WO2008030771A1 - Composés d'alkylidène cycliques en tant que modulateurs sélectifs des récepteurs des œstrogènes - Google Patents

Composés d'alkylidène cycliques en tant que modulateurs sélectifs des récepteurs des œstrogènes Download PDF

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WO2008030771A1
WO2008030771A1 PCT/US2007/077356 US2007077356W WO2008030771A1 WO 2008030771 A1 WO2008030771 A1 WO 2008030771A1 US 2007077356 W US2007077356 W US 2007077356W WO 2008030771 A1 WO2008030771 A1 WO 2008030771A1
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disease
syndrome
compound
bone
treatment
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PCT/US2007/077356
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WO2008030771A8 (fr
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William John Zuercher
Dennis Heyer
Aaron Bayne Miller
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • the present invention relates to novel compounds with a variety of therapeutic uses, more particularly novel substituted cycloalkylidene compounds that are particularly useful for selective estrogen receptor modulation.
  • Estrogens are well-known endocrine regulators in the cellular processes involved in the development and maintenance of the reproductive system. Estrogens have also been shown to have important effects in many non-reproductive tissues such as bone, liver, the cardiovascular system, and the central nervous system. The most widely accepted hypothesis of how estrogens exert their effects is by binding to an intracellular steroid hormone receptor. After the receptor and bound ligand are transferred to the nucleus of the cell, the complex binds to recognition sites in DNA, which allows for the modulation of certain genes. Additionally, it is now becoming apparent that estrogens may mediate their effects via membrane-initiated signaling cascade, though much of this work is still experimental. Kousteni et al., Journal of Clinical Investigation, (2003), 111, 1651-1664, herein incorporated by reference with regard to such teaching.
  • tissue selectivity allows functionality as estrogen agonists in certain tissues, while acting as estrogen antagonists in other tissues.
  • SERMs selective estrogen receptor modulators
  • Examples of SERMs include tamoxifen, raloxifene, lasofoxifene, clomiphene, and nafoxidine. The molecular basis for this tissue-selective activity is not completely understood.
  • estrogen receptor alpha Historically estrogens were believed to manifest their biological activity through a single estrogen receptor, now termed estrogen receptor alpha (ERa). More recently, however, there was the discovery of second subtype of estrogen receptor, termed estrogen receptor beta (ER ⁇ ). See, Kuiper et al., WO 97/09348 and Kuiper et al., Cloning of a Novel Estrogen Receptor Expressed in Rat Prostate and Ovary, Proc. Natl. Acad. Sci. U.S.A., 1996, pp. 5925-5930, herein incorporated by reference with regard to such subtype. ER ⁇ is expressed in humans. See, Mosselman et al., ER ⁇ : Identification and Characterization of a Novel Human
  • Estrogen Receptor FEBR S Lett., 1996, pp. 49-53, herein incorporated by reference with regard to such expression.
  • the discovery of this second subtype of estrogen receptor significantly increased the biological complexity of estrogen signaling and may be responsible for some of the tissue-selective actions of the currently available SERMs.
  • estrogens have important effects in many non-reproductive tissues.
  • estrogen modulation is believed useful in the treatment or prophylaxis of diseases and conditions associated with such tissues, including bone, liver, and the central nervous system.
  • osteoporosis is characterized by the net loss of bone mass per unit volume. Such bone loss results in a failure of the skeleton to provide adequate structural support for the body, thereby creating an increased risk of fracture.
  • One of the most common types of osteoporosis is postmenopausal osteoporosis, which is associated with accelerated bone loss subsequent to cessation of menses and declining levels of endogenous estrogen in women.
  • SERM tamoxifen
  • tamoxifen decreases the risk of recurrent breast cancer, contralateral breast cancer, and mortality as well as increases the disease-free survival rate of patients with breast cancer at multiple stages of the disease.
  • the profile of tamoxifen is not ideal due to potential interactive properties on reproductive tissues, such as uterine tissues.
  • reproductive tissues such as uterine tissues.
  • Cardiovascular disease is the leading cause of death among postmenopausal women.
  • estrogen replacement therapy and/or hormone replacement therapy may be useful in the treatment of vasomotor symptoms, genitourinary atrophy, depression, and diabetes.
  • vasomotor symptoms Over 75% of women experience vasomotor symptoms during the climacteric years.
