WO2011066582A1 - Anticancer compounds and screening method - Google Patents

Anticancer compounds and screening method Download PDF

Info

Publication number
WO2011066582A1
WO2011066582A1 PCT/US2010/058449 US2010058449W WO2011066582A1 WO 2011066582 A1 WO2011066582 A1 WO 2011066582A1 US 2010058449 W US2010058449 W US 2010058449W WO 2011066582 A1 WO2011066582 A1 WO 2011066582A1
Authority
WO
WIPO (PCT)
Prior art keywords
diene
optionally substituted
compound
optionally
methylandrost
Prior art date
Application number
PCT/US2010/058449
Other languages
French (fr)
Inventor
James M. Frincke
Original Assignee
Harbor Biosciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Harbor Biosciences, Inc. filed Critical Harbor Biosciences, Inc.
Priority to CA2782266A priority Critical patent/CA2782266A1/en
Priority to EP10834064.7A priority patent/EP2506855A4/en
Publication of WO2011066582A1 publication Critical patent/WO2011066582A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5085—Supracellular entities, e.g. tissue, organisms of invertebrates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/743—Steroid hormones

Definitions

  • the invention relates to methods to screen for and/or characterize compounds with activity as anticancer drugs that affect hormone signaling in vivo, including signaling by one or more steroid hormones.
  • Anticancer drugs and treatments typically are accompanied by significant toxicity or unwanted side-effects that limit the usefulness of drug treatments.
  • Methods to identify additional compounds that are useful in treating cancers are needed, particularly for common cancers and related conditions, e.g., lung cancer, colon cancer and neuroendocrine cancers such as prostate cancer and breast cancer.
  • the invention provides a method to identify a compound comprising (a) administering a test compound to a mammal(s) for a sufficient period of time to obtain treated mammal(s); (b) measuring systemic levels of one or more cholesterol metabolites in the treated mammal(s); and (c) selecting the compound of step (b) that decreases the systemic levels of one or more cholesterol metabolites in the treated mammal(s), whereby a compound having a potential to treat a cancer, optionally a neuroendocrine disorder or tumor is identified, wherein the test compound of step (a) has the structure
  • the method may optionally include treatment of the mammal(s) with vehicle (negative control) and/or other treatment control compounds, e.g., the 17a- hydroxylase/17,20 lyase inhibitor (CYP17A1 ), abiraterone or 17a- ethynylandrostane-3a, 17p-diol.
  • vehicle negative control
  • treatment control compounds e.g., the 17a- hydroxylase/17,20 lyase inhibitor (CYP17A1 ), abiraterone or 17a- ethynylandrostane-3a, 17p-diol.
  • the cholesterol metabolites include one or more of testosterone, dihydrotestosterone, 4-androstenedione, 5-androstenediol, 5a-androstane- 3 ⁇ ,17 ⁇ - ⁇ , 5a-androstane ⁇ , ⁇ -diol, estradiol, estrone,
  • DHEA dehydroepiandrosterone
  • pregnenolone progesterone
  • Cortisol optionally wherein the cholesterol metabolites are one, two or more of (i) testosterone, dihydrotestosterone, 4-androstenedione and 5-androstenediol, (ii) estradiol, estrone and 4-androstenedione or (iii) pregnenolone,
  • the decreased cholesterol metabolite is not progesterone and/or Cortisol.
  • a drug product for treating a cancer, or a neuroendocrine disorder or tumor in a human comprising, (a) a drug in a dosage form, optionally wherein the dosage form is a formulation for oral, parenteral or topical administration; and (b) packaging for the drug together with a package insert or label that includes information about the drug's efficacy, toxicity or mechanism of action wherein such information was obtained at least in part from a method comprising (A) administering a test compound to a mammal(s) for a sufficient period of time to obtain treated mammal(s); (B) measuring systemic levels of one or more cholesterol metabolites in the mammal(s); and (C) selecting a candidate compound that decreases the systemic levels of one or more cholesterol metabolites in the treated mammal(s).
  • the mammal(s) can be a feline but is preferably a rodent(s) or canine(s), optionally a mouse or rat.
  • the mammal(s) will not contain tumors, e.g., prostate xenograft tumors in mice, to allow assessment of effects of the test compound on normal animals.
  • the mammal(s) will have a spontaneous or implanted tumor and these animals can be used to assess the activity of the test compound on the tumor or cancer in such an in vivo environment.
  • the cancer or neuroendocrine disorder or tumor is prostate cancer, breast cancer or small cell lung cancer.
  • the neuroendocrine disorder or tumor is endometriosis or uterine fibroids.
  • Preferred optionally substituted alkyl groups are C1 -4 optionally substituted alkyl, which have 1 , 2, 3 or 4 carbon atoms and 0 or 1 hydroxyl groups.
  • Optionally substituted alkyl moieties are
  • alkyl moieties -CH 2 CH CH 2 or -CH 2 C ⁇ CH.
  • C1 -6 optionally substituted alkyl means moieties having 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • Alkyl means a collection of linked carbon atoms and include linear, branched or cyclic carbon chains or any combination thereof.
  • Alkyl moieties may further contain unsaturation, i.e., the alkyl group may comprise one, two, three or more independently selected double bonds or triple bonds.
  • Unsaturated alkyl groups contain moieties as described for alkenyl and alkynyl moieties are described below. Preferred unsaturated alkyl groups contain one alkenyl moiety or one alkynyl moiety.
  • the number of linked carbon atoms in an alkyl group or moiety can vary and typically is 1 to about 50, e.g., about 1 -30 or about 1 -20 linked carbon atoms, unless otherwise specified, e.g., d-s alkyl or C1-C8 alkyl means an alkyl moiety containing 1 , 2, 3, 4, 5, 6, 7 or 8 linked carbon atoms, Ci -7 alkyl or C1-C7 alkyl means an alkyl moiety containing 1 , 2, 3, 4, 5, 6 or 7 linked carbon atoms and Ci -4 alkyl or C1-C4 alkyl means an alkyl moiety containing 1 , 2, 3 or 4 linked carbon atoms,.
  • variable group when an alkyl group is specified as a variable group, as for R 1 , R 2 , R 3 or R 4 variable group substituents described herein, a saturated carbon of the alkyl moiety is directly attached to the site occupied by the variable group, as in the C1-, C7-, C16- or C17-position of a steroid ring system, using the numbering convention for cholesterol, as described herein [12]
  • species may include methyl, ethyl, 1 -propyl (n-propyl), 2-propyl (/ ' -propyl, -CH(CH 3 ) 2 ), 1- butyl (n-butyl), 2-methyl-1 -propyl (/ ' -butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-butyl, - CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (i-butyl, -
  • Preferred alkyl moieties are Ci -8 , Ci -7 or Ci- alkyl groups, including -CH 3
  • Preferred alkenyl groups contain 0 or 1 additional alkenyl or 0-1 alkynyl moieties.
  • the number of linked carbon atoms in an alkenyl group or moiety can vary and typically is 2 to about 50, e.g., about 2-30 or about 2-20, unless otherwise specified, e.g., C 2- 8 alkenyl or C2-8 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms and C 2 -6 alkenyl or C2-6 alkenyl means an alkenyl moiety containing 2, 3, 4, 5 or 6 carbon atom.
  • an alkenyl group is specified as a variable group, as for R 1 , R 2 , R 3 or R 4 variable group substituents described herein, a unsaturated carbon of the alkenyl moiety is directly attached to the site occupied by the variable group, as in the C1 -, C7-, C16- or exposition of a steroid ring system, using the numbering convention for cholesterol, as described herein.
  • Alkynyl means a collection of linked carbon atoms that contains one or more triple bonds (e.g., -C ⁇ C- moiety), e.g., 1 , 2, 3, 4, 5, 6 or more, preferably 1 or 2.
  • An alkenyl group may further contain saturated carbons including linked normal, secondary, tertiary or cyclic carbon atoms that form linear, branched or cyclic carbon chains, which may also include the triple bond moiety, or any
  • alkynyl groups contain 0 or 1 additional alkynyl or 0-1 alkenyl moieties.
  • the number of linked carbon atoms in an alkenyl group or moiety can vary and typically is 2 to about 50, e.g., about 2-30 or about 2-20, unless otherwise specified, e.g., C 2- s alkynyl or C2-8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms and C 2- 6 alkynyl or C2-6 alkynyl means an alkynyl moiety containing 2, 3, 4, 5 or 6 carbon atoms.
  • an alkynyl group is specified as a variable group, as for R 1 , R 2 , R 3 or R 4 variable group substituents described herein, a unsaturated carbon of the alkynyl moiety is directly attached to the site occupied by the variable group, as in the C1 -, C7- , C16- or C17-position of a steroid ring system, using the numbering convention for cholesterol, as described herein.
  • Aryl means an aromatic ring with no ring heteroatoms and includes, phenyl, naphthyl or a carbocyclic ring system containing 2n + 2 pi electrons where n is 0 or a positive integer.
  • the alkylaryl moiety is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R 1 , R 2 , R 3 or R 4 , i.e., alkyl-aryl-steroid, preferably R 4 .
  • Arylalkyl means a moiety where an alkyl group is bonded to an aryl group, i.e., -alkyl-aryl, where alkyl and aryl groups are as described above, e.g., -CH2-C6H5 or -CH 2 CH(CH 3 )-C6H5.
  • the arylalkyl moiety is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R 1 , R 2 , R 3 or R 4 , i.e., aryl-alkyl-steroid
  • Alkylaryl means a moiety where an aryl group is bonded to an alkyl group, i.e., -aryl-alkyl, where aryl and alkyl groups are as described above, e.g., -C 6 H 4 -CH 3 or -C 6 H 4 -CH 2 CH(CH 3 ).
  • the alkylaryl moiety is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R 1 , R 2 , R 3 or R 4 , i.e., alkyl-aryl-steroid, preferably R 4 .
  • Heteroaryl means a heterocycle comprised of an aromatic ring where the aromatic ring contains 1 , 2, 3 or more heteroatoms that participate in aromaticity of the ring, usually oxygen (-0-), nitrogen (-NX-), where X is -H, a protecting group, C -6 optionally substituted alkyl, an aryl or a heterocycle group, or sulfur (-S-), usually -H. Examples are as described for heterocycle.
  • the heteroaryl moiety is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R 1 , R 2 , R 3 or R 4 , i.e., heteroaryl-steroid, preferably R 4 .
  • Substituted alkyl means an alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl heterocycle, aryl, heteroaryl or other group or moiety as defined or disclosed herein that has a substituent(s) that replaces a hydrogen atom(s).
  • Substituted heterocycles may thus have a substituent bonded to a ring carbon of the heterocycle or a ring heteroatom .
  • Substituents for any of these moieties include 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more, preferable 1 or 2 independently selected heteroatoms, functional groups or other moieties described herein including nitrogen, oxygen, sulfur, phosphorous or silicon containing
  • substituents including -F, -CI, Br or -I, or acyl, amine, amide, ester, carbamate, carbonate, alkoxy, aryl, heterocycle or heteroaryl containing substituents.
  • Protecting group means a moiety that prevents or reduces the atom or functional group to which it is linked from participating in unwanted reactions.
  • R PR may be hydrogen or a protecting group for the oxygen atom found in a hydroxyl
  • R PR may be hydrogen or a carboxyl protecting group
  • R PR may be hydrogen or a protecting group for sulfur in thiols for instance
  • R PR may be hydrogen or a nitrogen atom protecting group for primary or secondary amines.
  • Hydroxyl, amine, ketones and other reactive groups as found in variable group substituents for R 1 , R 2 , R 3 or R 4 described herein may require protection against reactions taking place elsewhere in the molecule.
  • the protecting groups for oxygen, sulfur or nitrogen atoms are usually used to prevent unwanted reactions with electrophilic compounds, such as acylating agents used, e.g., in steroid chemistry.
  • Ester means a moiety that contains an organic moiety-C(0)-0- structure.
  • the organic moiety-C(0)-0- structure contains about 1 -50 carbon atoms (preferably 1 -6 carbon atoms) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), preferably 1 or 2 heteroatoms, where the organic moiety-C(0)-0- structure is bonded to a variable position of a steroid nucleus, replacing variable group substituents including R 1 , R 2 , R 3 or R 4 through the organic moiety-C(0)-0- structure, i.e., organic moiety-C(0)-0- steroid, preferably R 1 , R 2 or R 3 .
  • the organic moiety usually comprises one or more of any of the organic groups described herein, e.g., C-i-20 alkyl moieties (preferably C1 -8), C2-20 alkenyl moieties (preferably C2-8), C2-20 alkynyl moieties (preferably C2-8), aryl moieties (preferably phenyl), C1-9 heterocycles (preferably C2-5) or substituted derivatives of any of these, e.g., comprising 1 , 2, 3, 4 or more substituents, preferably 1 or 2 substituents, preferably oxygen or nitrogen containing substituent, or halogen or optionally substituted phenyl substituents, where each substituent is independently chosen.
  • substitutions for hydrogen atoms in these organic groups are as described above for substituted alkyl and other substituted moieties. Substitutions are independently chosen.
  • the organic moieties exclude obviously unstable moieties, e.g., -0-0-, except where such unstable moieties are transient species that one can use to make a compound with sufficient chemical stability for one or more of the uses described herein, including for synthesis of the formula 1 or other compounds.
  • the substitutions listed above are typically substituents that one can use to replace a hydrogen atom, e.g., aryl, heterocycle, heteroaryl, halogen, -NH 2 , -SH , -OH, alkoxy, ester, carbamate, carbonate or other functional group described herein.
  • Preferred optionally substituted esters are acetate, enanthate, propionate, isopropionate, isobutyrate, butyrate, valerate, caproate, isocaproate, hexanoate, heptanoate, octanoate, nonanoate, decanoate, undecanoate, phenylacetate or benzoate, which are representative hydroxyl esters.
  • Amide contains an organic moiety-C(0)-NR PR - structure, where R PR is -H or a protecting group, where organic moiety is as described for ester.
  • carbonate groups as used here comprise an organic moiety containing about 1 -50 carbon atoms
  • the organic moiety-C(0)NR PR - structure is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R 1 , R 2 , R 3 or R 4 , i.e., organic moiety-C(0)NR PR - steroid, preferably R 4 .
  • “Ether” or alkoxy group means an organic moiety that contains 1 , 2, 3, 4 or more -O- moieties, usually 1 , 2 or 3, preferably 1 .
  • carbonate groups as used here comprise an organic moiety containing about 1 -50 carbon atoms (preferably C1 -8) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), preferably 1 or 2 O, S or N heteroatoms or a combination thereof.
  • the organic moiety-O- structure is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R 1 , R 2 , R 3 or R 4 , i.e., organic moiety-O-steroid, preferably R 1 , R 2 or R 3 .
  • Carbonate means an organic moiety as described for ester that comprises 1 , 2, 3, 4 or more organic moiety -0-C(0)-0- structures, preferably 1 .
  • carbonate groups as used here comprise an organic moiety containing about 1 -50 carbon atoms (preferably C1 -8) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), preferably 1 or 2 O, S or N heteroatoms or a combination thereof, linked to a variable position of a steroid nucleus, replacing variable group substituents that include R 1 , R 2 , R 3 or R 4 through the organic moiety -0-C(0)-0- structure, i.e., organic moiety-O- C(0)-0-steroid, preferably R 1 , R 2 or R 3 .
  • “Carbamate” means an organic moiety as described for ester that comprises 1 , 2, 3, 4 or more -0-C(0)NR PR -organic moiety structures where R PR is -H, a protecting group or an organic moiety as described for ester.
  • carbamate groups as used here comprise an organic moiety containing about 1 -50 carbon atoms (preferably C1 -8) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), preferably 1 or 2 O, S or N heteroatoms or a combination thereof, linked to a variable position of a steroid nucleus, replacing variable group substituents that include R 1 , R 2 , R 3 or R 4 through the -O-C(O)- NR PR -organic moiety structure, i.e., organic moiety-0-C(0)-NR PR -steroid, preferably R 1 , R 2 or R 3 .
  • C1 -C4 optionally substituted alkyi means, e.g., 3 carbon alkyi, 4 carbon substituted alkyi and the like are disclosed and can be expressly referred to or named.
  • N-linked ring means a heterocycle moiety that is bonded at a variable group position of the steroid ring system through a ring nitrogen atom of the heterocycle.
  • the steroid ring system position for the N-linked ring substituents includes R 4 (i.e., 17-position) substituents.
  • N-linked rings include optionally substituted
  • a "C-linked ring” means a heterocycle or carbocyclic ring moiety bonded at a variable group position of the steroid ring system.
  • the rings can be saturated or unsaturated.
  • the steroid ring system position for the C-linked ring substituent includes R 4 (i.e., 17-position) substituents.
  • C-linked rings include aryls and C-linked heterocycles, including C-linked heteroaryls.
  • Exemplary C-linked rings include optionall substituted
  • 3-pyridine e.g., bonded to the steroid at the 17- position
  • 3-pyridyl or 3-pyridinyl e.g., 1-pyridinium
  • 1 -pyridinium bonded to the steroid
  • N-pyridyl, 1 -pyridyl, N- pyridinyl or 1 -pyridinyl bonded to the steroid
  • Compounds that can be used in the screening method include ones
  • N-linked amino acids have the structure -NH-CHR 7 -C(0)OR PR , - optionally substituted heterocycle or -optionally substituted cycle, including a C-linked ring (preferably a 5-membered ring or 6-membered ring) or an N- linked ring (preferably a 5-membered ring or 6-membered ring);
  • R 5 is -CH 3 , - C 2 H 5 , -CH 2 OH or -CH 2 (ester);
  • R 6 is -H, -CH 3 , -C 2 H 5 , -CH 2 OH or -CH 2 (ester);
  • R 7 is the side group of a natural amino acid (including -H, -CH 3 , -CH 2 OH, - CHOH-CH3, -CH 2 -CH-(CH 3 ) 2 or phenyl);
  • R PR is -H or a protecting group (including a C2-6 ester optionally acetate or propionate
  • Heterocycles at R 4 include N-linked or C-linked ring moieties including N-linked or C-linked heteroaryls.
  • heteroaryls include 1 -furanyl, 2-furanyl, 1 -oxolane, 2-oxolane, 1 -thiophene, 2- thiophene, 1 -pyrrole, 2-pyrrole, 3-pyrrole, 1 -pyrrolidine, 2-pyrrolidine, 3- pyrrolidine, 2-thiazolyl, 3-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1 -pyranyl, 2-pyranyl and 3-pyranyl.
  • Preferred heteroaryl heterocycles are 1 -pyridinyl, 3-pyridinyl, 1 - pyrimidinyl, 4-pyrimidinyl, and 5-pyrimidinyl.
  • N-linked heterocycles further include R 4 substituents -N-pyrrolidine, - N1 -pyrazolone, -N2-pyrazolone, -N-imidazolidin-2-one, -N1 -imidazole, -N1 - 4,5-dihydroimidazole, -N-morpholine, -N1 -pyridine, -N-piperidine, -N- piperazine, , optionally substituted at N4 with optionally substituted alkyl, optionally substituted aryl or optionally substuted heteroaryl, -N-indole, -N- indoline, -N-quinolidine, -NH-C(0)-CH 2 -CH 2 -C(0)-OH, -NH-C(0)-CH 2 -C(0)- OH, -NH-C(0)-CH 2 -CH 2 -C(0)-OR PR , -NH-C(0)-CH 2 -C(0)-C(0)
  • N-linked amino acids further include R 4 substituents -NH-CH(CH 3 )- C(0)OH, -NH-CH(CH 3 )-C(0)OR PR , -NH-CH(CH 2 OH)-C(0)OH, -NH- CH(CH 2 OH)-C(0)OR PR , -NH-CH 2 -CH 2 -C(0)-OH, -NH-CH 2 -C(0)-OH, -NH- CH 2 -CH 2 -C(0)-OR PR , -NH-CH 2 -C(0)-OR PR , -NH-(CH 2 ) 3 -C(0)-OH or -NH- (CH 2 ) 3 -C(0)-OR PR , wherein R PR is a protecting group.
  • N-linked or C-linked heterocycles further include R 4 substituents (1 ) -N- pyridine (N-linked) or -N-pyrimidinyl (N-linked), (2) -1 -pyridyl (C-linked), -2- pyridyl, -3-pyridyl, -1 -pyrimidinly (C-linked), -4-pyrimidinly or -5-pyrimidinly, (3) -N-piperidinyl, -1 -piperidinyl, -2-piperidinyl, -3-piperidinyl, or (4) -N-imidazole, - 2-imidazole or -4-imidazole.
  • compositions for use in the screening methods in animals will typically be provided as aqueous or organic solutions or suspensions, although such compositions may or may not be suitable for human use, e.g., if significant amounts of organic solvents are present. Such compositions are most suitable for administration to animals, e.g., rodents or dogs, which can be used in the screening method. The compositions for administration to animals will typically not need to be sterile. Such compositions will typically contain about 5 mg/mL to about 50 mg/mL of the compound as a solution or suspension.
  • the compounds are usually presented as pharmaceutical formulations that comprise one or more excipients and the compound.
  • Such formulations are usually prepared from purified compound that is mixed with other excipients.
  • the compound will usually be present as a purified solid, e.g., powder or granule, that is at least about 90% w/w pure or preferably at least about 95% w/w pure, e.g., about 95% w/w to about 99.8% w/w.
  • the formulations comprise the compound and one or more known excipients, e.g., fillers, binders, lubricants, dispersants or the like.
  • excipients may include one or more of a cellulose such as microcrystalline cellulose or
  • compositions can be present as unit dosages for oral, parenteral or another other route of administration.
  • Unit dosages e.g., tablets, capsules or gelcaps for oral human administration, will contain about 20 mg to about 1000 mg per unit dose, preferably about 20 mg to about 500 mg per unit dose.
  • One or two of such unit doses are taken once per day or twice per day, e.g., twice daily.
  • Oral dosing is preferably one or two unit dosages, most preferably one, that are taken once per day.
  • Individual unit doses may contain about 20 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg or about 750 mg of the compound in an oral formulation.
  • Formulations also include those for administration by other routes including parenteral and topical including buccal or sublingual.
  • Parenteral formulation for administration by, e.g., intravenous or intramuscular injection to patients will be sterile solutions or, for routes other than intravenous injection, suspensions, typically aqueous.
  • the compound will typically be present at a concentration of about 20 mg/mL to about 100 mg/mL along with other excipients, e.g., buffers to control pH, e.g., phosphate, saline or other agents to attain roughly isotonic conditions, water, thickening agents or preservatives such as EDTA.
  • Daily parenteral dosing will be about 10 mg/day to about 500 mg/day.
  • the drug products typically comprise (a) a drug in a dosage form such as a solid or liquid formulation suitable for, e.g., oral, parenteral, topical or aerosol administration.
  • a dosage form such as a solid or liquid formulation suitable for, e.g., oral, parenteral, topical or aerosol administration.
  • Packaging for the drug and/or a package insert or label will have information about the drug's efficacy, mechanism of action, the intended patient population, dosage, dose regimen, route of administration, effect of the drug or treatment.
  • the package insert or label can contain information about the patient population for which the drug product can be used or is approved.
  • a drug product as used herein means a product that has been reviewed and approved for marketing or sale by a regulatory agency or entity with authority to review or approve applications for sale or medical use. Uses of drug products include its marketing or sales and offers to sell or buy it for consideration. These activities will typically adhere to terms of the regulatory approval that may affect or govern marketing, sales, purchases or product handling.
  • the drug in a drug product can be a new drug, a generic drug, a biological, a medical device or a protocol for the use of any of these.
  • the drug product usually results from marketing approval by the U.S. Food and Drug Administration of a new drug application, an abbreviated new drug
  • Uses for the drug product include its sale to public or private buyers such as the U.S. Department of Defense, the U.S. Department of Energy, U.S. Department of Health and Human Services or a private drug buyer or distributor entity. Other uses include use of the drug to treat indicated or approved medical conditions and physician approved uses or off label uses.
  • Pre-approval drug products are other invention embodiments, which can be used, e.g., for preparing to make commercial scale product in anticipation of regulatory review or regulatory marketing approval and other drug development and review activities.
  • the intended patient population identified by the drug product can also specify excluded populations, if any, that may apply such as pediatric patients or elderly patients.
  • Information about dosage will typically specify daily doses of the drug, while the dose regimen will describe how often and how long the drug is to be administered or taken.
  • the route of administration will identify one or more routes that are suitable for use of the drug, although a given formulation will typically be approved for only one route of administration.
  • the compounds can be used to treat cancers such as neuroendocrine cancers such as prostate cancer or breast cancer.
  • cancers that can be treated include lung cancer, liver cancer and colon cancer. Cancers that can be treated further include ovarian cancer, bladder cancer and testicular. Cancers that can be treated further include endometrial cancer and cervical cancer.
  • Cancers that can be treated further include CNS cancers such as
  • neuroblastoma and glioma Additional cancers that can be treated are myeloma and thyroid cancer.
  • the compounds can also be used to treat other hormone responsive hyperproliferation conditions such as endometriosis and benign prostatic hypertrophy.
  • R 7 is the side group of a natural amino acid (including -H, -CH 3 , - CH 2 OH, -CHOH-CH3, -CH 2 -CH-(CH 3 ) 2 or phenyl); and R PR is -H or a protecting group (including a C2-6 ester optionally acetate or propionate, or benzoate), preferably -H.
  • 3-furanyl ( ⁇ °). These embodiments include 17-(2-furanyl) ⁇ - methylandrost-5,16-diene-3 ⁇ -ol, 17-(2-furanyl)-7 -methylandrost-5,16-diene- 3 ⁇ - ⁇ , 17-(2-furanyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3-furanyl) ⁇ - ethylandrost-5,16-diene-3 ⁇ -ol, 17-(3-furanyl)-7 -ethylandrost-5,16-diene-3 ⁇ -ol and 17-(3-furanyl) ⁇ -ethylandrost-5,16-diene-3cc-ol.
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16- position is substituted with an O-linked substituent, including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-furanyl) ⁇ - methylandrost-5,16-diene-3p,16-diol, 17-(3-furanyl) ⁇ -ethylandrost-5,16- diene ⁇ -ol-16-methyl ether and 17-(3-furanyl) ⁇ -ethylandrost-5,16-diene ⁇ - ol-16-acetate.
  • These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent, including an optionally substituted alkyl group.
  • Exemplary alkyl R 3 substituents include -CH 3 , -C 2 H 5 and -CH 2 CH 2 CH 3 to provide exemplary species that include 17-(2-furanyl) ⁇ ,16-dimethylandrost-5,16-diene ⁇ -ol and 17-(3-furanyl) ⁇ ,16-diethylandrost-5,16-diene ⁇ -ol. These compounds also include analogs of any of these compounds where the methyl at the 18- position (R 5 ) is -C 2 H 5 , including the analogs of the first and second named compounds in this embodiment.
  • These embodiments include 17-(2- ⁇ 8 ⁇ )-7 ⁇ - methylandrost-5,16-diene ⁇ -ol, 17-(2-oxolanyl)-7a-methylandrost-5,16- ⁇ -3 ⁇ - ⁇ , 17-(2-oxolanyl)-7a-methylandrost-5,16-diene-3cc-ol, 17-(3- oxolanyl) ⁇ -ethylandrost-5,16-diene ⁇ -ol, 17-(3-oxolanyl)-7cc-ethylandrost- 5,16-diene ⁇ -ol and 17-(3-oxolanyl)-7 ⁇ -ethylandrost-5,16-diene-3 -ol.
  • embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent, including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-oxolanyl) ⁇ - methylandrost-5,16-diene ⁇ ,16-diol and 17-(3-oxolanyl) ⁇ -ethylandrost- 5,16-diene ⁇ -ol-16-methyl ether.
  • These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is
  • R 3 substituents include -CH 3 , - C 2 H 5 and -CH 2 CH 2 CH 3 to provide exemplary species that include 17-(2- ⁇ 8 ⁇ )-7 ⁇ , 16-dimethylandrost-5, 16-diene ⁇ -ol and 17-(3- ⁇ 8 ⁇ )-7 ⁇ , 16- diethylandrost-5,16-diene ⁇ -ol.
  • R 5 the methyl at the 18-position
  • R 6 the methyl at the 19-position
  • R 6 is -C2H5
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-thiophenyl) ⁇ -methylandrost-5,16-diene-3 ,16-diol and 17-(3- thiophenyl) ⁇ -ethylandrost-5,16-diene ⁇ -ol-16-methyl ether.
  • inventions also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and -CH 2 CH 2 CH 3 to provide species that include 17-(2- thiophenyl) ⁇ ,16-dimethylandrost-5,16-diene ⁇ -ol and 17-(3-thiophenyl)- 7 ⁇ ,16-diethylandrost-5, 16-diene-3 ⁇ -ol.
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(1 -pyrrolyl)-7 ⁇ -methylandrost-5, 16-(_ ⁇ -3 ⁇ , 16-diol , 17-(2- ⁇ )-7 ⁇ - methylandrost-5,16-diene-3 ⁇ ,16-diol and 17-(3-pyrrolyl) ⁇ -ethylandrost-5,16- diene-3 ⁇ -ol-16-methyl ether.
  • These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • R 3 substituents include -CH 3 , -C 2 H 5 and -CH 2 CH 2 CH 3 to provide species that include 17-(1 -pyrrolyl) ⁇ ,16-dimethylandrost-5,16- diene-3p-ol, 17-(2-pyrrolyl)-7 ⁇ ,16-dimethylandrost-5,16-diene-3 ⁇ -ol and 17-(3- pyrrolyl) ⁇ ,16-diethylandrost-5,16-diene ⁇ -ol.
  • These compounds also include analogs of any of these compounds where the methyl at the 18- position (R 5 ) is -C 2 H 5 , including the analogs of the first and second named compounds in this embodiment.
  • R 4 is preferably 2-pyrrolyl or 3- pyrrolyl with preferred species including the 2-pyrrolyl and 3-pyrrolyl species listed above.
  • embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH3, -OC2H5, -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(1 -pyrrolidinyl) ⁇ - methylandrost-5,16-diene ⁇ ,16-diol, 17-(2-pyrrolidinyl) ⁇ -methylandrost-
  • Exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and -CH 2 CH 2 CH 3 to provide exemplary species that include -(1 -pyrrolidinyl)-7p,16- dimethylandrost-5,16-diene ⁇ -ol, 17-(2-pyrrolidinyl) ⁇ ,16-dimethylandrost- 5,16-diene-3 -ol and 17-(3-pyrrolidinyl)-7 ,16-diethylandrost-5,16- ⁇ -3 ⁇ - ⁇ .
  • These compounds also include analogs of any of these compounds where the methyl at the 18-position (R 5 ) is -C 2 H 5 , including the analogs of the first and second named compounds in this embodiment.
  • R 4 is preferably 2-pyrrolidinyl or 3-pyrrolidinyl with preferred species including the 2-pyrroldinyl and 3-pyrrolidinyl species listed above.
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-thiazolyl) ⁇ -methylandrost-5,16-diene ⁇ ,16-diol, 17-(3-thiazolyl) ⁇ -methylandrost-5,16-diene ⁇ ,16-diol, 17-(4-th iazolyl )-7 ⁇ - ethylandrost-5,16-diene ⁇ -ol-16-methyl ether, 17-(5-thiazolyl)-7p- ethylandrost-5,16-diene-3 ⁇ -ol-16-methyl ether and 17-(5-thiazolyl)-7p- ethylandrost-5,16-diene-3 ⁇ -ol-16-acetate.
  • embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and - CH 2 CH 2 CH 3 to provide exemplary species that include17-(2-thiazolyl) ⁇ ,16- dimethylandrost-5,16-diene ⁇ -ol, 17-(3-thiazolyl) ⁇ ,16-dimethylandrost- 5,16 ⁇ -3 ⁇ - ⁇ , 17-(4-thiazolyl)-7 ⁇ ,16-diethylandrost-5, 16-diene-3 ⁇ -ol and 17-(5-thiazolyl) ⁇ ,16-diethylandrost-5,16-diene ⁇ -ol.
  • R 4 is preferably 2-thiazolyl, 4- thiazolyl or 5-thiazolyl with preferred species including the 2-, 4- and 5- thiazolyl species listed above.
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16- position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC2H5, -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-tetrahydropyranyl)- 7 ⁇ -methylandrost-5,16-diene-3 ⁇ ,16-diol, 17-(3-tetrahydropyranyl) ⁇ - methylandrost-5,16-diene-3 ⁇ ,16-diol and 17-(4-tetrahydropyranyl) ⁇ - ethylandrost-5,16-diene-3 ⁇ -ol-16-methyl ether.
  • These embodiments also include analogs of these compounds where the hydrogen atom at the 16- position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • Exemplary alkyl group R 3 substituents include -CH 3 , - C 2 H 5 and -CH 2 CH 2 CH 3 to provide exemplary species that include 17-(2- tetrahydropyranyl) ⁇ , 16-dimethylandrost-5, 16-diene ⁇ -ol, 17-(3- tetrahydropyranyl) ⁇ , 16-dimethylandrost-5, 16-diene-3 ⁇ -ol and 17-(4- tetrahydropyranyl)-7 ⁇ ,16-diethylandrost-5,16-diene-3 ⁇ -ol.
  • These compounds also include analogs of any of these compounds where the methyl at the 18- position (R 5 ) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R 6 ) is -C2H5, including the analogs of the first and second named compounds in this embodiment.
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-(1 ,4- ⁇ 3 ⁇ ))-7 ⁇ - ⁇ 3 ⁇ 8 ⁇ -5,16- ⁇ -3 ⁇ ,16- ⁇ and 17-(2-(1 ,4- dioxanyl)) ⁇ -ethylandrost-5,16-diene ⁇ -ol-16-methyl ether.
  • These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • Exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and -CH 2 CH 2 CH 3 to provide exemplary species that include 17-(2-(1 ,4- 1 ⁇ 3 ⁇ ))-7 ⁇ , 16-dimethylandrost-5, 16- ⁇ -3 ⁇ - ⁇ and 17- (2-(1 ,4-dioxanyl)) ⁇ ,16-diethylandrost-5,16-diene ⁇ -ol.
  • These compounds also include analogs of any of these compounds where the methyl at the 18- position (R 5 ) is -C 2 H 5 , including the analogs of the first and second named compounds in this embodiment.
  • These embodiments include 17-(2-morpholinyl) ⁇ -methylandrost-5,16-diene- 3 ⁇ - ⁇ , 17-(2-morpholinyl)-7a-methylandrost-5,16-diene-3 -ol, 17-(2- morpholinyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3- ⁇ )-7 ⁇ - ethylandrost-5,16-diene-3 ⁇ -ol, 17-(3-morpholinyl)-7cc-ethylandrost-5,16-diene- 3 ⁇ - ⁇ , 17-(3- ⁇ )-7 ⁇ - ⁇ 3 ⁇ 8 ⁇ -5,16- ⁇ -3 ⁇ - ⁇ , 17-(4- morpholinyl) ⁇ -methylandrost-5,16-diene ⁇ -ol, 17-(4-morpholinyl)-7 - methylandrost-5,16-diene ⁇ -ol and 17-(4-morpholinyl)-7 -methylandrost- 5,16-diene-3
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and - OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-morpholinyl) ⁇ -methylandrost-5,16-diene ⁇ ,16- diol, 17-(3-morpholinyl)-7 -methylandrost-5,16-diene-3 ,16-diol, 17-(4- morpholinyl)-7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol-16-methyl ether and 17-(2- morpholinyl)-7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol-16-acetate.
  • embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and -CH 2 CH 2 CH 3 to provide exemplary species that include 17-(2-morpholinyl) ⁇ ,16-dimethylandrost-5,16-diene ⁇ -ol, 17-(3- morpholinyl) ⁇ ,16-dimethylandrost-5,16-diene ⁇ -ol and 17-(4-morpholinyl)- 7 ⁇ ,16- ⁇ 3 ⁇ 8 ⁇ -5, 16- ⁇ -3 ⁇ - ⁇ .
  • R 4 is preferably 2-morpholinyl or 3-morpholinyl with preferred species including the 2- and 3-morpholinyl species listed above.
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-oxazolyl) ⁇ -methylandrost-5,16-diene ⁇ ,16-diol, 17-(5-oxazolyl) ⁇ -methylandrost-5, 16-diene-3 ⁇ , 16-diol or 17-(4- ⁇ 8 ⁇ )-7 ⁇ - ethylandrost-5,16-diene-3 ⁇ -ol-16-methyl ether and 17-(5- ⁇ 8 ⁇ )-7 ⁇ - ethylandrost-5,16-diene-3 ⁇ -ol-16-acetate.
