J = 2.5 Hz), 6.86 (2H, dd, J = 8.5 Hz, J = 2.6 Hz), 7.54-7.58 (ÍH, m), 7.78-7.85 (3H, m), 8.25 (1H, s), 8.55 (HH, d, J = 1.4 Hz), 8.63 (HH, dd, J = 4.8 Hz, J = 1.6 Hz), 9.62 (1H, s) 9.72 (1H, s); MS m / z 342 ([M + H] +) .An.HPLC of 99.6% © 280 nm. Analysis for C22H? 5NO3 »0.2 H20: Calculated for C: 76.60; H: 4.50; H-: 4.06 - Found: C: 76.46; H: 4.53; H: 3.80 Example 51 7- (4-methoxy-3-pyridyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c. , g] chromene-3, 9-diol (343 mg, 1 mmol), and 4-methoxy-3-pyridinylboronic acid (168 mg, 1.1 mmol) as described above in Example 23 to produce a yellow solid (62.3 mg , 17%): melting point > 220 ° C; XH-NMR (DMSO-d6): d 3.94 (3H, s), 4.98 (2H, m), 6.64-6.67 (2H, m), 6.83 (1H, dd, J = 8.5 Hz, J = 2.4 Hz), 6.93 (1H, dd, J = 8.8 Hz, J = 2.3 Hz), 6.98 (ΔH, d, J = 8.5 Hz), 7.69 (1H, dd, J = 8.5 Hz, J = 2.4 Hz), 7.78-7.85 (2H, m), 8.13 (1H, d, J = 2.2 Hz), 8.22 (1H, s), 9.60 (1H, s), 9.73 (1H, s); MS m / z 372 ([M + H] +). An HPLC gives a purity of 98. 9% © 280 nm. Analysis for C23H? 7NO * 0 .2 H20: Calculated for C: 73. 67; H: 4 68; H: 3. 74 Found: C: 73.71; H: 4.40; H: 3.34 Example 52 7- (pyrimidyl-5 H -dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g] chromene-3, 9-diol (343 mg, 1 mmol), and pyrimidylboronic acid (370 mg, 3 mmol) as described above in Example 23 to produce a solid-dark (84.8 mg, 25%): melting point > 250 ° C; ^ - MR (DMSO-de): d 5.04 (2H, s), 6.62 (HH, d, J = 2.3 Hz), 6.65 (HH, d, J = 2.4 Hz), 6.85 (HH, dd, J = 8.5 Hz, 'J = 2.6 Hz), 6.97 (1H, dd, J = ll .8 Hz, J = 5.4 Hz), 7.82-7.86 (2H,), 8.31 (ÍH, s), 8.87 (2H, s), 9.26 (lH, s) 9.73 (2H, br s); MS m / z 343 ([M + H] +) .An.HPLC 96.8% © 300 nm. Analysis for C2? H? 4N2O3 »0.3 H20: Calculated for C: 72.53; N: 4.23; H: 8.06 Found: C: 72.48; N: .17; H: 7.68 Example 53 7- (5-methoxy-3-pyridyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c. , g] chromene-3, 9-diol (515 mg, 1.5 mmol), and 5-methoxy-3-pyridinylboronic acid (306 mg, 3 mmol) as described above in Example 23 to produce a dark solid (160.4 mg , 29%): melting point > 250 ° C; ^ -NMR (DMSO-d6): d 3.88 (3H, s), 5.00 (2H, s), 6.64 (IH, dd, J = 6.2 Hz, J = 2.4 Hz), 6.85 (lH, dd, J = 8.5 Hz, J = 2.6 Hz), 6.94 (ÍH, dd, J = 8.8 Hz, J = 2.3 Hz), 7.38 (lH, dd, J = 2.9 Hz, J = 1.7 Hz), 7.81-7.85 (2H, m) , 8.14 (lH, s), 9.25 (lH ,. s), 8.36 (lH, s) 9.61 (lH, br s), 9.72 (lH br s); MS m / z 372 ([M + H] +) .An. HPLC of 99.0% © 300 nm. Analysis for C23H? 7N0: Calculated for C: 74.38; N: 4.61; H: 3.77 Found: C: 74.27; N: 4.49; H: 3.31 Example 54 7- (2-pyridyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g] chromene -3,9-diol (686 mg, 2 mmol), and 2-pyridinyltributyltin acid (306 mg, 3 mmol) as described above in Example 23 to produce a dark solid (46.9 mg, 7%): fusion > 220 ° C; ^ - MR (DMSO-de): d 4.96 (2H, s), 6.57 (ÍH, d, J = 2.3 Hz), 6.64 (HH, d, J = 2.4 Hz), 6.85 (HH, dd, J = 8.5 Hz, J = 2.4 Hz), 6.92 (HH, dd, J = 8.8 Hz, J = 2.4 Hz), 7.40 -7.46 (lH, m), 7.47 (HH, dd, J = 6.9 Hz, J = 1.0 Hz), 7.78 (1H, d, J = 8.8 Hz), 7.84 (HH, d, J = 8.7 Hz) 7.90-7.94 (1H, m), 8.23 (HH, s), 8.75 (1H, d, J = 2.4 Hz), 9.52 (lH, br s), 9.71 (1H, br s); MS m / z 342 ([M + H] +). An HPLC gives a purity of 99.0% © 210 nm. Analysis for C22H? 5NO3 * 0.5 H20: Calculated for C: 75.42; N: 4.60; H: 4.00 Found: C 75.08; N: 4.20; H: 3.80 Example 55 7- (3,4-dichlorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g ] chromene-3, 9-diol (343 mg, 1 mmol), and 3,4-dichlorophenylboronic acid (572 mg, 3 mmol) as described above in Example 23 to produce a dark solid (220 mg, 54%) : melting point 1443-145 ° C; ^ -NMR (DMSO-de): d 4.99 (2H, s), 6.57 (ÍH, d, J = 2.4 Hz), 6.65 (IH, d, J = 2.3 Hz), 6.84 (IH, dd, J = 8.5 Hz, J = 2.6 Hz), 6.93 (IH, dd, J = 8.8 Hz, J = 2.4 Hz), 7.35 (ÍH, dd, J = 8.2 Hz, J = 2.1 Hz), 7.62 (lH, d, J = 1.9 Hz), 7.77-7.84 (3H, m), 8.24 (1H, s), 9.59 (1H, s), 9.72 (HH, S; MS m / z '407/409 (MH). "An HPLC gives purity of 97.7 280 280 nm Analysis for C22H 5 5NO3 0.3 0.3 H20 : Calculated for C: 66.62; H: 3.55 Found: C 66.40; H: 3.39 Example 56 7- (4-methylthiophenyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by