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Definitions

• Androgen signaling is mediated through the androgen receptor (AR) and is a nuclear signaling pathway of tremendous importance in mammals.
• AR androgen receptor
• this critical hormone signaling pathway affects a large number of non-sexual tissues including, bone, muscle, CNS, liver, etc.
• testosterone and dihydrotestosterone are the primary ligands that mediate AR- signaling. Both are high affinity ligands for AR, with dihydrotestosterone having somewhat higher affinity.
• Testosterone is converted to dihydrotestosterone through the action of 5a-reductase enzymes and is converted to 17p-estradiol (potent endogenous estrogen) through the action of P-450 aromatase enzymes.
• AR signaling is mediated by binding of an AR ligand to AR in the cellular cytosol, homodimerization of two AR receptors and nuclear location of the ligand bound dimer to the cell nucleus where the complex associates with various coactivators as well as Androgen Response Elements (palindrome-like sequences of DNA) which serve as activation sites for certain AR-mediated genes.
• both sexual and non-sexual, androgens such as testosterone and dihydrotestosterone have a number of potentially desirable actions as well as non-desirable actions depending on the particular individual's age, sex, therapeutic need, etc.
• certain positive consequences of AR-agonist signaling can be generalized as including increased bone mineral density and a corresponding reduction of risk of bone fractures.
• androgen supplementation can be very valuable in the prevention or treatment of osteoporosis where the osteoporosis might originate from any number of different causes, such as corticosteroid induced osteoporosis and age-related osteoporosis (e.g. postmenopausal).
• males and females respond to agonist supplementation with an increase in muscle mass and very often a decrease in fat mass.
• This is beneficial in a very large number of treatment modalities.
• Other muscle-wasting disorders such as muscular dystrophy in its many forms as well as related disorders might be treated to advantage with androgens.
• the increase in muscle mass with concomitant reduction in fat mass associated with anabolic androgen action has additional health benefits for many men and women including potentially increased sensitivity to insulin.
• Androgen supplementation is also associated with reduction of high triglycerides, though there is a general correlation with androgen use and decreased HDL levels and in some cases, increased LDL levels.
• numerous laudatory benefits have been associated with androgen supplementation including improved sexual desire and functioning, increased cognition, memory, sense of well being and possible decrease in risk of Alzheimer's disease.
• Androgen antagonists have been used in treating prostate cancer, where blockade of androgen signaling is desired whereas some androgens agonists (e.g. dihydrotestosterone) stimulate the hypertrophy of prostate tissue and may be a causative factor in prostate cancer. Androgen agonist activity is often associated with stimulation of benign prostate hyperplasia, a disease characterized by an enlarged prostate often accompanied by discomfort and difficulty in urination due to blockage of the urethra. As a result, androgen antagonists have efficacy in the reduction of the size of the prostate and the corresponding symptoms of benign prostate hyperplasia, though it is much more common to use a 5oc-reductase inhibitor (e.g.
• finasteride as such inhibitors do not decrease androgen signaling systemically to the same extent as a typical anti-androgen (e.g. bicalutamide), but rather reduce androgen drive more site specifically to where testosterone to DHT conversion occurs such as the prostate and scalp. Androgen antagonists also find utility in the treatment of hirsutism in women as well as the treatment of acne.
• a typical anti-androgen e.g. bicalutamide
• Androgen antagonists also find utility in the treatment of hirsutism in women as well as the treatment of acne.
• Androgens are generally contraindicated in conditions that are treated with androgen antagonists since they can exacerbate the symptoms that are being treated.
• an androgen would retain the benefits of androgen agonists while minimizing the stimulatory effects on the prostate in males as well as some of the other untoward effects of androgens including masculinization of women and increase in acne in both sexes.
• Androgens that demonstrate tissue selective effects compared to the benchmarks testosterone and/or dihydrotestosterone are typically referred to as androgen receptor modulators or more often, selective androgen receptor modulators (SARMs).
• SARMs selective androgen receptor modulators
• this invention describes a compound of formula I
• R x is CN, CI, Br, N0 2 or R x) ;
• R y is CH 3 , CF 3 , or halogen
• R z is hydrogen or optionally Ci- 3 alkyl, C 2-3 alkenyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, N0 2 , NH 2 , OMe, halogen or OH; or
• R y ' is optionally a substituent selected from the group consisting of halog Ci-3 alkyl, C 1-3 haloalkyl and OH;
• R xl is a 5 member heteroaryl, said heteroaryl selected from
• N N N N N R' is hydrogen or optionally Ci-C 2 alkyl, CF 3 , or halogen; or
• each R" is independently hydrogen or optionally CF 3 , or Ci-C 2 alkyl; Pi is hydrogen or a metabolically labile group;
• R a and R b are each independently selected from hydrogen or Ci-C 3 alkyl; and X is CH 2 , O or NR C ; wherein
• R c is hydrogen or Ci-C 3 alkyl
• this invention describes a compound of formula I
• R x is CN, CI, Br, N0 2 or R xl ;
• R y is CH 3 , CF 3 , or halogen
• R z is hydrogen or optionally C 3 alkyl, C 2-3 alkenyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, N
• R y - is optionally a substituent selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl and OH;
• heteroar l selected from
• R' is hydrogen or optionally C C 2 alkyl, CF 3 , or halogen
• each R" is independently hydrogen or optionally CF 3 , or Ci-C 2 alkyl; Pi is hydrogen or a metabolically labile group;
• R a and R b are each independently selected from hydrogen or C C 3 alkyl; and X is CH 2 , 0 or NR c ; wherein
• R c is hydrogen or C C 3 alkyl
• the compound of formula I is a compound of structure la:
• the compound of formula I is a compound of formula lb:
• the animal to be administered the compound of formula I, la or lb is a mammal. In some embodiments, that mammal is a human.
