WO2013067151A1 - Procédés de traitement utilisant des dérivés de diarylthiohydantoïne - Google Patents

Procédés de traitement utilisant des dérivés de diarylthiohydantoïne Download PDF

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Publication number
WO2013067151A1
WO2013067151A1 PCT/US2012/063016 US2012063016W WO2013067151A1 WO 2013067151 A1 WO2013067151 A1 WO 2013067151A1 US 2012063016 W US2012063016 W US 2012063016W WO 2013067151 A1 WO2013067151 A1 WO 2013067151A1
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Prior art keywords
substituted
alkyl
compound
cancer
aromatic
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PCT/US2012/063016
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English (en)
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Andrew A. Protter
David T. Hung
Sarvajit Chakravarty
Sabastian BERNALES
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Medivation Prostate Therapeutics, Inc.
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Publication of WO2013067151A1 publication Critical patent/WO2013067151A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the technical field is treatment of disorders or conditions involving androgen, estrogen, and/or progesterone receptors.
  • FIG. 1. Graph showing results from Example 1.
  • M0, Ml , M10, and M30 correspond to MDV3100 (RD162') at 0 (control), 1 , 10, and 3 ⁇ ) ⁇ , respectively.
  • FIG. 2. Graph showing results from Example 1.
  • FIG. 3. Graph showing results from Example 1.
  • alkyl denotes branched or unbranched hydrocarbon chains
  • having about 1 to about 8 carbons such as, methyl, ethyl, n-propyl, iso- propyl, n- butyl, sec-butyl, iso-butyi, tert-butyl, 2-methylpentyI pentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl pentyl, octyl, 2,2,4-trimethyIpentyl and the like.
  • Substituted alkyl includes an alkyl group optionally substituted with one or more functional groups which can be attached to such chains, such as, hydroxy!, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, alkylthio, heterocyclyi, aryl, heteroaryl, carboxyl, earbalkoyl, alkyl, alkenyl, nitro, amino, alkoxvl, amido, and the like to form alkyl groups such as trifluoro
  • cycloalkyl as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or more double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicaikyl, containing a total of 3 to 20 carbons forming the rings, In some embodiments, 3 to 10 carbons, forming the ring and which can be fused to 1 or 2 aromatic rings as described for ai l, which include cyclopropyl, cyclobutyl, cyclopentyl, cyelohexyl, cycloheptyl, cyclooctyi, cyclodecyl and cyclododecyl, cycloiiexenyl.
  • Substituted cycloalkyl includes a. cycloalkyl group optionally substituted with 1 or more substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylaniino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/or any of the substituents included in the definition of "substituted alky];” for example:
  • alkenyl refers to straight or branched chain radicals of 2 to 20 carbons, In some embodiments, 2 to 12 carbons, and In some embodiments, 2 to 8 carbons in the normal chain, which include one or more double bonds in the normal chain, such as vinyl, 2- i propenyl, 3-butenyl, 2-butenyl, 4 -pentenyl, 3-pentenyl, 2-hexenyl, 3 -hexenyl, 2- heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4- dodecenyl, 4,8 , 12-tetradecatrieny 1, and the like.
  • Substituted alkenyl includes an alkenyl group optionally substituted with one or more substituents, such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyi.” ] Unless otherwise indicated, the term “alkynyl” as used herein by itself or as part of
  • another group refers to straight or branched chain radicals of 2 to 20 carbons.
  • 2 to 8 carbons in the normal chain which include one or more triple bonds in the normal chain, such as 2-propynyl, 3- butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3- heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like.
  • Substituted alkynyl includes an alkynyl group optionally substituted with one or more substituents, such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyi.”
  • substituents such as the substituents included above in the definition of "substituted alkyl” and “substituted cycloalkyi.”
  • arylalkyl arylalkenyl
  • arylalkynyl as used alone or as part of another gro p refer to alkyl, alkenyl and alkynyl groups as described above having an aryl substituent.
  • arylalkyl include, but are not limited to, benzyl, 2 -phenyl ethyl, 3-phenylpropyI, phenethyl, henzhydryl and naphthylmethyl and the like.