making reacting 7-bromo-H-dibenzo [c, g] chromene-3,9-diol (343 mg, 1 mmol), and 2-methylthiophenylboronic acid (504 mg, 3 mmol) as described above in Example 23 for produce a dark solid (250 mg, 65%): melting point 195-198 ° C; ^ - MR (DMSO-de): d 2.56 (3H, s), 4.95 (2H, s), 6.65 (2H, dd , J = 10.6, J = 2.4 Hz), 6.84 (IH, dd, J = 8.5 Hz, J = 2.6 Hz), 6.91 (IH, dd, J = 8.8 Hz, J = 2.4 Hz), 7.28 (2H, d , J = 8.5 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.77 (IH, d, J = 8.7 Hz), 7.82 (IH, d, J = 8.6 Hz), 8.18 (IH, s), 9.52 (HH, s), 9.69 (lH, s); MS m / z 387 ([M + H] +). An HPLC gives purity of 99.4 280 280 nm Analysis for C24H 8 8SO3 0.3 0.3 H20: Calculated C leg : 73.56; H: 4.78 Enc ontrado: C: 73.66; H: 4.43. Example 57 7- (4-Cyanomethylphenyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g] chromene-3, 9-diol (343 mg, 1 mmol), and 4-cyanomethylphenylboronic acid (483 mg, 3 mmol) as described above in Example 23 to yield a dark solid (210 mg, 55%): mp 240-242 ° C; ^ - MR (DMSO-de): d 4.14 (2H, s), 4.95 (2H, s), 6.63 (2H, d, J = 2.3 Hz-), 6.85. (ÍH, dd, J = 8.5 Hz, J = 2.4 Hz), 6.92 (HH, dd, J = 8.8 Hz, J = 2.4 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.49 (2H, d, J = 8.3 Hz), 7.78 (HH, d, J = 8.9 Hz ), 7.83 (1H, d, J = 8.6 Hz), 8.20 (1H, s), 9.55 (HH, s), 9.70 (1H, s); MS m / z 380 ([M + H] +). An HPLC 'gives purity of 98.6 280 280 nm. Analysis for C25H? 7NO3 «0.2 H20: Calculated for C: 78.40; N: 4.58; H: 3.66 Found: C: 78.45; N: 4.30; H: 3.56 Example 58 7- (3-trifluoromethoxyphenyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g] chromene -3,9-diol (343 mg, 1 mmol), and 3-trifluoromethoxyphenylboronic acid (618 mg, 3 mmol) as described above in Example 23 to produce a dark solid (140 mg, 33%): melting point 110-112 ° C; aH-NMR (DMSO-de): d 4.98 (2H, s), 6.61 (1H, d, J = 2.3 Hz), 6.64. (HH, d, J = 1.9 Hz), 6.85 (HH, dd, J = 8.5 Hz, J = 2.4 Hz), 6.93 (HH, dd, J = 8.8 Hz, J = 2.3 Hz), 7.32 (1H, s ), 7.38-7.44 (2H, m), 7.64-7_.68 (lH, m), 7.80 (lH, d, J = 8.8 Hz), 7.83 (1H, d, J = 8.6 Hz), 8.23 (HH, s), 9.61 (lH, s), 9.72 (HH, s); MS m / z 425 ([M + H] +). An HPLC gives purity of 98.7 280 280 nm. Analysis for C24H? 5F3O4 * 0.5 H20: Calculated for C: 66.51; H.:3.72 Found: C: 66.57; H: 3.39 Example 59 7- (4-trifluoromethoxyphenyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g] chromene -3,9-diol (343 mg, 1 mmol), and 4-trifluoromethoxyphenylboronic acid (618 mg, 3 mmol) as described above in Example 23 to produce a dark solid (219 mg, 52%): melting point 245-248 ° C; ^ - MR (DMSO-de): d 4.97 (2H, s), 6.60 (lH, d, J = 2.3 Hz), 6.64 (IH, d, J = 2.5 Hz), 6.85 (1H, dd, J = 8.5 Hz, J = 2.5 Hz), 6.93 (ÍH, dd, J = 8.8 Hz, J = 2.3 Hz), 7.32 (1H, s), 7.38-7.44 (2H, m), 7.64-7.68 (lH, m), 7.80 (lH, d, J = 8.8 Hz), 7.83 (IH, d, J = 8.6 Hz), 8.22 (lH, s), 9.71 (1H, s); MS m / z 425 ([M + H] +). An HPLC gives purity of 99.9 © 280 nm. Analysis for C2Hi5F304: Calculated for C: 67.93; H: 3.56 Found: C: 67.76; H: 3.50 Example 60 7- (4-tert-butylphenyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g ] chromene-3, 9-diol (343 mg, 1 mmol), and 4-tert-butylphenylboronic acid (534 mg, 3 mmol) as described above in Example 23 to produce a white solid (144 mg, 36%) : melting point 162-165 ° C; ^ - MR (DMSO-de): d 1.38 (9H, s), 4.94 (2H, s), 6.63 (ÍH, d, J = 2.4 Hz), 6.68 (lH, d, J = 2.2 Hz), 6.84 (ÍH, dd, J = 8.5 Hz, J = 2.4 Hz), 6.90 (HH, dd, J = 8.8 Hz, J = 2.3 Hz), 7.27 (2H, d, J = 8.2 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.79 (ÍH, d, J = 7.6 Hz), 7.82 (HH, d, J = 8.6 Hz), 8.18 (1H, s), 9.54 (HH, s), 9.69 (HH, s); MS m / z 397 ([M + H] +). An HPLC gives a purity of 99.2 + 280 nm. Analysis for C27H2 SO3 »0. 5 H20: Calculated for C: 79 .98; H: 6 .21 Found: C: 79. 24; H: 6 Example 61 7- (naphthyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g] chromene-3, 9 -diol (343 mg, 1 mmol), and 1-naphthylboronic acid (516 mg, 3 mmol) as described above in Example 23 to produce a white solid (110 mg, 28%): mp 160-162 ° C; aH-NMR (DMSO-de): d 4.85 (2H, s), 6.24 (ΔH, d, J = 2.