  • These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • Exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and - CH 2 CH 2 CH 3 to provide exemplary species that include 17-(2- ⁇ 8 ⁇ )-7 ⁇ ,16- dimethylandrost-5,16-diene ⁇ -ol, 17-(5-oxazolyl) ⁇ ,16-dimethylandrost- 5,16-diene ⁇ -ol and 17-(4-oxazolyl)-7 ⁇ , 16-diethylandrost-5,16-diene-3 ⁇ -ol.
  • These compounds also include analogs of any of these compounds where the methyl at the 18-position (R 5 ) is -C 2 H 5 , including the analogs of the first and second named compounds in this embodiment.
  • These embodiments include 17-(2-imidazolyl) ⁇ - methylandrost-5,16-diene-3 ⁇ -ol, 17-(2-imidazolyl)-7a-methylandrost-5,16- diene ⁇ -ol, 17-(2-imidazolyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3- imidazolyl)-7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol, 17-(3-imidazolyl)-7 - ethylandrost-5,16-diene ⁇ -ol, 17-(3-imidazolyl) ⁇ -ethylandrost-5,16-diene- 3 -ol, 17-(4-imidazolyl)-7 ⁇ -methylandrost-5,16-diene-3 ⁇ -ol, 17-(4-imidazolyl)- 7a-methylandrost-5,16-diene ⁇ -ol, 17-(4-imidazolyl
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-imidazolyl) ⁇ -methylandrost-5, 16-diene ⁇ ,16-diol, 17-(3-imidazolyl) ⁇ -methylandrost-5, 16-diene ⁇ , 16-diol, 17-(4-imidazolyl)- 7 ⁇ -ethylandrost-5,16-diene ⁇ -ol-16-methyl ether, 17-(5-imidazolyl ⁇ - ethylandrost-5,16-diene-3 ⁇ -ol-16-methyl ether and 17-(5-imidazolyl ⁇ - ethylandrost-5,16-diene-3 ⁇ -ol-16-acetate.
  • embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and - CH 2 CH 2 CH 3 to provide exemplary species that include 17-(2-imidazolyl)- 7 ⁇ ,16-dimethylandrost-5,16-diene-3 ⁇ -ol, 17-(3-imidazolyl) ⁇ ,16- dimethylandrost-5,16-diene ⁇ -ol, 17-(4-imidazolyl) ⁇ ,16-diethylandrost- 5,16-diene ⁇ -ol and 17-(5-imidazolyl)-7 ⁇ ,16-diethylandrost-5,16-diene-3 ⁇ -ol.
  • R 4 is preferably 2-imidazolyl, 4- imidazolyl or 5-imidazolyl, with preferred species including the 2-, 4- and 5- imidazolyl species listed above.
  • piperidine 2-piperidine ), 3-piperidine ) or 4 piperidine These embodiments include 17-(2-piperidinyl)-7 - methylandrost-5,16- ⁇ -3 ⁇ - ⁇ , 17-(2-piperidinyl)-7 -methylandrost-5,16- ⁇ -3 ⁇ - ⁇ , 17-(2-piperidinyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3- piperidinyl)-7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol, 17-(3-piperidinyl)-7cc- ethylandrost-5,16-diene-3 ⁇ -ol, 17-(3-piperidinyl) ⁇ -ethylandrost-5,16-diene- 3cc-ol, 17-(4-piperidinyl)-7 ⁇ -methylandrost-5,16-diene-3 ⁇ -ol, 17-(4-piperidinyl)- 7 -methylandrost
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-piperidinyl) ⁇ -methylandrost-5,16-diene ⁇ ,16- diol, 17-(3-piperidinyl)-7 -methylandrost-5,16-diene-3 ,16-diol, 17-(4- piperidinyl) ⁇ -ethylandrost-5,16-diene ⁇ -ol-16-methyl ether, 17-(1 - piperidinyl)-7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol-16-methyl ether and 17-(1 - piperidinyl)-7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol-16-acetate.
  • embodiments also include analogs of these compounds where the hydrogen atom at the 16- position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , - C 2 H 5 and -CH2CH2CH3, to provide exemplary species that include 17-(2- piperidinyl) ⁇ ,16-dimethylandrost-5,16-diene ⁇ -ol, 17-(3-piperidinyl)-7 , 16- dimethylandrost-5,16-diene ⁇ -ol, 17-(4-piperidinyl)-7p, 16-diethylandrost- 5,16-diene ⁇ -ol and 17-(1 -piperidinyl)-7 , 6-diethylandrost-5,16- ⁇ -3 ⁇ - ⁇ .
  • R 4 is preferably 2-piperidinyl, 3-piperidinyl or 4-piperidinyl, with preferred species including the 2-, 3- and 4-piperidinyl species listed above.
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and - OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-piperazinyl) ⁇ -methylandrost-5,16-diene ⁇ ,16- diol, 17-(1 -piperazinyl)-7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol-16-methyl ether, 17- (1 -piperazinyl) ⁇ -ethylandrost-5,16- ⁇ -3 ⁇ - ⁇ -16-acetate and 17-(2- piperazinyl)-7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol-16-acetate.
  • embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and -CH 2 CH 2 CH 3 to provide exemplary species that include 17-(2-piperazinyl) ⁇ ,16-dimethylandrost-5,16-diene ⁇ -ol and 17-(1 piperazinyl)-7 ⁇ ,16-diethylandrost-5,16-diene-3 ⁇ -ol.
  • R 5 is -C2H5
  • These compounds also include analogs of any of these compounds where the methyl at the 19-position (R 6 ) is -C2H5, including the analogs of the first and second named compounds in this embodiment.
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-pyridinyl) ⁇ -methylandrost-5,16-diene ⁇ ,16-diol, 17-(3-pyridinyl)-7 -methylandrost-5,16-diene-3 ,16-diol, 17-(4- ⁇ (_ ⁇ )-7 ⁇ - ethylandrost-5,16-diene ⁇ -ol-16-methyl ether, 17-(1 -pyridinyl)-7p- ethylandrost-5,16-diene-3 ⁇ -ol-16-methyl ether and 7-(1 -pyridinyl)-7 - ethylandrost-5,16-diene-3 ⁇ -ol-16-acetate.
  • embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and - CH 2 CH 2 CH 3 to provide exemplary species that include 17-(2-pyridinyl)-7 ,16- dimethylandrost-5,16-diene ⁇ -ol, 17-(3-pyridinyl) ⁇ ,16-dimethylandrost- 5,16-diene-3 -ol, 17-(4-pyridinyl)-7 ⁇ ,16-diethylandrost-5,16-diene-3 ⁇ -ol and 17-(1 -pyridinyl) ⁇ ,16-diethylandrost-5,16-diene ⁇ -ol.
  • R 4 is preferably 2-pyridinyl, 3- pyridinyl or 4-pyridinyl with preferred species including the 2-pyridinyl, 3- pyridinyl and 4-pyridinyl species listed above.
  • the compound of embodiment 1 wherein R 4 is 1 -pyrazinium include 17-(2- pyrazinyl) ⁇ -methylandrost-5,16-diene ⁇ -ol, 17-(2-pyrazinyl)-7cc- methylandrost-5,16-diene ⁇ -ol, 17-(2-pyrazinyl)-7 -methylandrost-5,16- diene-3cc-ol, 17-(1 -pyrazinyl)-7 ⁇ -ethylandrost-5, 16- ⁇ -3 ⁇ - ⁇ , 17-(1 - pyrazinyl)-7 -ethylandrost-5,16-diene-3 ⁇ -ol and 17-(1 -pyrazinyl) ⁇ - ethylandrost-5,16-diene-3cc-ol.
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and - OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-pyrazinyl) ⁇ -methylandrost-5,16-diene ⁇ ,16-diol, 17-(1 -pyrazinyl) ⁇ -ethylandrost-5,16-diene ⁇ -ol-16-methyl ether, 17-(1 - pyrazinyl) ⁇ -ethylandrost-5,16-diene ⁇ -ol-16-acetate and 17-(2-pyrazinyl)- 7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol-16-acetate.
  • inventions also include analogs of these compounds where the hydrogen atom at the 16- position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , - C 2 H 5 and -CH2CH2CH3, to provide exemplary species that include 17-(2- pyrazinyl) ⁇ ,16-dimethylandrost-5,16-diene ⁇ -ol and 17-(1 - ⁇ 8 ⁇ )-7 ⁇ ,16- diethylandrost-5,16-diene-3 ⁇ -ol.
  • These compounds also include analogs of any of these compounds where the methyl at the 18-position (R 5 ) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R 6 ) is -C2H5, including the analogs of the first and second named compounds in this embodiment.
  • embodiments include 17-(2-pyrimidinyl)-7P- methylandrost-5,16-diene-3 ⁇ -ol, 17-(2-pyrimidinyl)-7a-methylandrost-5,16- diene-3 ⁇ -ol, 17-(2-pyrimidinyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(1 - pyrimidinyl) ⁇ -ethylandrost-5,16-diene ⁇ -ol, 17-(1 -pyrimidinyl)-7 - ethylandrost-5,16-diene-3 ⁇ -ol, 17-(1 -pyrimidinyl) ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol, 17-(1 -pyrimidinyl) ⁇ -ethylandrost-5,16-diene- 3 -ol, 17-(1 -pyrimidinyl) ⁇ -ethylandrost-5,16-diene- 3 -ol, 17-(
  • These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , - OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(2-pyrimidinyl) ⁇ -methylandrost-5,16- diene-3p,16-diol, 17-(1 -pyrimidinyl)-7 ⁇ -methylandrost-5,16-diene-3 ⁇ ,16-diol, 17-(4-pyrimidinyl)-7 ⁇ -ethylandrost-5, 16-diene ⁇ -ol-16-methyl ether, 17-(5- pyrimidinyl)-7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol-16-methyl ether and 17-(5- pyrimidinyl) ⁇ -ethylandrost-5,16-diene ⁇ -ol-16-acetate.
  • embodiments also include analogs of these compounds where the hydrogen atom at the 16- position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , - C2H5 or -CH 2 CH 2 CH3 to provide exemplary species that include17-(2- pyrimidinyl) ⁇ ,16-dimethylandrost-5,16-diene ⁇ -ol, 17-(1 -pyrimidinyl)-7 , 16- dimethylandrost-5,16-diene ⁇ -ol, 17-(4-pyrimidinyl) ⁇ ,16-diethylandrost- 5,16-diene ⁇ -ol and 17-(5-pyrimidinyl)-7 ⁇ ,16-diethylandrost-5,16-diene-3 ⁇ -ol.
  • R 4 is preferably 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl, with preferred species including the 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl species listed above.
  • These compounds include 17- (phenyl) ⁇ -methylandrost-5,16-diene ⁇ -ol, 17-(phenyl) ⁇ -methylandrost- 5,16-diene-3cc-ol, 17-(phenyl)androst-5,16-diene ⁇ -diol, 17- (phenyl)androst-5, 16-diene-3cc ⁇ -diol, 17-(phenyl)androst-5,16-diene ⁇ ,7cc- diol, 17-(phenyl)-7a-methylandrost-5,16-diene ⁇ -ol, 17-(m-methylphenyl) ⁇ - ethylandrost-5,16-diene ⁇ -ol, 17-(p-methoxyphenyl) ⁇ -ethylandrost-5,16- diene-3cc-ol and 17-( -fluorophenyl)-7 -ethylandrost-5,16-diene-3 ⁇ -ol.
  • These compounds include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include, -OCH3, -OC2H5, -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-( ⁇ )-7 ⁇ - methylandrost-5,16-diene-3 ⁇ ,16-diol, 17-(p-fluorophenyl) ⁇ -methylandrost- 5,16-diene-3p,16-diol and 17-(p-methoxyphenyl) ⁇ -ethylandrost-5,16-diene- 3 -ol-16-acetate.
  • These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • Exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and -CH 2 CH 2 CH 3 to provide exemplary species that include 17-(phenyl)-7a,16-dimethylandrost- 5,16-diene ⁇ -ol and 17-(o-hydroxyphenyl) ⁇ ,16-diethylandrost-5,16-diene- 3 ⁇ - ⁇ .
  • These compounds also include analogs of any of these compounds where the methyl at the 18-position (R 5 ) is -C 2 H 5 , including the analogs of the first and second named compounds in this embodiment.
  • These compounds also include analogs of any of these compounds where the methyl at the 19- position (R 6 ) is -C 2 H 5 , including the analogs of the first, second and third named compounds in this embodiment.
  • R is -H, -CH 3 , -C 2 H 5 , -CF 3 , -OH, - -OC2H5 or -F.
  • R when R is not -H, it is meta to the carbon that is bonded at the 17- position.
  • Preferred R are -H, -F, -OCH 3 and -OH.
  • These compounds include 17-(cyclohexyl) ⁇ -methylandrost-5,16-diene ⁇ -ol, 17-(cyclohexyl)androst- 5,16- ⁇ -3 ⁇ ,7 ⁇ - ⁇ , 17-(cyclohexyl)androst-5, 16-diene-3cc ⁇ -diol, 17-(p- (trifluoromethyl)cyclohexyl)-7 ⁇ -methylandrost-5,16-diene-3 ⁇ -ol, 17- (cyclohexyl) ⁇ -methylandrost-5,16-diene-3cc-ol, 17-(cyclohexyl)-7cc- methylandrost-5,16- ⁇ -3 ⁇ - ⁇ , 17-(m-hydroxycyclohexyl) ⁇ -ethylandrost- 5,16-diene ⁇ -ol, 17-( -methoxycyclohexyl)-7 ⁇ -ethylandrost-5,16-diene-3 -ol and 17-(p-fluor
  • These compounds include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH3, -OC2H5, -OC(0)CH 3 and -OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(cyclohexyl) ⁇ - methylandrost-5,16-diene-3 ⁇ ,16-diol and 17-(p-methoxycyclohexyl) ⁇ - ethylandrost-5,16-diene-3 -ol-16-acetate.
  • inventions also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , -C 2 H 5 and - CH 2 CH 2 CH 3 to provide exemplary species that include 17-(cyclohexyl)-7cc,16- dimethylandrost-5,16-diene ⁇ -ol and 17-(o-hydroxycyclohexyl) ⁇ ,16- diethylandrost-5,16-diene ⁇ -ol.
  • These compounds also include analogs of any of these compounds where the methyl at the 18-position (R 5 ) is -C 2 H 5 , including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R 6 ) is -C 2 H 5 , including the analogs of the first and second named compounds in this embodiment.
  • the structure compounds include 7 ⁇ -methylandrost-5, 16- diene ⁇ -ol-17-(pyran-3-en-2-one-3-yl), 7 ⁇ -ethylandrost-5,16-diene-3 ⁇ -ol-17- (pyran-3-en-2-one-3-yl), 7a-methylandrost-5,16-diene-3a-ol-17-(pyran-3-en-2- one-3-yl), 7cc-ethylandrost-5,16-diene ⁇ -ol-17-(pyran-3-en-2-one-3-yl), androst-5,16-diene ⁇ -diol-17-(pyran-3-en-2-one-3-yl), androst-5,16-diene- 3 ,7p-diol-17-(pyran-3-en-2-one-3-yl), androst-5,16-diene ⁇ ,7cc-diol-17- (pyran-3-en-2-one-3-yl)and 7a-ethylandrost-5
  • These compounds include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester.
  • O-linked ester and ether R 3 substituents include -OCH 3 , -OC 2 H 5 , -OC(0)CH 3 and - OC(0)CH 2 CH 3 .
  • Exemplary species of this embodiment with O-linked R 3 substituents include 17-(cyclohexyl) ⁇ -methylandrost-5,16-diene ⁇ ,16-diol and 17-( -methoxycyclohexyl)-7 ⁇ -ethylandrost-5,16-diene-3 -ol-16-acetate.
  • inventions also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
  • exemplary alkyl group R 3 substituents include -CH 3 , -C2H5 and -CH2CH2CH3 to provide exemplary species that include 17-(cyclohexyl)-7a,16-dimethylandrost-5,16-diene ⁇ -ol and17-(o-hydroxycyclohexyl)-7 ⁇ ,16-diethylandrost-5,16-diene-3 ⁇ -ol.
  • These compounds also include analogs of any of these compounds where the methyl at the 18-position (R 5 ) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 1 imposition (R 6 ) is -C2H5, including the analogs of the first and second named compounds in this embodiment.
  • R 3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH 3 , - CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH
  • R 2 is -H;
  • R 3 is -H or C1 -6 optionally substituted alkyl, optionally -CH 3 , -CF 3 , - C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 3 is C2-6 optionally substituted alkyl, optionally -C 2 H 5 , - CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 2 is optionally substituted C1 -6 alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 OH or -OCH(CH 3 ) 2 ;
  • R 3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 OH
  • R 3 is C2-6 optionally substituted alkyl, optionally -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is -OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is -OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is -OH, R 2 is -H
  • R 3 is C1-4 optionally substituted alkyl, preferably -CH 3
  • R 1 and R 2 are -OH, R 3 is - H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is - H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is 01 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is 01 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 3 is -H, or 01 -6 optionally substituted alkyl, optionally -CH 3 , - CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH
  • R 2 is -H;
  • R 3 is -H or 01 -6 optionally substituted alkyl, optionally -CH 3 , -CF 3 , -
  • R 3 is C2-6 optionally substituted alkyl, optionally -C 2 H 5 , - CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 2 is optionally substituted C1 -6 alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 OH or -OCH(CH 3 ) 2 ;
  • R 3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 3 is C2-6 optionally substituted alkyl, optionally -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1-4 optionally substituted, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1-4 optionally substituted alkyl preferably -CH 3 , -C 2 H 5 or CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is 01 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 3 is -H, or 01 -6 optionally substituted alkyl, optionally -CH 3 , - CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, - ⁇ 2 ⁇ 2
  • R 2 is -H;
  • R 3 is -H or 01 -6 optionally substituted alkyl, optionally -CH 3 , -CF 3 , - C 2 H 5 , -CH 2 CH 2 OH, - ⁇ 2 ⁇ 2 ⁇ 3 , -CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 3 is C2-6 optionally substituted alkyl, optionally -C 2 H 5 , - CH2CH2OH, - ⁇ 2 ⁇ 2 ⁇ 3 , -CH2CH2CH2OH or -CH(CH 3 ) 2 .
  • R 2 is optionally substituted 01 -6 alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, - ⁇ 2 ⁇ 2 ⁇ 3 , -CH 2 CH 2 CH 2 OH or -OCH(CH 3 ) 2 ;
  • R 3 is -H, or 01 -6 optionally substituted alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2
  • R 3 is C2-6 optionally substituted alkyl, optionally -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH. ing the structure
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH 3 , - CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2
  • R 2 is -H;
  • R 3 is -H or C1 -6 optionally substituted alkyl, optionally -CH 3 , -CF 3 , - C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 3 is C2-6 optionally substituted alkyl, optionally -C 2 H 5 , - CH2CH2OH, -CH 2 CH 2 CH 3 , -CH2CH2CH2OH or -CH(CH 3 ) 2 .
  • R 2 is optionally substituted C1 -6 alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 OH or -OCH(CH 3 ) 2 ;
  • R 3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2
  • R 3 is C2-6 optionally substituted alkyl, optionally -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl preferably -CH 3 , -C 2 H 5 or CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH. ing the structure
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 ,-C 2 H 5 or - CH 2 CH 2 OH.
  • R 3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 2 is -H;
  • R 3 is -H or C1 -6 optionally substituted alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 3 is C2-6 optionally substituted alkyl, optionally -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , - CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 2 is optionally substituted C1 -6 alkyl, optionally -CH 3 , -CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 OH or - OCH(CH 3 ) 2 ;
  • R 3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH 3 , - CF 3 , -C 2 H 5 , -CH 2 CH 2 OH, -CH
  • R 3 is C2-6 optionally substituted alkyl, optionally -C 2 H 5 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 OH or -CH(CH 3 ) 2 .
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl preferably -CH 3 , -C 2 H 5 or CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl preferably -CH 3 , -C 2 H 5 or CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl preferably -CH 3 , -C 2 H 5 or ⁇ CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • Rc R 1 and R 2 are -OH, R 3 is -CH 3
  • Re R 1 is - OH, R 2 is -H
  • R 3 is C1 -4 optionally substituted alkyl preferably -CH 3 , -C 2 H 5 or CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is C1 -4 optionally substituted alkyl preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • R 1 and R 2 are -OH, R 3 is -H
  • R 1 0, R 2 is -OH, R 3 is -H
  • R 1 and R 2 are -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 1 0, R 2 is -OH, R 3 is -CH 3
  • R 3 is C1 -4 optionally substituted alkyl, preferably -CH 3 , -C 2 H 5 or - CH 2 CH 2 OH.
  • [121] 70 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18 or 19, wherein R 1 is a C2-4 ester, optionally -OC(0)CH 3 or -OC(0)CH 2 CH 3 .
  • R 1 is a C2-4 ester, optionally -OC(0)CH 3 or -OC(0)CH 2 CH 3 .
  • These compounds include compounds or analogs of compounds described in embodiments 1 -19.
  • R 5 is -CH 2 CH 3 and R 6 is -CH 3 .
  • [161] 1 Use of a compound or composition containing a compound of any preceding embodiment, including a compound or genus described or defined in any of embodiments 1 -109, or a compound described in the claims for the preparation of a medicament. These compositions are used to make formulations comprising the compound and one or more excipients. Such formulations are preferably for oral or parenteral administration.
  • [162] 1 1 1 Use of a compound or composition containing a compound of any of embodiments 1 -109 or a compound described in the claims for the preparation of a medicament for the treatment or prophylaxis of cancer. These compositions are used to make formulations comprising the compound and one or more excipients. Such formulations are preferably for oral or parenteral administration.
  • a compound or composition containing a compound of any of embodiments 1 - 109 or a compound described in the claims for the preparation of a medicament for the treatment or prophylaxis of lung cancer, a precancer of the breast, uterine fibroids, ovarian cancer, uterine cancer or endometriosis.
  • a formulation comprising one or more excipients and a compound of any of embodiments 1 -109, or a compound described in the claims.
  • the formulation is for oral administration, including unit dosages exemplified by tablets, gelcaps or capsules, which may optionally contain amounts of structure 1 compounds that are described elsewhere herein, about 20 mg per unit dose to about 1000 mg per unit dose, including about 50 mg, about 100 mg or about 250 mg.
  • the formulation is for parenteral administration, including a sterile solution or suspension as described elsewhere herein.
  • Exemplary compounds include 17-(3-pyridyl) ⁇ -methylandrost-16-ene-3-one, 17-(3-pyridyl)-7p- ethylandrost-16-ene-3-one, 17-(3-pyridyl)-7a-methylandrost-16-ene-3-one, 17-(3-pyridyl)-7a-ethylandrost-16-ene-3-one, 17-(3-pyridyl)-7p-(2- hydroxyethyl)androst-16-ene-3-one, 17-(3-pyridyl)-7cc-(2- hydroxyethyl)androst-16-ene-3-one, 17-(3-pyridyl) ⁇ -(/7-propyl)androst-16- ene-3-one, 17-(3-pyridyl)-7a-(n-propyl)androst-16-ene-3-one, 17-N- pyrimidinyl ⁇
  • R 1 is -OR PR , protected hydroxyl, e.g., an ester, including -0-C(0)CH 3 , -0-C(0)CH 2 CH 3 or -O- C(0)CH 2 CH 2 CH 3 , or an ether, including methyl ether or ethyl ether
  • R 2 is - OR PR , protected hydroxyl, e.g., an ester, including acetate (-0-C(0)CH 3 ) or propionate (-0-C(0)CH 2 CH 3 ),or an ether, including methyl ether or ethyl ether, or optionally substituted C1 -8 alkyl, including -CH 3 , -C 2 H 5 , - CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 OR PR , -CH 2 CH 2 OR PR , -CH 2 CH 2 CH 2 OR PR or -CH 2 CH 2 CH 2 CH 2 OR PR , R
  • R 14 are both -OH or they independently are -CH 3 or - C 2 H 5 .
  • R 15 independently are C1 -4 saturated alkyl, including methyl or ethyl, with /7-butyl preferred.
  • R 1 and R 2 are protected hydroxyl, e.g., an ester, including acetate, or an ether including methyl ether, ethyl ether or n-propyl ether
  • deprotection leaves the free hydroxyl shown as 4.
  • R 2 is alkyl, e.g., C1 -6 alkyl, including methyl, ethyl, n-propyl or n-butyl
  • the deprotection step results in an analog of 4 where R 2 is the alkyl group instead of -OH, i.e., 7.
  • Structure 4 compounds thus include 17-(3-pyridyl)-androst-5,16-diene- 3 ⁇ , 7 -diol and 17-(3-pyridyl)-androst-5,16-diene-3cc, 7p-diol.
  • Structure 7 compounds include 17-(3-pyridyl) ⁇ -(/7-butyl)androst-5,16-diene ⁇ -ol, 17-(3- pyridyl) ⁇ -(/7-butyl)androst-5,16-diene-3cc-ol, 17-(3-pyridyl)-7cc-(/7- butyl)androst-5,16-diene-3 ⁇ -ol, 17-(3-pyrimidinyl) ⁇ -(/7-butyl)androst-5,16- diene-3 -ol, 17-(3-pyrimidinyl)-7a-(/7-butyl)androst-5,16-diene ⁇ -ol and 17- (3-pyrimidinyl) ⁇ -(/7-butyl)androst-5,16-diene ⁇ -ol.
  • R B is -OR or -R
  • Method A and B are most suitable when Ar is substituted to provide an electron donating heterocycle in the epoxidation step.
  • Ar is an electron withdrawing heterocycle
  • protection of the A 5 -ene functional group may be used to optimize yields, e.g., by conversion to a C5,C6-dibromo derivative.
  • Example 1 Duterated cholesterol (D6 cholesterol) and the adrenal cell line H295R were incubated with or without the test compound, 17a- ethynylandrostane-3a,' ⁇ -diol, to observe the test compound's effects on de novo steroidogenesis in the cells. One or more of eight different cholesterol metabolites from the two metabolic pathways shown below were measured. The duterated cholesterol was labeled at positions 2, 2, 3, 4, 4 and 6.
  • the H295R cells were obtained from ATCC and grown in T75 flasks in DMEM supplemented with insulin, transferrin, selenium, and 10% FBS. The cells were grown in charcoal-stripped medium for 48 hrs prior to the experiment. Each experiment was initiated by the addition of 10 ⁇ D6- cholesterol. After 48 hrs, the medium was removed, the cells were scraped in 5 ml methanol and the alcoholic cell suspension was lysed by sonication. The methanol lysate was dried under nitrogen and the cell contents were resuspended in 1 mL PBS. The suspension was extracted with 10 mL MTBE (methyl-i-butyl ether), which was evaporated under nitrogen.
  • MTBE methyl-i-butyl ether
  • the dried extract was derivatized with nicotinyl chloride and analyzed by LCMS/MS.
  • the cells were incubated with 300 ng/mL 17 -ethynylandrostane-3 ,17 ⁇ -diol.
  • the concentration of 17 -ethynylandrostane-3 ,17 ⁇ -diol was monitored and adjusted to 300 ng/mL at 8 hour intervals to maintain this concentration over time.
  • Example 2 Effects of the test compound 17cc-ethynylandrostane- 3 ⁇ ,17 ⁇ on steroidogenesis in dogs in vivo.
  • Samples were collected from male dogs (5/group) treated with 0, 20, 60 or 200 mg/kg of 17a- ethynylandrostane-3 ,17 ⁇ -diol before dosing on days 1 , 14, and 28. The animals were dosed daily for 28 days. The samples were analyzed for testosterone (T), androstendione (A4), and dehydroepiandrosterone (DHEA). Day 1 and day 28 vehicle and 60 mg/kg samples were assayed for luteinizing hormone. The compound was administered by oral administration of a 20 mg/mL 17a-ethynylandrostane-3cc,' ⁇ -diol solution made of 40% 2- hydroxypropyl ⁇ -cyclodextrin in water.
  • Plasma samples were processed by Iiquid/liquid extraction using MTBE.
  • the organic portions containing the analytes were evaporated and dried extracts were incubated at 60 ° C with a dansyl chloride solution.
  • the resulting steroid derivatives were analyzed on a Waters Xbridge Phenyl column by reversed-phase high-performance liquid chromatography (Agilent, Palo Alto, CA and Leap Technologies, Carrboro, NC) coupled with a tandem quadrupole mass spectrometer (Waters, Beverly, MA).
  • Calibration curves for standards and QC samples for HE3318 (Estradiol, E2) and Estrone (E1 ) were analyzed in parallel with the samples.
  • the quantifiable range of detection for T was 10.0 to 20000.0 pg/mL in rat (example 3) and dog (this example) samples.
  • the quantifiable range of detection for A4 was 10.0 to 20000.0 pg/mL in rats and 20.0 to 20000.0 pg/mL in dogs.
  • the quantifiable range of detection for DHEA was 50.0 to 200.0 pg/mL in both species. Values below the detection limit were identified as such.
  • EL ISA kits for the quantification of ACTH, LH, and FSH in rat plasma were obtained from USCN Life, Wuhan, China. All other reagents were obtained from Sigma Chemical Co, St. Louis, MO. ELISA results were measured on an ELx800 plate reader (Bio-Tek, Winooski, VT). Samples were assayed for ACTH, LH, and FSH concentration by means of an ELISA assay kit according to the manufacturer's instructions. For the rat samples, although 100 ⁇ of undiluted plasma were required for each assay, 300 ⁇ (ACTH), 100 ⁇ (LH), or 30 ⁇ (FSH) were used in order to obtain results in the quantifiable range of the assay.
  • systemic (serum) levels of testosterone, estradiol, estrone and DHEA had fallen by over 99% to essentially undetectable levels in the treated animals. Changes in LH, FSH and ACTH were not observed.
  • [189] 1A A method to identify a compound comprising (a) administering a test compound to a mammal(s) for a sufficient period of time to obtain treated mammal(s); (b) measuring systemic levels of one or more cholesterol metabolites in the treated mammal(s); and (c) selecting the compound of step (b) that decreases the systemic levels of one or more cholesterol metabolites in the treated mammal(s), whereby a compound having a potential to treat a cancer, optionally a neuroendocrine disorder or tumor is identified, wherein the test compound of step (a) has the structure
  • R 4 is (1 ) -N-pyridine (N- linked) or -N-pyrimidinyl (N-linked), (2) -1 -pyridyl (C-linked), -2-pyridyl, -3- pyridyl, -1 -pyrimidinly (C-linked), -4-pyrimidinly or -5-pyrimidinly, (3) -N- piperidinyl, -1 -piperidinyl, -2-piperidinyl, -3-piperidinyl, or (4) -N-imidazole, -2- imidazole or -4-imidazole.
  • [200] 12A The method of embodiment 1 A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A or 1 1 A wherein the sufficient period of time is at least about 5 days, optionally about 5 days to about 8 weeks, optionally daily for about 7 days, about 14 days, about 28 days, about 6 weeks or about 8 weeks, e.g., daily for 5 days, 7 days, 14 days, 28 days, 6 weeks or 8 weeks.
  • [201] 13A The method of embodiment 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A or 1 1 A wherein the neuroendocrine disorder or tumor is prostate cancer, breast cancer or small cell lung cancer and the candidate compound is administered to a human(s) having or diagnosed with, the neuroendocrine disorder or tumor.
  • [202] 14A The method of embodiment 1 A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A or 1 1 A wherein the neuroendocrine disorder or tumor is a precancer of the breast, uterine fibroids, ovarian cancer, uterine cancer or endometriosis and the candidate compound is administered to a human(s) having the neuroendocrine disorder or tumor.
  • the neuroendocrine disorder or tumor is a precancer of the breast, uterine fibroids, ovarian cancer, uterine cancer or endometriosis and the candidate compound is administered to a human(s) having the neuroendocrine disorder or tumor.
  • [203] 15A The method of embodiment 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A or 1 1 A wherein the neuroendocrine disorder or tumor is an adrenal tumor, benign prostatic hypertrophy or testicular cancer and the candidate compound is administered to a human(s) having the neuroendocrine disorder or tumor.
  • [204] 16A The method of embodiment 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1A or 12A wherein the mammal(s) is a canine (dog) or a rodent, optionally a mouse or rat.
  • 17A The method of embodiment 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1A or 12A further comprising administering to a control mammal(s) a control compound, optionally, 17a-ethynylandrostane-3cc,' ⁇ -diol, 17a- ethynylandrostane ⁇ ,' ⁇ -diol, 17cc-ethynylandrostane-3-one-' ⁇ -ol or an aromatase inhibitor and measuring systemic levels of the one or more cholesterol metabolites in the treated mammal(s).
  • a control compound optionally, 17a-ethynylandrostane-3cc,' ⁇ -diol, 17a- ethynylandrostane ⁇ ,' ⁇ -diol, 17cc-ethynylandrostane-3-one-' ⁇ -ol or an aromatase inhibitor and measuring system
  • a method to make a drug product for treating a cancer or neuroendocrine disorder or tumor in a human wherein the drug product comprises, (a) a drug in a dosage form, optionally wherein the dosage form is a formulation for oral, parenteral or topical administration, preferably oral administration; and (b) packaging for the drug together with a package insert or label that includes information about the drug's efficacy, toxicity or mechanism of action wherein such information was obtained at least in part from a method comprising (i) administering a test compound to a mammal(s) for a sufficient period of time to obtain treated mammal(s); (ii) measuring systemic levels of one or more cholesterol metabolites in the treated mammal(s); (iii) selecting the compound of step (ii) that decreases the systemic levels of one or more cholesterol metabolites in the treated mammal(s); and optionally (iv) administering to a control mammal(s) a control compound, optionally, 17a-
  • [207] 19A The drug product of embodiment 18A wherein the mammal(s) is a rodent(s) or canine(s), optionally a mouse or rat.
  • [210] 22A The drug product of embodiment 18A or 19A wherein the neuroendocrine disorder or tumor is an adrenal tumor, benign prostatic hypertrophy or testicular cancer.
  • R 1 is -H
  • R 2 is -OH and R 3 is -H
  • R 1 and R 2 are -OH and R 3 is - CH 3
  • R 1 0, R 2 is -OH and R 3 is -CH 3
  • R 1 is -OH
  • R 2 is -H and R 3 is C1 -4 optionally substituted alkyl , including -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R 5 is -C 2 H 5 , including species 7-(3-pyridinyl)-18-nor-18-ethylandrost-5,16- ⁇ -3 ⁇ ,7 ⁇ - ⁇
  • R 1 is -H
  • R 2 is -OH and R 3 is -H
  • R 1 and R 2 are -OH and R 3 is - CH 3
  • R 1 0, R 2 is -OH and R 3 is -CH 3
  • R 1 is -OH
  • R 2 is -H and R 3 is C1 -4 optionally substituted alkyl, including -C2H5 or -CH 2 CH 2 OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R 5 is -C 2 H 5 , including species 17-(3-pyridinyl)-18-nor-18-ethylandrost-5,16-diene ⁇ ,7cc-diol, which
  • R 4 is 3-pyridinyl or 17-(3-pyridinyl)-18-nor- 18-ethylandrost-5,16-diene-3a,7cc-diol or 17-(3-pyridinyl)-18-nor-18- ethylandrost-5,16-diene-3 ⁇ ,7 -diol-16-acetate.
  • R 1 is -H
  • R 2 is -OH and R 3 is -H
  • R 1 and R 2 are -OH and R 3 is - CH 3
  • R 1 0, R 2 is -OH and R 3 is -CH 3
  • R 1 is -OH
  • R 2 is -H and R 3 is C1 -4 optionally substituted alkyl, including -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R 5 is -CH 2 OH, including species 17-(3-pyridinyl)androst-5,16-diene ⁇ ,18-triol, 17-(3-pyridiny
  • [241] 53A A formulation comprising one or more excipients and a compound of any of embodiments 23A-52A.
  • [242] 54A The formulation of embodiment 52A wherein the formulation is for oral administration, wherein the unit dosage form of the formulation is a tablet, capsule, caplet or gelcap.
  • R 1 is -H
  • R 2 is -OH and R 3 is -H
  • R 1 and R 2 are -OH and R 3 is - CH 3
  • R 1 0, R 2 is -OH and R 3 is -CH 3
  • R 1 is -OH
  • R 2 is -H and R 3 is C1 -4 optionally substituted alkyl, including -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R 5 is -C 2 H 5 and R 6 is -H, including species 17-(3-pyridinyl)-18-nor-18-ethylandrost-5,16-diene
  • R 4 is 3-pyridinyl, 17-(3-pyridinyl)- 18,19-dinor-18-ethylandrost-5,16-diene-3 ,7 -diol, 17-(3-pyridinyl)- 18,19- dinor-18-ethylandrost-5,16-diene-3p,7p-diol-16-acetate, 17-(3-pyridinyl)- 18,19-dinor-18-ethyl ⁇ -ethylandrost-5,16-(_ ⁇ -3 ⁇ - ⁇ or 17-(3-pyridinyl)- 18,19-dinor-18-ethylandrost-5,16-diene ⁇ ,7cc-diol-16-methyl ether.
  • R 1 is -H
  • R 2 is -OH and R 3 is -H
  • R 1 and R 2 are -OH and R 3 is - CH 3
  • R 1 0, R 2 is -OH and R 3 is -CH 3
  • R 1 is -OH
  • R 2 is -H and R 3 is C1 -4 optionally substituted alkyl including -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R 5 is -CH 2 OH and R 6 is -H, including species 17-(3-pyridinyl)-19-nor-androst-5, 18-triol, 17-(
  • R 1 is -H
  • R 2 is -OH and R 3 is -H
  • R 1 and R 2 are -OH and R 3 is - CH 3
  • R 1 0, R 2 is -OH and R 3 is -CH 3
  • R 1 is -OH, R 2 is -H and R 3 is C1 -4 optionally substituted alkyl , including -CH 3 , -C 2 H 5 or -CH 2 CH 2 OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R 6 is -H.
  • 59A A formulation comprising one or more excipients and a compound of embodiment 56A, 57A or 58A.
  • 60A The formulation of embodiment 59A wherein the formulation is for oral administration, wherein the unit dosage form of the formulation is a tablet, capsule, caplet or gelcap.
  • 61 A The formulation of embodiment 59A wherein the formulation is for parenteral administration, including a sterile solution or a sterile suspension.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Cell Biology (AREA)
  • Organic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Microbiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention provides a method to identify or characterize compounds for treating cancer wherein the compounds have a capacity to decrease systemic levels of one or more cholesterol metabolites in treated mammal(s). Such compounds include 17-(3-pyhdyl)androst-5,16-diene-3β,7β-diol, 17-(2- morpholinyl)-7β-ethylandrost-5,16-diene-3β-ol, 17-(2-morpholinyl)-7β- ethylandrost-5,16-diene-3β-ol-16-acetate, 17-(4-oxazolyl)-7β-ethylandrost- 5,16-diene-3β-ol-16-methyl ether and 17-(4-oxazolyl)-7β-ethylandrost-5,16- diene-3β-ol. Compositions and formulations comprising the compounds and one or more excipients are also provided.