  • “Substituted arylalkyl” includes arylalkyl groups wherein the aryl portion is optionally substituted with one or more substituents, such as the substituents included above in the definition of "substituted alkyl” and “substituted cycloalkyi.”
  • halogen or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine.
  • halogenated alkyl refers to "alkyl”, “alkenyl” and “alkynyl” which are substituted by one or more atoms selected from fluorine, chlorine, bromine, fluorine, and iodine.
  • aryl or “Ar” as employed herein alone or as part of another group refers to monocyclic and polycyelie aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-na.phthyl and 2- naphthyl) and can optionally include one to three additional rings fused to a earbocyclic ring or a heterocyclic ring (such as aryi, cycloalkyl, heteroaryi or cycloheteroalkyl rings).
  • Substituted aryl includes an aryl group optionally substituted with one or more
  • halo haloaikyL alkyl, haloalkyl, alkoxy, haloaikoxy, alkenyl, trifluoroniethyl, trifluoromethoxy, alkynyl, eycloalkyl-alkyL cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryi, aryialkyl, aryloxy, aryloxyalkyl, aryialkoxy, alkoxycarbonyl, arylearbonyl, arylalkenyl, aminocaxbonylaryi, arylthio, axylsulfinyi, arvlazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroarvl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl, aryl
  • heterocyclic represents an unsubstituted or substituted stable 5- to 10-membered monocyclic ring system which can be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quaternized.
  • the heterocyclic ring can be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyi, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazoivl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl
  • heterocyclic aromatic as used here in alone or as part of another group refers to a 5- or 7-membered aromatic ring which includes 1 , 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur and such rings fused to an aryl, cycloalkyl, heteroaryl or
  • heterocycioalkyl ring e.g. beiizothiopheiiyL indolyl
  • substituted heteroaryl includes a heteroaryl group optionally substituted with 1 to 4 substituents. such as the substituents included above in the definition of "substituted aikyl” and “substituted cycloalkyl,” Examples of heteroaryl groups include the following:
  • the compound is a diarylhydantoin compound.
  • the compound is a compound of Formula I:
  • D is S or O and E is IN or O and G is alkyl, aryi, substituted alkyl or substituted aryl; or D is S or O and E-G together are C1 -C4 lower alkyl, wherein Rl and R2 together comprise eight or fewer carbon atoms and are selected from the group consisting of alkyl, substituted alkyl including haloalkyl, and, together with the carbon to which they are linked, a cycloalkyl or substituted cycloalkyl group, wherein R3 is selected from the group consisting of hydrogen, halogen, methyl, C I -C4 alkoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxy!, phenyl, amino, methylcarbamoyl, methoxycarbonyl , acetaraido, methanesulfonamino, methanesulfonyl, 4-raethanesulfonyl
  • the compound is a compound of Formula I- A:
  • R3 is selected from the group consisting of hydroxy, methylcarbamoyl methylcarbamoylpropyl, methylcarbamoylethyl, methy!carbarnoylmethyl, methylsulfonecarbamoylpropyl, methyiaminomethyi, dimethylaminomethyl, methylsulfonyloxymethyl, earbamoylmethyl, carbamoyl ethyl, carboxymethyl, methoxycarbonylmethyl, methanesulfonyl, 4-cyano-3- trifluoromethylphenylcarbamoylpropyl , carboxypropyl, 4-methaaesulfonyl- 1 -piperazinyi piperazinyl, methoxycarbonyl, 3-cyano-4-trifluoromethylphenylcarbamoyl,
  • RIO and Rl 1 are both H or, respectively, F and H, or H and F.
  • RIO and Rl 1 can both be H or, respectively, F and H, R3 can be methylcarbamoyl.
  • Rl and R2 are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms
  • R3 is selected from the group consisting of carbamoyl, alkylearbamoyl, carbamoylalkyl, and aikylcarbamoylalkyl
  • R4 is H or F or R4 is 3-fluoro.
