cas 143782-23-4, 3-Fluoro-4-methylphenylisothiocyanate

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Spirocyclic Thiohydantoin Antagonists of F877L and Wild-Type Androgen Receptor for Castration-Resistant Prostate Cancer
Androgen receptor (AR) transcriptional reactivation plays a key role in the development and progression of lethal castration-resistant prostate cancer (CRPC). Recurrent alterations in the AR enable persistent AR pathway signaling and drive resistance to the treatment of second-generation antiandrogens. AR F877L, a point mutation in the ligand binding domain of the AR, was identified in patients who acquired resistance to enzalutamide or apalutamide. In parallel to our previous structure-activity relationship (SAR) studies of compound 4 (JNJ-pan-AR) and clinical stage compound 5 (JNJ-63576253), we discovered additional AR antagonists that provide opportunities for future development. Here we report a highly potent series of spirocyclic thiohydantoins as AR antagonists for the treatment of the F877L mutant and wild-type CRPC.
Zhang, Zhuming,Connolly, Peter J.,Trabalón Escolar, Luis,Rocaboy, Christian,Pande, Vineet,Meerpoel, Lieven,Lim, Heng-Keang,Branch, Jonathan R.,Ondrus, Janine,Hickson, Ian,Bush, Tammy L.,Bischoff, James R.,Bignan, Gilles
p. 1245 - 1252
(2021)
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Rational design and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety
Prostate cancer is a major cause of male death worldwide and the identification of new and improved treatments is constantly required. Among the available options, different non-steroidal androgen receptor (AR) antagonists are approved also to treat castration-resistant forms. Most of these drugs show limited application due to the development of resistant mutants of their biological target. Following docking-based studies on a homology model for the AR open antagonist conformation, a series of novel 3,5-bis-trifluoromethylphenyl compounds was designed with the aim to improve the antiproliferative activity of anti-androgen drugs bicalutamide and enzalutamide. The new structural modifications might impede the receptor to adopt its closed agonist conformation also in the presence of adaptive mutations. Among the novel compounds synthesised, several displayed significantly improved in vitro activity in comparison with the parent structures, with IC50values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145, 22Rv1). Selected hits demonstrated full AR antagonistic behaviour and promising candidates for further development were identified.
Ferla, Salvatore,Bassetto, Marcella,Pertusati, Fabrizio,Kandil, Sahar,Westwell, Andrew D.,Brancale, Andrea,McGuigan, Christopher
p. 3636 - 3640
(2016)
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Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents
Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists.
Xu, Xi,Ge, Raoling,Li, Lei,Wang, Jubo,Lu, Xiaoyu,Xue, Siqi,Chen, Xijing,Li, Zhiyu,Bian, Jinlei
p. 1325 - 1344
(2018)
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Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models
Although the androgen receptor (AR) is a validated target for the treatment of prostate cancer, resistance to antiandrogens necessitates the development of new therapeutic modalities. Exploiting the ubiquitin-proteasome system with proteolysis-targeting chimeras (PROTACs) has become a practical approach to degrade specific proteins and thus to extend the portfolio of small molecules used for the treatment of a broader spectrum of diseases. Herein, we present three subgroups of enzalutamide-based PROTACs in which only the exit vector was modified. By recruiting cereblon, we were able to demonstrate the potent degradation of AR in lung cancer cells. Furthermore, the initial evaluation enabled the design of an optimized PROTAC with a rigid linker that degraded AR with a DC50 value in the nanomolar range. These results provide novel AR-directed PROTACs and a clear rationale for further investigating AR involvement in lung cancer models.
Bachmaier, Rafael D.,Baltes, Fabian,Bendas, Gerd,Gütschow, Michael,Gockel, Lukas M.,Pfeifer, Vladlena,Sosi?, Izidor,Steinebach, Christian,Wagner, Karl G.
(2022/02/16)

Synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile
The invention discloses a synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. The synthesis method comprises the following steps: with 3-trifluoromethyl-4-cyanobenzoic acid as an initial raw material, firstly, subjecting 3-trifluoromethyl-4-cyanobenzoic acid to reacting with diphenyl azidophosphate under an anhydrous condition to generate 4-isocyanato-2-(trifluoromethyl)benzonitrile, and then subjecting 4-isocyanato-2-(trifluoromethyl)benzonitrile to reacting with a Lawson reagent to obtain the compound 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. The method has the advantages of simple synthetic route, one-pot reaction, mild reaction conditions, simple post-treatment, high product yield (wherein total yield is greater than or equal to 83.9%), and easy industrial production.
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Paragraph 0012; 0026; 0029-0030-0031; 0034-0035

(2021/06/02)

ARYL HYDANTOIN HETEROCYCLES AND METHODS OF USE
Disclosed is a compound of formula (I) in which R1, R2, R3, X1, X2, X2', X3, X4, ring A, m, n, and o are as described herein. The compound of formula (I) is useful for treating a disorder associated with androgen receptor malfunction, such as a hyperproliferative disorder, in a subject in need thereof.
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Paragraph 0006; 0104-0105

(2021/07/31)

Design, synthesis and biological evaluation of novel thiohydantoin derivatives as potent androgen receptor antagonists for the treatment of prostate cancer
Prostate cancer (PC) is the most common malignancy in men worldwide. Here, two series of novel thiohydantoin derivatives of enzalutamide as potent androgen receptor (AR) antagonists were designed and synthesized. Among them, compound 31c was identified as an AR antagonist which is 2.3–fold more potent than enzalutamide. Molecular docking studies were performed to explain the improved potency of 31c at AR. In cell proliferation assays, 31c exhibited similar anti-proliferative activities with enzalutamide against hormone sensitive LNCaP cells and AR-overexpressing LNCaP/AR cells. These data indicate that 31c can be a good lead compound for further structure optimization for the treatment of prostate cancer.
Wang, Ao,Wang, Yawan,Meng, Xin,Yang, Yushe
(2021/01/07)

METHOD FOR PREPARING DEUTERATED IMIDAZOLE DIKETONE COMPOUND
A method for preparation of deuterated imidazole diketone compounds includes the following steps: (1) using compound of formula (I) and compounds of formula (II) as starting material, compounds of formula (III) can be obtained by a substitution reaction; (2) Compounds of formula (IV) can be prepared by esterification of carboxyl in compounds of formula (III); (3) Cyclization of compounds of formula (IV) and compound of formula (V) provides compounds of formula (VI); (4) Compounds of formula (VI) are deesterificated and react to produce compounds of formula (VII); (5) using compounds of formula (VII) and compounds of formula (VIII) as starting material, the deuterated imidazole diketone compounds of formula (IX) are obtained by the condensation reaction of amide.
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Paragraph 0050-0053

(2020/03/28)

SUBSTITUTED 3-((3-AMINOPHENYL)AMINO)PIPERIDINE-2,6-DIONE COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITH
Provided herein are piperidine dione compounds having the following structure (I) wherein RN, R1, R2, R3, R4, L,V, m, and n are as defined herein, compositions comprising an effective amount of a piperidine dione compound, and methods for treating or preventing an androgen receptor mediated disease.
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Paragraph 00345

(2020/07/14)

Synthesizing method for 3-trifluoromethyl-4-phenyl cyanothiocyanate
The invention discloses a synthesizing method for 3-trifluoromethyl-4-phenyl cyanothiocyanate. The synthesizing method comprises the following steps: S1, mixing and dissolving 3-trifluoromethyl-4-aminobenzonitrile and triethylene diamine in an organic solvent, reacting at room temperature, and then, filtering and collecting a filter cake; and S2, dissolving BTC (Bis(trichloromethyl)carbonate) in the organic solvent, adding a solution into the filter cake for reacting under the condition of ice bath, then, filtering, collecting filtrate, and drying the organic solvent by distillation to obtainthe 3-trifluoromethyl-4-phenyl cyanothiocyanate. According to the synthesizing method, the 3-trifluoromethyl-4-phenyl cyanothiocyanate is synthesized through a two-step one-pot method by taking the 3-trifluoromethyl-4-aminobenzonitrile, carbon disulphide, the triethylene diamine and the bis(trichloromethyl)carbonate as raw materials. The method is easy and safe to operate, low in cost and high inyield, and has the value of amplifying production.
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Paragraph 0023; 0024