Description

ANTICANCER COMPOUNDS AND SCREENING METHOD
CROSS REFERENCE TO RELATED APPLICATIONS
[01] This nonprovisional U.S. patent application claims priority from pending U.S. provisional application serial No. 61/265,294 , filed November 30, 2009, pending U.S. provisional application serial No. 61/266,092, filed December 2, 2009, pending U.S. provisional application serial No. 61/266,291 , filed December 3, 2009, pending U.S. provisional application serial No.
61/266,416, filed December 3, 2009, and pending U.S. provisional application serial No. 61/266,483, filed December 3, 2009, all of which are incorporated herein by reference.
FIELD OF THE INVENTION
[02] The invention relates to methods to screen for and/or characterize compounds with activity as anticancer drugs that affect hormone signaling in vivo, including signaling by one or more steroid hormones.
BACKGROUND
[03] Anticancer drugs and treatments typically are accompanied by significant toxicity or unwanted side-effects that limit the usefulness of drug treatments. Methods to identify additional compounds that are useful in treating cancers are needed, particularly for common cancers and related conditions, e.g., lung cancer, colon cancer and neuroendocrine cancers such as prostate cancer and breast cancer.
DESCRIPTION OF THE INVENTION
[04] Summary of invention embodiments. In some embodiments, the invention provides a method to identify a compound comprising (a) administering a test compound to a mammal(s) for a sufficient period of time to obtain treated mammal(s); (b) measuring systemic levels of one or more cholesterol metabolites in the treated mammal(s); and (c) selecting the compound of step (b) that decreases the systemic levels of one or more cholesterol metabolites in the treated mammal(s), whereby a compound having a potential to treat a cancer, optionally a neuroendocrine disorder or tumor is identified, wherein the test compound of step (a) has the structure
Figure imgf000003_0001
substituted ester (including -0-C(0)-optionally substituted C1 -7 alkyl or -O- C(0)-optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate), or an optionally substituted ether (including -O-optionally substituted C1 -8 alkyl or -O-optionally substituted aryl, including -O-optionally substituted phenyl, optionally a 01 -6 ether, including -OCH3, -OC2H5, -OCH2CH2CH3, - OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2); R2 is -OH, -SH, =0, an optionally substituted ester (including -0-C(0)-optionally substituted C1 -7 alkyl or -0-C(0)-optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate), or an optionally substituted ether (including -O-optionally substituted 01 -8 alkyl or -O-optionally substituted aryl, including -O-optionally substituted phenyl, optionally a 01 -6 ether, including methoxy or ethoxy), or optionally substituted 01 -8 alkyl (including -CH3, -CF3, -C2H5, -CH2CH2OH, - CH2CH2CH3, -CH2CH2CH2OH or -OCH(CH3)2) or R2 may also be -H when (i) R3 is not -H, (ii) R5 is -C2H5 or -CH2OH and/or (iii) R6 is -H, -C2H5 or -CH2OH; R3 is -H, -OH, 01 -8 optionally substituted alkyl, optionally methyl, ethyl, n- propyl, /'-propyl or 3-hydroxy-n-propyl, an optionally substituted ester
(including -0-C(0)-optionally substituted 01 -7 alkyl and -0-C(0)-optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate), an optionally substituted ether (including -O-optionally substituted 01 -8 alkyl or -O- optionally substituted aryl, including -O-optionally substituted phenyl, optionally a 01 -6 ether (including -OCH3, -OC2H5, -OCH2CH2CH3, - OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2), or optionally substituted C1 -8 alkyl (including -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2); R4 is -NH2, -NHCH3, -N(CH3)2, -NH-C(0)CH3, - NHOH, an N-linked amino acid, C1 -8 alkyl, optionally methyl, ethyl, n-propyl or /'-propyl, a C-linked ring or an N-linked ring; R5 is -CH3, -C2H5 or -CH2OH; and R6 is -H, -CH3, -C2H5 or -CH2OH. Other compounds or compositions that can be used in the method are described elsewhere, e.g., in the claims. The method may optionally include treatment of the mammal(s) with vehicle (negative control) and/or other treatment control compounds, e.g., the 17a- hydroxylase/17,20 lyase inhibitor (CYP17A1 ), abiraterone or 17a- ethynylandrostane-3a, 17p-diol.
[05] The cholesterol metabolites include one or more of testosterone, dihydrotestosterone, 4-androstenedione, 5-androstenediol, 5a-androstane- 3α,17β-άϊοΙ, 5a-androstane^,^-diol, estradiol, estrone,
dehydroepiandrosterone (DHEA), pregnenolone, progesterone and Cortisol, optionally wherein the cholesterol metabolites are one, two or more of (i) testosterone, dihydrotestosterone, 4-androstenedione and 5-androstenediol, (ii) estradiol, estrone and 4-androstenedione or (iii) pregnenolone,
progesterone and Cortisol. In preferred embodiments, the decreased cholesterol metabolite is not progesterone and/or Cortisol.
[06] Other embodiments include a drug product for treating a cancer, or a neuroendocrine disorder or tumor in a human comprising, (a) a drug in a dosage form, optionally wherein the dosage form is a formulation for oral, parenteral or topical administration; and (b) packaging for the drug together with a package insert or label that includes information about the drug's efficacy, toxicity or mechanism of action wherein such information was obtained at least in part from a method comprising (A) administering a test compound to a mammal(s) for a sufficient period of time to obtain treated mammal(s); (B) measuring systemic levels of one or more cholesterol metabolites in the mammal(s); and (C) selecting a candidate compound that decreases the systemic levels of one or more cholesterol metabolites in the treated mammal(s).
[07] In these and related embodiments, the mammal(s) can be a feline but is preferably a rodent(s) or canine(s), optionally a mouse or rat. In some preferred embodiments, the mammal(s) will not contain tumors, e.g., prostate xenograft tumors in mice, to allow assessment of effects of the test compound on normal animals. In other embodiments, the mammal(s) will have a spontaneous or implanted tumor and these animals can be used to assess the activity of the test compound on the tumor or cancer in such an in vivo environment.
[08] In preferred embodiments, the cancer or neuroendocrine disorder or tumor is prostate cancer, breast cancer or small cell lung cancer. In other embodiments, the neuroendocrine disorder or tumor is endometriosis or uterine fibroids.
[09] Detailed description. As used herein and unless otherwise stated or implied by context, terms that are used herein have the meanings defined below. Unless otherwise contraindicated or implied, e.g., by including mutually exclusive elements or options, in these definitions and anywhere the specification, claims or elsewhere herein, the terms "a" and "an" mean one or more and the term "or" means and/or, e.g., one or the other or both or all.
[10] The phrase "C1 -8 optionally substituted alkyl" means a linear or branched group or moiety containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms and one or more substituents, including -OH, halogen or =0, that replace one or more hydrogen atoms, e.g., -CH2CH2CH2OH. Preferably no more than one or two oxygen atoms are present. Preferred optionally substituted alkyl groups are C1 -4 optionally substituted alkyl, which have 1 , 2, 3 or 4 carbon atoms and 0 or 1 hydroxyl groups. Optionally substituted alkyl moieties are
preferably saturated, but may contain a double bond(s) or triple bond(s), including alkyl moieties -CH2CH=CH2 or -CH2C≡CH. C1 -6 optionally substituted alkyl means moieties having 1 , 2, 3, 4, 5 or 6 carbon atoms.
[11] "Alkyl", "alkyl group", "alkyl moiety" and the like as used herein means a collection of linked carbon atoms and include linear, branched or cyclic carbon chains or any combination thereof. Alkyl moieties, as used herein, may further contain unsaturation, i.e., the alkyl group may comprise one, two, three or more independently selected double bonds or triple bonds. Unsaturated alkyl groups contain moieties as described for alkenyl and alkynyl moieties are described below. Preferred unsaturated alkyl groups contain one alkenyl moiety or one alkynyl moiety. The number of linked carbon atoms in an alkyl group or moiety can vary and typically is 1 to about 50, e.g., about 1 -30 or about 1 -20 linked carbon atoms, unless otherwise specified, e.g., d-s alkyl or C1-C8 alkyl means an alkyl moiety containing 1 , 2, 3, 4, 5, 6, 7 or 8 linked carbon atoms, Ci-7 alkyl or C1-C7 alkyl means an alkyl moiety containing 1 , 2, 3, 4, 5, 6 or 7 linked carbon atoms and Ci-4 alkyl or C1-C4 alkyl means an alkyl moiety containing 1 , 2, 3 or 4 linked carbon atoms,. When an alkyl group is specified as a variable group, as for R1 , R2, R3 or R4 variable group substituents described herein, a saturated carbon of the alkyl moiety is directly attached to the site occupied by the variable group, as in the C1-, C7-, C16- or C17-position of a steroid ring system, using the numbering convention for cholesterol, as described herein [12] When an alkyl group is specified as a variable group substituent, species may include methyl, ethyl, 1 -propyl (n-propyl), 2-propyl (/'-propyl, -CH(CH3)2), 1- butyl (n-butyl), 2-methyl-1 -propyl (/'-butyl, -CH2CH(CH3)2), 2-butyl (s-butyl, - CH(CH3)CH2CH3 ), 2-methyl-2-propyl (i-butyl, -C(CH3)3), 1-pentyl (n-pentyl), 2- pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (- C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1 -butyl (-
CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl, 2-hexyl (- CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2- pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (- C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2- butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), cyclopropyl (-CH<CH2CH2), cyclobutyl (-CH<CH2CH2CH2), cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -(CH2)n-(CHCH3)m-(CH2)0-CH3, -(CH2)n-(CHC2H5)m- (CH2)o-CH3 where n, m and o independently are 0, 1 , 2, 3, 4, 5, 6, 7 or 8.
Preferred alkyl moieties are Ci-8, Ci-7 or Ci- alkyl groups, including -CH3
(methyl), -CH2CH3 (ethyl), -CH2CH2CH3 (propyl), -CH(CH3)2 (isopropyl) and - CH2CH2CH2CH3 (butyl).
[13] "Alkenyl", "alkenyl group", "alkenyl moiety" and the like as used herein means a collection of linked carbon atoms that contains one or more double bonds (e.g., -CH=CH- or =CH- moieties), e.g., 1 , 2, 3, 4, 5, 6 or more, preferably 1 or 2. An alkenyl group may further contain saturated carbons including linked normal, secondary, tertiary or cyclic carbon atoms that form linear, branched or cyclic carbon chains, which may also include the double bond moiety (e.g., -CH=CH- moiety) or any combination thereof or may contain other unsaturation including a triple bond moiety (i.e., -C≡C- moiety),. Preferred alkenyl groups contain 0 or 1 additional alkenyl or 0-1 alkynyl moieties. The number of linked carbon atoms in an alkenyl group or moiety can vary and typically is 2 to about 50, e.g., about 2-30 or about 2-20, unless otherwise specified, e.g., C2-8 alkenyl or C2-8 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms and C2-6 alkenyl or C2-6 alkenyl means an alkenyl moiety containing 2, 3, 4, 5 or 6 carbon atom. When an alkenyl group is specified as a variable group, as for R1 , R2, R3 or R4 variable group substituents described herein, a unsaturated carbon of the alkenyl moiety is directly attached to the site occupied by the variable group, as in the C1 -, C7-, C16- or exposition of a steroid ring system, using the numbering convention for cholesterol, as described herein. When an alkenyl group is specified as a variable group substituent, species may include methylene (=CH2),
methylmethylene (=CH-CH3), ethylmethylene (=CH-CH2-CH3), =CH-CH2-CH2- CH3, vinyl (-CH=CH2), -(CCH3=CH)-(CH2)m-CH3, -(CH=CCH3)-(CH2)m-CH3 and - (CH=CH) -(CH2)m-CH3, where m is 0, 1 , 2, 3, 4, 5, 6, 7 or 8, preferably 0-3. Preferred alkenyl moieties are C2-8, C2-6 or C2- alkenyl groups, including - CH=CH2 (vinyl), -CH=CH2CH3 ethenyl, -CH=HCH2CH3 (propenyl) and - CH=CH2CH2CH3 (butenyl).
[14] "Alkynyl", "alkynyl group", "alkynyl moiety" and the like as used herein means a collection of linked carbon atoms that contains one or more triple bonds (e.g., -C≡C- moiety), e.g., 1 , 2, 3, 4, 5, 6 or more, preferably 1 or 2. An alkenyl group may further contain saturated carbons including linked normal, secondary, tertiary or cyclic carbon atoms that form linear, branched or cyclic carbon chains, which may also include the triple bond moiety, or any
combination thereof, or may contain other unsaturation, including a double bond moiety (e.g., -CH=CH- moiety). Preferred alkynyl groups contain 0 or 1 additional alkynyl or 0-1 alkenyl moieties.
[15] The number of linked carbon atoms in an alkenyl group or moiety can vary and typically is 2 to about 50, e.g., about 2-30 or about 2-20, unless otherwise specified, e.g., C2-s alkynyl or C2-8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms and C2-6 alkynyl or C2-6 alkynyl means an alkynyl moiety containing 2, 3, 4, 5 or 6 carbon atoms. When an alkynyl group is specified as a variable group, as for R1, R2, R3 or R4 variable group substituents described herein, a unsaturated carbon of the alkynyl moiety is directly attached to the site occupied by the variable group, as in the C1 -, C7- , C16- or C17-position of a steroid ring system, using the numbering convention for cholesterol, as described herein. When an alkynyl group is specified, groups and species may include -C≡CH, -C≡CCH3, -C≡CCH2CH3, -C≡CC3H7, - C≡CCH2C3H7, -(C≡C)-(CH2)m-CH3, -(C≡C)0-r(CH2)m-CH2C≡CH and -(C≡C)0-r (CH2)n-CH2C=C(CH2)mH, where m independently are 0, 1 , 2, 3, 4, 5, 6, 7 or 8.
[16] "Aryl", "aryl group", "aryl moiety" and the like means an aromatic ring with no ring heteroatoms and includes, phenyl, naphthyl or a carbocyclic ring system containing 2n + 2 pi electrons where n is 0 or a positive integer. In some embodiments, the alkylaryl moiety is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R1 , R2, R3 or R4 , i.e., alkyl-aryl-steroid, preferably R4.
[17] "Arylalkyl" means a moiety where an alkyl group is bonded to an aryl group, i.e., -alkyl-aryl, where alkyl and aryl groups are as described above, e.g., -CH2-C6H5 or -CH2CH(CH3)-C6H5. In some embodiments, the arylalkyl moiety is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R1, R2, R3 or R4 , i.e., aryl-alkyl-steroid
[18] "Alkylaryl" means a moiety where an aryl group is bonded to an alkyl group, i.e., -aryl-alkyl, where aryl and alkyl groups are as described above, e.g., -C6H4-CH3 or -C6H4-CH2CH(CH3). In some embodiments, the alkylaryl moiety is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R1, R2, R3 or R4 , i.e., alkyl-aryl-steroid, preferably R4.
[19] "Heteroaryl", "aryl group", "aryl moiety" and the like means a heterocycle comprised of an aromatic ring where the aromatic ring contains 1 , 2, 3 or more heteroatoms that participate in aromaticity of the ring, usually oxygen (-0-), nitrogen (-NX-), where X is -H, a protecting group, C -6 optionally substituted alkyl, an aryl or a heterocycle group, or sulfur (-S-), usually -H. Examples are as described for heterocycle. In some embodiments, the heteroaryl moiety is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R1, R2, R3 or R4 , i.e., heteroaryl-steroid, preferably R4.
[20] "Substituted alkyl", "substituted alkenyl", "substituted alkynyl", substituted alkylaryl", "substituted arylalkyl", "substituted heterocycle", "substituted aryl", substituted heteroaryl and the like mean an alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl heterocycle, aryl, heteroaryl or other group or moiety as defined or disclosed herein that has a substituent(s) that replaces a hydrogen atom(s). Substituted heterocycles may thus have a substituent bonded to a ring carbon of the heterocycle or a ring heteroatom . Substituents for any of these moieties include 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more, preferable 1 or 2 independently selected heteroatoms, functional groups or other moieties described herein including nitrogen, oxygen, sulfur, phosphorous or silicon containing
substituents, halogen, including -F, -CI, Br or -I, or acyl, amine, amide, ester, carbamate, carbonate, alkoxy, aryl, heterocycle or heteroaryl containing substituents.
[21] "Protecting group" means a moiety that prevents or reduces the atom or functional group to which it is linked from participating in unwanted reactions. For example, for -ORPR, RPR may be hydrogen or a protecting group for the oxygen atom found in a hydroxyl, while for -C(0)-ORPR, RPR may be hydrogen or a carboxyl protecting group, for -SRPR, RPR may be hydrogen or a protecting group for sulfur in thiols for instance, and for -NHRPR or -N(RPR)2-, RPR may be hydrogen or a nitrogen atom protecting group for primary or secondary amines. Hydroxyl, amine, ketones and other reactive groups as found in variable group substituents for R1, R2, R3 or R4 described herein may require protection against reactions taking place elsewhere in the molecule. The protecting groups for oxygen, sulfur or nitrogen atoms are usually used to prevent unwanted reactions with electrophilic compounds, such as acylating agents used, e.g., in steroid chemistry.
[22] "Ester" means a moiety that contains an organic moiety-C(0)-0- structure. Typically, the organic moiety-C(0)-0- structure contains about 1 -50 carbon atoms (preferably 1 -6 carbon atoms) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), preferably 1 or 2 heteroatoms, where the organic moiety-C(0)-0- structure is bonded to a variable position of a steroid nucleus, replacing variable group substituents including R1, R2, R3 or R4 through the organic moiety-C(0)-0- structure, i.e., organic moiety-C(0)-0- steroid, preferably R1, R2 or R3. The organic moiety usually comprises one or more of any of the organic groups described herein, e.g., C-i-20 alkyl moieties (preferably C1 -8), C2-20 alkenyl moieties (preferably C2-8), C2-20 alkynyl moieties (preferably C2-8), aryl moieties (preferably phenyl), C1-9 heterocycles (preferably C2-5) or substituted derivatives of any of these, e.g., comprising 1 , 2, 3, 4 or more substituents, preferably 1 or 2 substituents, preferably oxygen or nitrogen containing substituent, or halogen or optionally substituted phenyl substituents, where each substituent is independently chosen. Exemplary substitutions for hydrogen atoms in these organic groups are as described above for substituted alkyl and other substituted moieties. Substitutions are independently chosen. The organic moieties exclude obviously unstable moieties, e.g., -0-0-, except where such unstable moieties are transient species that one can use to make a compound with sufficient chemical stability for one or more of the uses described herein, including for synthesis of the formula 1 or other compounds. The substitutions listed above are typically substituents that one can use to replace a hydrogen atom, e.g., aryl, heterocycle, heteroaryl, halogen, -NH2, -SH , -OH, alkoxy, ester, carbamate, carbonate or other functional group described herein. Preferred optionally substituted esters are acetate, enanthate, propionate, isopropionate, isobutyrate, butyrate, valerate, caproate, isocaproate, hexanoate, heptanoate, octanoate, nonanoate, decanoate, undecanoate, phenylacetate or benzoate, which are representative hydroxyl esters.
[23] "Amide", "amide group", "amide moiety and the like contains an organic moiety-C(0)-NRPR- structure, where RPR is -H or a protecting group, where organic moiety is as described for ester. Typically, carbonate groups as used here comprise an organic moiety containing about 1 -50 carbon atoms
(preferably C1 -8) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), preferably 1 or 2 O, S or N heteroatoms or a combination thereof. In some embodiments, the organic moiety-C(0)NRPR- structure is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R1, R2, R3 or R4, i.e., organic moiety-C(0)NRPR- steroid, preferably R4.
[24] "Ether" or alkoxy group means an organic moiety that contains 1 , 2, 3, 4 or more -O- moieties, usually 1 , 2 or 3, preferably 1 . Typically, carbonate groups as used here comprise an organic moiety containing about 1 -50 carbon atoms (preferably C1 -8) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), preferably 1 or 2 O, S or N heteroatoms or a combination thereof. In some embodiments, the organic moiety-O- structure is linked to a variable position of a steroid nucleus, replacing variable group substituents that include R1 , R2, R3 or R4 , i.e., organic moiety-O-steroid, preferably R1, R2 or R3.
[25] "Carbonate" means an organic moiety as described for ester that comprises 1 , 2, 3, 4 or more organic moiety -0-C(0)-0- structures, preferably 1 . Typically, carbonate groups as used here comprise an organic moiety containing about 1 -50 carbon atoms (preferably C1 -8) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), preferably 1 or 2 O, S or N heteroatoms or a combination thereof, linked to a variable position of a steroid nucleus, replacing variable group substituents that include R1, R2, R3 or R4 through the organic moiety -0-C(0)-0- structure, i.e., organic moiety-O- C(0)-0-steroid, preferably R1, R2 or R3.
[26] "Carbamate" means an organic moiety as described for ester that comprises 1 , 2, 3, 4 or more -0-C(0)NRPR-organic moiety structures where RPR is -H, a protecting group or an organic moiety as described for ester. Typically, carbamate groups as used here comprise an organic moiety containing about 1 -50 carbon atoms (preferably C1 -8) and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), preferably 1 or 2 O, S or N heteroatoms or a combination thereof, linked to a variable position of a steroid nucleus, replacing variable group substituents that include R1, R2, R3 or R4 through the -O-C(O)- NRPR-organic moiety structure, i.e., organic moiety-0-C(0)-NRPR-steroid, preferably R1 , R2 or R3.
[27] For any group or moiety described by a given range of carbon atoms, the designated range means that any individual number of carbon atoms is described. Thus, reference to, e.g., "C1 -C4 optionally substituted alkyi", "C2-6 alkenyl", or "C2-C6 optionally substituted alkenyl", specifically means that a 1 , 2, 3 or 4 carbon optionally substituted alkyi moiety as defined herein is present, or a 2, 3, 4, 5 or 6 carbon alkenyl or optionally substituted alkenyl moiety as defined herein is present. All such designations are expressly intended to disclose all of the individual carbon atom groups and thus "C1 -C4 optionally substituted alkyi" means, e.g., 3 carbon alkyi, 4 carbon substituted alkyi and the like are disclosed and can be expressly referred to or named.
[28] "Alkyi" means a linear or branched group or moiety containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Alkyi moieties are preferably saturated, but may contain a double bond(s) or triple bond(s), including alkyi moieties - CH2CH=CH2 or -CH2C≡CH, preferably only one double bond or one triple bond is present within the alkyl moiety.
[29] An "N-linked ring" means a heterocycle moiety that is bonded at a variable group position of the steroid ring system through a ring nitrogen atom of the heterocycle. The steroid ring system position for the N-linked ring substituents includes R4 (i.e., 17-position) substituents. N-linked rings include optionally substituted
Figure imgf000012_0001
[30] A "C-linked ring" means a heterocycle or carbocyclic ring moiety bonded at a variable group position of the steroid ring system. The rings can be saturated or unsaturated. The steroid ring system position for the C-linked ring substituent includes R4 (i.e., 17-position) substituents. C-linked rings include aryls and C-linked heterocycles, including C-linked heteroaryls.
Exemplary C-linked rings include optionall substituted
Figure imgf000012_0002
[31] Nomenclature for the rings may vary, but will be apparent from context.
Figure imgf000012_0003
For example, 3-pyridine ), e.g., bonded to the steroid at the 17- position, may be referred to as 3-pyridyl or 3-pyridinyl. Similarly, 1 -pyridinium
Figure imgf000012_0004
) bonded to the steroid may be referred to as N-pyridyl, 1 -pyridyl, N- pyridinyl or 1 -pyridinyl. [32] Compounds that can be used in the screening method include ones
R5 R4
having the structure R1 R2 wherein, R1 is -OH, =0, an optionally substituted ester (including -0-C(0)-optionally substituted C1 -7 alkyl or -0-C(0)-optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate), an optionally substituted ether (including -O-optionally substituted 01 -8 alkyl or -O-optionally substituted aryl, including -O-optionally substituted phenyl, optionally a C1 -6 ether, including methoxy or ethoxy), or -SH; R2 is - OH =0, an optionally substituted ester (including -0-C(0)-optionally substituted 01 -7 alkyl or -0-C(0)-optionally substituted aryl, including -O- optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate), an optionally substituted ether (including -O- optionally substituted 01 -8 alkyl or -O-optionally substituted aryl, including -O- optionally substituted phenyl, optionally a 01 -6 ether, including methoxy or ethoxy), or -SH, or R2 may also be -H when R3 is not -H; R3 is -H, halogen, optionally -Br, -CI or -F, -OH, optionally substituted ester (including -O-C(O)- optionally substituted 01 -7 alkyl or -0-C(0)-optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate), an optionally substituted ether (including -O-optionally substituted 01 -8 alkyl and -O-optionally substituted aryl, including -O-optionally substituted phenyl, optionally a 01 -6 ether, including methoxy or ethoxy), or 01 -8 optionally substituted alkyl (including 01 -4 hydroxyalkyl or 01 -4 haloalkyl, optionally methyl, fluoromethyl, trifluoromethyl, ethyl, n-propyl, /'-propyl, 3-fluoro-n-propyl or 3-hydroxy-n- propyl); R4 is -optionally substituted N-linked amide or an N-linked amino acid. Exemplary N-linked amino acids have the structure -NH-CHR7-C(0)ORPR, - optionally substituted heterocycle or -optionally substituted cycle, including a C-linked ring (preferably a 5-membered ring or 6-membered ring) or an N- linked ring (preferably a 5-membered ring or 6-membered ring); R5 is -CH3, - C2H5, -CH2OH or -CH2(ester); R6 is -H, -CH3, -C2H5, -CH2OH or -CH2(ester); R7 is the side group of a natural amino acid (including -H, -CH3, -CH2OH, - CHOH-CH3, -CH2-CH-(CH3)2 or phenyl); and RPR is -H or a protecting group (including a C2-6 ester optionally acetate or propionate, or benzoate), preferably -H.
[33] Heterocycles at R4 include N-linked or C-linked ring moieties including N-linked or C-linked heteroaryls. Exemplary N-linked and C-linked