  • Rl and R2 are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms
  • R3 is selected from the group consisting of cvano, hydroxy, methylcarbamoyl, methyicarbamoyl-substituted aikyl, methylsulfonecarbamoyl-substituted alkyl, methylaminometbyl,
  • the compound is a compound of Formula I-B:
  • R3 is selected from the group consisting of methvlcarbonvl, methoxvcarbonyl, acetamido, and methanesulfonamiclo
  • R4 is selected from the group consisting of F and H.
  • the compound is a compound of Formula I-C:
  • Rl and R2 together with the carbon to which they are linl ed, are
  • the compound is a compound selected from:
  • the compound is a compound disclosed in U.S. Patent 7,709,51 In some embodiments, the compound is a compound listed in Tier 1, Tier 2, Tier 3, and/or Tier 4 of U.S. Patent 7,709,517, reproduced below:
  • the compound is a compound selected from:
  • the compound is a compound of Formula I-D:
  • Rj and R 2 together include eight or fewer carbon atoms and are selected from the group consisting of alkyl, substituted alkyl, and, together with the carbon to which they are linked, a eycloalkyl or substituted cycloalkyl group.
  • R 3 is hydrogen, cya.no, formyl,
  • R4 is hydrogen, F, CI, Br, or I.
  • Rn and R 12 can be the same or different and are hydrogen or methyl
  • R 13 is hydrogen or -NR 14 R 15 .
  • R 14 and R15 can be the same or different and are hydrogen or methyl ,
  • R 2 can be independently methyl or, together with the carbon to which they are linked, cyciobiityl or cyclopenty!.
  • n and Ri2 can be both hydrogen or both methyl.
  • R 1 can be - ⁇ NH(CHi) or-N(CH ) 2 .
  • R 4 , Rn and R 12 are each hydrogen and when R-. and R 2 together with the carbon to which they are linked are cyclo butyl, then R 3 can be other than cyano and with i3 hydrogen, -NH 2 , -NH(C!3 ⁇ 4), or -N(CH 3 ) 2 .
  • Representati ve compounds of Formula 1 -D include:
  • the compound is a compound of Formula II:
  • R5 is CN or N02 or S02R 1 1 , wherein R6 is CF3, alkyl, substituted alkyl, aikenyl, substituted aikenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated aikenyl, halogenated alkynyl, halogen, wherein A is sulfur (S) or oxygen (O), wherein B is O or S or NR8, wherein R.8 is selected from the group consisting of H, methyl, aryl , substituted aryl, alkyl, substituted alkyl, aikenyl, substituted aikenyl, alkynyl, substituted alkynyl, arylalkyl, arylalkeny], arylalkyny!, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycioal
  • D is S or O and E id N or O and G is alkyl, aryl, substituted alkyl or substituted aryl; or D is S or O and E-G together are C1 -C4 lower alkyl, wherein R l and R2 are independently alkyl, haloaikyl , hydrogen, aryl, substituted alkyl, aikenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkenyl, halogenated alkynyi, arylalkyl, arylalkenyl, aiyialkynyl, heterocylie aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, or Rl and R2 are connected to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, or Rl and
  • R3, R4, and R7 are independently selected from the group consisting of hydrogen, halogen, methyl, methoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxy!, phenyl, amino, methylcarbamoyl, methylcarbamoyl-substituted alkyl, dimethylcarbamoyl- substituted alkyl, methoxy carbonyl, acetamido, methanesulfonami.no, carbamoyi- substituted alkyl, methanesulfonyl, 4-methanesulfonyl-lpiperazinyi, piperazinyl, hydroxyethylearbamoyl-substituted alkyl, hydroxyl-substituted alkyl, hydroxyl- substituted alkenyl, carbamoyl-substitute
  • aryl substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkenyl, halogenated alkynyl, S02R1 1 , NR!
  • heterocyclic aromatic cycloalkyl, or substituted cycloalkyl.
  • the compound is a metabolite of a diarylthiohydantoin compound, for example as disclosed in WO 2010/099238.
  • the compound is a compound of Formula III:
  • X is S or O
  • R 1 is OH or NH 2 ;
  • a compound of Formula III is:
  • Salts of compounds described above can be used in the disclosed methods. If a compound has, for example, at least one basic center, it can form an acid addition salt. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohaiic acid, with strong organic carboxyiic acids, such as alkanecarboxyiic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such
  • Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propyiamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine.
  • metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts
  • salts with ammonia or an organic amine such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl, ter
  • Corresponding internal salts can furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds or their pharmaceutically acceptable salts, are also included .
  • salts of compounds which contain a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate.
  • salts of compounds which contain an acid group include sodium, potassium and magnesium salts and
  • the salts are pharmaceutically acceptable (e.g., non-toxic, physiologically acceptable) salts.
  • Pharmaceutically acceptable salts retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobrormc acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • Acceptable organic bases include ethanolamine, cliefhanolamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et al.. Pharmaceutical Salts, J. Pharrn. Set 1977
  • a pharmaceutically acceptable salt can be prepared in situ in the manufacturing process, or by separately reacting a purified compound in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
  • a. reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
  • Solvates contain either stoichiometric or non-stoiehiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or aicoholates are formed when the solvent is alcohol.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
  • Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • Compounds disclosed herein can be used to treat disorders in which modulation of androgen, estrogen, and/or progesterone receptors would be beneficial. These disorders include indications discussed below and the therapeutic indications disclosed in U.S. Patent 7,709,517; US 201 1 /0003839; WO 2010/118354; WO 201 1/044327; and WO 2010/099238.
  • Compounds disclosed herein and related compounds may also be useful as modulators of other nuclear receptors, such as glucocorticoid receptor and peroxisome proliferator-activated receptor, and as therapeutic agents for diseases in which nuclear receptors play a role, diabetes, cardiac diseases, and metabolism- related diseases.
  • Treating is an approach for obtaining a beneficial or desired result, including, but not limited to, relief from a symptom, lessening of a symptom., and preventing a worsening of a symptom associated with the disease being treated.
  • treatment also includes, but is not limited to, any one or more of enhancing survi val time, enhancing progression-free survival time, and reducing tumor size.
  • Disorders that can be treated include, but are not limited to:
  • neurodegenerative disorders including, but not, limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, dementia with Lewy bodies, corticobasai degeneration, progressive supranuclear palsy, prion disorders, multiple system atrophy, hereditary spastic paraparesis, spinocerebellar atrophies, Friedreich's ataxia, amyloidosis, metabolic disease-related neurodegeneration, toxin-related neurodegeneration, multiple sclerosis, Charcot Marie Tooth syndrome;
  • cancer including, but not limited to, prostate cancer, bladder cancer, non- Hodgkin lymphoma, leukemia., thyroid cancer, breast cancer, ovarian cancer, glioblastoma, neuroblastoma, renal cancer, Wilms' tumor
  • nephroblastoma retinoblastoma
  • pancreatic cancer endometrial cancer, hepatocellular carcinoma, desmoplastic small-round-cell tumor, colorectal cancer, esophageal cancer, head and neck cancer, lung cancer, melanoma
  • endometrial cancer hepatocellular carcinoma
  • desmoplastic small-round-cell tumor desmoplastic small-round-cell tumor
  • colorectal cancer esophageal cancer
  • head and neck cancer lung cancer
  • melanoma melanoma
  • systemic hyperandrogenism seborrhea, hirsutism, precocious puberty, polycystic ovary syndrome, acne, alopecia, benign prostatic hyperplasia, intrauterine fibroids, endometriosis, glaucoma, meningiomas, Kennedy's disease (KD) or X-linked spinal and bulbar muscular atrophy.
  • disclosed compounds can be used for medical termination of intrauterine pregnancies.
  • disclosed compounds can be used as adjuvants to vaccines
  • Yersinia pseudotuberculosis Mycobacterium tuberculosis, Legionella pneumophila, Rickettsia, E. coii. Vibrio cholera, Salmonella typhi. Salmonella typhimurium. Listeria monocytogenes, Porphyromonas gingivalis, Tetanus, Borrelia burgdorferi, Haemophilus influenzae B, Klebsiella,
  • Neiserria gonorrhoeae Chlamydia pneumoniae, Chlamydia trachomatis, Treponema, Haemophilus ducreyi, Respiratory syncytial vims.