• R x is CN
• R y is CF 3 or CI.
• R z is C 1-3 alkyl, hydrogen, halogen, Ci -3 hydroxyalkyl or C 2 alkenyl.
• R z is hydrogen
• R x is CN
• R y is CF 3 or CI
• R z is CH 3 or hydrogen.
• X is C3 ⁇ 4.
• X is NCH 3 .
• X is O
• R a is hydrogen and R b is hydrogen.
• R a is C3 ⁇ 4 and
• Rb is hydrogen
• R a is hydrogen and Rb is methyl.
• R a and Rb are each methyl.
• Pj is hydrogen or a metabolically labile group that after oral administration in a mammal leaves V ⁇ as hydrogen.
• the mammal is a human.
• Pi is an alkyl acyl group containing up to 20 carbons, aryl acyl group containing up to 18 carbons, alkyl ether containing up to 12 carbons, sulfate, or phosphate.
• Pi is hydrogen
• R x is CN, R y is CF 3 or CI and R z is hydrogen or CH 3 ;
• R a is CH 3 and R b is hydrogen
• R x is CN, R y is CF 3 or CI and R z is hydrogen or CH 3 ;
• R a is hydrogen and R b is hydrogen
• Pi is hydrogen.
• this invention describes a compound of formula III, Ilia and Illb
• R a is CH 3 and R b is hydrogen
• R x is CN, R y is CF 3 or CI and R z is hydrogen or CH 3 ;
• R a is hydrogen and R b is hydrogen
• R x is CN, R y is CF 3 or CI and R z is hydrogen or C3 ⁇ 4;
• R a is CH 3
• R b is hydrogen and c is CH 3 ;
• R x is CN, R y is CF 3 or CI and R z is hydrogen or CH 3 ;
• R a is hydrogen, R b is hydrogen and R o is Q3 ⁇ 4;
• this invention includes a compound of formula I through IV wherein the compound of formula I through IV is predominately one diastereomer.
• predominately means the compound of formula I through IV is more than 50% of a single diastereomer.
• the compound of formula I through IV is more than 60% of a single diastereomer.
• the compound of formula I through IV is more than 70% of a single diastereomer. In some embodiments, the compound of formula I through IV is more than 80% of a single diastereomer.
• the compound of formula I through IV is more than 90% of a single diastereomer.
• the compound of formula I through IV is more than
• the compound of formula I through IV is more than 98% of a single diastereomer.
• the compound of formula I through IV is more than 99% of a single diastereomer.
• the compound of formula I through IV is more than 99.9% of a single diastereomer.
• this invention includes a compound of formula I through IV wherein the compound of formula I through IV is predominately one enantiomer.
• predominately means the compound of formula I through IV has an ee of greater than 50%.
• the compound of formula I through IV has an ee of greater than 60%.
• the compound of formula I through IV has an ee of greater than 70%.
• the compound of formula I through IV has an ee of greater than 80%.
• the compound of formula I through IV has an ee of greater than 90%.
• the compound of formula I through IV has an ee of greater than 95%.
• the compound of formula I through IV has an ee of greater than 98%.
• the compound of formula I through IV has an ee of greater than 99%. In some embodiments, the compound of formula I through IV has an ee of greater than 99.9%.
• the compound of formula I through IV is selected from the following list. (The compound names in the list were generated with the assistance of ChemDraw ® versions 8.0, 9.0 and/or 11.0
• the compound of formula I through IV is selected from the following list. (The compound names in the list were generated with the assistance of ChemDraw ® versions 8.0, 9.0 and/or 11.0
• the invention also relates to pharmaceutical compositions comprising a compound of formula I-IV or any of the structural embodiments described herein and at least one pharmaceutically acceptable excipient.
• the invention also provides a method of modulating an androgen receptor in a cell, comprising the administration of a compound to said cell wherein said compound has structural formula I-IV or any of the structural embodiments described herein, or a pharmaceutically acceptable salt thereof.
• This invention provides a method of identifying a compound capable of modulating an androgen receptor comprising contacting a cell expressing an androgen receptor with a compound according to formula I-IV, and monitoring the effect of the compound on the cell.
• This invention also provides a method of treating (e.g., preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of) a disease, syndrome, illness, or symptom associated with insufficient androgen levels in a mammal in need thereof, wherein said method comprises the administration to said mammal of an effective amount of a compound of formula I-IV, or any one of the structural embodiments described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I-IV, or one of the structural embodiments described herein, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
• the mammal is a human.