heteroaryls include 1 -furanyl, 2-furanyl, 1 -oxolane, 2-oxolane, 1 -thiophene, 2- thiophene, 1 -pyrrole, 2-pyrrole, 3-pyrrole, 1 -pyrrolidine, 2-pyrrolidine, 3- pyrrolidine, 2-thiazolyl, 3-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1 -pyranyl, 2-pyranyl and 3-pyranyl. Preferred heteroaryl heterocycles are 1 -pyridinyl, 3-pyridinyl, 1 - pyrimidinyl, 4-pyrimidinyl, and 5-pyrimidinyl.
[34] N-linked heterocycles further include R4 substituents -N-pyrrolidine, - N1 -pyrazolone, -N2-pyrazolone, -N-imidazolidin-2-one, -N1 -imidazole, -N1 - 4,5-dihydroimidazole, -N-morpholine, -N1 -pyridine, -N-piperidine, -N- piperazine, , optionally substituted at N4 with optionally substituted alkyl, optionally substituted aryl or optionally substuted heteroaryl, -N-indole, -N- indoline, -N-quinolidine, -NH-C(0)-CH2-CH2-C(0)-OH, -NH-C(0)-CH2-C(0)- OH, -NH-C(0)-CH2-CH2-C(0)-ORPR, -NH-C(0)-CH2-C(0)-ORPR, -NH-C(O)- (CH2)3-C(0)-OH or -NH-C(0)-(CH2)3-C(0)-ORPR, wherein RPR is a protecting group.
[35] N-linked amino acids further include R4 substituents -NH-CH(CH3)- C(0)OH, -NH-CH(CH3)-C(0)ORPR, -NH-CH(CH2OH)-C(0)OH, -NH- CH(CH2OH)-C(0)ORPR, -NH-CH2-CH2-C(0)-OH, -NH-CH2-C(0)-OH, -NH- CH2-CH2-C(0)-ORPR, -NH-CH2-C(0)-ORPR, -NH-(CH2)3-C(0)-OH or -NH- (CH2)3-C(0)-ORPR, wherein RPR is a protecting group.
[36] N-linked or C-linked heterocycles further include R4 substituents (1 ) -N- pyridine (N-linked) or -N-pyrimidinyl (N-linked), (2) -1 -pyridyl (C-linked), -2- pyridyl, -3-pyridyl, -1 -pyrimidinly (C-linked), -4-pyrimidinly or -5-pyrimidinly, (3) -N-piperidinyl, -1 -piperidinyl, -2-piperidinyl, -3-piperidinyl, or (4) -N-imidazole, - 2-imidazole or -4-imidazole.
[37] Identification of compounds that reduce the level of cholesterol metabolites, particularly androgens or estrogens, are useful as agents to treat cancers, particularly neuroendocrine cancers or related cancers that grow or progress in the presence of natural androgens and/or estrogens. [38] Some of these compounds are new per se and can be used in the methods described herein. When the compounds are used in the screening method described herein, they are typically present as compositions containing the compound in water and/or one or more solvents of low relatively toxicity, e.g., dimethylsulfoxide, ethanol and/or methanol. Parenteral compositions for use in the screening methods in animals will typically be provided as aqueous or organic solutions or suspensions, although such compositions may or may not be suitable for human use, e.g., if significant amounts of organic solvents are present. Such compositions are most suitable for administration to animals, e.g., rodents or dogs, which can be used in the screening method. The compositions for administration to animals will typically not need to be sterile. Such compositions will typically contain about 5 mg/mL to about 50 mg/mL of the compound as a solution or suspension.
[39] When use clinically, e.g., to treat cancer or another condition described herein, the compounds are usually presented as pharmaceutical formulations that comprise one or more excipients and the compound. Such formulations are usually prepared from purified compound that is mixed with other excipients. The compound will usually be present as a purified solid, e.g., powder or granule, that is at least about 90% w/w pure or preferably at least about 95% w/w pure, e.g., about 95% w/w to about 99.8% w/w. The formulations comprise the compound and one or more known excipients, e.g., fillers, binders, lubricants, dispersants or the like. Such excipients may include one or more of a cellulose such as microcrystalline cellulose or
carboxymethylcellulose, polysorbate 80, magnesium stearate, sodium lauryl sulfate, starch or lactose. The formulations can be present as unit dosages for oral, parenteral or another other route of administration.
[40] Unit dosages, e.g., tablets, capsules or gelcaps for oral human administration, will contain about 20 mg to about 1000 mg per unit dose, preferably about 20 mg to about 500 mg per unit dose. One or two of such unit doses are taken once per day or twice per day, e.g., twice daily. Oral dosing is preferably one or two unit dosages, most preferably one, that are taken once per day. Individual unit doses may contain about 20 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg or about 750 mg of the compound in an oral formulation.
[41] Formulations also include those for administration by other routes including parenteral and topical including buccal or sublingual. Parenteral formulation for administration by, e.g., intravenous or intramuscular injection to patients, will be sterile solutions or, for routes other than intravenous injection, suspensions, typically aqueous. In parenteral formulations, the compound will typically be present at a concentration of about 20 mg/mL to about 100 mg/mL along with other excipients, e.g., buffers to control pH, e.g., phosphate, saline or other agents to attain roughly isotonic conditions, water, thickening agents or preservatives such as EDTA. Daily parenteral dosing will be about 10 mg/day to about 500 mg/day.
[42] Drug products. The drug products typically comprise (a) a drug in a dosage form such as a solid or liquid formulation suitable for, e.g., oral, parenteral, topical or aerosol administration. Packaging for the drug and/or a package insert or label will have information about the drug's efficacy, mechanism of action, the intended patient population, dosage, dose regimen, route of administration, effect of the drug or treatment. When the disease to be treated is a cancer such as breast cancer or prostate cancer, the package insert or label can contain information about the patient population for which the drug product can be used or is approved.
[43] A drug product as used herein means a product that has been reviewed and approved for marketing or sale by a regulatory agency or entity with authority to review or approve applications for sale or medical use. Uses of drug products include its marketing or sales and offers to sell or buy it for consideration. These activities will typically adhere to terms of the regulatory approval that may affect or govern marketing, sales, purchases or product handling. The drug in a drug product can be a new drug, a generic drug, a biological, a medical device or a protocol for the use of any of these. The drug product usually results from marketing approval by the U.S. Food and Drug Administration of a new drug application, an abbreviated new drug
application, a biological license application or an application to market a medical device. Uses for the drug product include its sale to public or private buyers such as the U.S. Department of Defense, the U.S. Department of Energy, U.S. Department of Health and Human Services or a private drug buyer or distributor entity. Other uses include use of the drug to treat indicated or approved medical conditions and physician approved uses or off label uses.
[44] Pre-approval drug products are other invention embodiments, which can be used, e.g., for preparing to make commercial scale product in anticipation of regulatory review or regulatory marketing approval and other drug development and review activities.
[45] The intended patient population identified by the drug product can also specify excluded populations, if any, that may apply such as pediatric patients or elderly patients. Information about dosage will typically specify daily doses of the drug, while the dose regimen will describe how often and how long the drug is to be administered or taken. The route of administration will identify one or more routes that are suitable for use of the drug, although a given formulation will typically be approved for only one route of administration.
[46] The compounds, e.g., as described in the claims or numbered embodiments, can be used to treat cancers such as neuroendocrine cancers such as prostate cancer or breast cancer. Cancers that can be treated include lung cancer, liver cancer and colon cancer. Cancers that can be treated further include ovarian cancer, bladder cancer and testicular. Cancers that can be treated further include endometrial cancer and cervical cancer.
Cancers that can be treated further include CNS cancers such as
neuroblastoma and glioma. Additional cancers that can be treated are myeloma and thyroid cancer. The compounds can also be used to treat other hormone responsive hyperproliferation conditions such as endometriosis and benign prostatic hypertrophy.
[47] Compounds and compositions that can be used in the screening and treatment methods are described herein, e.g., in the claims and the following enumerated embodiments. 1 . A compound having the structure
R5 R4
R1 R2 wherein, R1 is -OH, -SH, =0, an optionally substituted ester (including -0-C(0)-optionally substituted C1 -7 alkyl or -0- C(0)-optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate), an optionally substituted ether (including -O-optionally substituted 01 -8 alkyl or -O-optionally substituted aryl, including -O-optionally substituted phenyl, optionally a 01 -6 ether, including -OCH3 (methoxy ether), -OC2H5 (ethoxy ether), -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2); R2 is -OH, -SH, =0, an optionally substituted ester (including -0-C(0)-optionally substituted C1 -7 alkyl or -0-C(0)-optionally substituted aryl, including -O- C(0)-optionally substituted phenyl, optionally a C2-6, ester, including acetate or propionate, or benzoate), an optionally substituted ether (including -O- optionally substituted C1 -8 alkyl or -O-optionally substituted aryl, including -O- optionally substituted phenyl, optionally a 01 -6 ether, including methyl ether or ethyl ether), or optionally substituted 01 -8 alkyl (including -CH3, -CF3, - C2H5, -CH2CH2OH, -CH2CH2CH3 or -CH2CH2CH2OH) or R2 may also be -H when (i) R3 is not -H, (ii) R5 is -C2H5 ,-CH2OH or -CH2(ester) and/or (iii) R6 is - H, -C2H5 ,-CH2OH or -CH2(ester); R3 is -H, halogen, optionally -Br, -CI or -F, - OH, C1 -8 optionally substituted alkyl, optionally methyl, ethyl, n-propyl, /'- propyl or 3-hydroxy-n-propyl, an optionally substituted ester (including -O- C(0)-optionally substituted C1 -7 alkyl or -0-C(0)-optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate), an optionally substituted ether (including -O-optionally substituted 01 -8 alkyl or -O-optionally substituted aryl, including -O-optionally substituted phenyl, optionally a 01 -6 ether, including - OCH3, -OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or - OCH(CH3)2), or optionally substituted C1 -8 alkyl (including -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2); R4 is -optionally substituted amide, an N-linked amino acid having the structure -NH-CHR7- C(0)OR , -optionally substituted heterocycle or -optionally substituted cycle, including a C-linked ring (preferably a 5-membered ring or 6-membered ring) or an N-linked ring (preferably a 5-membered ring or 6-membered ring); R5 is - CH3, -C2H5, -CH2OH or CH2(ester); R6 is -H, -CH3, -C2H5, -CH2OH or
CH2(ester); R7 is the side group of a natural amino acid (including -H, -CH3, - CH2OH, -CHOH-CH3, -CH2-CH-(CH3)2 or phenyl); and RPR is -H or a protecting group (including a C2-6 ester optionally acetate or propionate, or benzoate), preferably -H.
[49] 2. The compound of embodiment 1 wherein R4 is -N-pyrrolidine, -N1 - pyrazolone, -N2-pyrazolone, -N-imidazolidin-2-one, -N1 -imidazole, -N1 -4,5- dihydroimidazole, -N-morpholine, -N1 -pyridine, -N-piperidine, -N-piperazine, - N- piperazine, optionally substituted at N4 with optionally substituted alkyl or aryl, preferably methyl, phenyl or 2-pyridine, -N-indole, -N-indoline, -N- quinolidine, -NH-C(0)-CH2-CH2-C(0)-OH, -NH-C(0)-CH2-C(0)-OH, -NH- C(0)-CH2-CH2-C(0)-ORPR, -NH-C(0)-CH2-C(0)-ORPR, -NH-C(0)-(CH2)3- C(0)-OH or -NH-C(0)-(CH2)3-C(0)-ORPR, wherein RPR is a protecting group.
[50] 3. The compound of embodiment 1 wherein R4 is (1 ) -N-pyridine (relinked) or -N-pyrimidinyl (N-linked), (2) -1 -pyridyl (C-linked), -2-pyridyl, -3- pyridyl, -1 -pyrimidinly (C-linked), -4-pyrimidinly or -5-pyrimidinly, (3) -N- piperidinyl, -1 -piperidinyl, -2-piperidinyl, -3-piperidinyl, or (4) -N-imidazole, -2- imidazole or -4-imidazole.
[51] 4. The compound of embodiment 1 wherein R is 2-furanyl ( )or
3-furanyl ( ^^°). These embodiments include 17-(2-furanyl)^- methylandrost-5,16-diene-3β-ol, 17-(2-furanyl)-7 -methylandrost-5,16-diene- 3β-οΙ, 17-(2-furanyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3-furanyl)^- ethylandrost-5,16-diene-3β-ol, 17-(3-furanyl)-7 -ethylandrost-5,16-diene-3β-ol and 17-(3-furanyl)^-ethylandrost-5,16-diene-3cc-ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16- position is substituted with an O-linked substituent, including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-furanyl)^- methylandrost-5,16-diene-3p,16-diol, 17-(3-furanyl)^-ethylandrost-5,16- diene^-ol-16-methyl ether and 17-(3-furanyl)^-ethylandrost-5,16-diene^- ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent, including an optionally substituted alkyl group. Exemplary alkyl R3 substituents include -CH3, -C2H5 and -CH2CH2CH3 to provide exemplary species that include 17-(2-furanyl)^,16-dimethylandrost-5,16-diene^-ol and 17-(3-furanyl)^,16-diethylandrost-5,16-diene^-ol. These compounds also include analogs of any of these compounds where the methyl at the 18- position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds further include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment. [52] 5. The compound of embodiment 1 wherein R4 is 2-oxolane (
Figure imgf000020_0001
) or 3-oxolane ( \-/0). These embodiments include 17-(2-οχοΐ8ηνΙ)-7β- methylandrost-5,16-diene^-ol, 17-(2-oxolanyl)-7a-methylandrost-5,16- άϊΘηβ-3β-οΙ, 17-(2-oxolanyl)-7a-methylandrost-5,16-diene-3cc-ol, 17-(3- oxolanyl)^-ethylandrost-5,16-diene^-ol, 17-(3-oxolanyl)-7cc-ethylandrost- 5,16-diene^-ol and 17-(3-oxolanyl)-7β-ethylandrost-5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent, including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-oxolanyl)^- methylandrost-5,16-diene^,16-diol and 17-(3-oxolanyl)^-ethylandrost- 5,16-diene^-ol-16-methyl ether. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is
substituted with carbon a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, - C2H5 and -CH2CH2CH3 to provide exemplary species that include 17-(2- οχοΐ8ηνΙ)-7β, 16-dimethylandrost-5, 16-diene^-ol and 17-(3-οχοΐ8ηγΙ)-7β, 16- diethylandrost-5,16-diene^-ol. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including, the analogs of the first and second named compounds in this embodiment.
Figure imgf000021_0001
methylandrost-5,16-άϊΘηβ-3β-οΙ, 17-(2-thiophenyl)-7 -methylandrost-5,16- άϊΘηβ-3β-οΙ, 17-(2-thiophenyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3- thiophenyl)^-ethylandrost-5,16-diene^-ol, 17-(3-thiophenyl)-7cc- ethylandrost-5,16-diene^-ol and 17-(3-thiophenyl)^-ethylandrost-5,16- diene-3cc-ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-thiophenyl)^-methylandrost-5,16-diene-3 ,16-diol and 17-(3- thiophenyl)^-ethylandrost-5,16-diene^-ol-16-methyl ether. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and -CH2CH2CH3 to provide species that include 17-(2- thiophenyl)^,16-dimethylandrost-5,16-diene^-ol and 17-(3-thiophenyl)- 7β,16-diethylandrost-5, 16-diene-3β-ol. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment. [54] 7. The compound of embodiment 1 wherein R4 is 1 -pyrrole ( ^^ ),
2-pyrrole pyrrole ( ). These embodiments include 17-
(1 -pyrrolyl)-7β-methylandrost-5,16-diene-3β-ol, 17-(1 -pyrrolyl)-7 - methylandrost-5,16-diene-3β-ol, 17-(1 -pyrrolyl)-7a-methylandrost-5,16-diene- 3 -ol, 17-(2-pyrrolyl)^-methylandrost-5,16-diene^-ol, 17-(2-pyrrolyl)-7 - methylandrost-5,16-diene-3β-ol, 17-(2-pyrrolyl)-7a-methylandrost-5,16-diene- 3 -ol, 17-(3-pyrrolyl)-7 -ethylandrost-5, 16-diene-3p-ol, 17-(3-pyrrolyl)-7 - ethylandrost-5,16-diene-3β-ol and 17-(3-pyrrolyl)^-ethylandrost-5,16-diene- 3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3.
Exemplary species of this embodiment with O-linked R3 substituents include 17-(1 -pyrrolyl)-7β-methylandrost-5, 16-(_ιβηΘ-3β, 16-diol , 17-(2-ργιτοΙγΙ)-7β- methylandrost-5,16-diene-3β,16-diol and 17-(3-pyrrolyl)^-ethylandrost-5,16- diene-3β-ol-16-methyl ether. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and -CH2CH2CH3 to provide species that include 17-(1 -pyrrolyl)^,16-dimethylandrost-5,16- diene-3p-ol, 17-(2-pyrrolyl)-7β,16-dimethylandrost-5,16-diene-3β-ol and 17-(3- pyrrolyl)^,16-diethylandrost-5,16-diene^-ol.. These compounds also include analogs of any of these compounds where the methyl at the 18- position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment. In some of these embodiments, R4 is preferably 2-pyrrolyl or 3- pyrrolyl with preferred species including the 2-pyrrolyl and 3-pyrrolyl species listed above. [55] 8. The compound of embodiment 1 wherein R4 is 1 -pyrrolidine
( ), 2-pyrrolidine ( Π ) or 3-pyrrolidine ( N~/"" ). These embodiments include 17-(1 -pyrrolidinyl)^-methylandrost-5,16-diene^-ol, 17-(1 -pyrrolidinyl)-7 -methylandrost-5,16-diene-3β-ol, 17-(1 -pyrrolidinyl)-7cc- methylandrost-5,16-diene-3 -ol, 17-(2-pyrrolidinyl)^-methylandrost-5,16- diene-3β-ol, 17-(2-pyrrolidinyl)-7 -methylandrost-5,16-diene-3β-ol, 17-(2- pyrrolidinyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3-pyrrolidinyl)-7 - ethylandrost-5,16-diene^-ol, 17-(3-pyrrolidinyl)-7cc-ethylandrost-5,16-diene- 3β-οΙ and 17-(3-pyrrolidinyl)-7β-ethylandrost-5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(1 -pyrrolidinyl)^- methylandrost-5,16-diene^,16-diol, 17-(2-pyrrolidinyl)^-methylandrost-
5,16-diene-3 ,16-diol and 17-(3-pyrrolidinyl)^-ethylandrost-5, 16-(_ΪΘηβ-3β-οΙ- 16-methyl ether. These embodiments also include analogs of these
compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
Exemplary alkyl group R3 substituents include -CH3, -C2H5 and -CH2CH2CH3 to provide exemplary species that include -(1 -pyrrolidinyl)-7p,16- dimethylandrost-5,16-diene^-ol, 17-(2-pyrrolidinyl)^,16-dimethylandrost- 5,16-diene-3 -ol and 17-(3-pyrrolidinyl)-7 ,16-diethylandrost-5,16- ϊθηθ-3β-οΙ. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 1 imposition (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment. In some of these embodiments R4 is preferably 2-pyrrolidinyl or 3-pyrrolidinyl with preferred species including the 2-pyrroldinyl and 3-pyrrolidinyl species listed above. [56] 9. The com ound of embodiment 1 wherein R4 is 2-thiazole
Figure imgf000024_0001
3-thiazolium
Figure imgf000024_0002
). These embodiments include 17-(2-thiazolyl)^-methylandrost-5,16-diene^-ol, 17- (2-thiazolyl)-7 -methylandrost-5, 16-diene-3 -ol, 17-(2-thiazolyl)-7cc- methylandrost-5,16-diene-3a-ol, 17-(3-thiazolyl)^-ethylandrost-5,16-diene- 3β-οΙ, 17-(3-thiazolyl)-7cc-ethylandrost-5,16-diene^-ol, 17-(3-thiazolyl)-7 - ethylandrost-5,16-diene-3 -ol, 17-(4-thiazolyl)^-methylandrost-5,16-diene- 3β-οΙ, 17-(4-thiazolyl)-7 -methylandrost-5,16-diene^-ol, 17-(4-thiazolyl)-7cc- methylandrost-5,16-diene-3oc-ol, 17-(5-thiazolyl)^-methylandrost-5,16-diene- 3β-οΙ, 17-(5-thiazolyl)-7 -methylandrost-5,16-diene-3β-ol and 17-(5-thiazolyl)- 7 -methylandrost-5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-thiazolyl)^-methylandrost-5,16-diene^,16-diol, 17-(3-thiazolyl)^-methylandrost-5,16-diene^,16-diol, 17-(4-th iazolyl )-7β- ethylandrost-5,16-diene^-ol-16-methyl ether, 17-(5-thiazolyl)-7p- ethylandrost-5,16-diene-3β-ol-16-methyl ether and 17-(5-thiazolyl)-7p- ethylandrost-5,16-diene-3β-ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and - CH2CH2CH3 to provide exemplary species that include17-(2-thiazolyl)^,16- dimethylandrost-5,16-diene^-ol, 17-(3-thiazolyl)^,16-dimethylandrost- 5,16 ϋΘΠΘ-3β-οΙ, 17-(4-thiazolyl)-7β,16-diethylandrost-5, 16-diene-3β-ol and 17-(5-thiazolyl)^,16-diethylandrost-5,16-diene^-ol. These compounds also include analogs of any of these compounds where the methyl at the 18- position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2Hs including the analogs of the first and second named compounds in this embodiment. In some of these embodiments, R4 is preferably 2-thiazolyl, 4- thiazolyl or 5-thiazolyl with preferred species including the 2-, 4- and 5- thiazolyl species listed above.
[57] 10. The compound of embodiment 1 wherein R4 -tetrahydropyran tetrahydropyran-2-yl
Figure imgf000025_0001
tetrahydropyran-4-yl
Figure imgf000025_0002
These embodiments include 17-(2- tetrahydropyranyl)-7β-methylandrost-5,16-diene-3β-ol, 17-(2- tetrahydropyranyl)-7a-methylandrost-5,16-diene^-ol, 17-(2- tetrahydropyranyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3- tetrahydropyranyl)^-ethylandrost-5,16-diene^-ol, 17-(3-tetrahydropyranyl)- 7cc-ethylandrost-5,16-diene^-ol, 17-(3-tetrahydropyranyl)^-ethylandrost- 5,16-diene-3 -ol, 17-(4-tetrahydropyranyl)^-methylandrost-5,16-diene^-ol, 17-(4-tetrahydropyranyl)-7 -methylandrost-5, 16-άϊβηΘ-3β-οΙ and 17-(4- tetrahydropyranyl)-7 -methylandrost-5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16- position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-tetrahydropyranyl)- 7β-methylandrost-5,16-diene-3β,16-diol, 17-(3-tetrahydropyranyl)^- methylandrost-5,16-diene-3β,16-diol and 17-(4-tetrahydropyranyl)^- ethylandrost-5,16-diene-3β-ol-16-methyl ether. These embodiments also include analogs of these compounds where the hydrogen atom at the 16- position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, - C2H5 and -CH2CH2CH3 to provide exemplary species that include 17-(2- tetrahydropyranyl)^, 16-dimethylandrost-5, 16-diene^-ol, 17-(3- tetrahydropyranyl)^, 16-dimethylandrost-5, 16-diene-3β-ol and 17-(4- tetrahydropyranyl)-7β,16-diethylandrost-5,16-diene-3β-ol. These compounds also include analogs of any of these compounds where the methyl at the 18- position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment.
[58] 1 1 . The compound of embodiment 1 wherein R4 is 2-(1 ,4-dioxane) or
1 ,4-dioxan-2-yl
Figure imgf000026_0001
These embodiments include 17-(2-(1 ,4-dioxanyl))- 7β-methylandrost-5,16-diene-3β-ol, 17-(2-(1 ,4-dioxanyl))-7a-methylandrost- 5,16-diene^-ol and 17-(2-(1 ,4-dioxanyl))-7a-methylandrost-5,16-diene-3cc- ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3.
Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-(1 ,4-οΙϊοχ3ηγΙ))-7β-ΓΤΐΘίΐΊγΐ3ηοΐΓθ8ί-5,16-οΙΪΘηΘ-3β,16-οΙϊοΙ and 17-(2-(1 ,4- dioxanyl))^-ethylandrost-5,16-diene^-ol-16-methyl ether. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and -CH2CH2CH3 to provide exemplary species that include 17-(2-(1 ,4- 1ίοχ3ηγΙ))-7β, 16-dimethylandrost-5, 16- ϊθηθ-3β-οΙ and 17- (2-(1 ,4-dioxanyl))^,16-diethylandrost-5,16-diene^-ol. These compounds also include analogs of any of these compounds where the methyl at the 18- position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment. [59] 12. The compound of embodiment 1 wherein R4 is 2- - morpholin
Figure imgf000027_0001
or 4-morpho
These embodiments include 17-(2-morpholinyl)^-methylandrost-5,16-diene- 3β-οΙ, 17-(2-morpholinyl)-7a-methylandrost-5,16-diene-3 -ol, 17-(2- morpholinyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3-ΐΎΐοφηοΝηνΙ)-7β- ethylandrost-5,16-diene-3β-ol, 17-(3-morpholinyl)-7cc-ethylandrost-5,16-diene- 3β-οΙ, 17-(3-ηηοΓρΐΊθΝηγΙ)-7β-ΘίΐΊγΐ3ηοΐΓθ8ί-5,16-οΙΪΘηΘ-3α-οΙ , 17-(4- morpholinyl)^-methylandrost-5,16-diene^-ol, 17-(4-morpholinyl)-7 - methylandrost-5,16-diene^-ol and 17-(4-morpholinyl)-7 -methylandrost- 5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and - OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-morpholinyl)^-methylandrost-5,16-diene^,16- diol, 17-(3-morpholinyl)-7 -methylandrost-5,16-diene-3 ,16-diol, 17-(4- morpholinyl)-7β-ethylandrost-5,16-diene-3β-ol-16-methyl ether and 17-(2- morpholinyl)-7β-ethylandrost-5,16-diene-3β-ol-16-acetate. These
embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and -CH2CH2CH3 to provide exemplary species that include 17-(2-morpholinyl)^,16-dimethylandrost-5,16-diene^-ol, 17-(3- morpholinyl)^,16-dimethylandrost-5,16-diene^-ol and 17-(4-morpholinyl)- 7β,16-άϊΘίήγΐ3ηάΓθ8ί-5, 16-άϊΘΠΘ-3β-οΙ. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment. In some of these embodiments, R4 is preferably 2-morpholinyl or 3-morpholinyl with preferred species including the 2- and 3-morpholinyl species listed above.
[60] 13. The compound of embodiment 1 wherein R4 is 2-oxazolyl or 2- oxazole ( -O 0 ), 4-oxazole ( -O ^ ) or 5-oxazole ( -o 0 ). These embodiments include 17-(2-oxazolyl)^-methylandrost-5,16-diene^-ol, 17- (2-oxazolyl)-7 -methylandrost-5,16-diene-3β-ol, 17-(2-oxazolyl)-7cc- methylandrost-5,16-diene-3 -ol, 17-(5-oxazolyl)^-ethylandrost-5,16-diene- 3β-οΙ, 17-(5-oxazolyl)-7a-ethylandrost-5,16-diene-3^ol, 17-(5-οχ8ζοΙγΙ)-7β- ethylandrost-5,16-diene-3oc-ol, 17-(4-oxazolyl)^-methylandrost-5,16-diene- 3β-οΙ, 17-(4-oxazolyl)-7 -methylandrost-5,16-diene-3β-ol and 17-(4-oxazolyl)- 7 -methylandrost-5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-oxazolyl)^-methylandrost-5,16-diene^,16-diol, 17-(5-oxazolyl)^-methylandrost-5, 16-diene-3β, 16-diol or 17-(4-οχ8ζοΙνΙ)-7β- ethylandrost-5,16-diene-3β-ol-16-methyl ether and 17-(5-οχ8ζοΙνΙ)-7β- ethylandrost-5,16-diene-3β-ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and - CH2CH2CH3 to provide exemplary species that include 17-(2-οχ8ζοΙνΙ)-7β,16- dimethylandrost-5,16-diene^-ol, 17-(5-oxazolyl)^,16-dimethylandrost- 5,16-diene^-ol and 17-(4-oxazolyl)-7β, 16-diethylandrost-5,16-diene-3β-ol. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19- position (R6) is -C2Hs, including the analogs of the first and second named compounds in this embodiment. [61] 14. The compound of embodiment 1 wherein R4 is 2-imidazolyl or 2- imidazole
Figure imgf000029_0001
imidazole ( N ). These embodiments include 17-(2-imidazolyl)^- methylandrost-5,16-diene-3β-ol, 17-(2-imidazolyl)-7a-methylandrost-5,16- diene^-ol, 17-(2-imidazolyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3- imidazolyl)-7β-ethylandrost-5,16-diene-3β-ol, 17-(3-imidazolyl)-7 - ethylandrost-5,16-diene^-ol, 17-(3-imidazolyl)^-ethylandrost-5,16-diene- 3 -ol, 17-(4-imidazolyl)-7β-methylandrost-5,16-diene-3β-ol, 17-(4-imidazolyl)- 7a-methylandrost-5,16-diene^-ol, 17-(4-imidazolyl)-7a-methylandrost-5,16- diene-3 -ol, 17-(5-imidazolyl)-7β-methylandrost-5,16-diene-3β-ol, 17-(5- imidazolyl)-7 -methylandrost-5,16-diene-3β-ol and 17-(5-imidazolyl)-7 - methylandrost-5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-imidazolyl)^-methylandrost-5, 16-diene^,16-diol, 17-(3-imidazolyl)^-methylandrost-5, 16-diene^, 16-diol, 17-(4-imidazolyl)- 7β-ethylandrost-5,16-diene^-ol-16-methyl ether, 17-(5-imidazolyl ^- ethylandrost-5,16-diene-3β-ol-16-methyl ether and 17-(5-imidazolyl ^- ethylandrost-5,16-diene-3β-ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and - CH2CH2CH3 to provide exemplary species that include 17-(2-imidazolyl)- 7β,16-dimethylandrost-5,16-diene-3β-ol, 17-(3-imidazolyl)^,16- dimethylandrost-5,16-diene^-ol, 17-(4-imidazolyl)^,16-diethylandrost- 5,16-diene^-ol and 17-(5-imidazolyl)-7β,16-diethylandrost-5,16-diene-3β-ol. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, e.g., the analog of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, e.g., the analog of the first and second named compounds in this embodiment. In some of these embodiments, R4 is preferably 2-imidazolyl, 4- imidazolyl or 5-imidazolyl, with preferred species including the 2-, 4- and 5- imidazolyl species listed above.