  • Clinical signs such as vasomotor symptoms and genitourinary atrophy, abate upon treatment with estrogen replacement therapy.
  • Sagraves, R., J. Clin. Pharmacol. (1995), 35(9 Suppl):2S-10S herein incorporated by reference with regard to such teaching.
  • Preliminary data suggest that estradiol may alleviate depression during perimenopause and that the combination of estrogens and selective serotonin reuptake inhibitors may alleviate depression during the postmenopausal period.
  • hormone replacement therapy may improve glycemic control among women with diabetes. PaNn, S. L. et al., Diabetes Research and Clinical Practice, (2001 ), 54, 67- 77; Ferrara, A. et al., Diabetes Care, (2001 ), 24(7), 1 144-1150), each incorporated herein by reference with regard to such teaching. There is a need, however, for improved therapies that present better side effect profiles.
  • the present inventors discovered a novel group of cycloalkylidene compounds, which bind to and modulate estrogen receptor alpha and estrogen receptor beta.
  • SERMS these compounds are believed to be useful for the treatment and/or prophylaxis of menopausal or postmenopausal disorders, including vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, and the treatment and/or prevention of osteoporosis.
  • the present invention includes novel compounds.
  • the present invention includes compounds of formula (I): including salts, solvates, and pharmacologically functional derivatives thereof wherein
  • X is -(CH 2 )n- where n is 0, 1 , 2, or 3;
  • R 1 is -O-(Ci-6)-R 4 where Ci_6 is a branched or unbranched alkyl chain having the specified number of carbon atoms; each of R 2 and R 3 are selected from H and Ci -6 ; and R 4 is selected from NH 2 , N(Ci -6 )H, and N(Ci -6 )(Ci -6 ).
  • n is 1 and each of R 2 and each of R 3 is Ci -6 .
  • each of R 2 and each of R 3 is selected from H and CH 3 .
  • each of R 2 and R 3 is H.
  • n 2 or 3 and each of R 2 and R 3 is H
  • R 1 is -0-(CHz) 2 -N(CH 3 )(CH 3 ).
  • R 1 is -O-(CH 2 ) 2 -N(CH 3 )(CH 3 ), and n is 1.
  • R 1 is -O-(CH 2 ) 2 -N(CH 3 )(CH 3 ), n is 2 or 3, and each of R 2 and R 3 is H.
  • Particularly preferred compounds of the present invention include: 4-[cycloheptylidene(4- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ phenyl) methyl]phenol; 4-[(4- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ phenyl)(3,3,5,5- tetramethylcyclohexylidene)methyl]phenol; and
  • Another aspect of the present invention includes compounds of formula (I) substantially as hereinbefore defined with reference to any one of the Examples.
  • compositions comprising the compounds of formula (I) and a pharmaceutically acceptable carrier.
  • Another aspect of the present invention includes the compounds of formula (I) for use as an active therapeutic substance.
  • Another aspect of the present invention includes the compounds of formula (I) for use in the treatment or prophylaxis of conditions or disorders affected by selective estrogen receptor modulation.
  • the treatment or prophylaxis relates to the following conditions hereinafter collectively referred to as "List A”: osteoporosis, bone demineralization, reduced bone mass, density, or growth, osteoarthritis, acceleration of bone fracture repair and healing, acceleration of healing in joint replacement, periodontal disease, acceleration of tooth repair or growth, Paget's disease, osteochondrodysplasias, muscle wasting, the maintenance and enhancement of muscle strength and function, frailty or age-related functional decline (“ARFD”), sarcopenia, chronic fatigue syndrome, chronic myaligia, acute fatigue syndrome, acceleration of wound healing, maintenance of sensory function, chronic liver disease, AIDS, weightlessness, burn and trauma recovery, thrombocytopenia, short bowel syndrome, irritable bowel syndrome
  • the treatment or prophylaxis relates to menopausal or postmenopausal disorders, including vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis.
  • Another aspect of the present invention includes the use of the compounds in the manufacture of a medicament for use in the treatment or prophylaxis of conditions or disorders associated with selective estrogen receptor modulation.
  • the medicament is for use in the treatment or prophylaxis of those conditions selected from List A.
  • the condition or disorder is menopausal or postmenopausal disorders, including vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis.
  • Another aspect of the present invention includes a method for the treatment or prophylaxis of conditions or disorders associated with selective estrogen receptor modulation comprising the administration of the compounds.