Hz), 6.57 (ÍH, d, J = 2.3 Hz), 6.84-6.92 (3H, m), 7.26-7.51 (4H, m), 7.63-7.68 (1H, m), 7.83 (1H, dd, J = 8.1 Hz), 7.88 (ÍH, d, J = 8.5 Hz), 8.02 (HH, d, J = 8.2 Hz), 8.30 (1H, s), 9.39 (HH, s), 9. 70 (ÍH, s); MS m / z 389 ([M + H] +). An HPLC gives purity of 95. 4 © 280 nm. Analysis for C27H? 8O3 »0. 4 H20: Calculated for C: 81.55; H: 4.76 Found: C: 81.39; H-.4.87 EXAMPLE 62 7- (4-Ethylphenyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g] chromene-3,9-diol (343 mg, 1 mmol), and 4-ethylphenylboronic acid (450 mg, 3 mmol) as described above in Example 23 to yield a white solid (292 mg, 79%): fusion 203-205 ° C; XH-NMR (DMSO-d6): d 1.29 (3H, t, J = 7.6 Hz), 2.71 (2H, q, J = 2.2 Hz), 4.94 (2H, s), 6.65 (2H, dd, J = 13.7 Hz, J = 2.4 Hz), 6.85 (ΔH, dd, J = 8.5 Hz, J = 2.6 Hz), 6.90 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 7.25 (2H, d, J = 7.9 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.76 (IH, d, J = 8.8 Hz), 7.82 (1H, d, J = 8.6 Hz), 8.17 (lH, s), 9.51 (1H , s), 9.69 (ÍH, s); MS m / z 369 ([M + H] +). An HPLC gives purity of 99.8 280 280 nm. Analysis for C25H2o03 »0.5 H20: Calculated for C: 79.56; H: 5.61 Found: C: 79.86; H: 5.37 Example 63 7- (3,5-Dimethylphenyl) -5H-dibenzo [c, g] chromene-3,9-diol The title compound is prepared by reacting 7-bromo-H-dibenzo [c, g ] chromene-3,9-diol (343 mg, 1 mmol), and 3,5-dimethylphenylboronic acid (450 mg, 3 mmol) as described above in Example 23 to produce a white solid (270 mg, 73%) : melting point 220-223 ° C; XH-NMR (DMSO-de): d 2.34 (6H, s), 4.93 (2H,), 6.62 (2H, dd, J = 9.7, J = 2.4 Hz), 6.84 (ΔH, dd, J = 8.5 Hz, J = 2.4 Hz), 6.88-6.91 (3H, m), 7.04 (H, s), 7.76 (lH, d, J = 8.9 Hz), 7.82 (H, d, J = 8.6 Hz), 8.16 (H, s), 9.49 (1H, s), 9.69 (lH, s); MS m / z 369 ([M + H] +). An HPLC gives a purity of 97.2. 280 nm. Analysis for C2sH20O3 * 0. 25 H20: Calculated for C: 80. 52; H: 5 54 Found: C: 80. 64; H: 5 Example 64 Ability to compete with 17β-estradiol for both ERa and ERβ Representative examples of the invention are evaluated for their ability to compete with 17β-Estradiol for both ERa and ERβ. This test procedure provides the methodology for determining if a. particular compound binds to the estrogen receptor (and is therefore "estrogenic") and if there is selectivity for ERa or ERβ. The values in the Table below are shown and reported as IC50S- The 17ß-estradiol is included as a standard reference for comparison. The procedure used is described briefly below. An unpurified lysate of E. coli is prepared which expresses the ligand binding domains of the estrogen receptor (D, E, and F) of human ERa or ERβ. Both receptors and compounds are diluted in Dulbecco's PBS once (DPBS) supplemented with 1 M EDTA. Using a high-binding masked microtiter plate, 100 μl of the receptor (luG / well) is combined with 2 nM [3H] -17β -stradiol and various concentrations of the compound. After 5 to 15 hours at room temperature, the plates are washed with DPBS / 1 mM EDTA and bound radioactivity determined by liquid scintillation counting. The IC50 is defined as the concentration of the compound that decreases the binding of total 17β-estradiol by 50%. The results obtained are described in the following table.

The results obtained in the standard pharmacological test procedure demonstrate that the compounds of this invention are estrogenic compounds, some with strong preferential affinity for the ERβ receptor. The compounds of this invention are in the range that have high preferential affinity for ERβ on ERa for almost an equal affinity for both receptors. In this way, the compounds of this invention will extend a range of activity based, at least partially, on their receptor affinity selectivity profiles. Additionally, since each novel receptor ligand complex is unique and. in this way in interaction with several coregulatory proteins, the compounds of this invention will exhibit different modulator behavior depending on the cellular context in which they are. For example, in some cell types, it is possible for a compound to behave as an estrogen agonist while in other tissues, as an antagonist. Compounds with such activity have sometimes been referred to as SERMs (selective estrogen receptor modulators). Unlike estrogen, however, many of the SERMs do not cause increases in wet uterine weight. These compounds are antiestrogenic in the uterus and can completely antagonize the trophic effects of estrogen agonists in uterine tissue. These compounds, however, act as estrogen agonists in bone, cardiovascular and central nervous system systems. Due to this tissue-selective nature of these compounds, they are useful for treating or preventing conditions or syndromes of mammalian disease which are caused or associated with an estrogen deficiency (in certain tissues such as bone or cardiovascular) or an excess of estrogen. (in the uterus or mammary glands). Even beyond such cell-specific modulation, the compounds of this invention also have the potential to behave as agonists in one type of receptor while behaving as antagonists in the other. For example, it has been shown that the compounds can be an antagonist on ERβ while being an agonist in ERa (Meyers, Marvin J .; Sun, Jun; Carlson, Kathryn E .; Katzenellenboen, Benita S.; Katzenellenbogen John A., J. Med. Chem. (1999), 42 (13), 2456-2468). Such ERSAA activity (selective estrogen receptor agonist antagonist) provides pharmacologically distinct estrogenic activity within this series of compounds. Standard pharmacological test procedures are readily available to determine the activity profile of a given test compound. The following examples briefly summarize several representative test procedures. The standard pharmacological test procedures for SERM are also provided in U.S. Patents 4,418,068 and 5,998,402. EXAMPLE 65 Rat uterotrophic / antiuterotrophic test procedure The estrogenic and antiestrogenic properties of the compounds can be determined in an immature rat uterotrophic assay (4 days) as previously described by L. J. Black and R.L. Goode, Life Sciences, 26, 1453 (1980). Immature Sprague-Dawley rats (female, 18 days old) are tested in groups of six. They are treated. animals by ip injection daily with 10 uG of compound, 100 uG of compound, (100 uG of compound + 1 uG of 17β-estradiol) to check the antiestrogencity, and 1 uG of 17β-estradiol, with 50% DMSO / solution 50% saline as the injection vehicle. On day 4 the animals are sacrificed by asphyxiation with C02 and the uterus is removed and the excess lipids are removed, any fluid is removed and the wet weight is determined. A small horn section is subjected to histology and the remainder is used to isolate the total RNA in order to evaluate the gene expression of the complement component 3. Example 66 Test procedure of 6-week ovarianized rat-bone and cardioprotection the rats CD Sprague Dawley Female, ovx or sham ovx, 1 day after surgery Taconic Farm (weight range 240-275 g). They lodge 3 or 4 rats / cage in a room in program 12/12 (light / dark) and they are provided with food (Purina 5K96C rat food) and water ad libitum. Treatment for all studies begins 1 day after the animals arrive and are dosed 7 days per week as indicated for 6 weeks. A group of simulated sham-operated rats receive no treatment and serve as a control group replete with estrogen. intact for each study. All treatments are prepared in 1% Tween 80 in normal saline at defined concentrations such that the volume of treatment is 0.1 ml / 100 mg of body weight. 17β-estradiol is dissolved in corn oil (20 μg / ml) and supplied subcutaneously, 0.1 ml / rat. All doses are adjusted at three-week intervals according to the group's average body weight measurements. Five weeks after the start of treatment and one week before the end of the study, each rat is evaluated for bone mineral density (BMD). The total and trabecular density of the proximal tibia in anaesthetized rats is evaluated using an XCT-960 M (pQCT); Stratec Medizintechnik, Pforzheim, Germany). The measurements are made as follows: Fifteen minutes before the scan, each rat is anesthetized with an intraperitoneal injection of 45 mg / kg of ketamine, 8.5 mg / kg of xylazine, and 15 mg / kg of acetopromazine.