[62] 15. The compound of embodiment 1 wherein R4 is 1 -piperidinyl or 1 -
piperidine 2-piperidine ), 3-piperidine ) or 4 piperidine
Figure imgf000030_0001
These embodiments include 17-(2-piperidinyl)-7 - methylandrost-5,16-άϊΘηβ-3β-οΙ, 17-(2-piperidinyl)-7 -methylandrost-5,16- άϊΘηβ-3β-οΙ, 17-(2-piperidinyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3- piperidinyl)-7β-ethylandrost-5,16-diene-3β-ol, 17-(3-piperidinyl)-7cc- ethylandrost-5,16-diene-3β-ol, 17-(3-piperidinyl)^-ethylandrost-5,16-diene- 3cc-ol, 17-(4-piperidinyl)-7β-methylandrost-5,16-diene-3β-ol, 17-(4-piperidinyl)- 7 -methylandrost-5, 16-άϊΘηβ-3β-οΙ, 17-(4-piperidinyl)-7 -methylandrost-5, 16- diene-3cc-ol, 17-(1 -piperidinyl)-7β-methylandrost-5,16^ίβηβ-3β-οΙ, 17-(1 - piperidinyl)-7a-methylandrost-5,16-diene^-ol and 17-(1 -piperidinyl)-7 - methylandrost-5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-piperidinyl)^-methylandrost-5,16-diene^,16- diol, 17-(3-piperidinyl)-7 -methylandrost-5,16-diene-3 ,16-diol, 17-(4- piperidinyl)^-ethylandrost-5,16-diene^-ol-16-methyl ether, 17-(1 - piperidinyl)-7β-ethylandrost-5,16-diene-3β-ol-16-methyl ether and 17-(1 - piperidinyl)-7β-ethylandrost-5,16-diene-3β-ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16- position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, - C2H5 and -CH2CH2CH3, to provide exemplary species that include 17-(2- piperidinyl)^,16-dimethylandrost-5,16-diene^-ol, 17-(3-piperidinyl)-7 , 16- dimethylandrost-5,16-diene^-ol, 17-(4-piperidinyl)-7p, 16-diethylandrost- 5,16-diene^-ol and 17-(1 -piperidinyl)-7 , 6-diethylandrost-5,16-άϊβηΘ-3β-οΙ. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 1 imposition (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment. In some of these embodiments, R4 is preferably 2-piperidinyl, 3-piperidinyl or 4-piperidinyl, with preferred species including the 2-, 3- and 4-piperidinyl species listed above.
[63] 16. The compound of embodiment 1 wherein R4 is 1 -piperazine
Figure imgf000031_0001
These embodiments include 17-(2- piperazinyl)^-methylandrost-5,16-diene^-ol, 17-(2-piperazinyl)-7cc- methylandrost-5,16-diene^-ol, 17-(2-piperazinyl)-7a-methylandrost-5,16- diene-3cc-ol, 17-(1 -piperazinyl)^-ethylandrost-5, 16-άϊΘΠΘ-3β-οΙ, 17-(1 - piperazinyl)-7cc-ethylandrost-5,16-diene^-ol and 17-(1 -piperazinyl)^- ethylandrost-5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and - OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-piperazinyl)^-methylandrost-5,16-diene^,16- diol, 17-(1 -piperazinyl)-7β-ethylandrost-5,16-diene-3β-ol-16-methyl ether, 17- (1 -piperazinyl)^-ethylandrost-5,16-άϊΘΠΘ-3β-οΙ-16-acetate and 17-(2- piperazinyl)-7β-ethylandrost-5,16-diene-3β-ol-16-acetate. These
embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and -CH2CH2CH3 to provide exemplary species that include 17-(2-piperazinyl)^,16-dimethylandrost-5,16-diene^-ol and 17-(1 piperazinyl)-7β,16-diethylandrost-5,16-diene-3β-ol. These compounds also include analogs of any of these compounds where the methyl at the 18- position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment.
[64] 17. The com ound of embodiment 1 wherein R4 - ridinyl or 1 - pyridiniu
Figure imgf000032_0001
) or 4- pyridine
Figure imgf000032_0002
These embodiments include 17-(2-ργπάίηγΙ)-7β- methylandrost-5,16-diene-3β-ol, 17-(2-pyridinyl)-7a-methylandrost-5,16- diene-3β-ol, 17-(2-pyridinyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3- pyridinyl)-7β-ethylandrost-5,16-diene-3β-ol, 17-(3-pyridinyl)-7cc-ethylandrost- 5,16-diene-3 -ol, 17-(3-pyridinyl)^-ethylandrost-5,16-diene-3a-ol, 17-(4- pyridinyl)-7β-methylandrost-5,16-diene-3β-ol, 17-(4-pyridinyl)-7cc- methylandrost-5,16-diene-3β-ol, 17-(4-pyridinyl)-7a-methylandrost-5,16- diene-3 -ol, 17-(1 -pyridinyl)-7β-methylandrost-5, 16-άϊΘΠΘ-3β-οΙ, 17-(1 - pyridinyl)-7 -methylandrost-5,16-diene-3β-ol and 17-(1 -pyridinyl)-7oc- methylandrost-5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-pyridinyl)^-methylandrost-5,16-diene^,16-diol, 17-(3-pyridinyl)-7 -methylandrost-5,16-diene-3 ,16-diol, 17-(4-ργπ(_ϊηγΙ)-7β- ethylandrost-5,16-diene^-ol-16-methyl ether, 17-(1 -pyridinyl)-7p- ethylandrost-5,16-diene-3β-ol-16-methyl ether and 7-(1 -pyridinyl)-7 - ethylandrost-5,16-diene-3β-ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and - CH2CH2CH3 to provide exemplary species that include 17-(2-pyridinyl)-7 ,16- dimethylandrost-5,16-diene^-ol, 17-(3-pyridinyl)^,16-dimethylandrost- 5,16-diene-3 -ol, 17-(4-pyridinyl)-7β,16-diethylandrost-5,16-diene-3β-ol and 17-(1 -pyridinyl)^,16-diethylandrost-5,16-diene^-ol. These compounds also include analogs of any of these compounds where the methyl at the 18- position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment. In some of these embodiments, R4 is preferably 2-pyridinyl, 3- pyridinyl or 4-pyridinyl with preferred species including the 2-pyridinyl, 3- pyridinyl and 4-pyridinyl species listed above.
. The compound of embodiment 1 wherein R4 is 1 -pyrazinium
Figure imgf000033_0001
These embodiments include 17-(2- pyrazinyl)^-methylandrost-5,16-diene^-ol, 17-(2-pyrazinyl)-7cc- methylandrost-5,16-diene^-ol, 17-(2-pyrazinyl)-7 -methylandrost-5,16- diene-3cc-ol, 17-(1 -pyrazinyl)-7β-ethylandrost-5, 16-άϊΘΠΘ-3β-οΙ, 17-(1 - pyrazinyl)-7 -ethylandrost-5,16-diene-3β-ol and 17-(1 -pyrazinyl)^- ethylandrost-5,16-diene-3cc-ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and - OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-pyrazinyl)^-methylandrost-5,16-diene^,16-diol, 17-(1 -pyrazinyl)^-ethylandrost-5,16-diene^-ol-16-methyl ether, 17-(1 - pyrazinyl)^-ethylandrost-5,16-diene^-ol-16-acetate and 17-(2-pyrazinyl)- 7β-ethylandrost-5,16-diene-3β-ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16- position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, - C2H5 and -CH2CH2CH3, to provide exemplary species that include 17-(2- pyrazinyl)^,16-dimethylandrost-5,16-diene^-ol and 17-(1 -ρνΓ8ζίηνΙ)-7β,16- diethylandrost-5,16-diene-3β-ol. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment.
[66] 19. d of embodiment 1 wherein R4 is 1 - rimidin l or 1 - pyrimidiniu 2-pyrimidin or 5- pyrimidine
Figure imgf000034_0001
ese embodiments include 17-(2-pyrimidinyl)-7P- methylandrost-5,16-diene-3β-ol, 17-(2-pyrimidinyl)-7a-methylandrost-5,16- diene-3β-ol, 17-(2-pyrimidinyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(1 - pyrimidinyl)^-ethylandrost-5,16-diene^-ol, 17-(1 -pyrimidinyl)-7 - ethylandrost-5,16-diene-3β-ol, 17-(1 -pyrimidinyl)^-ethylandrost-5,16-diene- 3 -ol, 17-(4-pyrimidinyl)-7β-methylandrost-5,16-diene-3β-ol, 17-(4- pyrimidinyl)-7 -methylandrost-5,16-diene-3β-ol, 17-(4-pyrimidinyl)-7a- methylandrost-5,16-diene-3 -ol, 17-(5-pyrimidinyl)^-methylandrost-5,16- diene-3β-ol, 17-(5-pyrimidinyl)-7a-methylandrost-5,16-diene^-ol and 17-(5- pyrimidinyl)-7 -methylandrost-5,16-diene-3 -ol. These embodiments include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, - OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(2-pyrimidinyl)^-methylandrost-5,16- diene-3p,16-diol, 17-(1 -pyrimidinyl)-7β-methylandrost-5,16-diene-3β,16-diol, 17-(4-pyrimidinyl)-7β-ethylandrost-5, 16-diene^-ol-16-methyl ether, 17-(5- pyrimidinyl)-7β-ethylandrost-5,16-diene-3β-ol-16-methyl ether and 17-(5- pyrimidinyl)^-ethylandrost-5,16-diene^-ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16- position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, - C2H5 or -CH2CH2CH3 to provide exemplary species that include17-(2- pyrimidinyl)^,16-dimethylandrost-5,16-diene^-ol, 17-(1 -pyrimidinyl)-7 , 16- dimethylandrost-5,16-diene^-ol, 17-(4-pyrimidinyl)^,16-diethylandrost- 5,16-diene^-ol and 17-(5-pyrimidinyl)-7β,16-diethylandrost-5,16-diene-3β-ol. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 1 imposition (R6) is -C2H5, including the analog of the first and second named compounds in this embodiment. In some of these embodiments, R4 is preferably 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl, with preferred species including the 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl species listed above.
[67] 19A1 . The compound of embodiment 1 wherein R4 is optionally substituted pheny
Figure imgf000035_0001
wherein R is -H, -CH3, -C2H5, -CF3, -OH, - -OC2H5 or -F. In preferred embodiments, when R is not -H, it is meta
Figure imgf000035_0002
to the carbon that is bonded at the 17- position. Preferred R are -H, -CH3 and -OCH3. These compounds include 17- (phenyl)^-methylandrost-5,16-diene^-ol, 17-(phenyl)^-methylandrost- 5,16-diene-3cc-ol, 17-(phenyl)androst-5,16-diene^^-diol, 17- (phenyl)androst-5, 16-diene-3cc^-diol, 17-(phenyl)androst-5,16-diene^,7cc- diol, 17-(phenyl)-7a-methylandrost-5,16-diene^-ol, 17-(m-methylphenyl)^- ethylandrost-5,16-diene^-ol, 17-(p-methoxyphenyl)^-ethylandrost-5,16- diene-3cc-ol and 17-( -fluorophenyl)-7 -ethylandrost-5,16-diene-3β-ol. These compounds include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include, -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(ρηβηνΙ)-7β- methylandrost-5,16-diene-3β,16-diol, 17-(p-fluorophenyl)^-methylandrost- 5,16-diene-3p,16-diol and 17-(p-methoxyphenyl)^-ethylandrost-5,16-diene- 3 -ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group.
Exemplary alkyl group R3 substituents include -CH3, -C2H5 and -CH2CH2CH3 to provide exemplary species that include 17-(phenyl)-7a,16-dimethylandrost- 5,16-diene^-ol and 17-(o-hydroxyphenyl)^,16-diethylandrost-5,16-diene- 3β-οΙ. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19- position (R6) is -C2H5, including the analogs of the first, second and third named compounds in this embodiment.
[68] 19B. The compound of embodiment 1 wherein R4 is optionally
Figure imgf000036_0001
substituted cyclohexyl ), wherein R is -H, -CH3, -C2H5, -CF3, -OH, - -OC2H5 or -F. In preferred embodiments, when R is not -H, it is meta
Figure imgf000036_0002
to the carbon that is bonded at the 17- position. Preferred R are -H, -F, -OCH3 and -OH. These compounds include 17-(cyclohexyl)^-methylandrost-5,16-diene^-ol, 17-(cyclohexyl)androst- 5,16-άϊΘηΘ-3β,7β-άϊοΙ, 17-(cyclohexyl)androst-5, 16-diene-3cc^-diol, 17-(p- (trifluoromethyl)cyclohexyl)-7β-methylandrost-5,16-diene-3β-ol, 17- (cyclohexyl)^-methylandrost-5,16-diene-3cc-ol, 17-(cyclohexyl)-7cc- methylandrost-5,16-άϊΘηβ-3β-οΙ, 17-(m-hydroxycyclohexyl)^-ethylandrost- 5,16-diene^-ol, 17-( -methoxycyclohexyl)-7β-ethylandrost-5,16-diene-3 -ol and 17-(p-fluorocyclohexyl)-7 -ethylandrost-5,16-diene-3β-ol. These compounds include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and -OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(cyclohexyl)^- methylandrost-5,16-diene-3β,16-diol and 17-(p-methoxycyclohexyl)^- ethylandrost-5,16-diene-3 -ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and - CH2CH2CH3 to provide exemplary species that include 17-(cyclohexyl)-7cc,16- dimethylandrost-5,16-diene^-ol and 17-(o-hydroxycyclohexyl)^,16- diethylandrost-5,16-diene^-ol. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 19-position (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment.
[69] 19C. The compound of embodiment 1 wherein R4 is a lactone having
the structure
Figure imgf000037_0001
compounds include 7β-methylandrost-5, 16- diene^-ol-17-(pyran-3-en-2-one-3-yl), 7β-ethylandrost-5,16-diene-3β-ol-17- (pyran-3-en-2-one-3-yl), 7a-methylandrost-5,16-diene-3a-ol-17-(pyran-3-en-2- one-3-yl), 7cc-ethylandrost-5,16-diene^-ol-17-(pyran-3-en-2-one-3-yl), androst-5,16-diene^^-diol-17-(pyran-3-en-2-one-3-yl), androst-5,16-diene- 3 ,7p-diol-17-(pyran-3-en-2-one-3-yl), androst-5,16-diene^,7cc-diol-17- (pyran-3-en-2-one-3-yl)and 7a-ethylandrost-5,16-diene-3cc-ol-17-(pyran-3-en- 2-one-3-yl). These compounds include analogs of these compounds where the hydrogen atom at the 16-position is substituted with an O-linked substituent including -OH, an ether or an ester. Exemplary O-linked ester and ether R3 substituents include -OCH3, -OC2H5, -OC(0)CH3 and - OC(0)CH2CH3. Exemplary species of this embodiment with O-linked R3 substituents include 17-(cyclohexyl)^-methylandrost-5,16-diene^,16-diol and 17-( -methoxycyclohexyl)-7β-ethylandrost-5,16-diene-3 -ol-16-acetate. These embodiments also include analogs of these compounds where the hydrogen atom at the 16-position is substituted with a C-linked substituent including an optionally substituted alkyl group. Exemplary alkyl group R3 substituents include -CH3, -C2H5 and -CH2CH2CH3 to provide exemplary species that include 17-(cyclohexyl)-7a,16-dimethylandrost-5,16-diene^-ol and17-(o-hydroxycyclohexyl)-7β,16-diethylandrost-5,16-diene-3β-ol. These compounds also include analogs of any of these compounds where the methyl at the 18-position (R5) is -C2H5, including the analogs of the first and second named compounds in this embodiment. These compounds also include analogs of any of these compounds where the methyl at the 1 imposition (R6) is -C2H5, including the analogs of the first and second named compounds in this embodiment.
[70] 20. The compound of embodiment 4, 5 or 6 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a C1 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally -OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or - OCH(CH3)2; R3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH3, - CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2.
[71] 21 . The compound of embodiment 4, 5 or 6 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is -H; R3 is -H or C1 -6 optionally substituted alkyl, optionally -CH3, -CF3, - C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2. In some of these embodiments, R3 is C2-6 optionally substituted alkyl, optionally -C2H5, - CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2.
[72] 22. The compound of embodiment 4, 5 or 6 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is optionally substituted C1 -6 alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -OCH(CH3)2; R3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2. In some of these embodiments, R3 is C2-6 optionally substituted alkyl, optionally -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2.
[73] 23 the
structure
Figure imgf000039_0001
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or -CH2CH2OH.
the
Figure imgf000039_0002
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or -CH2CH2OH.
[75] 25 the
structure
Figure imgf000039_0003
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3 -C2H5 or -CH2CH2OH. [76] 26. The compound of embodiment 1 , 2, 3, 20, 21 or 22 having the
structure
Figure imgf000040_0001
or
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1-4 optionally substituted alkyl, preferably -CH3
Figure imgf000040_0002
[77] 27. The compound of embodiment 1 , 2, 3, 20, 21 or 22 having the
Figure imgf000040_0003
(a) R1 and R2 are -OH, R3 is - H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or -CH2CH2OH.
[78] 27. The compound of embodiment 1 , 2, 3, 20, 21 or 22 having the
Figure imgf000040_0004
(a) R1 and R2 are -OH, R3 is - H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is 01 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or -CH2CH2OH.
the
Figure imgf000041_0001
wherein
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is 01 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH.
[80] 29. The compound of embodiment 7, 8 or 9 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally -OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or - OCH(CH3)2; R3 is -H, or 01 -6 optionally substituted alkyl, optionally -CH3, - CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2.
[81] 30. The compound of embodiment 7, 8 or 9 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is -H; R3 is -H or 01 -6 optionally substituted alkyl, optionally -CH3, -CF3, -
C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2. In some of these embodiments, R3 is C2-6 optionally substituted alkyl, optionally -C2H5, - CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2.
[82] 31. The compound of embodiment 7, 8 or 9 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally -
OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is optionally substituted C1 -6 alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -OCH(CH3)2; R3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2. In some of these embodiments, R3 is C2-6 optionally substituted alkyl, optionally -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2.
the structure
Figure imgf000042_0001
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or -CH2CH2OH.
the structure
Figure imgf000042_0002
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or -CH2CH2OH.
the structure
Figure imgf000042_0003
optionally
wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1-4 optionally substituted, preferably -CH3, -C2H5 or - CH2CH2OH.
[86] 35. The compound of embodiment 29, 30 or 31 having the structure
Figure imgf000043_0001
, optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1-4 optionally substituted alkyl preferably -CH3, -C2H5 or CH2CH2OH.
embodiment 29, 30 or 31 having the structure
Figure imgf000043_0002
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH.
[88] 37. The compound of embodiment 29, 30 or 31 having the structure
Figure imgf000043_0003
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH. ing the structure
Figure imgf000044_0001
optionally wherein
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is 01 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH.
[90] 39. The compound of embodiment 10, 1 1 or 12 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally -OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or - OCH(CH3)2; R3 is -H, or 01 -6 optionally substituted alkyl, optionally -CH3, - CF3, -C2H5, -CH2CH2OH, -ΟΗ2ΟΗ2ΟΗ3, -CH2CH2CH2OH or -CH(CH3)2.
[91] 40. The compound of embodiment 10, 1 1 or 12 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is -H; R3 is -H or 01 -6 optionally substituted alkyl, optionally -CH3, -CF3, - C2H5, -CH2CH2OH, -ΟΗ2ΟΗ2ΟΗ3, -CH2CH2CH2OH or -CH(CH3)2. In some of these embodiments, R3 is C2-6 optionally substituted alkyl, optionally -C2H5, - CH2CH2OH, -ΟΗ2ΟΗ2ΟΗ3, -CH2CH2CH2OH or -CH(CH3)2.
[92] 41 . The compound of embodiment 10, 1 1 or 12 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a 01 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is optionally substituted 01 -6 alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -ΟΗ2ΟΗ2ΟΗ3, -CH2CH2CH2OH or -OCH(CH3)2; R3 is -H, or 01 -6 optionally substituted alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2. In some of these embodiments, R3 is C2-6 optionally substituted alkyl, optionally -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2.
the structure
Figure imgf000045_0001
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or -CH2CH2OH.
the structure
Figure imgf000045_0002
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or -CH2CH2OH.
the structure
Figure imgf000045_0003
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or -CH2CH2OH. the structure
Figure imgf000046_0001
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted, preferably -CH3, -C2H5 or - CH2CH2OH.
[97] 46. The compound of embodiment 39, 40 or 41 having the structure
Figure imgf000046_0002
wherein
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH.
[98] 47. The compound of embodiment 39, 40 or 41 having the structure
Figure imgf000046_0003
wherein
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH. ing the structure
Figure imgf000047_0001
optionally wherein
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH.
[100] 49. The compound of embodiment 13, 14 or 15 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a C1 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a C1 -6 ether, optionally -OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or - OCH(CH3)2; R3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH3, - CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2.
[101] 50. The compound of embodiment 13, 14 or 15 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a C1 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is -H; R3 is -H or C1 -6 optionally substituted alkyl, optionally -CH3, -CF3, - C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2. In some of these embodiments, R3 is C2-6 optionally substituted alkyl, optionally -C2H5, - CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2.
[102] 51 . The compound of embodiment 13, 14 or 15 wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a C1 -6 ether, optionally - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R2 is optionally substituted C1 -6 alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -OCH(CH3)2; R3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2. In some of these embodiments, R3 is C2-6 optionally substituted alkyl, optionally -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2.
the structure
Figure imgf000048_0001
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl preferably -CH3, -C2H5 or - CH2CH2OH.
the structure
Figure imgf000048_0002
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl preferably -CH3, -C2H5 or - CH2CH2OH.
the structure
Figure imgf000048_0003
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl preferably -CH3, -C2H5 or CH2CH2OH. the structure
Figure imgf000049_0001
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or -CH2CH2OH.
[107] 56. The compound of embodiment 49, 50 or 51 having the structure
Figure imgf000049_0002
wherein
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH.
[108] 57. The compound of embodiment 49, 50 or 51 having the structure
Figure imgf000049_0003
wherein
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH. ing the structure
Figure imgf000050_0001
optionally wherein
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3,-C2H5 or - CH2CH2OH.
[110] 59. The compound of embodiment 16, 17, 18, 19, 19A1 , 19B or 19C wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a C1 -6 ether, optionally -OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -
OCH2CH2CH2OH or -OCH(CH3)2; R2 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a C1 -6 ether, optionally -OC2H5, -OCH2CH2CH3, - OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2; R3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2.
[111] 60. The compound of embodiment 16, 17, 18, 19, 19A1 , 19B or 19C wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a C1 -6 ether, optionally -OC2H5, -OCH2CH2CH3, -OCH2CH2OH, - OCH2CH2CH2OH or -OCH(CH3)2; R2 is -H; R3 is -H or C1 -6 optionally substituted alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2. In some of these embodiments, R3 is C2-6 optionally substituted alkyl, optionally -C2H5, -CH2CH2OH, -CH2CH2CH3, - CH2CH2CH2OH or -CH(CH3)2.
[112] 61 . The compound of embodiment 16, 17, 18, 19, 19A1 , 19B or 19C wherein, R1 is -OH, =0, a C2-6 ester, optionally acetate or propionate, or a C1 -6 ether, optionally -OC2H5, -OCH2CH2CH3, -OCH2CH2OH, - OCH2CH2CH2OH or -OCH(CH3)2; R2 is optionally substituted C1 -6 alkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or - OCH(CH3)2; R3 is -H, or C1 -6 optionally substituted alkyl, optionally -CH3, - CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2. In some of these embodiments, R3 is C2-6 optionally substituted alkyl, optionally -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2.
the structure
Figure imgf000051_0001
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl preferably -CH3, -C2H5 or CH2CH2OH.
the structure
Figure imgf000051_0002
optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl preferably -CH3, -C2H5 or CH2CH2OH.
the structure
Figure imgf000051_0003
optionally
wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl preferably -CH3, -C2H5 or■ CH2CH2OH.
[116] 65. The compound of embodiment 59, 60 or 61 having the structure
Figure imgf000052_0001
, optionally wherein (a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is - OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl preferably -CH3, -C2H5 or CH2CH2OH.
embodiment 59, 60 or 61 having the structure
Figure imgf000052_0002
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl preferably -CH3, -C2H5 or - CH2CH2OH.
[118] 67. The compound of embodiment 59, 60 or 61 having the structure
Figure imgf000052_0003
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH. 119] 68. The compound of embodiment 59, 60 or 61 having the structure
Figure imgf000053_0001
wherein
(a) R1 and R2 are -OH, R3 is -H, (b) R1 is =0, R2 is -OH, R3 is -H, (c) R1 and R2 are -OH, R3 is -CH3, (d) R1 is =0, R2 is -OH, R3 is -CH3, (e) R1 is -OH, R2 is -H, R3 is C1 -4 optionally substituted alkyl, preferably -CH3, -C2H5 or - CH2CH2OH.
[120] 69. The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18 or 19, wherein R1 is -OH or =0. These compounds include compounds or analogs of compounds described in embodiments 1 - 19.
[121] 70. The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18 or 19, wherein R1 is a C2-4 ester, optionally -OC(0)CH3 or -OC(0)CH2CH3. These compounds include compounds or analogs of compounds described in embodiments 1 -19.
[122] 71 . The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 19A1 , 19B or 19C, wherein R1 is a C1 -4 ether, optionally -OCH3 or -OCH2CH3. These compounds include compounds or analogs of compounds described in embodiments 1 -19.
[123] 72. The compound of embodiment 69, 70 or 71 wherein R2 is -H.
[124] 73. The compound of embodiment 69, 70 or 71 wherein R2 is -OH.
[125] 74. The compound of embodiment 69, 70 or 71 wherein R2 is a C2-4 ester, optionally -OC(0)CH3 or -OC(0)CH2CH3.
[126] 75. The compound of embodiment 69, 70 or 71 wherein R2 is a C1 -4 ether, optionally -OCH3 or -OCH2CH3.
[127] 76. The compound of embodiment 72, 73, 74 or 75 wherein R3 is -H. [128] 77. The compound of embodiment 72, 73, 74 or 75 wherein R3 is -OH.
[129] 78. The compound of embodiment 72, 73, 74 or 75 wherein R3 is a C2- 4 ester, optionally -OC(0)CH3 or -OC(0)CH2CH3.
[130] 79. The compound of embodiment 72, 73, 74 or 75 wherein R3 is a C1 - 4 ether, optionally -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH3)2.
[131] 80. The compound of embodiment 72, 73, 74 or 75 wherein R3 is C1 -4 optionally substituted alkyl, optionally -CH3, -CH2CH3, -CH2CH2CH3 or - CH2CH2OH.
[132] 81 . The compound of embodiment 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79 or 80 wherein R5 is -CH3 and R6 is -CH3.
[133] 82. The compound of embodiment 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79 or 80 wherein R5 is -CH2OH and R6 is -CH3.