  • the treatment or prophylaxis relates to conditions selected from List A.
  • the condition or disorder is menopausal or postmenopausal disorders, including vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, or osteoporosis.
  • alkyl refers to a straight or branched chain hydrocarbon, preferably having from one to six carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n- butyl, tert-butyl, isopentyl, n-pentyl, and the like.
  • alkylene refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms.
  • alkylene examples include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted with at least one halogen.
  • branched or straight chained “haloalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, for example, fluoro, chloro, bromo, and iodo.
  • haloalkyl should be interpreted to include such substituents as perfluoroalkyl groups and the like.
  • alkoxy refers to the group -OR, where R is alkyl as defined above.
  • acyl refers to the group -C(O)R, where R is alkyl, aryl, heteroaryl, or heterocyclyl, as each is defined herein.
  • hydroxy refers to the group -OH.
  • carboxy refers to the group -C(O)OH.
  • nitro refers to the group -NO 2 .
  • amino refers to the group -NH 2 , or when referred to as substituted amino defines such groups substituted with alkyl.
  • cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring, preferably having from three to ten carbon atoms.
  • exemplary "cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • aryl refers to a benzene ring or to a benzene ring system fused to one or more additional benzene rings to form, for example, anthracene, phenanthrene, or naphthalene ring systems.
  • aryl groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, and the like.
  • heteroaryl refers to a monocyclic five to seven membered aromatic ring, or to a fused bicyclic aromatic ring system comprising two of such monocyclic five to seven membered aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen atoms, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • heteroaryl groups used herein include, but should not be limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, and the like.
  • heterocycle refers to a mono- or poly-cyclic ring system containing optionally one or more degrees of unsaturation and also containing one or more heteroatoms.
  • Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation.
  • Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s).
  • heterocyclic groups include, but are not limited to, tetrahydrofuran, pyran, 1 ,4-dioxane, 1 ,3- dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene.
  • the phrase "optionally substituted” or variations thereof denote an optional substitution, including multiple degrees of substitution, with one or more substituent group. The phrase should not be interpreted so as to be imprecise or duplicative of substitution patterns herein described or depicted specifically. Rather, those of ordinary skill in the art will appreciate that the phrase is included to provide for obvious modifications, which are encompassed within the scope of the appended claims.
  • Exemplary optional substituent groups include acyl; alkyl; alkenyl; alkynyl; alkylsulfonyl; alkoxy; cyano; halogen; haloalkyl; hydroxy; nitro; cycloalkyl, which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; heterocyclyl, which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; aryl, which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalky
  • the compounds of formulas (I) may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms (“polymorphs") are within the scope of formula (I).
  • Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I), as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise acid addition salts.
  • Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methylglucamine, oxalate, pam
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula I, or a salt or physiologically functional derivative thereof) and a solvent.
  • solvents for the purpose of the invention, should not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.
  • physiologically functional derivative refers to any pharmaceutically acceptable derivative of a compound of the present invention that, upon administration to a mammal, is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof.
  • Such derivatives may more specifically be considered to include salts, solvates, esters, amides, or salts or solvates of such esters or amides, and will be clear to those skilled in the art, without undue experimentation.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • compositions that include effective amounts of compounds of the formula (I) and salts, solvates, and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof, are as described above.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I) or salts, solvates, and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant physician or veterinarian.
  • an effective amount of a compound of formula (I) for the treatment of humans suffering from osteoporosis generally, should be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day. More usually the effective amount should be in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal the actual amount per day would usually be from 70 to 700 mg.
  • This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt, solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of formula (I) per se. Similar dosages should be appropriate for treatment of the other conditions referred to herein that are mediated by estrogen.
  • Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Such a unit may contain, as a non-limiting example, 0.5mg to 1 g of a compound of the formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by an oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual or transdermal
  • vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal) route.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each with aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • powders are prepared by comminuting the compound to a suitable fine size and mixing with an appropriate pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol.
  • Flavorings, preservatives, dispersing agents, and coloring agents can also be present.
  • Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or some other appropriate shell material.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the mixture before the encapsulation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • binders examples include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants useful in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture may be prepared by mixing the compound, suitably comminuted, with a diluent or base as described above.