  • Parainfluenza vims Poliovirus, Measles, Mumps, Rubella, Rabies, Flaviviridae viruses, Caliciviridae, HIV, Rotavirus, Pestivirus, Parvovirus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Hepatitis C vims, Delta- hepatitis virus, Hepatitis E virus, Hepatitis G virus, Varcicella roster virus, Epstein-Barr virus, Cytomegalovirus, Herpes simplex virus, human Herpes virus, human papillomavirus, Trichophyton menlagrophyles, Epidermophyton floccusum, Microsporum a douini, Microsporum canis, Microsporum distortum, Micro
  • Microsporum gypsum Microsporum nanum, Trichophyton concentricum, Trichophyton equinum.
  • Trichophyton gallinae Trichophyton gypseum, Trichophyton, raegnini
  • Trichophyton menlagrophyles Trichophyton quinckeanum, Trichophyton rubrum, Trichophyton schoenleinii Trichophyton tonsurans.
  • Trichophyton verrucosum T verrucosum var. album, var. discoides, var. ochraceum.
  • Trichophyton violaceum Trichoplylonfaviforme, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, Aspergillus terreus, Aspergillus sydowi, Aspergillus flavatus , Aspergillus glaucus, Blastoschizomyces capilatus, Candida albicans, Candida enolase, Candida tropic alis, Candida glabrata, Candida krusei, Candida parapsilosis, Candida stellatoidea, Candida kusei, Candida parakwsei, Candida lusitaniae, Candida
  • Compounds can be formulated in any type of pharmaceutical composition known in the art, including, but not limited to, tablets, troches, pills, capsules, syrups, elixirs, injectable solutions, and the like.
  • a pharmaceutical composition typically includes a pharmaceutically or
  • pharmacologically acceptable excipient or carrier a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • pharmaceutically acceptable carriers or excipients have met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound as an active ingredient.
  • excipient including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.:
  • J Tablets, troches, pills, capsules, and the like can also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring can be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • diary Ihydantoin compound can be incorporated into sustained-release preparations and devices.
  • a compound can be incorporated into time release capsules, time release tablets, and time release pills.
  • Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising a compound which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form typically is sterile, fluid, and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chiorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents are included, for example, sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating a compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • methods of preparation include vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Other solid carriers include nontoxic polymeric nanoparticies or microparticles.
  • Useful liquid carriers include water, alcohols or glycols or water/alcohol/glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty
  • alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver a compound to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat, No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559, 157) and Wortzman (U.S. Pat. No. 4,820,508).
  • the pharmaceutical composition is a unit dosage form.
  • unit dosage form is a physically discrete unit containing a predetermined quantity of active.
  • an effective amount intends such amount of a compound which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • Useful dosages of compounds can be determined by comparing their in vitro activity and/or in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • concentration of a compound in a liquid composition can be from about 0.1-25% by weight, or from about 0.5- 10% by weight.
  • concentration in a semi-solid or solid composition such as a gel or a powder can be about 0.1 -5% by weight, or about 0,5-2.5% by weight.
  • the amount of a compound required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will he ultimately at the discretion of the attendant physician or clinician.
  • Effective dosages and routes of administration of compounds are conventional.
  • the exact amount (effective dose) of the agent will vary from subject to subject, depending on, for example, the species, age, weight and general or clinical condition of the subject, the severity or mechanism of any disorder being treated, the particular agent or vehicle used, the method and scheduling of administration, and the like.
  • a therapeutically effective dose can be determined empirically, by conventional procedures known to those of skill in the art.
  • an effective dose can be estimated initially either in cell culture assays or in suitable animal models.
  • the animal model can also be used to determine the appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • a therapeutic dose can also be selected by analogy to dosages for comparable therapeutic agents.
  • the particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g., the subject, the disease, the disease state involved, and whether the treatment is prophylactic).
  • Treatment can involve daily or multi-daily doses of compound(s) over a period of a fe days to months, or even years.