[134] 83. The compound of embodiment 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79 or 80 wherein R5 is -CH3 and R6 is -CH2OH.
[135] 84. The compound of embodiment 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79 or 80 wherein R5 is -CH3 and R6 is -H.
[136] 85. The compound of embodiment 69, 70, 71 , 72, 73, 74, 75, 76, 77,
78, 79 or 80 wherein R5 is -CH2CH3 and R6 is -CH3.
[137] 86. The compound of embodiment 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79 or 80 wherein R5 is -CH2CH3 and R6 is -H.
[138] 87. The compound of embodiment 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79 or 80 wherein R5 is -CH2CH3 and R6 is -CH2OH.
[139] 88. The compound of embodiment 1 wherein the compound is 17-N- pyrimidinylandrost-5,16-diene^^-diol, 17-N-pyrimidinylandrost-5,16-diene- 3α,7β^ίοΙ, 17-N-pyrimidinylandrost-5,16-diene^,7cc-diol, 17-N- pyrimidinylandrost-5,16-diene-3 ,7 -diol, 17-(3-pyridyl)androst-5,16-diene- 3p,7p-diol, 17-(3-pyridyl)androst-5,16-diene-3cc^-diol, 17-(3-pyridyl)androst- 5,16-diene^,7cc-diol, 17-(3-pyridyl)androst-5,16-diene-3 ,7 -diol, 17-N- pyridylandrost-5, 16-diene^^-diol, 17-N-pyridylandrost-5, 16-diene-3cc^- diol, 17-N-pyridylandrost-5,16-diene^,7cc-diol or 17-N-pyridylandrost-5,16- diene-3a,7cc-diol.
[140] 89. The compound of embodiment 1 wherein the compound is 17-N- pyrimidinylandrost-5,16-diene^-ol-3-one, 17-N-pyrimidinylandrost-5,16- diene-7cc-ol-3-one, 17-(3-pyridyl)androst-5, 16-diene^-ol-3-one, 17-(3- pyridyl)androst-5,16-diene-7cc-ol-3-one, 17-N-pyridylandrost-5,16-diene^-ol- 3-one or 17-N-pyridylandrost-5,16-diene-7 -ol-3-one.
[141] 90. The compound of embodiment 1 wherein the compound is 17-N- pyrimidinylandrost-5,16-diene^-ol^-acetate, 17-N-pyrimidinylandrost-5,16- diene-7 -ol-3β-acetate, 17-N-pyrimidinylandrost-5, 16-diene-7β-ol-3 -acetate, 17-N-pyrimidinylandrost-5, 16-diene-7 -ol-3 -acetate, 17-(3-pyridyl)androst- 5,16-diene^-ol^-acetate, 17-(3-pyridyl)androst-5,16-diene-7cc-ol^- acetate, 17-N-pyridylandrost-5,16-diene-7β-ol-3β-acetate, 17-N- pyridylandrost-5, 16-diene-7cc-ol^-acetate, 17-(3-pyridyl)androst-5, 16-diene- 7β-οΙ-3 -3θβί8ίβ, 17-(3-pyridyl)androst-5, 16-diene-7a-ol-3cc-acetate, 17-N- pyridylandrost-5, 16-diene-7β-ol-3 -acetate or 17-N-pyridylandrost-5, 16-diene- 7 -ol-3 -acetate.
[142] 91 . The compound of embodiment 88, 89 or 90 wherein the compound is an analog wherein (i) the hydroxyl group at the 7-position is replaced with a C2-4 ester, optionally -0-C(0)CH3 or -0-C(0)CH2CH3, e.g., 17-(3- pyridyl)androst-5,16-diene^-ol^-acetate or 17-(3-pyridyl)androst-5,16- diene-3cc-ol^-acetate, or (ii) the hydroxyl group at the 7-position is replaced with a C2-4 ether, optionally -OCH3 (methyl ether) or -OCH2CH3 (ethyl ether) with exemplary species including one or more of 17-(3-pyridyl)androst-5,16- diene^-ol^-methyl ether and 17-(3-pyhdyl)androst-5,16-diene-3cc-ol^- ethyl ether.
[143] 92. The compound of claim 91 wherein the compound is an analog wherein the hydroxyl group at the 3-position is replaced with a C3-4 ester, optionally -0-C(0)CH2CH3 (propionate) with exemplary species including one or more of 17-(3-pyridyl)androst-5,16-diene^-ol^-propionate and 17-(3- pyridyl)androst-5,16-diene^-ol-3cc-propionate.
[144] 93. The compound of embodiment 1 wherein the compound is 17-N- piperidinylandrost-5,16-diene^^-diol, 17-N-piperidinylandrost-5,16-diene- 3α,7β-άϊοΙ, 17-N-pipehdinylandrost-5,16-diene^,7cc-diol, 17-N- piperidinylandrost-5,16-diene-3 ,7 -diol, 17-(2-piperidinyl)androst-5,16-diene- 3p,7p-diol, 17-(2-pipehdinyl)androst-5,16-diene-3cc^-diol, 17-(2- piperidinyl)androst-5,16-diene^,7cc-diol, 17-(2-piperidinyl)androst-5,16- diene-3a,7cc-diol, 17-(3-piperidinyl)androst-5,16-diene-3β,7β-diol, 17-(3- piperidinyl)androst-5,16-diene-3cc^-diol, 17-(3-piperidinyl)androst-5,16- diene-3β,7 -diol or 17-(3-piperidinyl)androst-5,16-diene-3 ,7 -diol.
[145] 94. The compound of embodiment 93 wherein the compound is an analog wherein the hydroxyl group at the 3-position is replaced with a C2-4 ester, optionally -0-C(0)CH3 (acetate) or -0-C(0)CH2CH3 (propionate) with exemplary species including one or more of 17-(3-piperidinyl)androst-5,16- diene^-ol^-acetate, 17-(3-piperidinyl)androst-5,16-diene^-ol-3cc-acetate and 17-(3-piperidinyl)androst-5,16-diene-7cc-ol^-acetate.
[146] 95. The compound of embodiment 93 or 94 wherein the compound is an analog wherein (i) the hydroxyl group at the 7-position is replaced with a C2-4 ester, optionally -0-C(0)CH3 or -0-C(0)CH2CH3 or (ii) the hydroxyl group at the 7-position is replaced with a C2-4 ether, optionally -OCH3 (methyl ether) or -OCH2CH3 (ethyl ether), with exemplary species including one or more of 17-(3-piperidinyl)androst-5,16-diene^-ol^-ethyl ether, 17-(3- piperidinyl)androst-5,16-diene-3cc-ol^-ethyl ether and 17-(3- piperidinyl)androst-5,16-diene^-ol-7cc-ethyl ether.
[147] 96. The compound of embodiment 1 wherein the compound is 17-N- piperidinylandrost-5,16-diene^-ol-3-one, 17-N-piperidinylandrost-5,16- diene-7cc-ol-3-one, 17-(2-piperidinyl)androst-5,16-diene^-ol-3-one, 17-(2- piperidinyl)androst-5,16-diene-7 -ol-3-one, 17-(3-piperidinyl)androst-5,16- diene^-ol-3-one, 17-(3-piperidinyl)androst-5, 16-diene-7cc-ol-3-one, 17-N- pyridinylandrost-5,16-diene^-ol-3-one, 17-N-pyridinylandrost-5,16-diene-7cc- ol-3-one, 17-(2-pyridinyl)androst-5,16-diene^-ol-3-one, 17-(2- pyridinyl)androst-5,16-diene-7 -ol-3-one, 17-(3-pyridinyl)androst-5,16-diene- 7β-οΙ-3-οηβ or 17-(3-pyridinyl)androst-5,16-diene-7 -ol-3-one or an analog of any of these compounds wherein (i) the hydroxyl group at the 7-position is replaced with a C2-4 ester, optionally -0-C(0)CH3 or -0-C(0)CH2CH3 or (ii) the hydroxyl group at the 7-position is replaced with a C2-4 ester, optionally - OCH3 or -OCH2CH3. [148] 97. The compound of claim 88, 89, 90, 91 , 92, 93, 94, 95 or 96 wherein the compound is an analog wherein the hydrogen atom at the 16-position is replaced with C1 -4 optionally substituted alkyl, optionally hydroxyalkyl or haloalkyl, optionally -CH3, -CF3, -C2H5, -CH2CH2CH3, -CH2CH2CH2CH3, - CH2CH2OH, -CH2CH2CH2OH or -CH2CH2CH2F, with exemplary species including one or more of 17-(3-pyridyl)-16-methylandrost-5,16-diene^^- diol, 17-(3-pyridyl)-16-methylandrost-5, 16-diene-3cc^-diol, 17-(3-pyridyl)-16- methylandrost-5,16-diene^,7cc-diol, 17-(3-pyridyl)-16-methylandrost-5,16- diene-3 ,7 -diol, 17-N-pyridyl-16-methylandrost-5,16-diene-3β,7β-diol, 17-N- pyridyl-16-methylandrost-5,16-diene-3 ,7β-diol, 17-N-pyridyl-16- methylandrost-5,16-diene-3β,7 -diol, 17-N-pyridyl-16-methylandrost-5,16- diene-3a,7cc-diol, 17-(3-pyridyl)-16-methylandrost-5,16-diene-7β-ol-3-one, 17- (3-pyridyl)-16-methylandrost-5,16-diene-7 -ol-3-one, 17-N-pyridyl-16- methylandrost-5,16-diene^-ol-3-one and 17-N-pyridyl-16-methylandrost- 5,16-diene-7cc-ol-3-one.
[149] 98. The compound of embodiment 1 wherein the compound is 17-N- pyrimidinyl^-methylandrost-5,16-diene^-ol, 17-N-pyrimidinyl-7p- methylandrost-5,16-diene-3 -ol, 17-N-pyrimidinyl-7 -methylandrost-5,16- diene-3β-ol, 17-(2-pyrimidinyl)^-methylandrost-5,16-diene^-ol, 17-(2- pyrimidinyl)^-methylandrost-5,16-diene-3a-ol, 17-(2-pyrimidinyl)-7 - methylandrost-5,16-diene^-ol, 17-(4-pyrimidinyl)^-methylandrost-5,16- diene-3β-ol, 17-(4-pyrimidinyl)-7β-methylandrost-5,16-diene-3 -ol, 17-(4- pyrimidinyl)-7 -methylandrost-5,16-diene-3β-ol, 7-(5-pyrimidinyl)-7P- methylandrost-5,16^ίβηβ-3β-οΙ, 17-(5-pyrimidinyl)-7β-methylandrost-5,16- diene-3cc-ol, 17-(5-pyrimidinyl)-7 -methylandrost-5,16-diene-3β-ol, or an analog of any of these compounds wherein the hydroxyl at the 3-position is replaced with a C2-6 ester, including acetate, with exemplary species including one or more of 17-N-pyrimidinyl^-methylandrost-5,16-diene^- acetate.
[150] 99. The compound of embodiment 1 wherein the compound is 17-(3- pyridyl)-7a-methylandrost-5,16-diene^-ol, 17-(3-pyridyl)-7 -ethylandrost- 5,16-diene^-ol, 17-(3-pyridyl)-7 -methylandrost-5,16-diene-3 -ol, 17-(3- pyridyl)-7 -ethylandrost-5,16-diene-3 -ol, 17-(3-pyridyl)^-methylandrost- 5,16-diene-3 -ol, 17-(3-pyridyl)-7 -ethylandrost-5,16-diene-3p-ol, 17-(3- pyridyl)-7β-methylandrost-5,16-diene-3 -ol, 17-(3-pyridyl)^-ethylandrost- 5,16-diene-3 -ol, or an analog of any of these compounds wherein the hydroxyl at the 3-position is replaced with a C2-6 ester, including acetate, with exemplary species including one or more of 17-(3-pyridyl)-7a-methylandrost- 5,16-diene^-acetate and 17-(3-pyridyl)-7 -ethylandrost-5, 16-diene^- acetate.
[151] 100. The compound of embodiment 1 wherein the compound is 17-N- pyridyl^-methylandrost-5, 16-άϊΘηβ-3β-οΙ, 17-N-pyridyl^-ethylandrost-5, 16- άϊΘΠΘ-3β-οΙ, 17-N-pyridyl-7 -methylandrost-5, 16-άϊΘΠΘ-3β-οΙ, 17-N-pyridyl-7cc- ethylandrost-5,16-diene^-ol, 17-N-pyridyl^-methylandrost-5,16-diene-3a- ol, 17-N-pyridyl^-ethylandrost-5,16-diene-3a-ol, 17-N-pyridyl-7 - methylandrost-5,16-diene-3 -ol, 17-N-pyridyl-7 -ethylandrost-5,16-diene-3 - ol, or an analog of any of these compounds wherein the hydroxyl at the 3- position is replaced with a C2-6 ester, including acetate, with exemplary species including one or more of 17-N-pyridyl^-methylandrost-5,16-diene-
Figure imgf000058_0001
[152] 101 . The compound of embodiment 1 wherein the compound is 17-(N- imidazolyl)^-methylandrost-5,16-diene^-ol, 17-(N-imidazolyl)-7a- methylandrost-5,16-diene-3a-ol, 17-(N-imidazolyl)^-ethylandrost-5,16- άϊΘηβ-3β-οΙ, 17-(N-imidazolyl)-7cc-ethylandrost-5,16-diene-3cc-ol, 17-(N- imidazolyl)-7β-(2-hydroxyethy)landrost-5,16-diene-3β-ol, 17-(N-imidazolyl)-7 - (2-hydroxyethyl)androst-5,16-diene-3 -ol, or an analog of any of these compound wherein the hydroxyl at the 3-position is replaced with a C2-4 ester, including acetate, with exemplary species including one or more of 17- (N-imidazolyl)^-methylandrost-5,16-diene^-acetate or 17-(N-imidazolyl)- 7cc-(2-hydroxyethy)landrost-5,16-diene^-ol.
[153] 102. The compound of embodiment 1 wherein the compound is 17-(3- pyridyl)^-methylandrost-5,16-diene-3-one, 17-(3-pyridyl)^-ethylandrost- 5,16-diene-3-one, 17-(3-pyridyl)-7 -methylandrost-5,16-diene-3-one, 17-(3- pyridyl)-7 -ethylandrost-5,16-diene-3-one, 7-(3-pyridyl)-7p-(2- hydroxyethyl)androst-5,16-diene-3-one, 17-(3-pyridyl)-7cc-(2- hydroxyethyl)androst-5,16-diene-3-one, 17-(3-pyridyl)^-(/7-propyl)androst- 5,16-diene-3-one or 17-(3-pyridyl)-7 -(n-propyl)androst-5, 16-diene-3-one.
[154] 103. The compound of embodiment 1 wherein the compound is 17-N- pyrimidinyl^-methylandrost-5,16-diene-3-one, 17-N-pyrimidinyl-7 - methylandrost-5,16-diene-3-one, 17-N-pyrimidinyl^-ethylandrost-5,16- diene-3-one, 17-N-pyrimidinyl-7 -ethylandrost-5,16-diene-3-one, 17-N- pyrimidinyl^-(2-hydroxyethyl)androst-5,16-diene-3-one or 17-N-pyrimidinyl- 7 -(2-hydroxyethyl)androst-5,16-diene-3-one.
[155] 104. The compound of embodiment 1 wherein the compound is 17-(2- pyrimidinyl)^-methylandrost-5,16-diene-3-one, 17-(2-pyrimidinyl)-7a- methylandrost-5,16-diene-3-one, 17-(2-pyrimidinyl)^-ethylandrost-5,16- diene-3-one, 17-(2-pyrimidinyl)-7 -ethylandrost-5,16-diene-3-one, 17-(2- pyrimidinyl)^-(2-hydroxyethyl)androst-5,16-diene-3-one or 17-(2- pyrimidinyl)-7 -(2-hydroxyethyl)androst-5,16-diene-3-one.
[156] 105. The compound of embodiment 1 wherein the compound is 17-(4- pyrimidinyl)^-methylandrost-5,16-diene-3-one, 17-(4-pyrimidinyl)-7 - methylandrost-5,16-diene-3-one, 17-(4-pyrimidinyl)-7β-ethylandrost-5,16- diene-3-one, 17-(4-pyrimidinyl)-7 -ethylandrost-5,16-diene-3-one, 17-(4- pyrimidinyl)-7β-(2-hydroxyethyl)androst-5,16-diene-3-one or 17-(4- pyrimidinyl)-7 -(2-hydroxyethyl)androst-5,16-diene-3-one.
[157] 106. The compound of embodiment 1 wherein the compound is 17-(N- piperidinyl)^-methylandrost-5,16-diene-3-one, 17-(N-piperidinyl)-7 - methylandrost-5,16-diene-3-one, 17-(N-piperidinyl)-7β-ethylandrost-5,16- diene-3-one, 17-(N-piperidinyl)-7 -ethylandrost-5,16-diene-3-one, 17-(N- piperidinyl)-7β-(2-hydroxyethyl)androst-5,16-diene-3-one or 17-(N-piperidinyl)- 7 -(2-hydroxyethyl)androst-5,16-diene-3-one.
[158] 107. The compound of embodiment 1 wherein the compound is 17-(3- piperidinyl)^-methylandrost-5,16-diene-3-one, 17-(3-piperidinyl)-7cc- methylandrost-5,16-diene-3-one, 17-(3-piperidinyl)^-ethylandrost-5,16- diene-3-one, 17-(3-piperidinyl)-7 -ethylandrost-5, 16-diene-3-one, 17-(3- piperidinyl)^-(2-hydroxyethyl)androst-5,16-diene-3-one or 17-(3-piperidinyl)- 7 -(2-hydroxyethyl)androst-5,16-diene-3-one.
[159] 108. The compound of embodiment 1 wherein the compound is 17-(N- piperidinyl)-7β-methylandrost-5,16-diene-3β-ol, 17-(N-piperidinyl)-7 - methylandrost-5,16-diene-3 -ol, 17-(2-piperidinyl)^-methylandrost-5,16- diene-3β-ol, 17-(2-piperidinyl)^-methylandrost-5,16-diene-3 -ol, 17-(3- piperidinyl)^-methylandrost-5,16-diene^-ol, 17-(3-piperidinyl)-7 - methylandrost-5,16-diene-3 -ol, 17-(4-piperidinyl)^-methylandrost-5,16- άϊΘηβ-3β-οΙ, 17-(4-piperidinyl)-7β-methylandrost-5,16-diene-3 -ol, or an analog of any of these compounds wherein the hydroxyl group at the 3- position is replaced with a C2-4 ester, optionally -0-C(0)CH3 or -O- C(0)CH2CH3, with exemplary species including one or more of 17-(3- piperidinyl)^-methylandrost-5,16-diene^-acetate, 17-(3-piperidinyl)-7 - methylandrost-5,16-diene-3 -acetate and 17-(3-piperidinyl)^-methylandrost- 5,16-diene^-acetate.
[160] 109. The compound of embodiment 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 , 102, 103, 104, 105, 106, 107 or 108 wherein the compound is an analog wherein the hydrogen atom at the 16-position is replaced with -OH, a C2-8 ester or a C1 -8 ether with exemplary species including one or more of 17-N-pyrimidinyl^-methylandrost-5,16-diene^,16- diol, 17-N-pyrimidinyl^-methylandrost-5,16-diene-3a,16-diol, 17-N- pyrimidinyl^-methylandrost-5, 16-diene^-ol-16-methyl ether, 17-N- pyrimidinyl^-methylandrost-5,16-diene^-ol-16-acetate, 17-(3-pyridyl)-7cc- methylandrost-5,16-diene^,16-diol, 17-(3-pyridyl)-7 -methylandrost-5,16- diene^-ol-16-methyl ether, 17-(3-pyridyl)-7a-methylandrost-5,16-diene^- ol-16-acetate, 17-N-pyridyl^-ethylandrost-5,16-diene^-ol-16-methyl ether, 17-N-pyridyl-7|3-ethylandrost-5, 16-αΊΘηΘ-3β-οΙ-16-ethyl ether, 17-(N- imidazolyl)-7β-methylandrost-5, 16-diene-3β-ol-16-methyl ether, 17-(N- imidazolyl)-7 -(2-hydroxyethy)landrost-5,16-diene-3β-ol-16-methyl ether, 17- (3-pyridyl)^-methylandrost-5,16-diene-3-one-16-methyl ether, 17-(3-pyridyl)- 7β-ethylandrost-5,16-diene-3-one-16-methyl ether, 17-N-pyrimidinyl^- methylandrost-5,16-diene-3-one-16-ethyl ether, 17-N-pyrimidinyl^- ethylandrost-5,16-diene-3-one-16-acetate, 17-(2-pyrimidinyl)^- methylandrost-5,16-diene-3-one-16-methyl ether, 17-(2-pyrimidinyl)^- ethylandrost-5,16-diene-3-one-16-methyl ether, 17-(4-pyrimidinyl)-7p- methylandrost-5,16-diene-3-one-16-methyl ether, 17-(4-pyrimidinyl)-7 - ethylandrost-5,16-diene-3-one-16-methyl ether, 17-(N-piperidinyl)-7 - ethylandrost-5,16-diene-3-one-16-methyl ether, 17-(N-piperidinyl)-7 - ethylandrost-5,16-diene-3-one-16-methyl ether, 17-(3-piperidinyl)-7 - ethylandrost-5,16-diene-3-one-16-methyl ether, 17-(3-piperidinyl)-7 - ethylandrost-5,16-diene-3-one-16-methyl ether, 17-(3-piperidinyl)-7 - methylandrost-5,16-diene^-ol-16-methyl ether and 17-(3-piperidinyl)-7 - methylandrost-5,16-diene-3 -ol-16-methyl ether.
[161] 1 10. Use of a compound or composition containing a compound of any preceding embodiment, including a compound or genus described or defined in any of embodiments 1 -109, or a compound described in the claims for the preparation of a medicament. These compositions are used to make formulations comprising the compound and one or more excipients. Such formulations are preferably for oral or parenteral administration.
[162] 1 1 1 . Use of a compound or composition containing a compound of any of embodiments 1 -109 or a compound described in the claims for the preparation of a medicament for the treatment or prophylaxis of cancer. These compositions are used to make formulations comprising the compound and one or more excipients. Such formulations are preferably for oral or parenteral administration.
[163] 1 12. Use of a compound or composition containing a compound of any of embodiments 1 -109 or a compound described in the claims for the preparation of a medicament for the treatment or prophylaxis of a
neuroendocrine disorder or tumor, optionally prostate cancer. Use of a compound or composition containing a compound of any of embodiments 1 - 109 or a compound described in the claims for the preparation of a
medicament for the treatment or prophylaxis of breast cancer. Use of a compound or composition containing a compound of any of embodiments 1 - 109 or a compound described in the claims for the preparation of a medicament for the treatment or prophylaxis of lung cancer, a precancer of the breast, uterine fibroids, ovarian cancer, uterine cancer or endometriosis.
[164] 1 13. A formulation comprising one or more excipients and a compound of any of embodiments 1 -109, or a compound described in the claims. In some of these embodiments, the formulation is for oral administration, including unit dosages exemplified by tablets, gelcaps or capsules, which may optionally contain amounts of structure 1 compounds that are described elsewhere herein, about 20 mg per unit dose to about 1000 mg per unit dose, including about 50 mg, about 100 mg or about 250 mg. In other embodiments, the formulation is for parenteral administration, including a sterile solution or suspension as described elsewhere herein.
[165] 1 14. Compounds, compositions, formulations and uses as described in any of embodiments 1 -1 13, e.g., embodiment 52, 53, 54, 55, 93, 94, 95 or 96, wherein the double bond at the 5-position is absent and the compound has a hydrogen atom at the 5-position in the a-configuration. Exemplary compounds include 17-(3-pyridyl)^-methylandrost-16-ene-3-one, 17-(3-pyridyl)-7p- ethylandrost-16-ene-3-one, 17-(3-pyridyl)-7a-methylandrost-16-ene-3-one, 17-(3-pyridyl)-7a-ethylandrost-16-ene-3-one, 17-(3-pyridyl)-7p-(2- hydroxyethyl)androst-16-ene-3-one, 17-(3-pyridyl)-7cc-(2- hydroxyethyl)androst-16-ene-3-one, 17-(3-pyridyl)^-(/7-propyl)androst-16- ene-3-one, 17-(3-pyridyl)-7a-(n-propyl)androst-16-ene-3-one, 17-N- pyrimidinyl^-methylandrost-16-ene-3-one, 17-N-pyrimidinyl-7a- methylandrost-16-ene-3-one, 17-N-pyrimidinyl^-ethylandrost-16-ene-3-one, 17-N-pyrimidinyl-7a-ethylandrost-16-ene-3-one, 17-N-pyrimidinyl^-(2- hydroxyethyl)androst-16-ene-3-one, 17-N-pyrimidinyl-7a-(2- hydroxyethyl)androst-16-ene-3-one, 17-(2-pyrimidinyl)^-methylandrost-16- ene-3-one, 17-(2-pyrimidinyl)-7a-methylandrost-16-ene-3-one, 17-(2- pyrimidinyl)^-ethylandrost-16-ene-3-one, 17-(2-pyrimidinyl)-7a-ethylandrost- 16-ene-3-one, 17-(2-pyrimidinyl)^-(2-hydroxyethyl)androst-16-ene-3-one, 17-(2-pyrimidinyl)-7a-(2-hydroxyethyl)androst-16-ene-3-one, 17-(4- pyrimidinyl)^-methylandrost-16-ene-3-one, 17-(4-pyrimidinyl)-7a- methylandrost-16-ene-3-one, 17-(4-pyrimidinyl)-7β-ethylandrost-16-ene-3- one, 17-(4-pyrimidinyl)-7 -ethylandrost-16-ene-3-one, 17-(4-pyrimidinyl)^- (2-hydroxyethyl)androst-16-ene-3-one, 17-(4-pyrimidinyl)-7a-(2- hydroxyethyl)androst-16-ene-3-one, 17-(N-piperidinyl)^-methylandrost-16- ene-3-one, 17-(N-pipehdinyl)-7 -methylandrost-16-ene-3-one, 17-(N- piperidinyl)^-ethylandrost-16-ene-3-one, 17-(N-piperidinyl)-7cc-ethylandrost-
16- ene-3-one, 17-(N-pipehdinyl)-7β-(2-hydroxyethyl)androst-16-ene-3-one,
17- (N-pipehdinyl)-7 -(2-hydroxyethyl)androst-16-ene-3-one, 17-(3- pipehdinyl)-7β-methylandrost-16-ene-3-one, 17-(3-piperidinyl)-7cc- methylandrost-16-ene-3-one, 17-(3-piperidinyl)^-ethylandrost-16-ene-3-one, 17-(3-pipehdinyl)-7 -ethylandrost-16-ene-3-one, 17-(3-piperidinyl)-7p-(2- hydroxyethyl)androst-16-ene-3-one, 17-(3-piperidinyl)-7cc-(2- hydroxyethyl)androst-16-ene-3-one, 17-(N-pipehdinyl)-7β-methylandrost-16-
Figure imgf000063_0001
pipehdinyl)^-methylandiOst-16-Θηβ-3β-οΙ, 17-(2-pipeπdinyl)-7β- methylandrost-16-ene-3cc-ol, 17-(3-piperidinyl)-7β-methylandrost-16-βηβ-3β- ol, 17-(3-piperidinyl)-7β-methylandrost-16-ene-3 -ol, 17-(4-piperidinyl)-7p- methylandrost-16-Θηβ-3β-οΙ, 17-(4-pipe dinyl)-7β-methylandrost-16-ene-3 - ol, or an analog of any of these compounds wherein (i) the keto group at the 3-position is replaced with -OH in the a- or β-configuration, preferably the β- configuration or (ii) the hydroxyl group at the 3-position is replaced with a C2- 4 ester, optionally -0-C(0)CH3 or -0-C(0)CH2CH3, with exemplary species including one or more of 17-(3-piperidinyl)^-methylandrost-16-ene^- acetate, 17-(3-pipehdinyl)^-methylandrost-16-ene-3cc-acetate and 17-(3- piperidinyl)^-methylandrost-16-ene^-acetate.
[166] Synthesis methods. Methods A, B and C shown below can be used to prepare 17-C-heterocyclic-5,16-diene steroids and their salts. Related synthesis methods have been described, e.g., synthesis methods in US 2006- 21776, US 2008-51380, US 5,994,335, US 5,965,548, US 5,914,325, US 5,677,293, US 5,604,213, US 5,424,304, EP 1336602, EP 721461 , EP 551952, WO 09120565 and WO 0693993, which are incorporated by reference herein. [167] For compound in methods A, B and C, R1 is -ORPR, protected hydroxyl, e.g., an ester, including -0-C(0)CH3, -0-C(0)CH2CH3 or -O- C(0)CH2CH2CH3, or an ether, including methyl ether or ethyl ether, R2 is - ORPR, protected hydroxyl, e.g., an ester, including acetate (-0-C(0)CH3) or propionate (-0-C(0)CH2CH3),or an ether, including methyl ether or ethyl ether, or optionally substituted C1 -8 alkyl, including -CH3, -C2H5, - CH2CH2CH3, -CH2CH2CH2CH3, -CH2ORPR, -CH2CH2ORPR, -CH2CH2CH2ORPR or -CH2CH2CH2CH2ORPR, R5 is -CH3, -C2H5 or -CH2ORPR and R6 is -H, -CH3, - C2H5 or -CH2ORPR, where RPR is as described for R1 and R2.
Meth - carbonyl addition and dehydration
Figure imgf000064_0001
Method B - palladium cross coupling
5 4
Figure imgf000064_0002
Ars^ / R 15
Sn
R'5/
[168] For method B, R14 are both -OH or they independently are -CH3 or - C2H5. R15 independently are C1 -4 saturated alkyl, including methyl or ethyl, with /7-butyl preferred.
[169] Method C - triflate displacement
Figure imgf000064_0003
Ar - M - X deprotection
6 ► 3 4
[170] In methods A, B and C, when R1 and R2 are protected hydroxyl, e.g., an ester, including acetate, or an ether including methyl ether, ethyl ether or n-propyl ether, deprotection leaves the free hydroxyl shown as 4. When R2 is alkyl, e.g., C1 -6 alkyl, including methyl, ethyl, n-propyl or n-butyl, then the deprotection step results in an analog of 4 where R2 is the alkyl group instead of -OH, i.e., 7.
Figure imgf000065_0001
[171] Structure 4 compounds thus include 17-(3-pyridyl)-androst-5,16-diene- 3β, 7 -diol and 17-(3-pyridyl)-androst-5,16-diene-3cc, 7p-diol. Structure 7 compounds include 17-(3-pyridyl)^-(/7-butyl)androst-5,16-diene^-ol, 17-(3- pyridyl)^-(/7-butyl)androst-5,16-diene-3cc-ol, 17-(3-pyridyl)-7cc-(/7- butyl)androst-5,16-diene-3β-ol, 17-(3-pyrimidinyl)^-(/7-butyl)androst-5,16- diene-3 -ol, 17-(3-pyrimidinyl)-7a-(/7-butyl)androst-5,16-diene^-ol and 17- (3-pyrimidinyl)^-(/7-butyl)androst-5,16-diene^-ol.
[172] As is apparent from the foregoing synthesis methods, when R1 and R2 are both in the β-configuration, compound 1 is obtained by protecting the hydroxyls at the 3- and 7-positions of precursor 7-oxodehydroepiandrosterone (androst-5-ene^, 7β-άϊοΙ-17-οηΘ), a known compound (P. Wuts et al, Organic Letters, 5:1483 - 1486, 2003). Similarly, when R1 is in the cc- configuration and R2 is in the β-configuration, compound 1 is obtained by protecting the hydroxyls at the 3- and 7-positions of precursor androst-5-ene- 3a,
Figure imgf000065_0002
which is also a known compound.
[173] O-linked and C-linked substituents at position-16 are introduced by one of the following methods. Method A- Nucleo hillic Epoxide Opening at C-16
Figure imgf000066_0001
RB is -OR or -R
Figure imgf000066_0002
[174] Method A and B are most suitable when Ar is substituted to provide an electron donating heterocycle in the epoxidation step. When Ar is an electron withdrawing heterocycle, protection of the A5-ene functional group may be used to optimize yields, e.g., by conversion to a C5,C6-dibromo derivative.
[175] Other variations and modifications of the embodiments, claims and the remaining portions of this disclosure will be apparent to the skilled artisan after a reading thereof, e.g., portions on one disclosed embodiment or method can be combined with some or all of other embodiments, methods or portions of methods that are compatible therewith. Such variations and modifications are within the scope of this invention. All citations herein are incorporated herein by reference in their entirety. All citations herein are incorporated herein by reference with specificity. These citations are optionally appended to this paragraph or at new paragraphs following this paragraph.
[176] Examples. The following examples further illustrate the invention and they are not intended to limit it in any way. Variations and embodiments of these examples that are included in the invention include, e.g., variations of any of the examples described below as incorporated into the claims.
[177] Example 1. Duterated cholesterol (D6 cholesterol) and the adrenal cell line H295R were incubated with or without the test compound, 17a- ethynylandrostane-3a,'^-diol, to observe the test compound's effects on de novo steroidogenesis in the cells. One or more of eight different cholesterol metabolites from the two metabolic pathways shown below were measured. The duterated cholesterol was labeled at positions 2, 2, 3, 4, 4 and 6.
Pathway 1
D6-cholesterol→ D6-pregnenolone→ D4-progesterone→ D4-cortisol Pathway 2
D6-cholesterol→ D6 DHEA→ D6 5-androstenediol and D4 androstenedione → D4 testosterone→ D4 dihydrotestosterone
[178] The H295R cells were obtained from ATCC and grown in T75 flasks in DMEM supplemented with insulin, transferrin, selenium, and 10% FBS. The cells were grown in charcoal-stripped medium for 48 hrs prior to the experiment. Each experiment was initiated by the addition of 10 μΜ D6- cholesterol. After 48 hrs, the medium was removed, the cells were scraped in 5 ml methanol and the alcoholic cell suspension was lysed by sonication. The methanol lysate was dried under nitrogen and the cell contents were resuspended in 1 mL PBS. The suspension was extracted with 10 mL MTBE (methyl-i-butyl ether), which was evaporated under nitrogen. The dried extract was derivatized with nicotinyl chloride and analyzed by LCMS/MS. The cells were incubated with 300 ng/mL 17 -ethynylandrostane-3 ,17β-diol. The concentration of 17 -ethynylandrostane-3 ,17β-diol was monitored and adjusted to 300 ng/mL at 8 hour intervals to maintain this concentration over time.
[179] Similar protocols can be used with radiolabeled cholesterol, e.g., cholesterol labeled with 3H or 14C.