• this invention provides a method of treating (e.g., preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of) sarcopenia, frailty, multiple sclerosis, osteoporosis, anemia, cognitive impairment, cachexia, muscular dystrophy, weak appetite, low body weight, anorexia nervosa, acne, seborrhea, polycystic ovarian syndrome, hair loss, AIDs wasting, chronic fatigue syndrome, short stature, low testosterone levels, diminished libido, benign prostate hypertrophy, infertility, erectile dysfunction, vaginal dryness, premenstrual syndrome, postmenopausal symptoms, female hormone replacement therapy, male hormone replacement therapy, depression, Type II diabetes, mood disorders, sleep disorders, memory disorders, neurodegenerative disorders,
• Alzheimer's dementia attention deficit disorder, senile dementia, coronary artery disease, hirsutism, pain, myalgia, myocardial infarction, stroke, clotting disorders, thromboembolisms, congestive heart disorder, low insulin sensitivity, low glucose utilization, high blood sugar, organ transplant, metabolic syndrome, diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, tooth injury, tooth disease, periodontal disease, liver disease, thrombocytopenia, fatty liver conditions, endometriosis, hot flushes, hot flashes, vasomotor disturbance, stress disorders, dwarfism, dyslipidemia, cardiovascular disease, coronary artery disease, renal disease, thin skin disorders, lethargy, osteopenia, dialysis, irritable bowel syndrome, Crohn's disease, Paget' s disease, osteoarthritis, connective tissue disease or disorders, injury, burns, trauma, wounds, bone fracture, atherosclerosis, cachexia, cancer cachexia, and obesity, in a mammal
• this invention describes a method of treating (e.g., preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of) prostate cancer, breast cancer, endometrial cancer, hepatocellular cancer, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer in a mammal in need thereof comprising the administration to said mammal of a compound according to a structure of formula I-IV, or one of the structural embodiments described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of structural formula I-IV, or one of the structural embodiments described herein including pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.
• the mammal is a human.
• formula I through IV is meant to, in each instant, include compounds of formula I, la, lb, II, Ila, lib, III, Ilia, Illb, IV, IVa and lVb
• a process for the preparation of a compound of formula I, la and lb wherein X is O comprises a process for the preparation of a compound of formula B, comprising: a) reacting a compound of formula A with a carbonylating reagent
• R x , R y , R z , R a and Rb are each independently as defined for frmula I or any of its related embodiments and;
• Ri is a hydrogen or a suitable carboxylic acid protecting group.
• the process of preparing the compound of formula B is conducted in the presence of a base.
• Ri is C 1-6 alkyl, benzyl or an organosilane.
• said carbonylating agent is phosgene, triphosgene, N, N'-carbonyldiimadazole or a dialkylcarbonate.
• a process for the production of a compound of formula II, Ila and lib comprising the reaction of a compound of formula C with a reagent capable of generating a trifluoromethyl anion addition equivalent followed by a proton-donating work-up:
• the trifluoromethyl anion generating equivalent comprises a trifluoromethylsilane.
• the trifluoromethyl- containing silane is trimethylsilyltrifluoromethane.
• said trifluoromethyl anion is generated from a trifluoromethylsilane in the presence of a fluoride anion.
• alkenyl refers to a hydrocarbon backbone radical, having the number of carbon atoms falling within the specified range.
• C 2-3 alkenyl means that a hydrocarbon radical is attached that may contain anywhere from 2 to 3 carbon atoms with the remaining valence filled in by hydrogen atoms unless specified otherwise. The term also includes each permutation as though it were separately listed. Thus, C 2-3 alkenyl includes ethenyl, 1 -propenyl and 2- propenyl.
• alkyl refers to both straight and branch chain hydrocarbon radicals, having the number of carbon atoms falling within the specified range.
• Ci_4 alkyl means that a hydrocarbon radical is attached that may contain anywhere from 1 to 4 carbon atoms with the remaining valence filled in by hydrogen atoms.
• the definition also includes separately each permutation as though it were separately listed.
• C 1-2 alkyl includes methyl and ethyl.
• C 1-3 alkyl includes methyl, ethyl, propyl and 2-propyl.
• C ⁇ .
• C 4 alkyl includes methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl and tert- butyl.
• C 1-5 alkyl includes methyl, ethyl, 2-propyl, n-butyl, 2-methylbutyl, tert-butyl, n-pentyl, pentan-2-yl, pentan-3-yl, and tert-pentyl, iso-pentyl.
• halogen refers to a fluorine, chlorine, bromine or iodine radical.
• haloalkyl refers to an alkyl radical wherein said alkyl radical is the same as defined for the term “alkyl” except that the alkyl radical additionally has from 1 to 5 halogen atoms attached to the alkyl chain.
• C 1 haloalkyl includes
• C 2 haloalkyl includes -CH 2 F, CHF 2 , CF 3 , - CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CHF 2 , -CF 2 CF 3 and the like.
• d -3 haloalkyl is defined to include -C3 ⁇ 4F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCF 3 , -CF 2 CF 3 , -CHC1CH 3 , - CH 2 CH 2 C1, -CH 2 CH 2 CF 3 , and the like.
• CM haloalkyl is defined to include -CH 2 F, - CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCF 3 , -CF 2 CF 3 , -CHC1CH 3 , -CH 2 CH 2 C1, -CH 2 CH 2 CF 3 , - CH 2 CH 2 CH 2 CF 3 , CHC1CF 2 CH 2 CH 3 , CF 2 CH 2 CH 2 CHF 2 , CH 2 CH 2 CH 2 CH 2 F, CH 2 CH 2 CH 2 CH 2 C1, and the like.