  • a suitable dose will be in the range of from about 0.001 to about 100 nig/kg, e.g. , from about 0.01 to about 100 mg/kg of body weight per day, such as above about 0.1 mg per kilogram, or in a range of from about 1 to about 10 mg per kilogram body weight, of the recipient per day.
  • a suitable dose can be about 1 mg/kg, 10 mg/kg, or 50 mg/kg of body weight per day.
  • a compound is conveniently administered in unit dosage form; for example, containing 0.05 to 10000 mg, 0.5 to 10000 mg, 5 to 1000 mg, or about 100 mg of active ingredient per unit dosage form.
  • a compound can be administered to achieve peak plasma concentrations of, for example, from about 0.5 to about 75 ⁇ , about 1 to 50 ⁇ , about 2 to about 30 ⁇ , or about 5 to about 25 ⁇ .
  • Exemplary desirable plasma concentrations include at least or no more than 0.25, 0.5, 1 , 5, 10, 25, 50, 75, 100 or 200 ⁇ ,
  • plasma levels can be from about 1 to 100 micromolar or from about 10 to about 25 micromoiar.
  • Such levels can be obtained by intermittent infusions containing about 0.0002-20 mg per kg body weight, for example, at least or no more than 0.0002, 0.002, 0.02, 0.2, 2, 20, or 50 mg of a compound per kg of body weight.
  • a compound can conveniently be presented in a single dose or as divided doses
  • sub-dose administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself can be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator.
  • a compound can be administered using pharmaceutical compositions comprising a
  • a compound can be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable carrier or diluent, in a variety of forms adapted to the chosen route of administration, for example, orally, nasally, intraperitoneally, or parenterally, by intravenous, intramuscular, topical or subcutaneous routes, or by injection into tissue, ]
  • a compound can be systemically administered, e.g., orally, in combination with a
  • compositions and preparations contain at least 0, 1 %
  • diarylhydantoin or hydantoin compound The percentage of the compositions and preparations can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of a given unit dosage form.
  • the amount of diarylhydantoin or hydantoin compound in such therapeutically useful compositions is such that an effective dosage level will be obtained,
  • a compound can also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of a compound can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.
  • combinations of one or more compounds are used.
  • “combination” compounds includes one or more compounds administered substantially simultaneously, whether or not in the same pharmaceutical composition, or sequentially, compounds can, but need not be, chemically similar (i.e., two compounds of Formula I, one compound of Formula II and one compound of Formula III, etc).
  • one or more androgen, estrogen, and/or progesterone receptor antagonists is used in combination with one or more compounds of Formula I, II, or III.
  • Such antagonists include, but are not limited to, Bicalutamide (e.g., CASODEX ® ), Cyproterone Acetate (e.g., ANDROCUR ® , CYPROSTAT ® , CYPROTERON ® ,
  • PROCUR ® CYPRONE ® , CYPROHEXAL ® , CIPROTERONA ® , CYPROTERONUM ® , NEOPROXIL ® , SITERONE ® ), Dienogest (e.g., VISANNE ® ), Flutamide (e.g. ,