[180] Example 2. Effects of the test compound 17cc-ethynylandrostane- 3α,17β^ίοΙ on steroidogenesis in dogs in vivo. Samples were collected from male dogs (5/group) treated with 0, 20, 60 or 200 mg/kg of 17a- ethynylandrostane-3 ,17β-diol before dosing on days 1 , 14, and 28. The animals were dosed daily for 28 days. The samples were analyzed for testosterone (T), androstendione (A4), and dehydroepiandrosterone (DHEA). Day 1 and day 28 vehicle and 60 mg/kg samples were assayed for luteinizing hormone. The compound was administered by oral administration of a 20 mg/mL 17a-ethynylandrostane-3cc,'^-diol solution made of 40% 2- hydroxypropyl^-cyclodextrin in water.
[181] Plasma samples were processed by Iiquid/liquid extraction using MTBE. The organic portions containing the analytes were evaporated and dried extracts were incubated at 60°C with a dansyl chloride solution. The resulting steroid derivatives were analyzed on a Waters Xbridge Phenyl column by reversed-phase high-performance liquid chromatography (Agilent, Palo Alto, CA and Leap Technologies, Carrboro, NC) coupled with a tandem quadrupole mass spectrometer (Waters, Beverly, MA). Calibration curves for standards and QC samples for HE3318 (Estradiol, E2) and Estrone (E1 ) were analyzed in parallel with the samples. Sample responses were acquired and concentrations were determined based on the calibration using Masslynx analysis software (Waters, Beverly, MA). Determination of QC statistics was performed by subtracting the endogenous concentration determined in native plasma from the total concentration found in the QC sample. No PK calculations were performed on this study. The quantifiable range of detection for E2 was 5.0 to 200.0 pg/mL. The quantifiable range of detection for E1 was 10.0 to 200.0 pg/mL. Values below the detection limit were identified as such and reported.
[182] T, A4 and DHEA assay. Plasma samples were processed by
Iiquid/liquid extraction using MTBE (methyl-i-butyl ether). The organic portions containing the free steroids were evaporated and the dried extracts were incubated at 60°C with a hydroxylamine hydrochloride solution. The resulting steroid-oxime derivatives were extracted with MTBE. The organic portions containing the steroid-oxime derivatives were evaporated to dryness, reconstituted in 80/20 water/acetonitrile, and analyzed on a Waters Xbridge Phenyl column by reversed-phase high-performance liquid chromatography (Agilent, Palo Alto, CA and Leap Technologies, Carrboro, NC) coupled with a tandem quadrupole mass spectrometer (Waters, Beverly, MA). Calibration curves prepared in water and QC samples prepared in native plasma for T (4- androstene-3-one-17β-ol), A4 (4-androstene-3,17-dione), and DHEA were analyzed in parallel with the samples. Sample responses were acquired and concentrations were determined based on the calibration curve using
Masslynx analysis software (Waters, Beverly, MA). Determination of QC statistics was performed by subtracting the endogenous concentration determined in native plasma from the total concentration found in the QC sample.
[183] The quantifiable range of detection for T was 10.0 to 20000.0 pg/mL in rat (example 3) and dog (this example) samples. The quantifiable range of detection for A4 was 10.0 to 20000.0 pg/mL in rats and 20.0 to 20000.0 pg/mL in dogs. The quantifiable range of detection for DHEA was 50.0 to 200.0 pg/mL in both species. Values below the detection limit were identified as such.
[184] Peptide Hormone Assays. EL ISA kits for the quantification of ACTH, LH, and FSH in rat plasma were obtained from USCN Life, Wuhan, China. All other reagents were obtained from Sigma Chemical Co, St. Louis, MO. ELISA results were measured on an ELx800 plate reader (Bio-Tek, Winooski, VT). Samples were assayed for ACTH, LH, and FSH concentration by means of an ELISA assay kit according to the manufacturer's instructions. For the rat samples, although 100 μΐ of undiluted plasma were required for each assay, 300 μΐ (ACTH), 100 μΐ (LH), or 30 μΐ (FSH) were used in order to obtain results in the quantifiable range of the assay. Samples from Day 14 were assayed in duplicate; samples from Day 0 and Day 7 were assayed singly due to the small sample volume available. Concentrations were calculated from an eight-point standard curve. Thirty-five μΐ of dog plasma was used for the LH assay.
[185] By the end of 28 days of dosing, analysis of T and A4 in dogs indicated that levels of these hormones were decreased by about 99% compared to vehicle control treated animals. Levels of DHEA decreased by about 90% in the treated animals. Significant toxicity was not observed in the animals. The results that were obtained for testosterone are shown below.
Figure imgf000069_0001
14 559.7 2768.5 2345.5 210.0 3123.8
28 2323.5 1250.8 1228.7 309.7 41 16.9
A1 1 1 M A1 12M A1 13M A1 14M A1 15M
20 1 1747.2 1677.0 668.6 771 .4 2450.6
14 67.8 51 .1 344.9 90.1 94.4
28 19.3 60.8 143.8 173.0 BQL
A121 M A122M A123M A124M A125M
60 1 46.9 71 1 .2 723.8 1371 .3 1659.6
14 173.7 38.5 1 10.4 144.1 338.0
28 18.9 BQL BQL BQL BQL
A131 M A132M A133M A134M A135M
200 1 503.3 350.3 NS 1816.6 1891 .0
14 BQL BQL 1 19.5 236.6 18.1
28 BQL NS BQL 1 1 .2 10.2
Lower Limit of Detection is 10.0 pg/mL
BQL: Below the limit of quantitation
NS - No sample
[186] Example 3. The compound 17a-ethynylandrostane-3cc,^-diol (100 mg/kg) was administered to rats (n = 5) daily for 14 days. The compound was a 20 mg/mL solution made of 30% 2-hydroxypropyl^-cyclodextrin in water. Vehicle lacking the compound was administered to control animals (n = 5). By day 7 in the dosing period, systemic (serum) levels of testosterone, estradiol, estrone and DHEA had fallen by over 99% to essentially undetectable levels in the treated animals. Changes in LH, FSH and ACTH were not observed.
[187] To the extent not already indicated, it will be understood by those of ordinary skill in the art that any of the various specific embodiments, analysis methods, compounds or compositions described herein may be modified to incorporate other appropriate features, e.g., as shown in any other of the specific embodiments disclosed herein.
[188] Other enumerated embodiments 1A-61 A are as described below.
[189] 1A. A method to identify a compound comprising (a) administering a test compound to a mammal(s) for a sufficient period of time to obtain treated mammal(s); (b) measuring systemic levels of one or more cholesterol metabolites in the treated mammal(s); and (c) selecting the compound of step (b) that decreases the systemic levels of one or more cholesterol metabolites in the treated mammal(s), whereby a compound having a potential to treat a cancer, optionally a neuroendocrine disorder or tumor is identified, wherein the test compound of step (a) has the structure
Figure imgf000071_0001
R1 is -OH, -SH, =0, an optionally substituted ester (including -0-C(0)-optionally substituted C1 -7 alkyl or -O- C(0)-optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate) or an optionally substituted ether (-O-optionally substituted 01 -8 alkyl or -O- optionally substituted aryl , optionally a 01 -6 ether, including -OCH3, -OC2H5, - OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2); R2 is -OH, - SH, =0, an optionally substituted ester (including -0-C(0)-optionally substituted C1 -7 alkyl or -0-C(0)-optionally substituted aryl, including -O- C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate) an optionally substituted ether (-O-optionally substituted C1 -8 alkyl or -O-optionally substituted aryl, including -O-optionally substituted phenyl, optionally a 01 -6 ether, including methoxy or ethoxy) or an optionally substituted 01 -8 alkyl (including -CH3, -CF3, -C2H5, -CH2CH2OH, - CH2CH2CH3, -CH2CH2CH2OH or -OCH(CH3)2) or R2 may also be -H when (i) R3 is not -H, (ii) R5 is -C2H5 or -CH2OH and/or (iii) R6 is -H, -C2H5 or -CH2OH; R3 is -H, -OH, C1 -8 optionally substituted alkyl (optionally methyl, ethyl, n- propyl, /'-propyl or 3-hydroxy-n-propyl), an optionally substituted ester (-0- C(0)-optionally substituted C1 -7 alkyl or -0-C(0)-optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester such as acetate or propionate, or benzoate), an optionally substituted ether (-0- optionally substituted C1 -8 alkyl or -O-optionally substituted aryl, including or - O-optionally substituted phenyl, optionally a 01 -6 ether, including -OCH3, - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2) or optionally substituted C1 -8 alkyl (including -CH3, -CF3, -C2H5, -CH2CH2OH, - CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2); is -NH2, -NHCH3, -N(CH3)2, - NH-C(0)CH3, -NHOH, an N-linked amino acid, C1 -8 alkyl, optionally methyl, ethyl, /7-propyl or /'-propyl, a C-linked ring or an N-linked ring; R5 is -CH3, -C2H5 or -CH2OH; and R6 is -H, -CH3, -C2H5 or -CH2OH.
[190] 2A. The method of embodiment 1 A wherein the test compound of step
(a) has the structure
Figure imgf000072_0001
[191] 3A. The method of embodiment 1 A wherein the test compound of step
(a) has the structure
Figure imgf000072_0002
[192] 4A. The method of embodiment 1 A wherein the test compound of step
(a) has the structure
Figure imgf000072_0003
[193] 5A. The method of embodiment 1 A wherein the test compound of step
(a) has the structure
Figure imgf000072_0004
[194] 6A. The method of embodiment 1 A, 2A, 3A, 4A or 5A wherein R4 is a C-linked ring or an N-linked ring.
[195] 7A. The method of embodiment 6A wherein R4 is (1 ) -N-pyridine (N- linked) or -N-pyrimidinyl (N-linked), (2) -1 -pyridyl (C-linked), -2-pyridyl, -3- pyridyl, -1 -pyrimidinly (C-linked), -4-pyrimidinly or -5-pyrimidinly, (3) -N- piperidinyl, -1 -piperidinyl, -2-piperidinyl, -3-piperidinyl, or (4) -N-imidazole, -2- imidazole or -4-imidazole.
[196] 8A. The method of embodiment 1 A, 2A, 3A, 4A, 5A, 6A or 7A wherein R1 is =0, -OH, -OC(0)CH3, -OC(0)CH2CH3, -OCH3 or -OC2H5.
[197] 9A. The method of embodiment 1 A, 2A, 3A, 4A, 5A, 6A, 7A or 8A wherein R2 is =0, -OH, -OC(0)CH3, -OC(0)CH2CH3, -OCH3 or -OC2H5.
[198] 10A. The method of embodiment 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A or 9A wherein R3 is methyl, ethyl, n-propyl, /'-propyl, n-butyl, sec-butyl, /'-butyl or t- butyl.
[199] 1 1 A. The method of embodiment 1 A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A or 10A wherein the cholesterol metabolites are one or more of testosterone, dihydrotestosterone, 4-androstenedione, 5-androstenediol, estradiol, estrone, dehydroepiandrosterone, pregnenolone, progesterone and Cortisol, (A) optionally wherein the cholesterol metabolites are one, two or more of (i) testosterone, dihydrotestosterone, 4-androstenedione, 5-androstenediol, 5a- androstane-3cc-^-diol or 5cc-androstane^-^-diol (ii) estradiol, estrone and 4-androstenedione or (iii) pregnenolone, progesterone and Cortisol, (B) optionally wherein the cholesterol metabolites are (a) one, two or more of testosterone, dihydrotestosterone, 4-androstenedione, 5-androstenediol or (b) one or both of estradiol and estrone.
[200] 12A. The method of embodiment 1 A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A or 1 1 A wherein the sufficient period of time is at least about 5 days, optionally about 5 days to about 8 weeks, optionally daily for about 7 days, about 14 days, about 28 days, about 6 weeks or about 8 weeks, e.g., daily for 5 days, 7 days, 14 days, 28 days, 6 weeks or 8 weeks.
[201] 13A. The method of embodiment 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A or 1 1 A wherein the neuroendocrine disorder or tumor is prostate cancer, breast cancer or small cell lung cancer and the candidate compound is administered to a human(s) having or diagnosed with, the neuroendocrine disorder or tumor.
[202] 14A. The method of embodiment 1 A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A or 1 1 A wherein the neuroendocrine disorder or tumor is a precancer of the breast, uterine fibroids, ovarian cancer, uterine cancer or endometriosis and the candidate compound is administered to a human(s) having the neuroendocrine disorder or tumor.
[203] 15A. The method of embodiment 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A or 1 1 A wherein the neuroendocrine disorder or tumor is an adrenal tumor, benign prostatic hypertrophy or testicular cancer and the candidate compound is administered to a human(s) having the neuroendocrine disorder or tumor.
[204] 16A. The method of embodiment 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1A or 12A wherein the mammal(s) is a canine (dog) or a rodent, optionally a mouse or rat.
[205] 17A. The method of embodiment 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1A or 12A further comprising administering to a control mammal(s) a control compound, optionally, 17a-ethynylandrostane-3cc,'^-diol, 17a- ethynylandrostane^,'^-diol, 17cc-ethynylandrostane-3-one-'^-ol or an aromatase inhibitor and measuring systemic levels of the one or more cholesterol metabolites in the treated mammal(s).
[206] 18A. A method to make a drug product for treating a cancer or neuroendocrine disorder or tumor in a human, wherein the drug product comprises, (a) a drug in a dosage form, optionally wherein the dosage form is a formulation for oral, parenteral or topical administration, preferably oral administration; and (b) packaging for the drug together with a package insert or label that includes information about the drug's efficacy, toxicity or mechanism of action wherein such information was obtained at least in part from a method comprising (i) administering a test compound to a mammal(s) for a sufficient period of time to obtain treated mammal(s); (ii) measuring systemic levels of one or more cholesterol metabolites in the treated mammal(s); (iii) selecting the compound of step (ii) that decreases the systemic levels of one or more cholesterol metabolites in the treated mammal(s); and optionally (iv) administering to a control mammal(s) a control compound, optionally, 17a-ethynylandrostane-3a,^-diol, 17a- ethynylandrostane-3β,17β-diol, 17α-ethynylandrostane-3-one-17β-ol or an aromatase inhibitor and measuring systemic levels of the one or more cholesterol metabolites in the mammal(s) and optionally comparing the effect of the control compound on the treated mammals with the effect of the test compound on the treated mammals, whereby a compound having a potential to treat a neuroendocrine disorder or tumor is identified, wherein the test compound of step (a) has the structure defined in embodiment 1 .
[207] 19A. The drug product of embodiment 18A wherein the mammal(s) is a rodent(s) or canine(s), optionally a mouse or rat.
[208] 20A. The drug product of embodiment 18A or 19A wherein the neuroendocrine disorder or tumor is prostate cancer, breast cancer or small cell lung cancer.
[209] 21 A. The drug product of embodiment 18A or 19A wherein the neuroendocrine disorder or tumor is a precancer of the breast, uterine fibroids, ovarian cancer, uterine cancer or endometriosis.
[210] 22A. The drug product of embodiment 18A or 19A wherein the neuroendocrine disorder or tumor is an adrenal tumor, benign prostatic hypertrophy or testicular cancer.
[211] 23A. A compound having the structure
Figure imgf000075_0001
R1 is -OH, -SH, =0, an optionally substituted ester (including -0-C(0)-optionally substituted C1 -7 alkyl or -O- C(0)-optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate) or an optionally substituted ether (-O-optionally substituted C1 -8 alkyl or -O- optionally substituted C1 -8 aryl, including -O-optionally substituted phenyl, optionally a C1 -6, including-OCH3, -OC2H5, -OCH2CH2CH3, -OCH2CH2OH, - OCH2CH2CH2OH or -OCH(CH3)2); R2 is -OH, -SH, =0, an optionally substituted ester (-O-C(O)-optionally substituted 01 -7 alkyl or -O-C(O)- optionally substituted aryl, including -0-C(0)-optionally substituted phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate), an optionally substituted ether (-O-optionally substituted 01 -8 alkyl or -O- optionally substituted aryl, including -O-optionally substituted phenyl, optionally a C1 -6 ether, including methoxy or ethoxy), or an optionally substituted C1 -8 alkyl (including -CH3, -CF3, -C2H5, -CH2CH2OH, - CH2CH2CH3, -CH2CH2CH2OH or -OCH(CH3)2) or R2 may also be -H when (i) R3 is not -H, (ii) R5 is -C2H5 or -CH2OH and/or (iii) R6 is -H, -C2H5 or -CH2OH; R3 is -H, -OH, C1 -8 optionally substituted alkyl (optionally methyl, ethyl, n- propyl, /'-propyl or 3-hydroxy-n-propyl), an ester (including -0-C(0)-optionally substituted C1 -7 alkyl or -0-C(0)-optionally substituted aryl, including -O- C(0)-optionally substituted C1 -7 phenyl, optionally a C2-6 ester, including acetate or propionate, or benzoate), an optionally substituted ether (including -O-optionally substituted C1 -8 alkyl or -O-optionally substituted aryl, including -O-optionally substituted phenyl, optionally a C1 -6 ether, including -OCH3, - OC2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2) or an optionally substituted C1 -8 alkyl (including -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2); R4 is an optionally substituted heterocycle or optionally substituted cycle, wherein the heterocycle or cycle is a C-linked ring (bonded to the 17-position through a ring carbon), preferably a 5-membered ring or 6-membered ring; R5 is -CH3, -C2H5 or -CH2OH; and R6 is -H, -CH3, -C2H5 or -CH2OH.
[212] 24A. The compound of embodiment 23A wherein R4 is 2-pyridyl, 3- pyridyl or 4-pyridyl, optionally wherein (i) R1 and R2 are -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[213] 25A. The compound of embodiment 23A wherein R4 is 2-pyrimidinlyl, 4-pyrimidinly or 5-pyrimidinly, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[214] 26A. The compound of embodiment 23A wherein R4 is 2-piperidinyl, 3- piperidinyl or 4-piperidinyl, optionally wherein (i) R1 and R2 are -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[215] 27A. The compound of embodiment 23A wherein R4 is 2-imidazole or 4-imidazole, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -H.
[216] 28A. The compound of embodiment 23A wherein R4 is 2-furanyl or 3- furanyl, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[217] 29A. The compound of embodiment 23A wherein R4 is 2-oxolanyl or 3- oxolanyl, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -H.
[218] 30A. The compound of embodiment 23A wherein R4 is 2-thiophenyl or 3-thiophenyl, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -H.
[219] 31 A. The compound of embodiment 23A wherein R4 is 2-pyrrolyl or 3- pyrrolyl, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -H.
[220] 32A. The compound of embodiment 23A wherein R4 is 2-pyrrolidinyl or 3-pyrrolidinyl, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -H.
[221] 33A. The compound of embodiment 23A wherein R4 is 2-thiazolyl, 4- thiazolyl or 5-thiazolyl, optionally wherein (i) R1 and R2 are -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[222] 34A. The compound of embodiment 23A wherein R4 is 2-oxolanyl (2- tetrahydropyranyl), 3-oxolanyl or 4-oxolanyl, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[223] 35A. The compound of embodiment 23A wherein R4 is 2-(1 ,4-dioxanyl), optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are - CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[224] 36A. The compound of embodiment 23A wherein R4 is 2-morpholinyl or 3-morpholinyl, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -H.
[225] 37A. The compound of embodiment 23A wherein R4 is 2-oxazolyl, 4- oxazolyl or 5-oxazolyl, optionally wherein (i) R1 and R2 are -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[226] 38A. The compound of embodiment 23A wherein R4 is 2-imidazolyl, 4- imidazolyl or 5-imidazolyl, optionally wherein (i) R1 and R2 are -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[227] 39A. The compound of embodiment 23A wherein R4 is 2-piperidinyl, 3- piperidinyl or 4-piperidinyl, optionally wherein (i) R1 and R2 are -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[228] 40A. The compound of embodiment 23A wherein R4 is 2-piperazinyl, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are - CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[229] 41 A. The compound of embodiment 23A wherein R4 is 2-pyridinyl, 3- pyridinyl or 4-pyridinyl, optionally wherein (i) R1 and R2 are -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[230] 42A. The compound of embodiment 23A wherein R4 is 2-pyrazinyl, optionally wherein (i) R1 and R2 are -OH in the β-configuration, R5 and R6 are - CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[231] 43A. The compound of embodiment 23A wherein R4 is 2-pyrimidinyl, 4- pyrimidinyl or 5-pyrimidinyl, optionally wherein (i) R1 and R2 are -OH in the β- configuration, R5 and R6 are -CH3 and R3 is -CH3 or (ii) R1 is =0, R2 is -OH in the β-configuration, R5 and R6 are -CH3 and R3 is -H.
[232] 44A. The compound of embodiment 23A, 24A, 25A, 26A, 27A, 28A, or
Figure imgf000079_0001
is -H, (b) R1 is =0, R2 is -OH and R3 is -H, (c) R1 and R2 are -OH and R3 is - CH3, (d) R1 is =0, R2 is -OH and R3 is -CH3, or (e) R1 is -OH, R2 is -H and R3 is C1 -4 optionally substituted alkyl , including -CH3, -C2H5 or -CH2CH2OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R5 is -C2H5, including species 7-(3-pyridinyl)-18-nor-18-ethylandrost-5,16-άϊΘηΘ-3β,7β-άϊοΙ, which
Figure imgf000080_0001
where R4 is 3-pyridinyl, 7-(3-pyridinyl)-18-nor-18- ethylandrost-5,16-diene-3 ,7β-diol or 7-(3-pyridinyl)-18-nor-18-ethylandrost- 5,16-diene-3β,7β-diol-16-acetate.
[234] 46A. The compound of embodiment 23A, 24A, 25A, 26A, 27A, 28A,
39A, 40A, 41 A, 42A or
Figure imgf000080_0002
[235] 47A. The compound of embodiment 23A, 24A, 25A, 26A, 27A, 28A, or
Figure imgf000080_0003
is -H, (b) R1 is =0, R2 is -OH and R3 is -H, (c) R1 and R2 are -OH and R3 is - CH3, (d) R1 is =0, R2 is -OH and R3 is -CH3, or (e) R1 is -OH, R2 is -H and R3 is C1 -4 optionally substituted alkyl, including -C2H5 or -CH2CH2OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R5 is -C2H5, including species 17-(3-pyridinyl)-18-nor-18-ethylandrost-5,16-diene^,7cc-diol, which
is
Figure imgf000081_0001
where R4 is 3-pyridinyl or 17-(3-pyridinyl)-18-nor- 18-ethylandrost-5,16-diene-3a,7cc-diol or 17-(3-pyridinyl)-18-nor-18- ethylandrost-5,16-diene-3β,7 -diol-16-acetate.
[236] 48A. The compound of embodiment 23A, 24A, 25A, 26A, 27A, 28A, or
Figure imgf000081_0002
is -H, (b) R1 is =0, R2 is -OH and R3 is -H, (c) R1 and R2 are -OH and R3 is - CH3, (d) R1 is =0, R2 is -OH and R3 is -CH3, or (e) R1 is -OH, R2 is -H and R3 is C1 -4 optionally substituted alkyl, including -CH3, -C2H5 or -CH2CH2OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R6 is -C2H5, including species17-(3-pyridinyl)-19-nor-19-ethylandrost-5,16-diene-3β,7β-diol, which
Figure imgf000082_0001
where R4 is 3-pyridinyl, 17-(3-pyridinyl)-19-nor-19- ethylandrost-5,16-diene-3cc^-diol or 17-(3-pyridinyl)-19-nor-19-ethylandrost- 5,16-diene-3β,7β-diol-16-acetate.
[237] 49A. The compound of embodiment 23A, 24A, 25A, 26A, 27A, 28A, or
Figure imgf000082_0002
is -H, (b) R1 is =0, R2 is -OH and R3 is -H, (c) R1 and R2 are -OH and R3 is - CH3, (d) R1 is =0, R2 is -OH and R3 is -CH3, or (e) R1 is -OH, R2 is -H and R3 is C1 -4 optionally substituted alkyl, including -CH3, -C2H5 or -CH2CH2OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R5 is -CH2OH, including species 17-(3-pyridinyl)androst-5,16-diene^^,18-triol, 17-(3-pyridinyl)-7 - methylandrost-5,16-diene^,18-diol, 17-(3-pyridinyl)^-methylandrost-5,16- diene^, 18-diol-16-methyl ether or 17-(3-pyridinyl)-7 -methylandrost-5, 16- diene-3cc, 18-diol-16-methyl ether. [238] 50A. The compound of embodiment 44A, 45A, 46A, 47A, 48A or 49A wherein R2 is -OH.
[239] 51 A. The compound of embodiment 44A, 45A, 46A, 47A, 48A or 49A wherein R1 is -OH or =0 and R2 is -OH.
[240] 52A. The compound of embodiment 44A, 45A, 46A, 47A, 48A or 49A wherein (a) R3 is -CH3 and R2 is -OH, or (b) R3 is -CF3, -C2H5, -CH2CH2OH or -CH2CH2CH3 and R2 is -OH.
[241] 53A. A formulation comprising one or more excipients and a compound of any of embodiments 23A-52A.
[242] 54A. The formulation of embodiment 52A wherein the formulation is for oral administration, wherein the unit dosage form of the formulation is a tablet, capsule, caplet or gelcap.
[243] 55A. The formulation of embodiment 52 wherein the formulation is for parenteral administration, including a sterile solution or a sterile suspension.
[244] 56A. The compound of embodiment 23A, 24A, 25A, 26A, 27A, 28A, or
Figure imgf000083_0001
is -H, (b) R1 is =0, R2 is -OH and R3 is -H, (c) R1 and R2 are -OH and R3 is - CH3, (d) R1 is =0, R2 is -OH and R3 is -CH3, or (e) R1 is -OH, R2 is -H and R3 is C1 -4 optionally substituted alkyl, including -CH3, -C2H5 or -CH2CH2OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R5 is -C2H5 and R6 is -H, including species 17-(3-pyridinyl)-18-nor-18-ethylandrost-5,16-diene^,7cc-
diol, which is
Figure imgf000084_0001
where R4 is 3-pyridinyl, 17-(3-pyridinyl)- 18,19-dinor-18-ethylandrost-5,16-diene-3 ,7 -diol, 17-(3-pyridinyl)- 18,19- dinor-18-ethylandrost-5,16-diene-3p,7p-diol-16-acetate, 17-(3-pyridinyl)- 18,19-dinor-18-ethyl^-ethylandrost-5,16-(_ϊβηΘ-3β-οΙ or 17-(3-pyridinyl)- 18,19-dinor-18-ethylandrost-5,16-diene^,7cc-diol-16-methyl ether.
[245] 57A. The compound of embodiment 23A, 24A, 25A, 26A, 27A, 28A, or
Figure imgf000084_0002
is -H, (b) R1 is =0, R2 is -OH and R3 is -H, (c) R1 and R2 are -OH and R3 is - CH3, (d) R1 is =0, R2 is -OH and R3 is -CH3, or (e) R1 is -OH, R2 is -H and R3 is C1 -4 optionally substituted alkyl including -CH3, -C2H5 or -CH2CH2OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R5 is -CH2OH and R6 is -H, including species 17-(3-pyridinyl)-19-nor-androst-5,
Figure imgf000085_0001
18-triol, 17-(3-pyridinyl)-19-nor^-methylandrost-5,16-diene^,18-diol, 17-(3- pyridinyl)-19-nor-7β-methylandrost-5,16-diene-3β,18-diol-16-methyl ether or 17-(3-pyridinyl)-19-nor-7 -methylandrost-5, 16-diene-3 , 18-diol-16-methyl ether.
[246] 58A. The compound of embodiment 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31 A, 32A, 33A, 34A, 35A, 36A, 37A, 38A, 39A, 40A, 41 A, 42A or
Figure imgf000085_0002
is -H, (b) R1 is =0, R2 is -OH and R3 is -H, (c) R1 and R2 are -OH and R3 is - CH3, (d) R1 is =0, R2 is -OH and R3 is -CH3, or (e) R1 is -OH, R2 is -H and R3 is C1 -4 optionally substituted alkyl , including -CH3, -C2H5 or -CH2CH2OH, or optionally wherein the compound is an analog of a compound named in enumerated embodiment 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A or 19A, wherein in the analog, R6 is -H.
[247] 59A. A formulation comprising one or more excipients and a compound of embodiment 56A, 57A or 58A.
[248] 60A. The formulation of embodiment 59A wherein the formulation is for oral administration, wherein the unit dosage form of the formulation is a tablet, capsule, caplet or gelcap. [249] 61 A. The formulation of embodiment 59A wherein the formulation is for parenteral administration, including a sterile solution or a sterile suspension.