(2019/04/17)

A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF5) and pentafluoroethyl (C2F5) substituents: Improved antiproliferative agents against prostate cancer
SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145 and 22Rv1), showing up to 48-fold increase in comparison with the parent structures. In particular, SF5 enobosarm analogues were found to be most potent compounds, full AR antagonists and with favourable ADME properties. The most promising compound (48a) was evaluated for its in vivo efficacy in PC xenograft mouse model (22Rv1) with results comparable to the standard-of-care docetaxel.
Pertusati, Fabrizio,Ferla, Salvatore,Bassetto, Marcella,Brancale, Andrea,Khandil,Westwell, Andrew D.,McGuigan, Christopher
supporting information
p. 1 - 14
(2019/07/10)

Prostatic cancer treatment medicine
The invention relates to a compound with a prostatic cancer treatment function and nontoxic pharmaceutically acceptable salt of the compound. The structure of the compound is as shown in a formula I,wherein X is C or N, R1 is alkyl of C1-C3 or halogen substituted alkyl, R2 is alkyl of C1-C3 and halogen substituted alkyl or halogen, R3 and R4 are independently selected from H, alkyl and substituted alkyl, and R3 and R4 are connected to form cycloalkyl. The compound has high inhibiting effects on in-situ prostate cancer and transfer of the prostate cancer, and eclamptogenic side effects are lower.
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Paragraph 0016-0018

(2019/03/26)

Synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile
The invention discloses a synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. In the method, 1-[2-cyano-3-(trifluoromethyl)phenyl]thiourea reacts at 95-110 DEG C to obtain 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. Since the generated ammonia gas is neutralized by acid salt, the reaction can be conducted very thoroughly, and the generation of coupled hydrolysis and other impurities is avoided. The method has the advantages of simple steps, low equipment requirements, simple aftertreatment, low consumption of solvent and energy, high product purity, high yield and environmental friendliness and is suitable for industrial production.
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Paragraph 0015; 0032-0035

(2018/07/30)

A two-aryl thio hydantoin derivatives and use thereof
The invention provides a novel diarylthiohydantoin derivative with the structure represented by formula I, and its application. In the formula, X is O or S; R1 and R2 can bee same to or different from each other, respectively represent hydrogen, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-8 naphthenic base, and a C3-8 alkenyl group; R3 represents hydrogen, halogen atoms, a hydroxyl group, a cyano group and a nitro group; R4 and R5 can be same to or different from each other, and respectively represent hydrogen, halogen atoms, -C=(O)-N-(C1-4alkyl) and -(C1-4alkyl)-C(=O)-N-(C1-4 alkyl); and n is 1, 2, 3, or 4. The invention also relates to the application of the above compounds in excessive proliferative diseases.
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Paragraph 0141-0144

(2018/03/26)

Production Method of Enzalutamide Crystal Form
The present invention aims to provided a novel production method of an enzalutamide crystal form in which wet crystals of enzalutamide are obtained in a step of crystallizing in the production process of the enzalutamide crystal form, and then 2-propanol which is solvated with enzalutamide and the B-type crystals are reduced. The present invention relates to a production method of an enzalutamide crystal form, which comprises a step of crystallizing for obtaining wet crystals of enzalutamide, and a step of drying the wet crystals, and comprises a step of washing using a mixed solvent of a good solvent and a poor solvent after the step of crystallizing.
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Paragraph 0080

(2018/06/09)

Synthetic method of 4-isothiocyanato-2-(trifluoromethyl) benzonitrile
The invention discloses a synthetic method of 4-isothiocyanato-2-(trifluoromethyl) benzonitrile. The synthetic method comprises following two steps: step 1, 3-trifluoromethyl-4-cyanoaniline (I) is taken as an initial raw material, and is reacted with phenyl chlorothionocarbonate in an organic solvent such as dichloromethane so as to obtain an intermediate (II); and step 2, the intermediate (II) is subjected to backflow reaction in toluene so as to remove one molecular phenol so as to obtain the finished product 4-isothiocyanato-2-(trifluoromethyl) benzonitrile represented by formula (III). The reaction equation is discloses in the invention. The synthetic method is low in cost, is safe, is friendly to the environment, is simple in operation, and is suitable for industrialized production.
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Paragraph 0042; 0043; 0045