  • Optional ingredients include binders, such as carboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone, solution retardants, such as paraffin, resorption accelerators such as a quaternary salt and/or abr sorption agents such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be wet-granulated with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials, and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated generally by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners; and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of formula (I) and salts, solvates, and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • the compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • the formulations may be applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.
  • compositions adapted for nasal administration where the carrier is a solid, include a coarse powder having a particle size for example in the range 20 to 500 microns.
  • the powder is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insufflators.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question.
  • formulations suitable for oral administration may include flavoring agents.
  • Osteoporosis combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a salt, solvate, or physiologically functional derivative thereof, and the use of at least one other osteoporosis treatment method.
  • combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a salt, solvate, or physiologically functional derivative thereof, and at least one other osteoporosis treatment agent, for example, a bone building agent.
  • the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of formula (I) salts, solvates, or physiologically functional derivatives thereof with other osteoporosis treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including each compound; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other(s) subsequently or vice versa. Such sequential administration may be close in time or remote in time.
  • the compounds of the present invention and their salts, solvates, and physiologically functional derivatives thereof may be employed alone or in combination with other therapeutic agents for the treatment of the conditions herein described.
  • combination may be had with other anabolic or osteoporosis therapeutic agents.
  • osteoporosis combination therapies would thus comprise the administration of at least one compound of the present invention or a salt, solvate, or physiologically functional derivative thereof, and the use of at least one other osteoporosis therapy.
  • combination therapies according to the present invention inlcude the administration of at least one compound of the present invention or a salt, solvate, or physiologically functional derivative thereof, and at least one other osteoporosis treatment agent, for example, an anti-bone resorption agent.
  • the compound(s) of the present invention and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compound(s) and the agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention including salts, solvates, or physiologically functional derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • Bone building agents can lead to increases in parameters such as bone mineral density that are greater than those than can be achieved with anti-resorptive agents. In some cases, such anabolic agents can increase trabecular connectivity leading to greater structural integrity of the bone.
  • Other potential therapeutic combinations include the compounds of the present invention combined with other compounds of the present invention, growth promoting agents, growth hormone secretagogues, growth hormone releasing factor and its analogs, growth hormone and its analogs, somatomedins, alpha-ardenergic agonists, serotonin 5-HT D agonists, selective serotonin reuptake inhibitors, agents that inhibit somatostatin or its release, 5- ⁇ -reductase inhibitors, aromatase inhibitors, GnRH inhibitors, parathyroid hormone, bisphosphonates, estrogen, testosterone, SERMs, progesterone receptor agonists, and/or with other modulators of nuclear hormone receptors.
  • the compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions.
  • suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions.
  • Non- limiting examples include combinations of the present invention with anti-diabetic agents, anti-osteoporosis agents, anti-obesity agents, anti-inflammatory agents, antianxiety agents, anti-depressants, anti-hypertensive agents, anti-platelet agents, antithrombotic and thrombolytic agents, cardiac glycosides, cholesterol or lipid lowering agents, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, kinase inhibitors, thyroid mimetics, anabolic agents, viral therapies, cognitive disorder therapies, sleeping disorder therapies, sexual dysfunction therapies, contraceptives, cytotoxic agents, radiation therapy, anti-proliferative agents, and anti
  • An aspect of the present invention is the use of the compounds of the present invention for the treatment or prophylaxis of a variety of disorders including, but not limited to, conditions selected from List A.
  • the compounds of the present invention are believed useful, either alone or in combination with other agents, in the treatment of menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, female sexual dysfunction, breast cancer, depressive symptoms, diabetes, bone demineralization, and the treatment and/or prevention of osteoporosis.
  • the compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I).