• hydroxyalkyl refers to an alkyl radical wherein said alkyl radical is the same as defined for the term “alkyl” except that the alkyl radical additionally has from 1 or 2 hydroxyl groups attached to the alkyl chain.
• C 2- 4 hydroxyalkyl includes 2-hydroxyethyl, 2-hydroxypropyl, 2,4-dihydroxybutyl and the like.
• 5-member heteroaryl refers to a heteroaryl ring system radical wherein said heteroaryl contains at least one heteroatom selected from the groups consisting of N, O and S and up to 3 additional heteroatoms selected from the group consisting of N, O and S. If not otherwise defined, the 5-member rings system is optionally substituted with 1-2 substituents selected from halogen, C 1-2 alkyl, Cj -2 haloalkyl, or CN. The points of attachment of the optional substituent(s) as well as the rest of the molecule maybe selected from any position wherein there is an open valence.
• 5-member heteroaryls include:
• metabolically labile group refers to a group that some time after administration to an organism, is metabolized in such a way that the metabolically labile group becomes hydrogen.
• the metabolically labile group is attached to an oxygen so that when that group is metabolically removed within the target organism, it is eventually replaced by a hydrogen at some point in the metabolic scheme.
• the metabolism referred to here is typically enzyme assisted but does not have to be so. Therefore, the metabolically labile group can be removed chemically provided that chemical removal occurs after administration to an organism.
• certain metabolically labile groups might be removed by simple chemical hydrolysis in the stomach, gut or blood.
• Metabolically labile groups relate to the concept of prodrugs for which those of ordinary skill in the art appreciate are well-known for secondary alcohols. These metabolically labile groups include esters, carbonates, carbamates, simple alkyl groups, phosphates, phosphites, sulfites, sulfates and the like.
• the organism referred to is a mammal. In some embodiments, the mammal is a human.
• the compounds of this invention may be present as solids and when so present, may be in an amorphous form or they may be crystalline. When the compounds of this invention are in the crystalline form, they might be present as a single polymorph or a mixture of polymorphs or even as a mixture of amorphous material together with one or more distinct polymorphs - the invention is not limited according to any particular solid or liquid state form.
• the compounds of this invention contain at least one stereocenter and therefore, exist in various stereoisomeric forms.
• Stereoisomers are compounds which differ only in their spatial arrangement.
• Enantiomers are pairs of
• stereoisomers whose mirror images are not superimpo sable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
• "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable.
• Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms, "if” and "5" represent the configuration of substituents around one or more chiral carbon atoms.
• "if” and “S” denote the relative configurations of substituents around one or more chiral carbon atoms .
• the stereochemistry of a disclosed compound is named or depicted by structure
• the named or depicted stereoisomer is at least 50%, 60%, 70%>, 80%, 90%>, 95%, 98%o, 99%o or 99.9% by weight pure relative to the other stereoisomers.
• the depicted or named enantiomer is at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.9% by weight optically pure.
• Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
• the compounds of the invention may be prepared as individual isomers by incorporating or starting with a specific isomer, isomer-specific synthesis, separation of diastereomers or resolution from an isomeric mixture.
• Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by
• acid addition salts can be made and this invention includes such acid addition salts.
• Some representative (non-limiting) acid addition salts include hydrochloride, hydrobromide, hydroiodide, acetate, benzenesulfonate, mesylate, besylate, benzoate, tosylate, citrate, tartrate, sulfate, bisulfate, lactate, maleate, mandelate, valerate, laurate, caprylate, propionate, succinate, phosphate, salicylate, napsylate, nitrate, tannate, resorcinate and the like, including multiprotic salts as well as mixtures of the acid addition salts.
• this invention also embraces quaternized ammonium salts of those amines. It should be appreciated that N-oxides of amines are also embraced within the definition of the compounds of this invention.
• compounds of this invention include one or more acid sites such as carboxylic acids, phenols and the like, basic addition salts can be made and this invention includes such basic addition salts.
• some representative (non-limiting) acidic compounds of this invention may be present as their lithium, sodium, potassium, ammonium, trialkyammonium, calcium, magnesium, barium and the like.
• solvates can also be present as solvates and such solvates are embraced within the scope of this invention even where not explicitly described.
• Such solvates are preferably hydrates but can be solvates comprised of other solvents, preferably where those solvents are considered to be non-toxic or at least acceptable for administration to mammals, preferably humans.
• the solvates can be stoichiometric or non-stoichiometric, singular or in combination.
• Some exemplary solvates include water, ethanol, acetic acid and the like.
• the therapeutic utility of these compounds includes "treating" a mammal, preferably a human where treating is understood to include treating, preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of the syndrome, illness, malady or condition being considered,
• the compounds of this invention can also be useful in states or conditions where no clear deficit, illness or malady per se is perceived but rather, where a preferred condition, sensation, performance, capability or state is obtainable through therapeutic intervention with a compound of this invention.
• the compounds of this invention when used as therapeutics can be administered by any method known to one of skill in the art such as orally, bucally, intravenously, subcutaneously, intramuscularly, transdermally, intradermally, intravascularly, intranasally, sublingually, intracranially, rectally, intratumorally, intravaginally, intraperitonealy, pulmonary, ocularly and intratumorally.