The right rear leg is passed through a polycarbonate tube with a diameter of 25 mm and covered with an acrylic box with the ankle joint at a 90 ° angle and the knee joint at 180 °. The polycarbonate tube is fixed in a sliding platform that maintains its perpendicular to the pQCT opening. The platform is adjusted in such a way that the distal end of the femur and the proximal end of the tibia can be in the sweep field. A two-dimensional explorer view is run by a length of 10 mm and a line resolution of 0.2 mm. After the exploratory view is displayed on the monitor, the proximal end of the tibia is located. The pQCT scan is started 3.4 mm distal from this point. The pQCT scan is 1 mm thick, has a voxel size (three-dimensional pixel) of 0.140 mm, and consists of 145 projections through the cut. After the pQCT is completed, the image is displayed on the monitor. A region of interest including the tibia but excluding the fibula is indicated. The soft tissue is automatically removed using an iterative algorithm. The density of the rest of the bone (total density) is reported in mg / cm3. The outer 55% of the bone is removed in a concentric spiral. The density of the remaining bone (Trabecular Density) is reported in mg / cm3. One week after the BMD evaluation, the rats are euthanized by suffocation of carbon dioxide and the blood is collected for cholesterol determination. The uterus is removed and the weights are taken. Total cholesterol is determined - using a Boehringer-Mannhei Hitachi 911 clinical analyzer using the Cholesterol / HP equipment. The statistics are compared using a one-variance analysis with Dunnet's test. EXAMPLE 67 Antiproliferative Test Method MCF-7 / ERE Provision solutions of test compounds (usually 0.1 M) are prepared in DMSO and then diluted 10 to 100 times with DMSO to make development solutions of 1 or 10 mM. The provisions of DMSO are stored at either 4o (0.1 M) or -20 ° C (<0.1 M). The cells are passed MCF-7 twice a week with growth medium [D-MEM / F-12 medium containing 10% heat inactivated fetal bovine serum (v / v), Penicillin-Streptomycin 1% (v / v), and 2 mM glutaMax-1]. The cells are kept in flasks vented in 37 ° C inside a 5% C02 / 95% humidified air incubator. One day before the treatment, cells are plated with growth medium at 25,000 / well in plates with 96 wells and incubated at 37 ° C overnight. Cells are infected for 2 hours at 37 ° C with 50 μl / well of a 1:10 dilution of adenovirus 5-ERE-tk-luciferase in experimental medium [red phenol-free D-MEM / F-12 medium containing separate fetal bovine serum with 10% heat activated charcoal (v / v), 1% Penicillin-Streptomycin (v / v), glutaMax-1, 1 mM sodium pyruvate]. The wells are then washed once with 150 μ? of experimental medium. Finally, the cells are treated for 24 hours at 37 ° C in duplicates of 8 wells / treatment with 150 μ? / Well vehicle (<0.1% DMSO v / v) or compound that is diluted > 1000 times in experimental medium. The initial screening of the test compound is done in a single dose of 1 μM which is tested alone (agonist mode) or in combination with 0.1 nM 17β-estradiol (EC8o, antagonist mode). Each 96-well plate also includes a vehicle control group (0.1% DMSO v / v) and an agonist control group (either 17β-estradiol 0.1 or 1 nM). The dose response experiments are performed in either the agonist and / or antagonist modes on active compounds in log increments of 10 ~ 14 to 10"5 M. From these dose response curves, EC50 and IC50 values are generated. The final well in each treatment group contains 5 μl of M IC-182,780 3 xlO "5 (final concentration 10" 6M) as an ER antagonist control After the treatment, the cells are used in a shaker for 15 minutes. minutes with 25 μl / well of cell culture lysis reagent 1 time (Promega Corporation) Cell lysates (20 μl) are transferred to a 96-well luminometer plate and the activity of luciferaza is measured in a MicroLumat Lb luminometer 96 P (EG & G Berthold) using 100 μl / well of luciferaza substrate (Promega Corporation). Before the injection of the substrate, a background measurement of 1 second is made for each well. After injection of the substrate, the activity of the luciferase is measured for 10 seconds after a delay of 1 second. The data is transferred to a Macintosh personal computer and analyzed using the JMP (SAS Institue) software: this program subtracts the above reading from the luciferaza measurement for each well and then determines the average and standard deviation of each treatment. The luciferaza data are transformed by algorithms, and the Huber M estimate is used to decrease the weight of the underlined transformed observations. The software is used to analyze the transformed and weighted data for ANOVA in one way (Dunnett's test). The treatments of the compound are compared to the vehicle control results in the agonist mode, or the positive agonist control results (0.1 nM 17β-estradiol) in the antagonist mode. For the initial single dose experiment, if the results of the compound treatment are significantly different from the appropriate control (p <0.05), then the results are reported as the percent relative to the control of 17β-estradiol [ie, ( (Compound-vehicle control) / (control of 17ß-estradiol-vehicle control)) x 100]. The JMP software is also used to determine the EC50 and / or IC50 values from the non-linear dose response curves. Example 68 Inhibition of LDL oxidation-antioxidant activity Porcine aortas are obtained from a slaughterhouse, washed, transported in cold PBS, and aortic endothelial cells are harvested. To harvest the cells, the intercostal vessels of the aorta are tied, and one end of the aorta is held. The 0.2% collagenase, sterile filtered, fresh (Sigma Type I) is placed in the beaker and the other end of the beaker is clamped to form a closed system. The aorta is incubated at 37 ° C for 15-20 minutes, after which the collagenase solution is collected and centrifuged for 5 minutes at 2000 x g. Each granule is suspended in 7 ml of endothelial cell culture medium consisting of FEM medium DMEM / Ham free of phenol red supplemented with FBS separated with carbon / 5%), NuSerum (5%), L-glutamine (4 mM) ), penicillin-streptomycin (1000 U / ml, 100 μg / ml) and gentimycin (75 μg / ml), is seeded in 100 mm petri dishes and incubated at 37 ° C in 5% C02. After 20 minutes, the cells are rinsed with PBS and fresh medium is added, this is repeated again in 24 hours. The cells are confluent after about 1 week. The endothelial cells are fed routinely twice a week and, when they converge, trypsinize and are sown in a 1: 7 ratio. Cell-mediated oxidation of 12.5 μg / ml of LDL is allowed to proceed in the presence of the compound to be evaluated (5 μM) for 4 hours at 37 ° C. the results are expressed as the percent inhibition of the oxidative process as measured by the TBARS method (thiobarbituric acid reactive substances) for analysis of free aldehydes (Yagi K., Biochemical Méd 15: 212-216 (1976)). EXAMPLE 69 D12 Hypothalmic Cell Test Procedure Dotal rat hypothalamic cells are subcloned from the parental cell line RCF17 and stored frozen. Routinely grown in DMEM: F12 (1: 1), glutaMAX-1 (2 mM), penicillin (100 U / ml) -streptomycin (100 mg / ml), plus 10% fetal bovine serum (FBS). The cells are plated in phenol red free medium (DMEM-F12, glutaMAX, penicillin-streptomycin) containing separate FBS with 2-10% carbon at a confluent density (1-4 x 10 <6> cells). / 150 mm disk). The cells are fed 24 hours later with medium containing 2% separate serum: To test the agonist activity, the cells are treated with 17β-estradiol nM or several doses of test compound (lmM or a range of 1 pM to 1 mM). To test the antagonist activity cells are treated with 0.1 nM 17β-estradiol in the absence or presence of varied doses (100 pM to 1 mM) of test compound. The control boxes are also treated with DMSO as a negative control. Forty-eight hours after the addition of the hormone, the cells are lysed and the binding test procedure is performed. For each binding test procedure, 100-150 mg of protein is incubated with 10 nM 3H-R5020 + 100 times excess of R5020 in a volume of 150 ml. Triplicate reactions (three with R5020, three without R5020) are prepared in a 96-well plate. The protein extract is first added followed by 3H-R5020 + lOOx not labeled R5020. The reaction is carried out for 1-2 hrs at room temperature. The reaction is stopped by the addition of 100 ml of 5% carbon (Norit SX-4), 0.5% dextran 69K (Pharmacia) in TE pH 7.4. After 5 minutes at room temperature, bound and unbound ligand are separated by centrifugation (5 minutes, 100 RCF, 4 ° C). The supernatant solution is removed (-150 ml) is removed and transferred to a scintillation vial. After the addition of scintillation fluid (Beckman Ready Protein +), the samples are counted for 1 minute in a scintillation counter. EXAMPLE 70 Progesterone Receptor in the Preoptic Area of the CNS Sixty (60) day old female Sprague-Dawley rats are ovarioctomized. The animals are housed in an animal care facility with a photoperiod of 12 hours of light, 12 hours of darkness and free access to running water and rodent food. The ovariectomized animals are randomly divided into groups that are injected with vehicle (50% DMSO, 40% PBS, 10% ethanol vehicle), 17β-estradiol (200 ng / kg) or the compound to be tested. The additional animals are injected with the test compound 1 hour before the injection of 17β-estradiol to evaluate the antagonistic properties of this compound. Six hours after the s.c. injection, the animals are euthanized with a lethal dose of C02 and their brains are collected and frozen. The tissue collected from animals is cut in a cryostat at -16 ° C and collected in slides on a slide coated with silane. Sectioned cuts are then dried in a cutting heater maintained at 42 ° C and stored in cut-off boxes at -80 ° C. Before processing, the dissected cutting boxes are heated slowly to room temperature (-20 ° C for 12-16 hours, 4 ° C for 2 hours, room temperature for 1 hour) to eliminate the formation of condensation in cuts and from this shape minimizes tissue and degradation of AKN. The dry cuts are loaded onto metal shelves, post-set in 4% paraformaldehyde (pH 9.0) for 5 minutes and processed as previously described.