  • EULEXIN ® Galeterone (TO -OOl), Nilutamide (e.g., ML ANDRON ® ) , Spironolactone (e.g., ALDACTONE ® ), Abiraterone (e.g., ZYTIGA ® ), radium-223 chloride (e.g., ALPH ARADTN ® ) , TAK 700, OGX 1 1 1 , Cabozantinib (XL184), Dasatinib (e.g., SPRYCEL ® ), an mTOR inhibitor (e.g., Everolimus, Ridaforolimus, Rapamycin, Temsirolimus), an HDAC inhibitor (e.g., Vorinostat, CI-994, MS-275, BML-210, M344, NVP-LAQ824, Panobinostat, Mocetinostat, PXDI OI), Sipuleucel-T (e.g., PROVENCE 18 ),
  • cancer therapies such as internal or externa! radiation, surgery, and chemotherapies, including:
  • anthracyclines such as doxorubicin (e.g., ADRJAMYCTN ® , DGXIL*), including liposomal doxorubicin, epirubicin (e.g., ELLENCETM), and daunorubicin (e.g., CERUB1DINE ® , DAUNOXOME ® );
  • taxanes such as tamoxifen (e.g., NOLVADEX ® , SOLTAMOX ® , ISTUBAL' VALODEX ® ), docetaxel (e.g., TAXOTERE ® ), paclitaxei (e.g., TAXOL ® , ABRAXANE ® ), and protein-bound paclitaxei (e.g., ABRAXANE ® );
  • tamoxifen e.g., NOLVADEX ® , SOLTAMOX ® , ISTUBAL' VALODEX ®
  • docetaxel e.g., TAXOTERE ®
  • paclitaxei e.g., TAXOL ® , ABRAXANE ®
  • protein-bound paclitaxei e.g., ABRAXANE ®
  • cyclophosphamide e.g., CYTOXAN ®
  • capecitabine e.g., XELODA ®
  • 5-fluorouracil or 5 FU e.g., ADRUCIL ®
  • vinorelbine e.g., NAVELBINE ®
  • gemcitabine e.g., GEMZAR ®
  • trastuzumab e.g., HERCEPTIN ®
  • trastuzumab e.g., HERCEPTIN ®
  • carboplatin e.g., PARAPLATIN ®
  • eribulin e.g., HALAVEN ®
  • ixabepilone e.g., IXEMPRA ®
  • methotrexate e.g., AMETHOPTERIN ® , MEXATE ® , FOLEX ®
  • mutamycin e.g., MITOMYCIN ®
  • mitoxantrone e.g., N O V ANT RON E ®
  • thiotepa e.g., THIOPLEX ®
  • vincristine e.g., ONCOVIN ® , VINCASAR PES ® , VINCREX ® );
  • aromatase inhibitors such as anastrozole (e.g., ARIMIDEX), exemestane (AROMASIN), and letrozole (FEMARA);
  • raloxifene e.g., EVISTA*
  • toremifene e.g., FARESTON ®
  • fulvestrant e.g., FASLODEX ®
  • lapatinib e.g., TYKERB ®
  • doxorubicin and docetaxei e.g., "AT,” ADRIAMYCIN ® and TAXOTERE ® );
  • doxorubicin and cyclophosphamide with or without paclitaxel or docetaxei (e.g. "AC ⁇ T. " ADRIAMYCIN ® and CYTOXAN ® , with or without
  • cyclophosphamide, methotrexate, and fSuorouracil e.g., "CMF,” CYTOXAN ® , methotrexate, and fiuorouracil
  • cyclophosphamide, epirubicin, and fiuorouracil e.g., "CEF,” CYTOXAN ® , ELLENCE ® , and fiuorouracil
  • fluorouracil, doxorubicin, and cyclophosphamide e.g., "FAC,” fluorouracil, ADRIAM YCIN ® , and CYTOXAN : or "CAF,” CYTOXAN ® , ADRIAM Y ON ® , and fluorouracil
  • docetaxel, doxorabicin, and cyclopho9sphamide e.g., "TAC,” TAXOTERE ® , ADRIAM Y ON ® , and CYTOXAN ® ): and
  • gemcitabine e.g., "GET,” GEMZAR*, ELLENCE ® , and TAXOL ® ).
  • Androgen receptor-expressing human urothelial carcinoma UM-UC-3 cells purchased from the American Type Culture Collection, Manassas, VA, USA) were maintained in MEM medium (Gibco, 51200) supplemented with glutamine, non-essential amino acids, and 10% fetal bovine serum (FBS) at 37°C in a humidified atmosphere of 5% C0 2 .
  • MEM medium Gibco, 51200
  • FBS fetal bovine serum
  • Cells were cultured in phenol red-free medium supplemented with 5% charcoal-stripped FBS (CSS) at least 24 h before experimental treatment.
  • DHT dihydro testosterone

Abstract

La présente invention a trait à des composés qui sont utiles pour le traitement de troubles impliquant des récepteurs d'androgènes, d'œstrogènes et/ou de la progestérone.
