- RETINOID COMPOUND AND PHARMACEUTICAL COMPOSITION
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PROBLEM TO BE SOLVED: To provide a novel retinoid compound that is low in teratogenicity, and a pharmaceutical composition containing said retinoid compound. SOLUTION: Provided are a retinoid compound which is a compound represented by the following formula (1) or a salt thereof, and a pharmaceutical composition containing said retinoid compound. In the formula, R1 represents a halogen atom, and R2 and R3 each independently represent a silyl group. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
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Paragraph 0029; 0033-0034
(2020/04/17)
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- Continuous synthesis method for substituted benzoic acid organic matter
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The invention provides a continuous synthesis method for a substituted benzoic acid organic matter. The continuous synthesis method comprises the following steps: in the presence of a catalyst and anorganic solvent, continuously putting an organic matter of a formula (I) shown in the specification, and oxygen into a continuous reaction device, carrying out a continuous oxidation reaction so as toobtain the substituted benzoic acid organic matter, and continuously discharging the substituted benzoic acid organic matter, wherein the substituted benzoic acid organic matter is of a structure ofa formula (II) shown in the specification. Oxygen is a green reagent and is cheap and easy to obtain, a great amount of wastes are not generated after reactions are completed, and the system is easy to treat. Due to continuous reaction operation, the risk that the solvent has flash evaporation explosion because of high-concentration oxygen in in-batch reactions can be reduced. Under same oxidationconditions, due to a continuous preparation process, escape of oxygen can be reduced, the utilization rate of oxygen can be greatly increased, operation can be also simplified, the security of reactions can be improved, and the yield of the substituted benzoic acid organic matter can be increased.
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Paragraph 0123-0125; 0138
(2019/10/01)
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- Prostatic cancer treatment medicine
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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 0031-0034
(2019/03/26)
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- Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents
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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
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p. 1325 - 1344
(2017/11/13)
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- PROCESS FOR THE PREPARATION OF ENZALUTAMIDE
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The present invention provides a process for the preparation of enzalutamide.
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Page/Page column 8
(2015/05/19)
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- Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC)
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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
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experimental part
p. 2779 - 2796
(2010/09/05)
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- 1(2)H-tetrazol-5-yl-phenyl-oxazolidinones as antibacterial agents
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The present invention provides a class of phenyl-oxazolidinones of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1 is a radical of formula (i) or formula (ii): methods of preparing such compounds, pharmaceutical compositions comprising one or more of such compounds, and the use thereof in the manufacture of a medicament which is used in the treatment of bacterial infections.
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Page/Page column 10
(2009/07/17)
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- NOVEL OXAZOLIDINONE COMPOUNDS AS ANTIINFECTIVE AGENTS
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The present invention relates to novel oxazolidinone compounds of formula (I) with antibacterial activity, their pharmaceutically acceptable salts, their stereoisomers, their prodrugs, pharmaceutical compositions comprising the same and to their use as therapeutic agents
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Page/Page column 49
(2009/01/20)
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- Diarylthiohydantoin compounds
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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 6
(2008/06/13)
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- DIARYLHYDANTOIN COMPOUNDS
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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 78
(2008/06/13)
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- Effects of positional and geometrical isomerism on the biological activity of some novel oxazolidinones
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Some novel oxazolidinone derivatives have been synthesized and tested for antibacterial activity. Compound 13 was found to be active against Gram-positive pathogens whereas compound 14 was less active. Either less active or inactive molecules were obtained, when benzotriazole was replaced with benzimidazole, benzthiazole, or benzoxazole. However, thioacetamide analogue of 13 produced a potent molecule similar to linezolid in vitro. Some novel oxazolidinone derivatives with benzotriazole as pendant have been synthesized and tested for antibacterial activity. Linearly attached benzotriazole derivative showed more potency compared to angular one in vitro. Out of E/Z-isomers of angularly attached derivatives E-isomer was found to be more potent than Z-isomer. Either less active or inactive molecules were obtained, when benzotriazole was replaced with benzimidazole, benzthiazole, or benzoxazole. Finally, thioacetamide analogue of linear compound gave a lead having activity similar to linezolid in vitro.