• the term "effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
• the compounds and compositions of this invention maybe given once daily or with multiple daily doses such as twice per day, three times per day and four times per day.
• the compound is administered orally where it can be formulated for solid dosage administration or liquid dosage administration.
• Solid dosage administration can be in the form of a tablet, granule, capsule, pill, pellet, powder and the like.
• Liquid dosage formulations include syrups, solutions, gels, suspensions, elixirs, emulsions, colloids, oils, and the like.
• the compounds of this invention may be solids and when present as solids, they maybe of defined particle size. Where the compound of this invention is not particularly water soluble, it is sometimes preferable to administer the compound with a certain particle size - a particle size with a preferred range where the average mean particle size diameter is under 100 microns, or 75 microns, or 50 microns, or 35 microns, or 10 microns or 5 microns.
• Solid dosage formulations will comprise at least one compound of this invention together with one or more pharmaceutical excipients.
• excipients include, by way of non-limiting example diluents (monosaccharides, disaccharides and polyhydric alcohols including starch, mannitol, dextrose, sucrose, microcrystalline cellulose, maltodextrin, sorbitol, xylitol, fructose and the like), binders (starch, gelatin, natural sugars, gums, waxes and the like), disintegrants (alginic acid, carboxymethylcellulose (calcium or sodium), cellulose, crocarmellose, crospovidone, microcrystalline cellulose, sodium starch glycolate, agar and the like), acidic or basic buffering agents (citrates, phoshphates, gluconates, acetates, carbonates, bicarbonates and the like), chelating agents (edetic acid, edetate
• the solid dosage formulations of this invention can be prepared in different forms including most commonly, tablets and capsules.
• the tablets can be formulated by a wide variety of methods known to one of skill in the art including, for example, preparing a dry powder mixture of the drug substance in combination with one or more of the excipients granulating the mixture and pressing to together into a tablet and optionally coating the tablet with an enteric or non-enteric coating.
• the final coat typically includes a light protective pigment such as titanium oxide and a shellac or wax to keep the tablet dry and stable. While not intending to be limited by theory or example, in some instances it might be preferred to prepare the tablets by wet granulating the drug with one or more of the excipients and then extruding the granulated material.
• the solid dosage forms of this invention also include capsules wherein the drug is enclosed inside the capsule either as a powder together with optional excipients or as granules containing usually including one or more excipients together with the drug and wherein the granule in turn can be optionally coated, for example, enterically or non-enterically.
• the solid dosage formulations of this invention are formulated in a sustained release formulation.
• sustained release formulations are known to those of skill in the art and generally rely on the co-formulation of the drug with one or more matrix forming substances that slow the release of the androgen receptor modulator thus extending the compound's lifetime in the digestive track and thereby extend the compounds half-life.
• matrix forming substances include hydroxypropyl methylcellulose, carbopol, sodium carboxymethylcellulose and the like.
• the compounds are formulated for delivery other than via a solid oral dosage form.
• a pulmonary route of administration typically means that the compound of this invention is inhaled into the lung where it is absorbed into the circulation.
• Such a route of administration has the advantage of avoiding a first pass liver effect thereby possibly increasing bioavailability as well as decreasing or eliminating undesirable androgen agonist effects on the liver such as increasing liver enzymes and/or decreasing HDL.
• Formulating a compound of the invention for pulmonary delivery can be accomplished by micronizing the compound of the invention to a very fine size particle, typically with a mean average diameter of less than 20 microns, or less than 10 microns or between 2 and 5 microns.
• the powder may then be inhaled by itself or more likely mixed with one or more excipients such as lactose or maltose.
• the powder can then be inhaled in a dry powder inhaling device either once or multiple times per day depending on the particular compound and the patients need.
• Other types of pulmonary dosage forms are also embraced by this invention.
• the compound of this invention may be suspended in an aerosolizing medium and inhaled as a suspension through a meter dosed inhaler or a nebulizer.
• the compounds of this invention can be formulated for transdermal delivery.
• the compounds of this invention maybe formulated for passive diffusion patches where they are preferably embedded in a matrix that allows for slow diffusion of the compound into the treated subject's circulation.
• the compound is preferably dissolved or suspended in solvents including by way of non-limiting examples one or more of ethanol, water, propylene glycol, and Klucel HF.
• a polymer matrix e.g. acrylate adhesive
• the transdermal formulations maybe designed to be compatible with alternate transdermal delivery technologies.
• some transdermal technologies achieve greater and/or more consistent delivery by creating micropores in the skin using radio frequency, heat, ultrasound or electricity.
• the compounds of this invention can be used with microneedle technology wherein the compound is loaded into or onto very small needles which do not need to penetrate the dermis to be effective.
• the compounds of this invention may be employed alone or in combination with other therapeutic agents.
• the compounds of this invention can be used in combination with anti-lipidemics (statins, fibrates, omega-3 oils, niacinates and the like), bone anti-resorptives (bisphosponates, estrogens, selective estrogen receptor modulators (SERMs), calcitonin, and the like), bone anabolic agents (PTH and fragments e.g teriparatide, PTHRP and analogues e.g. Ba058), anti-diabetics (e.g. insulin sensitizers, glucose absorption and synthesis inhibitors (e.g.