(2017/12/27)

PROTEIN-PROTEIN INTERACTION INDUCING TECHNOLOGY
The present disclosure is based on the surprising and unexpected discovery that a ligand molecule with certain characteristics is able to bind to two protein molecules simultaneously and recruit them to form a transient or stable protein-protein interaction complex. The protein-protein interaction and other cross-domain interactions gained in this process contribute additional stabilization energy to the complex beyond the combination of the binary binding energies, and therefore, largely increase the binding potency of the ligand. Accordingly, the present disclosure provides a Protein-Protein Interaction Inducing Technology (PPIIT), which includes a method to design and identify the tripartite or bifunctional compounds and use such compounds to induce protein-protein interactions in various contexts. The present disclosure also provides a composition for the purpose of inducing protein-protein interactions.
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Paragraph 0187; 0188

(2017/10/17)

PROCESS FOR PREPARATION OF ANDROGEN RECEPTOR ANTAGONIST
The present invention provides an isopropanol solvate of enzalutamide. The present invention also provides a process for the preparation of androgen receptor antagonist. In particular, the present invention provides a process for the preparation of enzalutamide or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof.
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Paragraph 0119

(2017/06/27)

PROCESS FOR THE PREPARATION OF ENZALUTAMIDE
A process for the preparation of enzalutamide. The disclosed process may be effectively implemented on an industrial scale. In some implementations, the following reaction step is employed in the production of enzalutamide.
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Page/Page column 8

(2016/04/20)

AN IMPROVED PROCESS FOR THE PREPARATION OF ENZALUTAMIDE
The present invention relates to an improved process for the preparation of enzalutamide by conventional synthesis, which avoids utilization of microwave irradiation and noxious reagents. The present invention also relates to an improved process for preparation of 4- isothiocyanato-2-(trifluoromethyl) benzonitrile, which is an intermediate in the synthesis of Enzalutamide.
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Page/Page column 28

(2016/04/26)

Sulfo-imidazole-diketone and imidazole-diketone compound and applications thereof
The invention discloses a sulfo-imidazole-diketone and imidazole-diketone compound and applications thereof. The invention provides the formula (I) compound (please see the specification) or pharmaceutical salt, solvate, prodrug, stereoisomer, tautomer and metabolite thereof, wherein X, Y, Z, R1, R2, R3 and A are defined in the formula. The invention further provides a preparing method for the compound and applications of the compound serving as an androgen receptor antagonist to treating diseases related to an androgen receptor, such as prostatic cancer, prostatic hyperplasia, acne, feather-loss disorder, hair hyperplasia, breast cancer and poor male sexual function.
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Paragraph 0094 - 0096

(2017/01/02)

Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer
Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.
Bassetto, Marcella,Ferla, Salvatore,Pertusati, Fabrizio,Kandil, Sahar,Westwell, Andrew D.,Brancale, Andrea,McGuigan, Christopher
supporting information
p. 230 - 243
(2016/05/10)

A "one-pot synthesis" method of synthesizing graciousness mixed Lu An
The invention provides a one-pot method for synthetizing enzalutamide and belongs to the field of medicinal chemical synthesis. The method comprises the following steps: firstly, carrying out copper-catalyzed Buchwald reaction on N-methyl-4-bromo-2-fluoro-benzamide and 2-methyl alanine, adding halogenated hydrocarbon, reacting to generate ester, finally adding a key intermediate 4-isothiocyano-2-(trifluoromethyl) cyanophenyl and carrying out bucherer-Bergs reaction to generate the enzalutamide. The method is simple in operation and high in product yield and has the advantages that the intermediate products are not needed to be separated and directly reacted, so that the process flow cycle is shortened; the final product is easy to separate and purify.
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Paragraph 0017-0020

(2017/03/14)

A kind of diaryl hydanto?n derivatives, its preparation method, pharmaceutical composition and application
Provided are a compound as represented by formula I, or pharmaceutically acceptable salt, solvate, precursor drug, stereoisomer, tautomer, polymorph or metabolite thereof, pharmaceutical composition containing same, and uses thereof in the preparation of drugs for treating androgen receptor related diseases.
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Paragraph 0114