- Das, Jagattaran,Rao, C.V. Laxman,Sastry,Roshaiah,Sankar, P. Gowri,Khadeer, Abdul,Kumar, M. Sitaram,Mallik, Arundhuti,Selvakumar,Iqbal, Javed,Trehan, Sanjay
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p. 337 - 343
(2007/10/03)
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- Novel oxazolidinone-quinolone hybrid antimicrobials
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Antimicrobial compounds incorporating oxazolidinone and quinolone pharmacophore substructures have been synthesized and evaluated. Representative analogues 2, 5, and 6 display an improved potency versus linezolid against gram-positive and fastidious gram-negative pathogens. The compounds are also active against linezolid- and ciprofloxacin-resistant Staphylococcus aureus and Enterococcus faecium strains. The MOA for these new antimicrobials is consistent with a combination of protein synthesis and gyrase A/topoisomerase IV inhibition, with a structure-dependent degree of the contribution from each inhibitory mechanism.
- Gordeev, Mikhail F.,Hackbarth, Corinne,Barbachyn, Michael R.,Banitt, Lee S.,Gage, James R.,Luehr, Gary W.,Gomez, Marcela,Trias, Joaquim,Morin, Sara E.,Zurenko, Gary E.,Parker, Christian N.,Evans, Jonathan M.,White, Richard J.,Patel, Dinesh V.
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p. 4213 - 4216
(2007/10/03)
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- New enzymes and prodrugs for ADEPT
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The present invention relates to nucleic acid molecules encoding mutant human carboxypeptidase A enzymes, and encoding conjugates of targeting molecules and mutant human carboxypeptidase A enzymes. The invention further relates to vectors and cell lines containing such nucleic acid molecules.
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- Irreversible inhibitors of tyrosine kinases
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The present invention provides compounds that are irreversible inhibitors of tyrosine kinases. Also provided is a method of treating cancer, restenosis, atherosclerosis, endometriosis, and psoriasis and a pharmaceutical composition that comprises a compound that is an irreversible inhibitor of tyrosine kinases.
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Page column 70
(2008/06/13)
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- Oxazolidinone compounds and compositions, and methods of using the same
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Oxazolidinones and methods for their synthesis are provided. Further provided are methods of making biologically active oxazolidinones as well as pharmaceutically acceptable compositions comprising the oxazolidinones. Oxazolidinones as disclosed herein can be readily synthesized and used in a variety of applications including use as antimicrobial agents. In one embodiment, a variety of thioamidomethyloxazolidinones and methods for their synthesis and use are provided.
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- Exploiting subsite S1 of trypsin-like serine proteases for selectivity: Potent and selective inhibitors of urokinase-type plasminogen activator
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A nonselective inhibitor of trypsin-like serine proteases, 2-(2-hydroxybiphenyl-3-yl)-lH-indole-5-carboxamidine (1) (Verner, E.; Katz, B. A.; Spencer, J.; Allen, D.; Hataye, J.; Hruzewicz, W.; Hui, H. C.; Kolesnikov, A.; Li, Y.; Luong, C.; Martelli, A.; Radika. K.; Rai, R.; She, M.; Shrader, W.; Sprengeler, P. A.; Trapp, S.; Wang, J.; Young, W. B.; Mackman, R. L. J. Med. Chem. 2001, 44, 2753-2771) has been optimized through minor structural changes on the S1 binding group to afford remarkably selective and potent inhibitors of urokinase-type plasminogen activator (uPA). The trypsin-like serine proteases1 that comprise drug targets can be broadly categorized into two subfamilies, those with Ser190 and those with Ala190. A single-atom modification, for example, replacement of hydrogen for chlorine at the 6-position of the 5-amidinoindole P1 group on 1, generated up to 6700-fold selectivity toward the Ser190 enzymes and against the Alal90 enzymes. The larger chlorine atom displaces a water molecule (H2O1s1) that binds near residue 190 in all the complexes of 1, and related inhibitors, in uPA, thrombin, and trypsin. The water molecule, H2O1s1, in both the Ser190 or Ala190 enzymes, hydrogen bonds with the amidine N1 nitrogen of the inhibitor. When it is displaced, a reduction in affinity toward the Ala190 enzymes is observed due to the amidine N1 nitrogen of the bound inhibitor being deprived of a key hydrogen-bonding partner. In the Ser190 enzymes the affinity is maintained since the serine hydroxyl oxygen Oγser190 compensates for the displaced water molecule. Highresolution crystallography provided evidence for the displacement of the water molecule and validated the design rationale. In summation, a novel and powerful method for engineering selectivity toward Ser190 proteases and against Ala190 proteases without substantially increasing molecular weight is described.