• the compounds of this invention may be co- formulated or co-administered wherein said co -administration does not require dosing at exactly the same time but rather indicates that the patient is undergoing treatment with one or more of the additional agents during the timeframe of treatment with the selective androgen modulators of this invention.
• the additional drug(s) for combination treatment can be administered concomitantly, sequentially or separately from the compounds of this invention.
• the compounds of this invention may be administered according to different dosage scheduling and the dosage may be adjusted as deemed necessary by the subject or preferably by the subject in consultation with a qualified practitioner of medicine. Dosing of the compounds of this invention can take place by multiple routes and consequently, the dosing schedule and amounts are dependent not only on the particular subject's weight, sex, age, therapy contemplated, etc but also by the route of the drug chosen.
• the compounds of this invention may be considered for dosing by the oral route in a once daily, twice daily, three times daily or more than three times per day depending on the particular needs of that subject, the formulation of the drug, etc.
• the dosage will typically be from about 0.01 mg to 500 mg of drug per daily dosage, for example from about 0.1 mg to about 10 mg, such as from about 0.1 mg to about 3 mg, or from about 0.1 mg to about 250 mg of drug per daily dosage, or from about 1 mg to about 150 mg of drug per daily dosage, or from aobut 5 mg to about 100 mg of drug per daily dosage.
• the amount of compound dosed per day can be administered every day, every other day, every 2 days, every 3 days, every 4 days, every 5 days, etc.
• a 5 mg per day dose can be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, etc.
• a compound of this invention is dosed once every seven days.
• the compounds of this invention can also be dosed on a monthly basis meaning that administration is done once per month.
• the compounds of this invention can be dosed on a weekly basis (once a week), every other week, every three weeks or every four weeks for a single day or multiple days. It should be appreciated that the dose interval for the compounds of this invention can be adjusted according to the particular compound used, its dosage, the indication being treated and the patient and/or physician's judgment.
• the compounds of this invention can also be dosed on an as needed or "pro re nata" "prn" schedule, and "on demand".
• the compouonds of this invention are administered in a therapeutically effective dose at some time prior to commencement of an activity wherein the therapeutic effect of the compounds of this invention is desirable.
• Administration can be immediately prior to such an activity, including about 0 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours prior to such an activity, depending on the formulation.
• the compounds of this invention can be prepared by a variety of synthetic routes and techniques known to those of skill in the art.
• the processes disclosed herein should not be construed as limiting the examples or scope of the invention in any way but rather are provided as just some of the representative ways that the compounds of this invention can be or were prepared.
• protective groups are employed in the synthesis of the compounds of this invention and it should be appreciated that there are a diverse array of protective groups and strategies that can be employed in organic synthesis (T.W.Green and P.G.M.Wuts (2006) Greene's Protective Groups in Organic Synthesis, herein incorporated by reference in its entirety) and that where a protective group is referred to generically, any appropriate protective group should be considered.
• leaving groups are employed in the synthesis of compounds of this invention. Where a specific leaving group is referred to, it should be appreciated that other leaving groups might also be used. Leaving groups typically include those groups that can stabilize an anion. In the case of nucleophilic aromatic substitutions, the leaving group may be an anion or a neutrally charged group. In some cases, the leaving group for nucleophilic aromatic substitution may be a group that is not typically considered to be a stabilized anion (e.g. fluoride or hydride).
• nucleophilic leaving groups include halogens, sulfonates (O-mesylates, O-tosylates, etc), hydrides, quaternized amines, nitro, and the like. Additional discussion and examples can be found in leading textbooks on organic chemistry including, for example, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th Edition, which is herein incorporated in its entirety.
• Example 20 was the less polar isomer and was shown to have the structure shown, having 4(R) side chain stereochemistry in accordance with the Cahn-Ingold- Prelog priority rules. Since Example 20 had the 4(R) side chain stereochemistry, Example 19 was assigned as the other diastereomer with 4(S) stereochemistry in accordance with the Cahn-Ingold-Prelog priority rules. In addition, Example 20 also demonstrated lower androgen receptor binding affinity than Example 19:
• each diastereomeric pair included one isomer that was clearly less polar than the other (EtOAc/hexanes on silica gel thin layer chromatography).
• the less polar isomer also had weaker affinity for the androgen receptor as measured by assays described herein. Accordingly, the less polar isomer which was also, in every case, the less active isomer was assigned the same 4(R) side chain stereochemistry as the compound of Example 20.
• Example 1 Example 2 Examples 1 and 2
• N-(4-chloro-3-(trifluoromethyl) phenyl) pivalamide (3b) (3 g, 10.7 mmol) was dissolved in dry THF (30 mL), cooled to 0°C, and n-BuLi (15.6 mL, 25.7 mmol) was added. After 3 h, a solution of Mel (0.66 mL, 10.56 mmol) in THF (7 mL) was added to the reaction mixture maintaining the temperature at 0°C and stirred for further 3 h. and quenched with aqueous NH 4 C1 solution. The reaction mixture was extracted with EtOAc (3 ⁇ 30 mL).
• the reaction mixture was brought to room temperature, diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (2 x 20 mL), dried over Na 2 S0 4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to provide the bromo 3f (0.6 g, 60%) as a tan colored solid.