A plasmid that "contains an 815 bp fragment of the PR 9 cDNA (ligand binding domain) and is used to generate a probe labeled S 35 -UTP that is complementary to a portion of the rat mRNA PR is linearized. Processed section assemblies are hybridized with 20 ml of hybridization mixture containing the riboprobe (4-6 xlO 6 DPM / cut) and 50% formamide and incubated overnight in a humidified chamber at 55 ° C. , the sections are placed in metallic shelves that are immersed in 2xSSC (0.15 M NaCl, 0.015 M sodium citrate, pH 7.) / 10 mM DTT The shelves are all transferred to a large container and washed in 2xSSC / DTT 10 M for 15 minutes at room temperature with gentle shaking.The cuts are then washed in RNase buffer at 37 ° C for 30 minutes, treated with RNase A (2 mg / ml) for 30 minutes at 37 ° C, and wash for 15 minutes at room temperature IX SSC Subsequently, the cuts are washed (2 x 20 minutes) at 65 ° C in 0.1X SSC to remove the non-specific label, rinse at room temperature 0.1X SSC for 15 minutes and dehydrate with a graduated series of ammonium acetate: alcohol (70%, 95% and 100%). The air-dried cuts are opposed to an X-ray film for 3 days and then processed photographically. The cuts from all the animals are hybridized, washed, exposed and photographically processed among themselves to eliminate the differences due to the interassay variation in the conditions.

Example 71 Rat fights-effects in the CNS Ovarianized, Sprague-Dawlye rats are obtained from 60 days of age after surgery. Surgeries are done a minimum of 8 days before the first treatment. Animals are individually housed under a 12-hour light / dark cycle and given standard rat food and water ad libitum. Two control groups are included in each study.

Doses are prepared based on mg / kg body weight of the medium group in either 10% DMSO in castor oil (sc studies) or 1.0% tween 80 in saline (studies po). The animals are administered with the test compounds in doses in the range of 0.01 to 10 mg / kg of body weight of the medium group. Vehicle and ethinyl estradiol (EE) controls (0.1 mg / kg, sc or 0.3 mg / kg po) control groups are included in each test. When the compounds are tested for their antagonistic activity. EE is coadministered 0. 1 or 0.3 mg / kg for sc or po studies, respectively. The test compounds are administered until the day when the skin temperature of the tail is measured. After the acclimatization period of four days, the animals are treated once daily with the compound of interest. There are 10 animals / treatment group. The administration of the compound is either by sc injection of 0.1 ml into the neck of the neck or po into a volume of 0.5 ml. On the third day . of the treatment, a granule of morphine (75 mg of morphine sulfate) is implanted subcutaneously. On the 5th day of treatment, one or two additional morphine granules are implanted. On day eight, approximately half of the animals are injected with Ketamine (80 mg / kg, intramuscularly) and a thermocouple connected with a MacLab Data Acquisition system (API Instruments, Milford, MA) is capped with the tail approximately one inch ( 2.54 cm) of the root of the tail. This system allows the continuous measurement of tail fur temperature. The baseline temperature is measured for 15 minutes, then sc (0.2 ml) naloxone (1.0 mg / kg) is given to block the effect of morphine and the tail skin temperature is measured for one hour after this. On day nine, the rest of the animals are fixed and analyzed similarly. Example 72 Vasomotor function in isolated rat aortic rings The Sprage-Dawley rats (240-260 grams) are divided into 4 groups: 1. Non-ovarian normal (intact) 2. ovarianized (ovex) treated with vehicle 3. ovarianized treated with 17β -estradiol (1 mg / kg / day). . ovarianized animals treated with test compound (ie, 1 mg / kg / day) Animals are ovarianized approximately 3 weeks prior to treatment. Each animal receives 1 mg / kg / day of either 17β-estradiol sulfate or test compound suspended in deionized water distilled with 1% Tween-80 by gastric gavage. The vehicle treated animals receive an appropriate volume of vehicle used in the drug treated groups. The animals are euthanized by CO 2 inhalation and exsanguination. Their thoracic aortas are rapidly removed and placed at 37 ° C in physiological solution with the following composition (mM); NaCl (54.7), KCl / 5.0), NaHCO3 (25.0), MgCl2 2H20 (2.5), D-glucose (11.8) and CaCl2 (0.2) gasified with C02-02, 95% / 5% for a final pH of 7.4. The adventitia is removed from the outer surface and the recipient is placed in 2-3 mm wide rings. The rings are suspended in 10 ml of tissue bath with one end attached to the bottom of the bath and the other end to a force transducer. A remaining tension of 1 gram is placed in the rings. The rings are balanced for 1 hour, the signals are acquired and analyzed. After equilibration, the rings are exposed to increased concentrations of phenylephrine (10 ~ 8 to 10 ~ 4 M) and the tension recorded. The baths are then rinsed 3 times with fresh buffer. After washing, 200 mM L-NAME is added to the tissue bath and equilibrated for 30 minutes. The phenylephrine concentration response curve is then repeated.

EXAMPLE 73 Radial Limb Deck of Eight Arms - Increase in Cognition Female Cd, Sprague-Dawley rats (Charles River, Kingston, NY) weighing 200-250 g on arrival are used. For one week, the rats are housed, six per cage, with standard laboratory food and water available ad libitum. The accommodation is a quarter of colony maintained at 22 ° C and has a cycle of 12 light / dark hours with light at 6:00 AM. After becoming accustomed to the installation, the animals are housed individually and kept at 85% free weight. Once stable weights are obtained, the rats are acclimated to the radial mallet of the arm 8. The mallet structure is an adaptation of that of Peele and Baron (Pharmacology, Biochemistry, and Behavior, 29: 143-150, 1988). The mallet is raised to a height of 75.5 cm and is composed of a circular area surrounded by 8 arms radiating from the center, equidistant from each other. Each arm is 58 cm long x 13 cm high. A clear plexilliary cylinder is loaded to enclose the animal in the central portion of the deck before the start of each session. Each arm of the deck is equipped with 3 groups of interconfronted photocells to a data acquisition unit, which in turn interconfronts a computer. The photocells are used to track the movement of the tag in the deck.