- Mackman,Katz,Breitenbucher,Hui,Verner,Luong,Liu,Sprengeler
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p. 3856 - 3871
(2007/10/03)
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- Oxazolidinone combinatorial libraries, compositions and methods of preparation
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Oxazolidinones and methods for their synthesis are provided. Also provided are combinatorial libraries comprising oxazolidinones, and methods to prepare the libraries. Further provided are methods of making biologically active oxazolidinones as well as pharmaceutically acceptable compositions comprising the oxazolidinones. The methods of library preparation include the attachment of oxazolidinones to a solid support. The methods of compound preparation in one embodiment involve the reaction of an iminophosphorane with a carbonyl containing polymeric support.
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- Synthesis of [1]Benzothieno[3,2-d]pyrimidines Substituted with Electron Donating Substituents on the Benzene Ring
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Various 2-fluorobenzonitriles were converted to the corresponding 3-amino[1]benzothiophenecarboxylic acid esters, which in turn were annulated with formamidine or various equivalents to produce the desired tricyclic benzothienopyrimidines. Various methoxy and nitro/amino substituants were placed on the phenyl ring, requiring several different strategies to prepare the desired benzothiophenes. Several different pyrimidone annulations were also required. The use of an electron rich 2-bromobenzonitrile in a four-step one-pot low temperature lithiation sequence to produce highly electron-rich amino[1]benzothiophenecarboxylate esters is also described. The synthesis of 7-amino-8-fluoro[1]benzothieno[3,2-d]pyrimid-4(3H)-one was relatively straightforward, but synthesis of the corresponding 7-amino-8-protio analogue proved to be very difficult, and required several approaches before a successful one was found.
- Bridges, Alexander J.,Zhou, Hairong
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p. 1163 - 1172
(2007/10/03)
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- Retinoid-like compounds
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The present invention relates to a compound of formula I STR1 or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, in whichX is --O--CO--, --NH--CO--, --CS--NH--, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH 2 --, --CH 2 --CH 2 --, --C C--, --CH 2 --NH--, --COCH 2 --, --NHCS--, --CH 2 S--, --CH 2 O--, --OCH 2 --, --NHCH 2 -- or --CR 5 CR 6 --;R m and R k are independently hydrogen, halogen, C 1-6 alkyl, hydroxy, C 1-6 alkyloxy or nitro;n is zero or one;R 4 is --(CH 2) t --Y, C 1-6 alkyl, or C 3-6 cycloalkyl;R 1 is --CO 2 Z, C 1-6 alkyl, CH 2 OH, --CONHR y, or CHO;R 2 and R 3 are independently hydrogen or C 1-6 alkyl;R a and R b are independently hydrogen or C 1-6 alkyl; but when n is one, R a and R b together can form a radical of the formula STR2 Y is naphthyl or phenyl, both radicals can be optionally substituted with one to three same or different C 1-6 alkyl or halogen;Z is hydrogen or C 1-6 alkyl;R 5, R 6 and R y are independently hydrogen or C 1-6 alkyl; andt is zero to six.