(2016/10/20)

IMIDAZOLINE DERIVATIVES, PREPARATION METHODS THEREOF, AND THEIR APPLICATIONS IN MEDICINE
New imidazoline derivatives represented by formula (I), preparation methods thereof, pharmaceutical compositions comprising such derivatives, and applications of such derivatives in preparing androgen receptor antagonists and medicaments for treating diseases such as prostate cancer.
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Paragraph 0112; 0114

(2015/07/22)

IMIDAZOLINE DERIVATIVES, PREPARATION METHODS THEREOF, AND THEIR APPLICATIONS IN MEDICINE
New imidazoline derivatives represented by formula (I): preparation methods thereof, pharmaceutical compositions comprising such derivatives, and applications of such derivatives in preparing androgen receptor antagonists and medicaments for treating diseases such as prostate cancer are described.
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Paragraph 0133; 0136

(2015/09/22)

PROCESS FOR THE PREPARATION OF ENZALUTAMIDE
The present invention provides a process for the preparation of enzalutamide.
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Page/Page column 11

(2015/05/19)

PROCESS FOR PREPARATION OF ANDROGEN RECEPTOR ANTAGONIST
The present invention provides an isopropanol solvate of enzalutamide. The present invention also provides a process for the preparation of androgen receptor antagonist. In particular, the present invention provides a process for the preparation of enzalutamide or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof.
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Paragraph 0086

(2015/08/04)

IMIDAZOLIDINEDIONE COMPOUNDS AND THEIR USES
Provided are imidazolidinedione compounds of formula (I), processes for preparation, uses and pharmaceutically compositions thereof. Said imidazolidinedione compounds posses androgen receptor antagonist activity and can be used for preventing and treating diseases and disorders related to androgen receptor, such as prostate cancer, alopecia, hair regeneration, acne and adolescent acne.
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Paragraph 0061; 0062

(2014/10/29)

Substituted Phenylcarbamoyl Alkylamino Arene Compounds and N,N'-BIS-Arylurea Compounds
Substituted phenylcarbamoyl alkylamino arenes; substituted phenylthiocarbamyl alkylamino arenes; substituted phenylcarbamoyl alkylamino heteroarenes; substituted phenylthiocarbamyl alkylamino heteroarenes; N-substituted aryl, N′-substituted aryl urea compounds; N-substituted aryl, N′-substituted heteroaryl urea compounds; N-substituted aryl, N′-substituted aryl thiourea compounds and N-substituted aryl, N′-substituted heteroaryl thiourea compounds are provided and may find use as androgen receptor modulators. The compounds may find particular use in treating prostate cancer, including castration-resistant prostate cancer and/or hormone-sensitive prostate cancer.
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Paragraph 0165; 0166

(2013/04/10)

ANDROGEN RECEPTOR ANTAGONISTS AND USES THEREOF
Disclosed are substituted thioimidazolidinone compounds and pharmaceutical compositions comprising such compounds. The compounds and compositions can be used for treatment of androgen receptor-associated diseases or disorders, such as prostate cancer, benign prostatic hypertrophy, male hair loss and hypertrichosis.
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Page/Page column 122

(2012/09/22)

Discovery of diarylhydantoins as new selective androgen receptor modulators
A novel selective androgen receptor modulator scaffold has been discovered through structural modifications of hydantoin antiandrogens. Several 4-(4-hydroxyphenyl)-N-arylhydantoins displayed partial agonism with nanomolar in vitro potency in transactivation experiments using androgen receptor (AR) transfected cells. In a standard castrated male rat model, several compounds showed good anabolic activity on levator ani muscle, dissociated from the androgenic activity on ventral prostate, after oral dosing at 30 mg/kg. (+)-4-[3,4-Dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl] -2-(trifluoromethyl)benzonitrile ((+)-11b) displayed anabolic potency with a strong dissociation between levator ani muscle and ventral prostate (A 50 = 0.5 mg/kg vs 70 mg/kg). The binding modes of two compounds, including (+)-11b, within the AR ligand-binding domain have been studied by cocrystallization experiments using a coactivator-like peptide. Both compounds bound to the same site, and the overall structures of the AR were very similar.
Nique, Francois,Hebbe, Severine,Peixoto, Christophe,Annoot, Denis,Lefrancois, Jean-Michel,Duval, Eric,Michoux, Laurence,Triballeau, Nicolas,Lemoullec, Jean-Michel,Mollat, Patrick,Minet, Dominique,Clement-Lacroix, Philippe,Robin-Jagerschmidt, Catherine,Fleury, Damien,Guedin, Denis,Deprez, Pierre,Thauvin, Maxime,Prange, Thierry
supporting information
p. 8225 - 8235,11
(2020/09/15)