The granule feeders located above the cups of food at the end of each arm, dispense two chocolate granules of 45 mg when the outer photocell of the arm is activated for the first time in a given session. The arm is placed in a test room with black and white geometric posters on each wall to serve as visual inputs. During all training and testing procedures, white noise (-70 db) is audible. The training procedure consists of five phases, each with daily sessions that last 5 or 10 minutes. A second delay is imposed between the time the rat is placed in the central portion of the deck and when the cylinder is increased to start the session. During phase I, restricted rat food pairs are placed in the bundle for 10 minutes with 45 mg chocolate feed granules in all 8 arms of the bundle. During Phase II, each rat is placed individually in the deck for a period of 10 minutes, with granules scattered from the middle of the photocell to the food cup of each arm. During Phase III, each rat is placed in the bundle for a period of 10 minutes, with food pellets that are located only in and around cups of food in each arm. In Phase IV, each rat is allowed 10 minutes to collect two granules from each arm. Reentry in an arm is considered an error. Rats are trained daily in this manner until they achieve criterion behavior with less than or equal to 2 total errors on three consecutive days of training. The total habituation and training time is approximately 3 weeks. The test compound is prepared in a buffered saline solution and administered in a volume of 1 ml / kg. Scopolamine HBr (0.3 mg / kg s.c.) serves as the damaging agent, which produces an increase in error ratio (memory loss). The test compound is given intraperitoneally simultaneously with scopolamine, 30 minutes before the first exposure to the mallet on any given test day. To evaluate the test compound, a balanced 8 x 8 Latin box for repeated measurements is designed, in order to achieve high experimental efficiency with at least a number of animals. Eight experimental sessions, two per week, are performed with the 8 treatments (vehicle, scopolamine, 3 dsis of test compound in combination with scopolamine) randomly within each session. Each treatment follows each other treatment the same number of times. Therefore, the residual effect of each treatment can be estimated and removed from the treatment effect. After ANOVA, multiple comparisons are made using a two-sided Dunnett test in the adjusted medium.

Animals that do not make 4 correct choices within 5 minutes during the first exposure, or that do not make a total of 8 choices by the end of the second exposure, are considered to be "out of time" for that session. Any animal that is "out of time" after the administration of more than one dose of the test compound is excluded from the analysis. Example 74 Neuroprotection Inhibition of time-dependent death of cells in primary cortical neuronal cultures Primary cortical neurons are produced from rat brains that are 0-1 day old using a variation of methods described by Monyer et al. 1989, Brain Research 483: 347-354. The brain tissue dispersed in % DMEM / PDHS (pregnant donor horse serum) for three days and then treated with cytosine arabinoside (ARC) for two days to remove the contaminating glia cells. On day 5, the ARC medium is removed and replaced with 10% DMEM / PDHS. Neuronal cells are cultured for an additional 4-7 days before use. The primary control neuronal cultures show progressive cell death between days 12 and 18 in culture. The twelve cultures are evaluated on days 12 and 16 for lactate dehydrogenase (LD) enzyme levels after adding the test compound to 6 cultures maintained in DMEM and 10% PDHS on day 9 and keeping the remaining cultures as the controls. LD is tested using a variation of the method by Wroblewski et al. 1955, Proc. Soc. Exp. Biol .. Med. 90: 210-213. LD is a cytosolic enzyme while it is commonly used in both clinical and basic research to determine tissue viability. An increase in mean LD is directly related to cell death. Neuroprotection against hypoglycemia-induced cytotoxicity C6 glioma cells obtained from ATTC in RPMl medium are plated with FBS at a concentration of 1 x 10 < 1 > cells / ml in FALCON 25 cm2 of tissue culture flasks. Four hours before the onset of hypoglycemia, the maintenance medium is discarded, the monolayers are washed twice in the appropriate medium and then incubated for four hours at 37 ° C in either serum-free or serum-free test compound. plus Kreb's Ringer's phosphate buffer is used to wash the monolayers twice before adding the appropriate treatment with glucose. The RPMl medium contains 2 mg glucose / ml; the flasks are divided into groups of 5 each receiving 100% glucose (2 mg / ml), 80% glucose (1.6 mg / ml), 50% glucose (1.2 mg / ml), or 0% glucose ( buffer) or supplemented with test compound. All flasks are incubated for 20 hours and then evaluated for number of dead, live, and total cells using triptan blue. Neuroprotection against excitotoxic amino acids Five culture plates containing SK-N-SH neuroblastoma cells are treated with test compound and 5 culture plates are treated with RPMl medium. Four hours later, all cells are treated with NMDA (500 mu M) for 5 minutes. The total living cells and the dead cells are then determined. Neuroprotection against oxygenated glucose dehydration Analysis of piknotic nuclei to measure apoptosis: Cortical neurons are prepared from rat fetus E18 and placed on plates in slices of. 9-well chamber pre-coated with poly-D-lysine (10 ng / ml) and serum at a density of 100,000 cells / well. The cells are plated in DMEM concentrated in glucose containing 10% FCS and kept in the incubator at 37 ° C with 10% C02 / 90% air. On the next day, the serum is removed by replacing it with culture medium with concentrated DMEM in glucose containing B27 supplemented and the cells are kept in the incubator without also changing the medium until the day of the experiment. On day 6, the cuts were divided into two groups, control group and OGD group. Cells in the control group receive DMEM with glucose and B27 to taste (without antioxidant). The cells in the OGD group receive DMEM without glucose with B27 to taste, which has been degassed under vacuum for 15 minutes. The cells are flowed with 90% N2 / 10% CO2 for 10 minutes in an air chamber and incubated at 37 ° C for 6 hours. After 6 hours, both the control and the OGD cells are subjected to replacement of medium containing either the vehicle (DMSO) or test compound in DMEM containing glucose with B27 to taste. The cells are returned to a normoxic incubator at 37 ° C. After 24 hours, the cells are fixed in 4% PFA for 10 minutes at 4 ° C and stained with Topro (fluorescent nuclear binding dye). Apoptosis is evaluated using Scanning Cytometer for measuring piknotic nuclei. Measurement of LDH release as an