Claims

What is claimed is: 1 . A method to identify a compound comprising
(a) administering a test compound to a mammal(s) for a sufficient period of time to obtain treated mammal(s);
(b) measuring systemic levels of one or more cholesterol metabolites in the treated mammal(s); and
(c) selecting the compound of step (b) that decreases the systemic levels of one or more cholesterol metabolites in the treated mammal(s), whereby a compound having a potential to treat a cancer, optionally a neuroendocrine cancer is identified, wherein the test compound of step (a) is 17a-ethynylandrostane-3cc, 1 Ζβ-diol or a compound that has the structure
Figure imgf000087_0001
or a salt thereof; wherein the dotted line is a double bond or hydrogen is present at the 5-position in the cc-configuration,
R1 is -OH, -SH, =0, an optionally substituted ester, wherein the ester is -0-C(0)-optionally substituted C1 -7 alkyl or 0-C(0)-optionally substituted aryl, optionally acetate, propionate or benzoate, or an optionally substituted ether, wherein the ether is -O-optionally substituted 01 -8 alkyl, optionally -0CH3, - 0C2H5, -OCH2CH2CH3, -OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2;
R2 is -OH, -SH, =0, an optionally substituted ester, wherein the ester is -0-C(0)-optionally substituted C1 -7 alkyl or 0-C(0)-optionally substituted aryl, optionally acetate, propionate or benzoate, an optionally substituted ether, wherein the ether is -O-optionally substituted 01 -8 alkyl, optionally methoxy or ethoxy, or an optionally substituted 01 -8 alkyl group, wherein the alkyl group is -CH3, -CF3, -C2H5, -CH2CH2OH, -CH2CH2CH3, -CH2CH2CH2OH or - OCH(CH3)2, or R2 is -H when (i) R3 is not -H, (ii) R5 is -C2H5 or -CH2OH or (iii) R6 is -H, -C2H5 or -CH2OH; R3 is -H, -OH, optionally substituted C1 -8 alkyl, optionally methyl, ethyl, /7-propyl, /'-propyl or 3-hydroxy-n-propyl, halogen, an optionally substituted ester, wherein the ester is -0-C(0)-optionally substituted C1 -7 alkyl or -O- C(0)-optionally substituted C1 -7 aryl, optionally acetate, propionate or benzoate, an optionally substituted ether, wherein the ether is -O-optionally substituted C1 -8 alkyl, optionally -OCH3, -OC2H5, -OCH2CH2CH3, - OCH2CH2OH, -OCH2CH2CH2OH or -OCH(CH3)2), or an optionally substituted C1 -8 alkyl group, wherein the alkyl group is -CH3, -CF3, -C2H5, -CH2CH2OH, - CH2CH2CH3, -CH2CH2CH2OH or -CH(CH3)2;
R4 is a C-linked ring or an N-linked ring, wherein the ring is a 5- or 6- membered ring;
R5 is -CH3, -C2H5 or -CH2OH; and
R6 is -H, -CH3, -C2H5 or -CH2OH.
2. The method of claim 1 wherein the cholesterol metabolite is one or more of testosterone, dihydrotestosterone, 4-androstenedione, 5- androstenediol, 5a-androstane-3cc,^-diol, 5cc-androstane^,^-diol, estradiol, estrone, dehydroepiandrosterone, pregnenolone, progesterone and Cortisol.
3. The method of claim 1 wherein the cholesterol metabolite is one or more of 5a-androstane-3cc,^-diol or 5cc-androstane^,^-diol.
4. The method of claim 1 wherein the cholesterol metabolite is one or more of dehydroepiandrosterone, testosterone, dihydrotestosterone, 4- androstenedione or 5-androstenediol.
5. The method of claim 1 wherein the cholesterol metabolite is one or more of pregnenolone, progesterone or Cortisol.
6. The method of claim 1 wherein the cholesterol metabolite is one or more of 17-hydroxypregnenolone, 1 1 -deoxycortisol or Cortisol.
7. The method of claim 1 wherein the compound has the structure
Figure imgf000089_0003
Figure imgf000089_0001
wherein
R1 is -OH or an ester;
R2 is -H, -OH or =0;
R3 is -OH, halogen, an ester, an ether or an alkyl group; and
R4 is a C-linked ring or an N-linked ring, wherein the C-linked ring is a heterocycle.
8. The method of claim 7 wherein R is 1 -furanyl, 2-furanyl, 1 -oxolane, 2-oxolane, 1 -thiophene, 2-thiophene, 1 -pyrrole, 2-pyrrole, 3-pyrrole, 1 - pyrrolidine, 2-pyrrolidine, 3-pyrrolidine, 2-thiazolyl, 3-thiazolyl, 4-thiazolyl, 5- thiazolyl, 1 -pyranyl, 2-pyranyl or 3-pyranyl.
9. The method of claim 7 wherein R4 is -N-pyrrolidine, -N1 -pyrazolone, -N2-pyrazolone, -N-imidazolidin-2-one, -N1 -imidazole, -N1 -4,5- dihydroimidazole, -N-morpholine, -N1 -pyridine, -N-piperidine, -N- piperazine, optionally substituted at N4 with optionally substituted alkyl, aryl or heteroaryl, -N-indole, -N-indoline or -N-quinolidine.
10. The method of claim 7 wherein R4 is optionally substituted
Figure imgf000089_0002
1 1 . The method of claim 7 wherein R4 is optionally substituted
Figure imgf000090_0001
12. The method of claim 7 wherein R4 is (1 ) -N-pyridine or -N- pyrimidinyl, (2) -1 -pyridyl, -2-pyridyl, -3-pyridyl, -1 -pyrimidinly, -4-pyrimidinly or -5-pyrimidinly, (3) -N-piperidinyl, -1 -piperidinyl, -2-piperidinyl, -3-piperidinyl, or (4) -N-imidazole, -2-imidazole or -4-imidazole.
13. The method of claim 1 wherein the compound has the structure
Figure imgf000090_0002
4. The method of claim 1 wherein the compound has the structure
Figure imgf000091_0001
15. The method of claim 1 wherein the compound has the structure
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000094_0001
18. The method of claim 13 wherein the hydroxyl at the 7-position is replaced with -OCH3, optionally wherein the compound is the first, second or third compound shown in claim 13.
19. The method of claim 14 wherein the hydroxyl at the 7-position is replaced with -OCH3, optionally wherein the compound is the first, second or third compound shown in claim 14.
20. The method of claim 15 wherein the hydroxyl at the 7-position is replaced with -OCH3, optionally wherein the compound is the first, second or third compound shown in claim 15.
21 . The method of claim 16 wherein the hydroxyl at the 7-position is replaced with -OCH3, optionally wherein the compound is the first, second or third compound shown in claim 16.
22. The method of claim 17 wherein the hydroxyl at the 7-position is replaced with -OCH3, optionally wherein the compound is the first, second or third compound shown in claim 17.
23. The method of claim 1 wherein the test compound is 17a- ethynylandrostane-3a, 17p-diol.
24. The method of claim 2 wherein the test compound is 17 a- ethynylandrostane-3a, 17p-diol.
25. The method of claim 1 wherein the test compound is a compound of any of claims 8-22.
26. The method of claim 6 wherein the test compound is a compound of any of claims 8-22.
PCT/US2010/058449 2009-11-30 2010-11-30 Anticancer compounds and screening method WO2011066582A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA2782266A CA2782266A1 (en) 2009-11-30 2010-11-30 Anticancer compounds and screening method
EP10834064.7A EP2506855A4 (en) 2009-11-30 2010-11-30 Anticancer compounds and screening method

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US26529409P 2009-11-30 2009-11-30
US61/265,294 2009-11-30
US26609209P 2009-12-02 2009-12-02
US61/266,092 2009-12-02
US26629109P 2009-12-03 2009-12-03
US26641609P 2009-12-03 2009-12-03
US26648309P 2009-12-03 2009-12-03
US61/266,483 2009-12-03
US61/266,416 2009-12-03
US61/266,291 2009-12-03

Publications (1)

Publication Number Publication Date
WO2011066582A1 true WO2011066582A1 (en) 2011-06-03

Family

ID=44066970

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/058449 WO2011066582A1 (en) 2009-11-30 2010-11-30 Anticancer compounds and screening method

Country Status (4)

Country Link
US (1) US20110129423A1 (en)
EP (1) EP2506855A4 (en)
CA (1) CA2782266A1 (en)
WO (1) WO2011066582A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103382213B (en) * 2013-07-03 2015-07-01 湖南大学 17-(2', 5'-disubstituted oxazolyl)-androstane-4, 16-diene-3-ketone, and preparation method and applications thereof
KR20210136072A (en) 2019-03-06 2021-11-16 프로펠라 쎄라퓨틱스, 인크. abiraterone prodrug
US11957696B2 (en) 2021-02-15 2024-04-16 Propella Therapeutics, Inc. Abiraterone prodrugs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060211059A1 (en) * 2005-03-18 2006-09-21 Taneja Samir S Methods of improving screening, diagnosis and staging of prostate cancer using serum testosterone
US20080021006A1 (en) * 1999-09-30 2008-01-24 Hollis-Eden Pharmaceuticals, Inc. Pharmaceutical Compositions
US20080221074A1 (en) * 2006-11-17 2008-09-11 Jaime Flores-Riveros Drug Screen and Treatment Method

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3050519A (en) * 1960-05-13 1962-08-21 Olin Mathieson Cyclocarbonate esters of 16alpha, 17alpha-dihydroxypregnenes
US5028631A (en) * 1987-11-25 1991-07-02 Schwartz Arthur G Homoandrostan-17-one and homoandrosten-17-ones
US4898694A (en) * 1987-11-25 1990-02-06 Schwartz Arthur G 17-Hydroxy-steroids
US5461042A (en) * 1988-12-30 1995-10-24 Loria; Roger M. Regulation of the immune system
US5372996A (en) * 1989-03-10 1994-12-13 Endorecherche, Inc. Method of treatment of androgen-related diseases
ES2121570T3 (en) * 1989-07-07 1998-12-01 Endorecherche Inc ANDROGEN DERIVATIVES FOR USE IN THE INHIBITION OF THE ACTIVITY OF SEXUAL STEROIDS.
ATE230994T1 (en) * 1989-07-07 2003-02-15 Endorech Inc METHOD OF TREATING ANDROGEN-RELATED DISEASES
DK0547151T3 (en) * 1990-08-29 2003-03-17 Humanetics Corp Method of promoting weight loss using a substituted delta-5 androstene
US5506223A (en) * 1990-08-29 1996-04-09 Humanetics Corporation Δ5-androstenes useful for promoting weight maintenance or weight loss and treatment process
US5292730A (en) * 1990-08-29 1994-03-08 Humanetics Corporation Modulation of immune system with Δ5-androstenes
US5206008A (en) * 1991-04-15 1993-04-27 Virginia Commonwealth University Enhancement of immune response
US5264427A (en) * 1992-01-29 1993-11-23 Research Corporation Technologies, Inc. 20-substituted pregnene derivatives and their use as androgen synthesis inhibitors
US5604213A (en) * 1992-03-31 1997-02-18 British Technology Group Limited 17-substituted steroids useful in cancer treatment
FR2696934B1 (en) * 1992-10-20 1995-06-02 Conservatoire Nal Arts Metiers Derivatives of natural hydroxyl 3B steroids having properties of triggering and stimulating immunity, composition containing them and process for obtaining them.
US5387583A (en) * 1993-04-20 1995-02-07 Loria; Roger M. Compositions containing corticosteroids or analogues thereof and corticosteroid buffering effective amounts of 5-androstene 3B, 17B or 5-androstene 3B, 7B, 17B triol or analogues thereof
US5994334A (en) * 1997-02-05 1999-11-30 University Of Maryland Androgen synthesis inhibitors
US5912240A (en) * 1997-04-10 1999-06-15 Loria; Roger M. 5-androstene 3β, 17α diol as an inhibitor of tumor growth
US5859900A (en) * 1997-08-19 1999-01-12 At&T Corp Universal call access with reverse billing
US5994335A (en) * 1997-10-17 1999-11-30 The University Of Maryland, Baltimore 17-azolyl steroids useful as androgen synthesis inhibitors
US20030060425A1 (en) * 1998-11-24 2003-03-27 Ahlem Clarence N. Immune modulation method using steroid compounds
US20060079492A1 (en) * 1999-10-25 2006-04-13 Ahlem Clarence N Compositions and treatment methods
US20070129282A1 (en) * 1998-11-24 2007-06-07 Ahlem Clarence N Pharmaceutical treatments and compositions
US6667299B1 (en) * 2000-03-16 2003-12-23 Hollis-Eden Pharmaceuticals, Inc. Pharmaceutical compositions and treatment methods
EP1539183A4 (en) * 2002-08-28 2007-04-25 Hollis Eden Pharmaceuticals Therapeutic treatment methods
US20050101581A1 (en) * 2002-08-28 2005-05-12 Reading Christopher L. Therapeutic treatment methods 2
CA2522784C (en) * 2003-04-01 2012-06-19 Hollis-Eden Pharmaceuticals, Inc. Antiandrogens with marginal agonist activity and methods of use
US7910755B2 (en) * 2004-09-29 2011-03-22 Harbor Biosciences, Inc. Stem cell expansion and uses
AU2005330504B2 (en) * 2004-09-29 2010-10-28 Harbor Biosciences, Inc. Steroid analogs and characterization and treatment methods
US20060073099A1 (en) * 2004-10-01 2006-04-06 Frincke James M Treatment screening methods
AU2006218711B2 (en) * 2005-03-02 2010-11-11 University Of Maryland, Baltimore Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activities, pharmacokinetics and antitumor activity
US20080153792A1 (en) * 2006-11-17 2008-06-26 Frincke James M Drug Identification and Treatment Method
CN101939009B (en) * 2008-02-05 2013-07-17 哈博生物科学公司 Pharmaceutical solid state forms

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080021006A1 (en) * 1999-09-30 2008-01-24 Hollis-Eden Pharmaceuticals, Inc. Pharmaceutical Compositions
US20060211059A1 (en) * 2005-03-18 2006-09-21 Taneja Samir S Methods of improving screening, diagnosis and staging of prostate cancer using serum testosterone
US20080221074A1 (en) * 2006-11-17 2008-09-11 Jaime Flores-Riveros Drug Screen and Treatment Method

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NEGRO-VILAR.: "Selective Androgen Receptor Modulators (SARMs): A Novel Approach to Androgen Therapy for the New Millennium.", J. CLIN. ENDOCRINOL. METAB., vol. 84, 1999, pages 3459 - 3462, XP002193249 *
OFFNER ET AL.: "An Orally Bioavaifabfe Synthetic Analog of an Active Dehydroepiandrosterone Metabolite Reduces Established Disease in Rodent Models of Rheumatoid Arthritis.", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 329, no. 3, 2009, pages 1100 - 1109, XP055025351 *

Also Published As

Publication number Publication date
EP2506855A1 (en) 2012-10-10
EP2506855A4 (en) 2014-07-30
CA2782266A1 (en) 2011-06-03
US20110129423A1 (en) 2011-06-02

Similar Documents

Publication Publication Date Title
US6660726B2 (en) Estrogenic compounds, pharmaceutical compositions thereof, and methods of using same
CHATZ et al. Lipoidal derivative of estradiol: the biosynthesis of a nonpolar estrogen metabolite
US7989436B2 (en) Estrogenic compounds and pharmaceutical formulations comprising the same
JP3219408B2 (en) Steroid sulfatase inhibitor
US20070142307A1 (en) Novel estrogenic compounds
JP4871274B2 (en) Novel disubstituted D-homo-estradi-1,3,5 (10) -trienes as inhibitors of 17β-hydroxysteroid dehydrogenase type 1
JP2009215317A (en) Steroid sulfamate, method for producing it, and use thereof
JPH05503531A (en) steroid sulfatase inhibitors
Santa Derivatization in liquid chromatography for mass spectrometric detection
EP1042354A2 (en) Estrone sulfamate inhibitors of estrone sulfatase, and associated pharmaceutical compositions and methods of use
AU2010319697B2 (en) Mammalian metabolites of steroids
US20020107233A1 (en) Steriodal derivatives
WO2006003013A2 (en) NOVEL 2-SUBSTITUTED ESTRA-1,3,5(10)-TRIEN-17-ONES USED IN THE FORM OF INHIBITORS OF 17β-HYDROXYSTEROIDDEHYDROGENASE OF TYPE 1
Yadav et al. Synthesis of some novel androstanes as potential aromatase inhibitors
EP0728140B1 (en) New steroids with radical-attracting aromatic substituents, process for the production thereof and pharmaceutical compounds containing the said substances
WO2011066582A1 (en) Anticancer compounds and screening method
Djurendić et al. Synthesis of some epoxy and/or N-oxy 17-picolyl and 17-picolinylidene-androst-5-ene derivatives and evaluation of their biological activity
Baydoun et al. Microbial transformation of anti-cancer steroid exemestane and cytotoxicity of its metabolites against cancer cell lines
Nobilis et al. High-performance liquid chromatographic determination of ursodeoxycholic acid after solid phase extraction of blood serum and detection-oriented derivatization
Mohamed et al. Cu (I) catalyzed alkyne-azide 1, 3-dipolar cycloaddition (CuAAC): Synthesis of 17α-[1-(substituted phenyl)-1, 2, 3-triazol-4-yl]-19-nor-testosterone-17β-yl acetates targeting progestational and antipro-liferative activities
Huang et al. C21-steroidal pregnane sapogenins and their derivatives as anti-inflammatory agents
JPH04117394A (en) New steroid compounds having substituted ethyl group in position 10, their manufacture, their use as medicines and pharmaceutical compositions containing them
JP6041125B2 (en) Ultrasensitive measurement method of estrogen
Schneider et al. Stereocontrolled synthesis of the four 16-hydroxymethyl-19-nortestosterone isomers and their antiproliferative activities
Gaši et al. Synthesis and anti-aromatase activity of some new steroidal D-lactones

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10834064

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2782266

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2010834064

Country of ref document: EP