PROCESSES FOR THE SYNTHESIS OF DIARYLTHIOHYDANTOIN AND DIARYLHYDANTOIN COMPOUNDS
Processes are provided for the synthesis of diarylthiohydantoin and diarylhydantoin compounds, such as compounds of the formula: wherein X, Y1, Y2, R1, and R2 are as defined herein. Medicinal products containing the same find particular use in treating prostate cancer, including castration-resistant prostate cancer and/or hormone-sensitive prostate cancer.
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Page/Page column 45

(2011/09/30)

Aldol derivatives of Thioxoimidazolidinones as potential anti-prostate cancer agents
The paper discusses the synthesis and stereochemical aspects of the anti aldol products, 3-(substituted phenyl)-5-[(substituted phenyl) hydroxy methyl]-5-methyl-4-oxo-2-thioxoimidazolidines. The stereochemistry observed in the aldol reactions with benzaldehydes was explained by transition state model of the endocyclic (E)-enolate formed from the rigid 4-oxo-2-thioxoimidazolidine skeleton. Proton NMR and ROESY spectral analyses were carried out to identify the syn and anti conformations of the aldol diastereomers. Configurations of the enantiomers of the representative anti aldol product 3-(4-chlorophenyl)-5-[(4- chlorophenyl) hydroxy methyl]-5-methyl-4-oxo-2-thioxoimidazolidine was determined by single crystal XRD studies. The compounds were screened in vitro against prostate cancer cell lines, PC-3 and LNCaP and the most potent derivatives were identified.
Khatik, Gopal L.,Kaur, Jasmine,Kumar, Varun,Tikoo, Kulbhushan,Venugopalan,Nair, Vipin A.
experimental part
p. 3291 - 3301
(2011/08/04)

SUSTITUTED ( HETEROARYLMETHYL ) THIOHYDANTOINS AS ANTICANCER DRUGS
The invention relates to substituted (heteroarylmethyl) thiohydantoin compounds of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, and their use for the preparation of medicaments for the treatment and/or prophylaxis of disorders, in particular of prostate cancer.
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Page/Page column 46

(2011/04/18)

Lithium perchlorate-induced electrophilic activation: one-pot synthesis of 3-aryl-2-thioxotetrahydropyrimidin-4-one derivatives from aryl isothiocyanates
A novel methodology for the synthesis of N-substituted-3-aryl-2-thioxotetrahydropyrimidin-4(1H)-one derivatives had been developed by the condensation of aryl isothiocyanates with β-amino esters using lithium perchlorate as a catalyst and triethylamine as a base. This strategy not only overcomes the disadvantages of the reported methods but also provides high yield of the product in short span of time by an easily workable procedure.
Kumar, Varun,Nair, Vipin A.
body text
p. 966 - 969
(2010/04/29)

Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC)
A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.
Jung, Michael E.,Ouk, Samedy,Yoo, Dongwon,Sawyers, Charles L.,Chen, Charlie,Tran, Chris,Wongvipat, John
experimental part
p. 2779 - 2796
(2010/09/05)

SUBSTITUTED DI-ARYLHYDANTOIN AND DI-ARYLTHIOHYDANTOIN COMPOUNDS AND METHODS FOR USE THEREOF
Substituted di-arylhydantoin and di-arylthiohydantoins are provided and may find use as androgen receptor modulators. The compounds may find particular use in treating prostate cancer, including CRPC and/or hormone- sensitive prostate cancer.
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Page/Page column 36

(2010/11/03)