  • the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. ENeI, S. H. Wilen, and L. N. Mander (Wiley-
  • Tr retention time
  • TFA trifluoroacetic acid
  • TEA triethylamine
  • THF tetrahydrofuran
  • TFAA trifluoroacetic anhydride
  • CD 3 OD deuterated methanol
  • CDCI 3 deuterated chloroform
  • DMSO dimethylsulfoxide
  • SiO 2 (silica); atm (atmosphere);
  • EtOAc EtOAc
  • CHCI 3 chloroform
  • MgSO 4 magnesium sulfate
  • CH 3 CN acetonitrile
  • K 2 CO 3 potassium carbonate
  • TiCI 4 titanium tetrachloride
  • EtOAc EtOAc
  • CO 2 carbon dioxide
  • P(o-tolyl) 3 tri-o-tolylphosphine
  • Na 2 SO 4 sodium sulfate
  • NaI sodium iodide
  • NaOH sodium hydroxide
  • AICI 3 aluminum chloride
  • (C 2 H 5 O) 2 P(O)H diethyl phosphite
  • NaN 3 sodium azide
  • CBr 4 carbon tetrabromide
  • PPh triphenylphosphine
  • CuI copper (I) iodide
  • Pd(Ph 3 P) 4 tetrakis(triphenylphosphine)palladium (O)
  • LiHMDS lithium bis(trimethylsilyl)amide
  • EDC ( ⁇ /-(3-dimethylaminopropyl)- ⁇ /'-ethyl-carbodimide; dpppe (1 ,5-bis(diphenylphosphanyl)pentane;
  • HPLC high performance liquid chromatography
  • tmeda ⁇ /, ⁇ /, ⁇ /', ⁇ /',-tetramethylethylenediamine
  • Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), m (multiplet), or br (broad).
  • APCI Atmospheric Pressure Chemical Ionization
  • ESI ESI Ionization
  • HRMS High resolution mass spectral data
  • the amine substituted symmetric alkylidene compounds III can be prepared as described in Scheme 1.
  • McMurry coupling between substituted benzophenones I, Il or IV and ketone V provides the cycloalkylidene diphenylethylenes VII, III or Vl respectively.
  • Amine substituted side chains can be introduced by standard alkylation procedures prior to or following McMurry coupling.
  • one of the phenol groups of I can be protected (such as IV) using synthetic procedures appreciated by those skilled in the art.
  • McMurry coupling of IV to yield Vl followed by alkylation and deprotection yields compound III.
  • Ketone V is either commercially available or may be prepared by synthetic methods appreciated by those skilled in the art.
  • Step 1 4,4'-(Cycloheptylidenemethanediyl)diphenol (V) To a stirred suspension of zinc powder (15.0 g, 0.23 mol) in THF (300 ml.) was slowly added TiCI 4 (12.5 ml_, 0.115 mol) via a syringe at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 1 h. A solution of bis(4-hydroxyphenyl)methanone (4.9 g, 0.023 mol) and cycloheptanone (7.74 g, 0.07 mol) in THF (100 ml.) was added to the reaction mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for an additional 2 h.
  • the reaction mixture was allowed to cool to room temperature.
  • the reaction mixture was poured into a 10% aqueous K 2 CO3 (1 L).
  • the reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc.
  • the filtrate was transferred to a separatory funnel and the layers were separated.
  • the aqueous phase was further extracted with EtOAc (4 x 250 ml_).
  • the combined organic phase was washed with brine (2 x 100 ml_), dried (Na 2 SO 4 ), filtered, and then concentrated under reduced pressure to give the crude product as a gold-yellow oil.
  • Step 2 4-[cycloheptylidene(4- ⁇ [2- (dimethylamino)ethyl]oxy ⁇ phenyl)methyl]phenol (2)
  • Cs 2 CO 3 (1.94 g, 5.94 mmol)
  • 2-(dimethylamino)ethyl chloride hydrochloride (0.154 g, 1.07 mmol)
  • NaI 0.178 g, 1.19 mmol
  • the reaction mixture was allowed to cool to room temperature then it was quenched with saturated NH 4 CI and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and the filtrate was concentrated to give the crude product as an oil.
  • the crude oil was purified by flash chromatography over silica gel using
  • Step 1 (4- ⁇ [2-(dimethylamino)ethyl]oxy ⁇ phenyl)(4-hydroxyphenyl)methanone (3)
  • the reaction mixture was cooled to room temperature and diluted with water (10 ml.) followed by 10% K 2 CO3 (10 ml_).
  • the reaction mixture was filtered over a pad of celite and the celite pad was washed with EtOAc.
  • the filtrate was extracted with EtOAc and the combined organics then washed with brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • the crude material was dissolved in MeOH and purified using reverse phase HPLC with CH 3 CN:H 2 O (50 to 100% CH 3 CN) to afford an amorphous solid.
  • the solid was partitioned between saturated K 2 CO 3 and EtOAc and the organic layer dried (Na 2 SO 4 ), filtered and concentrated.