PCT/US2012/063016 2011-11-02 2012-11-01 Procédés de traitement utilisant des dérivés de diarylthiohydantoïne WO2013067151A1 (fr)

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CN104003939A (zh) * 2014-06-06 2014-08-27 山东大学 二芳基取代乙内酰硫脲类化合物及其制备方法与应用
US20140371284A1 (en) * 2011-12-14 2014-12-18 Hc Pharmaceutical Co., Ltd. Imidazolidinedione compounds and their uses
CN104803919A (zh) * 2014-01-26 2015-07-29 上海医药工业研究院 用于制备恩杂鲁胺中间体的方法
US10000502B2 (en) 2016-01-11 2018-06-19 Janssen Pharmaceutica Nv Substituted thiohydantoin derivatives as androgen receptor antagonists
US11292782B2 (en) 2018-11-30 2022-04-05 Nuvation Bio Inc. Diarylhydantoin compounds and methods of use thereof
US11739069B2 (en) * 2012-10-26 2023-08-29 Memorial Sloan-Kettering Cancer Center Modulators of resistant androgen receptor

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WO2010057197A1 (fr) * 2008-11-17 2010-05-20 The Regents Of The University Of Michigan Compositions de vaccins contre le cancer et leurs méthodes d’utilisation
WO2010099238A1 (fr) * 2009-02-24 2010-09-02 Medivation Prostate Therapeutics, Inc. Composés spécifiques de type diarylhydantoïne et diarylthiohydantoïne
WO2010118354A1 (fr) * 2009-04-09 2010-10-14 Medivation Prostate Therapeutics, Inc. Composés consistant en di-arylhydantoïnes et di-arylthiohydantoïnes substituées et leurs procédés d'utilisation
WO2011106570A1 (fr) * 2010-02-24 2011-09-01 Medivation Prostate Therapeutics, Inc. Procédés pour la synthèse de composés diarylthiohydantoïnes et diarylhydantoïnes

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WO2010057197A1 (fr) * 2008-11-17 2010-05-20 The Regents Of The University Of Michigan Compositions de vaccins contre le cancer et leurs méthodes d’utilisation
WO2010099238A1 (fr) * 2009-02-24 2010-09-02 Medivation Prostate Therapeutics, Inc. Composés spécifiques de type diarylhydantoïne et diarylthiohydantoïne
WO2010118354A1 (fr) * 2009-04-09 2010-10-14 Medivation Prostate Therapeutics, Inc. Composés consistant en di-arylhydantoïnes et di-arylthiohydantoïnes substituées et leurs procédés d'utilisation
WO2011106570A1 (fr) * 2010-02-24 2011-09-01 Medivation Prostate Therapeutics, Inc. Procédés pour la synthèse de composés diarylthiohydantoïnes et diarylhydantoïnes

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140371284A1 (en) * 2011-12-14 2014-12-18 Hc Pharmaceutical Co., Ltd. Imidazolidinedione compounds and their uses
US9346764B2 (en) * 2011-12-14 2016-05-24 Hinova Pharmaceuticals Inc. Imidazolidinedione compounds and their uses
AU2012350482B2 (en) * 2011-12-14 2017-02-16 Hinova Pharmaceutical Inc. Imidazolidinedione compounds and their uses
US11739069B2 (en) * 2012-10-26 2023-08-29 Memorial Sloan-Kettering Cancer Center Modulators of resistant androgen receptor
CN104803919A (zh) * 2014-01-26 2015-07-29 上海医药工业研究院 用于制备恩杂鲁胺中间体的方法
CN104003939A (zh) * 2014-06-06 2014-08-27 山东大学 二芳基取代乙内酰硫脲类化合物及其制备方法与应用
US10000502B2 (en) 2016-01-11 2018-06-19 Janssen Pharmaceutica Nv Substituted thiohydantoin derivatives as androgen receptor antagonists
US10501469B2 (en) 2016-01-11 2019-12-10 Janssen Pharmaceutica Nv Substituted thiohydantoin derivatives as androgen receptor antagonists
US10981926B2 (en) 2016-01-11 2021-04-20 Janssen Pharmaceutica Nv Substituted thiohydantoin derivatives as androgen receptor antagonists
US11292782B2 (en) 2018-11-30 2022-04-05 Nuvation Bio Inc. Diarylhydantoin compounds and methods of use thereof

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