SPECIFIC DIARYLHYDANTOIN AND DIARYLTHIOHYDANTOIN COMPOUNDS
Compositions, such as pharmaceutical compositions, comprising specific diarylhydantoin and diarylthiohydantoin compounds, or salts or solvates thereof, are provided. Isolated and purified forms of the compounds are also described, as are unit dosage forms, compositions of substantially pure compound and kits comprising the compounds. The compounds and pharmaceutical compositions thereof may find use in the prevention and/or treatment of a variety of conditions, including prostate cancer, Parkinson's disease, Alzheimer's disease, and others.
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Page/Page column 34

(2010/09/17)

DIARYLHYDANTOIN COMPOUNDS
The present invention relates to diarylhydantoin compounds and methods for synthesizing them and using them in the treatment of hormone refractory prostate cancer.
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Page/Page column 5-6

(2009/05/28)

Anti-androgenic pyrrolidines with tumor-inhibiting action
This invention relates to anti-androgenic N-[ω-[3-[4-cyano-3-(trifluoromethyl)-phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]alkyl]-substituted pyrrolidines of general formula I, with a strongly pronounced antiproliferative profile of action; process for the production of the compounds of general formula I, pharmaceutical preparations and the use for the production of pharmaceutical agents.
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Page/Page column 20; 22

(2009/10/18)

Discovery of an orally-active nonsteroidal androgen receptor pure antagonist and the structure-activity relationships of its derivatives
The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC50=130 nM) with no agonistic activity even at 10000 nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED50=7 mg/kg).
Tachibana, Kazutaka,Imaoka, Ikuhiro,Shiraishi, Takuya,Yoshino, Hitoshi,Nakamura, Mitsuaki,Ohta, Masateru,Kawata, Hiromitsu,Taniguchi, Kenji,Ishikura, Nobuyuki,Tsunenari, Toshiaki,Saito, Hidemi,Nagamuta, Masahiro,Nakagawa, Toshito,Takanashi, Kenji,Onuma, Etsuro,Sato, Haruhiko
experimental part
p. 1555 - 1561
(2009/10/10)

Diarylthiohydantoin compounds
The present invention relates to diarylthiohydantoin compounds and methods for synthesizing them and using them in the treatment of hormone refractory prostate cancer.
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Page/Page column 7

(2008/06/13)

DIARYLHYDANTOIN COMPOUNDS
The present invention relates to diarylhydantoin compounds, including diarylthiohydantoins, and methods for syntheszing them and using them in the treatment of hormone refractory prostate cancer.
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Page/Page column 21; 79

(2008/06/13)

Helix 12 directed non-steroidal antiandrogens
Compounds having the structure (or their salts): are used to treat or reduce the likelihood of acquiring androgen-dependent diseases, such as prostate cancer, benign prostatic hyperplasia, polycystic ovarian syndrome, acne, hirsutism, seborrhea, androgenic alopecia and male baldness. The compounds can be formulated together with pharmaceutically acceptable diluents or carriers or otherwise made into any pharmaceutical dosage form. Combinations with other active pharmaceutical agents are also disclosed.
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Page/Page column 50-51

(2010/11/25)

ANTITUMORAL ANTIADROGENIC PYRROLIDINES
The invention relates to substituted antiadrogenic pyrrolidines N-[ω-[3-[4-cyan-3-(trifluoromethyl)-phenyl]-5.5-dimethyl-4-oxo2-thioxoimidazoline-1-yle]alkyl] of formula (I) having a salient antiproliferative effect profile. Said invention also relates to a method for producing compounds of the formula (I), pharmaceutical preparations and to the use thereof for producing drugs.
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Page/Page column 28; 30-31

(2008/06/13)

Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents
This invention relates to 2-arylimino heterocycles, including 2-arylimino-1,3-thiazolidines, 2-arylimino-2,3,4,5-tetrahydro-1,3-thiazines, 2-arylimino-1,3-thiazolidin-4-ones, 2-arylimino-1,3-thiazolidin-5-ones, and 2-arylimino-1,3-oxazolidines, and their use in modulating progesterone receptor mediated processes, and pharmaceutical compositions for use in such therapies.
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Page column 112-113

(2010/02/05)