  • Step 2 4-(Cyclooctylidene ⁇ 4-[benzyloxy]phenyl ⁇ methyl)phenol (6)
  • TiCI 4 (0.64 ml_, 5.8 mmol
  • the reaction mixture was then heated to 65 0 C.
  • a mixture of 4-benzyloxy-4'- hydroxybenzophenone (5) (0.82 g, 2.7 mmol) and cyclooctanone (0.57 g, 4.5 mmol) in THF (5 ml.) was added, and heating was continued overnight.
  • reaction mixture was then added to 10% aqueous NaHCO 3 (50 ml_), and the resulting suspension was filtered. The residue was washed with EtOAc (3 x 25 ml_), and the filtrates were combined, concentrated, and purified by flash column chromatography on silica gel (50 to 100% CH 2 CI 2 :hexanes elution) to yield 6 (0.56 g, 52%) as a viscous yellow oil which solidified upon standing.
  • Step 4 4-[Cyclooctylidene(4- ⁇ [2- (dimethylamino)ethyl]oxy ⁇ phenyl)methyl]phenol (8)
  • To a stirring solution of (2- ⁇ [4-(cyclooctylidene ⁇ 4-[benzyloxy]phenyl ⁇ methyl) phenyl]oxy ⁇ ethyl)dimethylamine (7) (0.19 g, 0.40 mmol) in EtOAc (20 ml.) was added 10% Pd/C (50 mg). The flask was flushed with H 2 and allowed to stir.
  • reaction mixture was filtered through celite, and the filtrate was purified by flash column chromatography on silica gel (0 to 10% MeOH in CH 2 CI 2 elution) to yield compound 8 as a white solid (136 mg, 88%).
  • Polylysine coated Yttrium Silicate SPA beads (Amersham #RPNQ 0010) are resuspended in assay buffer [10 mM potassium phosphate buffer pH 7.0 containing 2 mM EDTA, 50 mM NaCI, 1 mM DTT, 2 mM CHAPS, 10% glycerol] to a concentration of 1 g/60ml. 30 ul (0.5 mg) of the SPA beads are then added to each well of a Packard OptiPlate (Packard
  • the ERa or ER ⁇ protein is diluted to the appropriate concentration (empirically determined for each protein prep by generating a protein curve using 0.5 to 10 ug total protein and 1 nM [3H] Estradiol and selecting a protein concentration that does not deplete the radioligand) and added as 30 ⁇ l aliquots to each well. [2, 4, 6, 7, 16, 17-3H(N)]-Estradiol is added as a 30 ⁇ l aliquot to give a final assay concentration of 1 nM.
  • test compound solution typically in 10% DMSO as solvent
  • solvent containing no test compound to determine total binding, T
  • solvent containing 17-b-estradiol at 100 ⁇ M to determine non-specific binding, NS
  • At least two binding curves were generated for each compound.
  • the compounds of the Examples 1-3 exhibited plC 50 values ranging from 10 ⁇ M to 1 nM.
  • Test compounds were employed in free or salt form.

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  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne de nouveaux composés ayant diverses utilisations thérapeutiques, plus particulièrement de nouveaux composés d'alkylidène cycliques substitués qui sont particulièrement utiles pour la modulation sélective des récepteurs des œstrogènes.
PCT/US2007/077356 2006-09-08 2007-08-31 Composés d'alkylidène cycliques en tant que modulateurs sélectifs des récepteurs des œstrogènes WO2008030771A1 (fr)

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CN102786394A (zh) * 2012-07-30 2012-11-21 中国医学科学院医药生物技术研究所 取代双芳基亚甲基环烷基衍生物及其制备方法和应用
WO2017212059A1 (fr) * 2016-06-10 2017-12-14 Paris Sciences Et Lettres - Quartier Latin Synthèse de cyclofène-oh en cage photoactivable et de ses dérivés

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786394A (zh) * 2012-07-30 2012-11-21 中国医学科学院医药生物技术研究所 取代双芳基亚甲基环烷基衍生物及其制备方法和应用
WO2017212059A1 (fr) * 2016-06-10 2017-12-14 Paris Sciences Et Lettres - Quartier Latin Synthèse de cyclofène-oh en cage photoactivable et de ses dérivés
EP3266771A1 (fr) 2016-06-10 2018-01-10 Paris Sciences Et Lettres - Quartier Latin Synthèse de cyclofen-oh en cage photoactivable et ses dérivés

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