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- Retinoid-like compounds
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The present invention relates to a compound of formula STR1 or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, in which X is --O--CO--, --NH--CO--, --CS--NH--, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH2 --, --CH2 --CH2 --, --C C--, --CH2 --NH--, --COCH2 --, --NHCS--, --CH2 S--, --CH2 O--, --OCH2 --, --NHCH2 -- or --CR5 =CR6 --; Rm and Rk are independently hydrogen, halogen, C1-6 alkyl, hydroxy, C1-6 alkyloxy or nitro; n is zero or one; R4 is --(CH2)t --Y, C1-6 alkyl, or C3-6 cycloalkyl; R1 is --CO2 Z, C1-6 alkyl, CH2 OH, --CONHRy, or CHO; R2 and R3 are independently hydrogen or C1-6 alkyl; Ra and Rb are independently hydrogen or C1-6 alkyl; but when n is one, Ra and Rb together can form a radical of the formula STR2 Y is naphthyl or phenyl, both radicals can be optionally substituted with one to three same or different C1-6 alkyl or halogen; Z is hydrogen or C1-6 alkyl; R5, R6 and Ry are independently hydrogen or C1-6 alkyl; and t is zero to six.
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- Anti-cancer quinazoline derivatives
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A compound of formula I: STR1 wherein R is hydrogen; oran alkyl, alkenyl or alkynyl group of up to 6 carbon atoms; nis O; 1 or 2; Z represents --CH=CH-- or --S--; each X independently represents halogeno, C1 -C4 alkyl, C1 -C4 alkoxy, nitro or trifluoromethyl; and Y represents a group of formula: STR2 or a pharmaceutically acceptable salt or ester thereof.
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- Quinazoline Antifolate Thymidylate Synthase Inhibitors: 2'-Fluoro-N10-propargyl-5,8-dideazafolic Acid and Derivatives with Modifications in the C2 Position
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The synthesis of 2'-fluoro-10-propargyl-5,8-dideazafolic acid and its 2-desamino, 2-desamino-2-hydroxymethyl, and 2-desamino-2-methoxy analogues is described.In general the synthetic route involved the coupling of diethyl N--L-glutamate (15) with the appropriate 6-(bromomethyl)quinazoline followed by deprotection with mild alkali.These four compounds together with the 2-desamino-2-methyl analogue were tested for their activity against L1210 thymidylate synthase (TS).They were also examined for their inhibition of the growth of the L1210 cell line and of two mutant L1210 cell lines, the L1210:R7A that overproduces dihydrofolate reductase (DHFR) and the L1210:1565 that has impaired uptake of reduced folates.Compared with their nonfluorinated parent compounds, the 2'-fluoro analogues were all ca. 2-fold more potent as TS inhibitors.Similarly, they also showed improved inhibition of L1210 cell growth (1.5-5-fold), and this activity was prevented by co-incubation with thymidine.All had retained or improved activity against both the L1210:R7A and L1210:1565 cell lines.
- Jackman, Ann L.,Marsham, Peter R.,Thornton, Timothy J.,Bishop, Joel A. M.,O'Connor, Brigid M.,et al.
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p. 3067 - 3071
(2007/10/02)
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- Novel Fluorinated Antifolates. Enzyme Inhibition and Cytotoxicity Studies on 2'- and 3'-Fluoroaminopterin
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Two novel analogues of aminopterin with a single fluorine substitution in the 2' (compound 8) or in the 3' (compound 9) position of the p-aminobenzoyl group were synthesized and evaluated as inhibitors of dihydrofolate reductase from two bacterial species and from human HeLa cells.The 2'fluoro compound was bound essentially the same as aminopterin itself, while the 3'-fluoro derivative bound two- to threefold more tightly in all cases.UV spectral shifts indicated normal binding of the pteridine.Cytotoxicity studies against mouse leukemia L1210 cells and the human stomach cancer line HuTu80 indicated equivalent toxicity of the parent drug with the 2'-fluoro analogue. 3'-Fluoroaminopterin was, however, twice as toxic as aminopterin to both cell lines.
- Henkin, Jack,Washtien, Wendy L.
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p. 1193 - 1196
(2007/10/02)
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