indication of cell death: Cortical neurons are prepared from rat El8 fetus and placed in 48-well culture plates pre-coated with poly-D-lysine (10 ng / ml) and serum in a density of 150,000 cells / well. Cells are plated in DMEM with high glucose concentration containing 10% FCS and kept in the incubator at 37 ° C with 10% C02 / 90% air. The next day, serum is removed by replacing culture medium with DMEM with high concentration of glucose containing B27 complement. On day 6, the cells are divided into two groups: the control group and the OGD group. Cells in the control group receive DMEM without glucose with B27 to taste, which has been degassed under vacuum for 15 minutes. The cells are flowed with 90% N2 / 10% CO2 for 10 minutes in a fixed air chamber and incubated at 37 ° C for 6 hours. After 6 hours, the control cells and OGD are subjected to replacement of medium containing either vehicle (DMSO) or test compound in DMEM containing glucose with B27 to taste. The cells are returned to a normoxic incubator at 37 ° C. After 24 hours, cell death is assessed by measuring the cellular release of LDH (lactate dehydrogenase) in the culture medium. For the LDH assay, an aliquot of 50 μl of culture medium is transferred into the 96-well plate. After the addition of 140 μl of 0.1 M potassium phosphate buffer (pH 7.5) and 100 μl of 0.2 mg / mg of NADH, the plate is left in the dark at room temperature for 20 minutes. Retraction is initiated by the addition of 10 μl of sodium pyruvate. The plate is read immediately at 340 mM on a thermometer plate reader (Molecular Devices). Absorbance is recorded, an index of concentration of NADH, every 6 seconds for 5 minutes and the slope indicating the rate of disappearance of NADH is used to calculate LDH activity. LDH activity (U / ml) = (? A / min) (TCF) (20) (0.0833) / (.78) Where: 0.0833 = constant of proportionality 0.78 = length of light path of the instrument (cm) Example 75 Test procedure Rat HLA- Crohn's Disease and Intestinal Inflammatory Disorders Male HLA-B27 rats are obtained from Taconic and provide unrestricted access to a food (PMI Lab diet 5001) and water. At the start of the study, the rats are 22-26 weeks old. The rats are dosed subcutaneously once per day per site days with one of the formulations listed below. There are five rats in each group and the last dose is administered two hours before euthanasia. • vehicle (50% DMSO / 50% Dulbecco PBS) - • 17a-ethynyl-17β-estradiol (10 μg / kg) • test compound The quality of the feces is observed and they are graduated according to the following scale. Diarrhea = 3, soft stools = 2; normal stools = l. At the end of the test procedure, the serum is collected and stored at -70 ° C. One is prepared. section of the colon for histological analysis and an additional segment for myeloperoxidase activity is analyzed. The following method is used to measure myeloperoxidase activity. The colon tissue is harvested and quick frozen in liquid nitrogen. A representative sample of the entire colon is used to ensure consistency between samples. The tissue is stored at -80 ° C until use. Then, the tissue is weighed (approximately 500 mg) and homogenized in 1:15 p / v of 5 mM H2KP0 (pH 6) wash buffer. The tissue is rotated at 20,000 x g in a Sorvall RC 5B centrifuge for 45 minutes at 2-8 ° C. The supernatant is then discarded. The tissue is resuspended and homogenized in 2.5 ml (1: 5 p / v) of 50 mM H2KP04 with 10 mM EDTA and 0.5% ammonium bromide hexane to help solubilize the intracellular MPO. The tissue is frozen in liquid Nitrogen, thawed in a 37 ° C water bath and sonicated for 15 seconds to ensure membrane lysis. The procedure is repeated 3 times. The samples are then kept on ice for 20 minutes and centrifuged at 12,000 x g for 15 minutes at 2-8 ° C. The supernatant is analyzed following these steps. The test mixture is prepared by adding 2.9 ml of 50 mM H2KP04 with 0.167 O-dianisidine / ml with 0.0005% H202 in a reaction tube. When hydrogen peroxide is degraded, O-dianisidine is oxidized and absorbed at 460 nm in a concentration-dependent manner. The mixture is heated to 25 ° C. One hundred (100) μl of the tissue supernatant is added to the reaction tube, incubated for 1 minute at 25 ° C, then 1 ml is transferred to a disposable plastic cup. The OD is measured every 2 minutes reaction time at 460 nm against a blank containing 2.9 ml of the reaction mixture and 100 μl of the 0.5% ammonium bromide solution.

Enzyme activity units are quantified by comparison of absorbance © 460 for a standard curve prepared with purified human MPO 31.1 units / Vial. The MPO is reconstituted and serially diluted using 50 mM H2KP0 with 10 mM EDTA and 0.5% Ammonium Bromide Hex at four known concentrations. Sample absorbances are compared against this curve to determine activity. The histological analysis is carried out as follows: the colonic tissue is immersed in 10% neutral buffered formalin. Each colon specimen is separated into four samples for evaluation. Solid tissues with formalin are processed in a vacuum infiltration processor for paraffin embedded. The samples are sectioned at 5 μm and then stained with hematoxylin and eosin (H &E) for blind histological evaluations using a modified scale after Boughton-Smith.

After the classifications are completed the samples are not blind, and the data are tabulated and analyzed by linear ANOVA modeling with multiple mean comparisons. All patents, publications, and other documents cited herein are incorporated herein by reference in their entirety. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present disclosure of the invention.

Claims

Having described the invention as above, the content of the following claims is claimed as property: 1. A compound having the formula characterized in that R1, R2, R3, R5, R6, R7 and R8 are each, independently, selected from hydrogen, hydroxyl, Ci-Ce alkyl, Ci-Ce alkoxy, or halogen; R4 is hydrogen, Ci-Ce alkyl, halogen, Ci-Ce alkoxy, -CN, C2-C8 alkenyl, -CHO, aryl, furyl, thienyl, pyrimidinyl or pyridinyl; With the proviso that at least one of R1-R8 is different from H; Each of the alkyl, alkoxy, alkenyl, aryl, furyl, thienyl, pyrimidinyl or pyridinyl groups are optionally substituted; and O a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that R4 is selected from Ci-Ce alkyl, halogen, Ci-Ce alkoxy, -CN, C2-C7 alkenyl, -CHO, phenyl, furyl, thienyl, pyrimidinyl and pyridinyl.
3. The compound according to claim 1, characterized in that R4 is selected from hydrogen, Ci-Ce alkyl, halogen, Ci-Cβ alkoxy, -CN, C2-C7 alkenyl, furyl, thienyl, and pyridinyl.
4. The compound according to any of claims 1 to 3, characterized in that R5, R7 and R8 10 are each, independently, hydrogen or halogen.
5. The compound according to any of claims 1 to 4, characterized in that R1, R2, R3 and R6 are each independently hydrogen, halogen or hydroxyl.