• the alcohol 3i (0.29 g, 0.97 mmol) was dissolved in CH 3 CN (10 mL), cooled to 0°C, and Dess-Martin periodinane (0.62 g, 1.46 mmol) was added and stirred for 3 h. After completion of reaction (by TLC), the reaction mixture was quenched with aqueous NaHC0 3 solution (20 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with water (2 x 20 mL), separated, dried over Na 2 S0 4 and concentrated under reduced pressure to furnish the aldehyde 3j (0.22 g, crude) as a white solid which was taken to the next step without
• reaction mixture was diluted with water (30 mL) neutralized with saturated NaHC0 3 solution and extracted with Et 2 0 (3 x 35 mL). The combined organic extracts were dried over Na 2 S0 4 and concentrated under reduced pressure to give the crude compound was purified by column chromatography to give the bromo 5e (0.25 g, 35%).
• the crude aldehyde 5i (0.15 g, 0.6 mmol) was dissolved in dry THF (10 mL), cooled to 0°C, CsF (90 mg, 0.6 mmol) followed by CF 3 TMS (0.8 mL, 60.0 mmol) were added. The resulting reaction mixture was warmed to room temperature and stirred for 1 h. After completion of reaction (by TLC), the reaction mixture was quenched with aqueous NH 4 C1 solution (20 mL) and extracted with EtOAc (3 ⁇ 20 mL). The combined organic extracts were dried over Na 2 S0 4 and concentrated under reduced pressure to provide the silyl ether 5j as a mixture of diastereomers (0.15 g, crude) which was taken to the next step without purification.
• Example 5 (0.020 g) and Example 6 (0.011 g) both as white solids.
• reaction mixture was slowly warmed to room temperature and stirred for 16 h. After completion of reaction (by TLC), the reaction mixture was poured into ice-cold water (60 mL) and extracted with CH 2 C1 2 (2 ⁇ 100 mL). The combined organic extracts were dried over Na 2 S0 4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to afford the oxazolidinone 7d (0.091 g, 84%) as syrup.
• reaction mixture was quenched with 0. IN NH 4 C1 solution (30 mL) and extracted with EtOAc (2 x 80 mL). The combined organic extracts were dried over Na 2 S0 4 and concentrated under reduced pressure to afford the silyl ether 7g as a mixture of diastereomers (0.3 g, crude). The crude residue was taken for the next step without further purification.
• the organic extract was washed with saturated brine solution (2 x 15 mL), separated, dried over Na 2 S0 4 and concentrated under reduced pressure to provide the crude compound.
• the crude material was purified by column chromatography to afford the oxazolidinone 9d (0.95 gm, 79%) as a white solid.
• Example 11 Example 12 11a to l ib
• Example 11 Example 12 l le to 1 If
• the crude aldehyde 13g (0.36 g, 1.2 mmol) was dissolved in THF (20 mL), cooled to 0°C, and CsF (174 mg, 1.15 mmol) followed by CF 3 TMS (1.8 mL, 12.0 mmol) was added. The reaction mixture was stirred at 0°C for 4 h. After the completion of reaction (by TLC), the reaction mixture was quenched with saturated NH 4 C1 solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over Na 2 S0 4 and concentrated under reduced pressure to provide the silyl ether 13h as a mixture of diastereomers (0.3 g, crude). The crude material was taken to the next step without purification.
• reaction mixture was diluted with ice-cold water (40 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the crude compound.
• the crude material was purified by silica gel column chromatography to afford the oxazolidinone 15c (1.5 g, 81%) as a white solid.
• the aqueous layer was acidified by citric acid (pH 2-3) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with ice-cold water (5 * 30 mL), dried over Na 2 S0 4 and concentrated under reduced pressure to give the crude product. The crude material was triturated with 10% EtOAc/Hexane to afford the acid 17a (2.0 g, 42%) as an off-white solid.
• the oxazolidinone 17c (1.2 gm, 4.0 mmol) was taken in EtOH (20 mL), cooled to 0°C, and NaBH 4 (0.176 g, 4.6 mmol) was added and stirred at 0°C for 4 h. After completion of reaction (by TLC), the volatiles were evaporated under reduced pressure and the residue was diluted with aqueous NH 4 C1 (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with aqueous NH 4 CI (2 50 mL). The organic layer was separated, dried over Na 2 S0 4 , and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to furnish the alcohol 17d (1.0 g, 91%) as an off-white solid.
• the crude aldehyde 19f (0.7 g, 2.35 mmol) was dissolved in THF (20 mL) and cooled to 0°C. To the reaction, CsF (0.356 g, 2.34 mmol) followed by CF 3 TMS (3.3 g, 23.2 mmol) was added maintaining the temperature at 0°C. The reaction was stirred at 0°C for 3 h and quenched with saturated NH 4 C1 solution (50 mL). The reaction mixture was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were dried over Na 2 S0 4 and concentrated under reduced pressure to give the crude compound. The crude residue was passed through a short silica pad to afford the silyl ether 19g as a mixture of diastereomers (0.360 g, 24%) which was immediately used for the next step without any purification.