6. The compound according to any of claims 1 to 5, characterized by at least one of R1, R2, R3 and R6 is hydroxyl.
7. The compound according to any of claims 1 to 6, characterized in that R2 and R6 are each hydroxyl. The compound according to claim 1, characterized in that it is one of the following: (a) 5 H -dibenzo [c, g] chromene-3,9-diol 5 (b) 8-chloro-5 H -dibenzo [c , g] chromene-3, 9-diol (c) 7-chloro-5H-dibenzo [c, g] chromene-3,9-diol; (d) 7-bromo-5H-dibenzo [c, g] chromene-3,9-diol (e) 3,9-dihydroxy-5H-dibenzo [c, g] chromene-7-carbonitrile (f) 7-methoxy-5H-dibenzo [c, g] chromene-3,9-diol (g) 7-vinyl-5H-dibenzo [c, g] chromene-3,9-diol (h) 12-bromo -7-methoxy-5H-dibenzo [c, g] chromene-3,9-diol (i) 12-chloro-7-methoxy-5H-dibenzo [c, g] chromene-3,9-diol (j) 7 -methyl-5H-dibenzo [c, g] chromene-3,9-diol (k) 7- [2- (hydroxymethyl) f-enyl] -5H-dibenzo [c, g] chromene-3,9-diol (1 7-f-enyl-5H-dibenzo [c, g] chromene-3, 9-diol (m) 7- (2-tolyl) -5H-dibenzo [c, g] chromene-3,9-diol (n) 7- (3-tolyl) -5H-dibenzo [c, g] chromene-3,9-diol (o) 7- (4-tolyl) -5H-dibenzo [c, g] chromene-3,9-diol ( p) 7- (4-methoxyphenyl) -5H-dibenzo [c, g] chromene-3, 9-diol (q) 7- (4-chlorophenyl) -5H-dibenzo [c, g] chromene-3, 9- diol (r) 7- (4-f luorofenyl) -5H-dibenzo [c, g] chromene-3,9-diol (s) 7-thien-2-yl-5H-dibenzo [c, g] chromene- 3,9-diol (t) 7-thien-3-yl-5H-dibenzo [c, g] chromene-3,9-diol (u) 7- (3-fluoro-enyl) -5H-dibenzo [c, g] ] chromene-3, 9-diol (v) 7- (3-chlorophenyl) -5H-dibenzo [c, g] chromene-3,9-diol (w) 7- (3-methoxy-enyl) -5H-dibenzo [ c, g] chromene-3, 9-diol (x) 7- (2-cl orophenyl) -5H-dibenzo [c, g] chromene-3, 9-diol (y) 7- (3, 4-difluorofenyl) -5H-dibenzo [c, g] chromene-3, 9-diol (z ) 7- (4-pyridyl) -5H-dibenzo [c, g] chromene-3,9-diol (aa) 7- (2-fluorofenyl) -5Hjdibenzo [c, g] chromene-3,9-diol ( bb) 7- (3, 4-dimethylphenyl) -5H-dibenzo [c, g] chromene-3,9-diol (ce) 7- (4-cyanophenyl) -5H-dibenzo [c, g] chromene-3 , 9-diol (dd) 7- (3-fluoro-4-methylphenyl) -5H-dibenzo [c, g] chromene-3,9-diol (ee) 7- (3,4-dimethoxyphenyl) -5H-dibenzo [c, g] chromene-3, 9-diol (ff) 7- (3-trif luoromethylphenyl) -5H-dibenzo [c, gjeromeno-3,9-diol (gg) 7- (3, 5-dif luorof enyl) -5H-dibenzo [c, g] chromene-3, 9-diol (hh) 7- (3, 5-dichlorofenyl) -5H-dibenzo [c, g] chromene-3, 9-diol (ii) 7- (3-methyl-4-f-luo-phenyl) -5H-dibenzo [c, g] chromene-3,9-diol (jj) 7- (3-furyl) -5H-dibenzo [c, g] chromene-3 , 9-diol (kk) 7- (2-furyl) -5H-dibenzo [c, g] chromene-3, 9-diol (11) 7-butyl) -5H-dibenzo [c, g] chromene-3, 9-diol (mm) 7- (3-pyridinyl) -5H-dibenzo [c, g] chromene-3,9-diol (nn) 7- (4-methoxy-3-pyr) dil) -5H-dibenzo [c, g] chromene-3, 9-diol (oo) 7- (pyrimidyl-5H-dibenzo [c, g] chromene-3,9-diol (PP) 7- (5-methoxy -3-pyridyl) -5H-dibenzo [c, g] chromene-3,9-diol (qq) 7- (2-pyridyl) -5H-dibenzo [c, g] chromene-3,9-diol (rr) 7- (3,4-dichlorof nyl) -5H-dibenzo [c, g] chromene-3,9-diol (ss) 7- (4-methyl thiofenyl) -5H-dibenzo [c, g] chromene-3,9-diol (tt) 7- (4-cyanomethyl-enyl) -5H-dibenzo [c, g] chromene-3,9-diol (uu) 7- (3-trifluoromethoxy-enyl) -5H-dibenzo [c, g] chromene - 3,9-diol (w) 7- (4-trifluoromethoxyphenyl) -5H-dibenzo [c, g] chromene-3,9-diol (ww) 7- (4-tert-butylphenyl) -5H-dibenzo [c, g] chromene-3, 9-diol (xx) 7- (naphthyl) -5H-dibenzo [c, g] chromene-3, 9-diol (yy) 7- (4-ethylphenyl) -5H- dibenzo [c, g] chromene-3,9-diol (zz) 7- (3, 5-dimethylphenyl) -5H-dibenzo [c, g] chromene-3,9-diol 9. A pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 8, and a pharmaceutical carrier. A method for inhibiting osteoporosis in a mammal in need thereof, characterized in that it comprises providing the mammal with an effective amount of a compound according to any of claims 1 to 8. 11. A method for inhibiting osteoarthritis, hypocalcemia, hypercalcemia, Paget's disease, osteomalacia, osteohalistresis, multiple myeloma or other forms of cancer that have harmful effects on bone tissues in a mammal in need thereof, characterized in that it comprises providing the mammal with an effective amount of a compound in accordance with any of the claims 1 to 8. A method for inhibiting growth of abnormal benign or malignant tissue in a mammal in need thereof, characterized in that it comprises providing the mammal with an effective amount of a compound according to any of claims 1 to 8. The method according to claim 12, characterized because the growth of abnormal tissue is prostatic hypertrophy, uterine leiomyomas, breast cancer, endometriosis, endometrial cancer, polycystic ovary syndrome, endometrial polyps, benign breast disease, adenomyosis, ovarian cancer, melanoma, prostate cancer, colon cancers , or CNS cancers. 14. A method to decrease cholesterol, triglycerides, Lp (a), or LDL levels; or to inhibit hypercholesterolemia; hyperlipidemia; cardiovascular disease; atherosclerosis; peripheral vascular disease; restenosis, or vasospasm; or to inhibit vascular wall damage from cellular events leading to vascular damage mediated by immunity in a mammal in need thereof, characterized in that it comprises providing the mammal with an effective amount of a compound according to any one of claims 1 to 8. 15. A method for inhibiting disease states induced by free radicals in a mammal in need thereof, characterized in that it comprises providing the mammal with an effective amount of a compound according to any of claims 1 to 8. 16. A method for providing increased cognition- or neuroprotection, or treating or inhibiting senile dementia, Alzheimer's disease, cognitive decline, or neurodegenerative disorders in a mammal in need thereof, characterized in that it comprises providing the mammal with an effective amount of a compound in accordance with with any of claims 1 to 8. 17. A method to inhibit inflammatory bowel disease, ulcerative proctitis, Crohn's disease, - colitis, hot flushes, vaginal or vulvar atrophy, atrophic vaginitis, vaginal dryness, pruritus, dyspareunia, dysuria, frequent urination, urinary incontinence, urinary tract infections, symptoms vasomotor, male pattern baldness; skin atrophy; acne, type II diabetes, dysfunctional uterine bleeding; or infertility in a mammal in need thereof, characterized in that it comprises providing the mammal with an effective amount of a compound according to any one of claims 1 to 8. 18. A method for inhibiting leukemia, endometrial ablations, chronic kidney or liver disease. , or diseases or coagulation disorders in a mammal in need thereof, characterized in that it comprises providing the mammal with an effective amount of a compound according to any of claims 1 to
8. The compound according to any of claims 1 to 8 characterized in that use as a pharmaceutical is used.-