• Example 21 Example 22 21e to 21f
• the alcohol 21e (0.7 g, 2.77 mmol) was dissolved in CH 3 CN (50 mL) and Dess-Martin periodinane (2.3 g, 5.42 mmol) was added portion wise at 0°C. The resulting reaction mixture was slowly warmed to 15°C and stirred for 2 h. After completion of reaction (by TLC), the reaction mixture was diluted with saturated NaHC0 3 solution (30 mL) and extracted with CH 2 C1 2 (3 ⁇ 30 mL). The combined organic extracts were again washed with NaHC0 3 solution (30 mL) followed by water (30 mL). The combined organic extracts were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to afford the aldehyde 21f (0.5 g, crude) as a syrup which was used for the next step without purification.
• the aldehyde 21f (0.5 g, 2.0 mmol) was dissolved in dry THF (50 mL) and CsF (0.3 g, 2.0 mmol) followed by CF 3 -TMS (3.0 mL, 20.3 mmol) was added at 0°C under nitrogen atmosphere. The resulting reaction mixture was stirred for 2 h at 0°C and quenched with aqueous NH 4 C1 solution (50 mL). The reaction mixture extracted with EtOAc (3 x 30 mL) and the combined organic extracts were dried over Na 2 S04 and concentrated under reduced pressure to afford the silyl ether 21 g as a mixture of diastereomers (0.7 g, crude) which was taken forward for the next step without further purification.
• reaction mixture was diluted with water (30 mL) and extracted with
• the alcohol 23e (1.6 g, 5.1 mmol) was dissolved in CH 3 CN (30 mL), cooled to 0°C, and Dess-Martin periodinane (4.8 g, 11.3 mmol) was added under nitrogen atmosphere. The resulting reaction mixture was stirred at 0°C for 4 h. After completion of reaction (by TLC), saturated NaHC0 3 solution (50 mL) was added to the reaction mixture and extracted with CH 2 C1 2 (2 x 30 mL). The combined organic extracts were again washed with saturated NaHC0 3 solution (2 x 30 mL). The organic layer was separated, dried over Na 2 S0 4 and concentrated under reduced pressure to afford the aldehyde 23f (1.2 g, crude) as a white solid. The crude material was taken to the next step without purification.
• reaction mixture After completion of reaction (by TLC), the reaction mixture was poured into saturated NaCl solution and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over Na 2 S0 4 and concentrated under reduced pressure to half of the volume; PhMe (15 mL) was added and heated to 80°C for 4 h. After completion (by TLC), the reaction mixture was poured into saturated NaCl solution and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over Na 2 S0 4 and purified by column chromatography to afford 25a (0.11 g, 44%) as a brown sold.
• the resulting reaction mixture was then heated to 100°C for 5 h. After completion (by TLC), the reaction mixture was filtered through celite bed. The celite bed was washed with EtOAc (2 x 5 mL), the filtrates were combined, dried over Na 2 S0 4 and concentrated under reduced pressure to give the crude compound. The crude residue was purified by column chromatography to provide 25d (0.075 g, 46%) as a colourless syrup.
• an androgen receptor binding assay was performed wherein many of the compounds of this invention are shown to demonstrate significant affinity for the androgen receptor.
• the assay was performed as specified by the manufacturer (Invitrogen, Madison, WI). Briefly, ⁇ of lOmM compound was added to 500 ⁇ 1 of AR screening buffer in a 1.5ml eppendorf tube to make a 2xlO "5 M stock. 10-fold serial dilutions of the test compounds were prepared ranging in concentration from 10 "5 M to 10 "12 M. Each dilution was added in triplicate to a black 384-microtiter plate. The test compounds will be diluted 2-fold in the final reaction.
• 2x AR-FluormoneTM complex was prepared with 2nM Flourmone AL GreenTM and 30nM AR. 25 ⁇ 1 of 2x complex was aliquoted to each reaction well, such that the final reaction volume was 50 ⁇ 1 per well. Plate was sealed with a foil cover and incubated in the dark at room temperature for 4 h. Polarization values for each well were measured. The polarization values were plotted against the concentration of the test compound. The concentration of the test compound that results in half-maximum shift equals the IC 50 of the test compound. As a control, a competition curve for
• R1881(methyltrienolone) was performed for each assay. Curve Fitting was performed using GraphPad Prism® software from GraphPadTM Software Inc.
• this assay looks primarily at the ability of the selective androgens of this invention to increase muscle size in an immature, castrated rat.
• androgenic effects are looked at primarily by weighing the prostate and seminal vesicles. Selective compounds will show a greater increase in the levator ani relative to the prostate and seminal vesicles when compared to testosterone treated, castrated animals or to intact animals that have not been treated.
• Immature Sprague Dawley male rats were obtained Charles River Laboratories (Stoneridge, NY). All animals were maintained in a temperature and humidity controlled room with a 12hr light: 12 hr dark cycle, with ad lib access to food (TD 291615, Teklad, Madison, WI) and water. Rats were anesthetized and
• GDX orchidectomized
• SHAM sham surgery
• LABC prostate, seminal vesicle and levator ani and bulba cavernous
• Compounds of this invention may also be assayed in vivo to determine their effect on preventing bone loss in animal models of bone loss.
• Animal models of bone loss are well-known to those of ordinary skill in the art.
• bone loss models include the rat and mouse ovariectomized models. Examples of such models are replete in the art, some non-limiting methods and examples are provided in Cesnjaj, et al European Journal of Clinical Chemistry and Clinical Biochemistry (1991), 29(4), 21 1-219; Y.L.
• Example 17 13 yes

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