- Enantioselective hydroarylation or hydroalkenylation of benzo[b]thiophene 1,1-dioxides with organoboranes
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An efficient protocol for the asymmetric hydroarylation and hydroalkenylation of benzo[b]thiophene 1,1-dioxides with organoboranes has been developed. The combination of a rhodium(I) precatalyst and a chiral diene ligand constitutes the catalytic system, which enables the facile synthesis of 2,3-dihydrobenzo[b]thiophene 1,1-dioxides in good yields with high enantioselectivities. The merging of this asymmetric hydroarylation with the downstream alkylations delivers 2,3-dihydrobenzo[b]thiophene 1,1-dioxides that contain two continuous quaternary stereocenters with high enantioselectivities in a diastereodivergent manner.
- Hu, Fangdong,Jia, Jie,Li, Ximing,Xia, Ying
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p. 896 - 901
(2021/02/01)
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- Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
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Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.
- Taylor, Nicholas J.,Emer, Enrico,Preshlock, Sean,Schedler, Michael,Tredwell, Matthew,Verhoog, Stefan,Mercier, Joel,Genicot, Christophe,Gouverneur, Véronique
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p. 8267 - 8276
(2017/06/27)
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- Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?
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The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 μM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 μM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 ± 0.37 μM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors.
- Terzi?, Natasa,Konstantinovi?, Jelena,Tot, Miklo?,Burojevi?, Jovana,Djurkovi?-Djakovi?, Olgica,Srbljanovi?, Jelena,?tajner, Tijana,Verbi?, Tatjana,Zlatovi?, Mario,Machado, Marta,Albuquerque, Inês S.,Prudêncio, Miguel,Sciotti, Richard J.,Pecic, Stevan,D'Alessandro, Sarah,Taramelli, Donatella,?olaja, Bogdan A.
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p. 264 - 281
(2016/01/29)
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- C-benzo five-membered heteroaromatic aryl glucoside derivative as well as preparation method and application thereof
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The invention discloses a C-benzo five-membered heteroaromatic aryl glucoside derivative shown in the general formula (I) (in the description), a preparation method of the derivative or an intermediate of the derivative, as well as application of the derivative. In the general formula (I), R, R1, R2, R3, R4, X and Y are defined in the description. The C-benzo five-membered heteroaromatic aryl glucoside derivative is novel in structure, has quite strong inhibitory activity on SGLT-2, has high selection ratio for SGLT-1 and SGLT-2, and can be used for preparing drugs for treating and preventing diseases relevant to SGLT-2.
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- GLUCOSYLCERAMIDE SYNTHASE INHIBITORS FOR THE TREATMENT OF DISEASES
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Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).
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- NOVEL GLUCITOL DERIVATIVE, PRODRUG THEREOF AND SALT THEREOF, AND THERAPEUTIC AGENT CONTAINING THE SAME FOR DIABETES
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The invention provides a glucitol derivative having the function of reducing a blood sugar level and having preferable properties required of medicines, such as long-lasting drug activity; and a medicinal composition for use in the prevention or treatment of diseases attributable to hyperglycemia, such as diabetes, complications of diabetes, and obesity. The derivative is a compound represented by the formula (I): wherein m is an integer selected among 1-3; R1 to R4 each independently is optionally substituted alkyl, etc.; Ar1 is optionally substituted naphthyl; and A is optionally substituted heteroaryl, a prodrug of the compound, or a pharmaceutically acceptable salt of either. Also provided are a medicine, a medicinal composition, and the like each containing the compound.
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Page/Page column 18-19
(2008/06/13)
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- 3-AMINO CHOMAN AND 2-AMINO TETRALIN DERIVATIVES
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3-Amino chroman and 2-amino tetralin derivatives and compositions containing such compounds are disclosed. Methods of using the 3-amino chroman and 2-amino tetralin compounds and compositions containing such compounds in the treatment of serotonin disorders, such as depression and anxiety, are also disclosed.
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Page/Page column 81-82
(2010/02/10)
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- Design and Synthesis of a Fluoroindolocarbazole Series as Selective Topoisomerase I Active Agents. Discovery of Water-Soluble 3,9-Difluoro-12,13-dihydro-13-[6-amino-β-D-glucopyranosyll]-5H,13H-benzo[b] -thienyl[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (BMS-251873) with Curative Antitumor Activity against Prostate Carcinoma Xenograft Tumor Model
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A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.
- Balasubramanian, Balu N.,St. Laurent, Denis R.,Saulnier, Mark G.,Long, Byron H.,Bachand, Carol,Beaulieu, Francis,Clarke, Wendy,Deshpande, Milind,Eummer, Jeffrey,Fairchild, Craig R.,Frennesson, David B.,Kramer, Robert,Lee, Frank Y.,Mahler, Mikael,Martel, Alain,Naidu, B. Narasimhulu,Rose, William C.,Russell, John,Ruediger, Edward,Solomon, Carola,Stoffan, Karen M.,Wong, Henry,Zimmermann, Kurt,Vyas, Dolatrai M.
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p. 1609 - 1612
(2007/10/03)
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- C17,20-lyase inhibitors I. Structure-based de novo design and SAR study of C17,20-lyase inhibitors.
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Novel nonsteroidal C(17,20)-lyase inhibitors were synthesized using de novo design based on its substrate, 17 alpha-hydroxypregnenolone, and several compounds exhibited potent C(17,20)-lyase inhibition. However, in vivo activities were found to be short-lasting, and in order to improve the duration of action, a series of benzothiophene derivatives were evaluated. As a result, compounds 9h, (S)-9i, and 9k with nanomolar enzyme inhibition (IC(50)=4-9 nM) and 9e (IC(50)=27 nM) were identified to have powerful in vivo efficacy with extended duration of action. The key structural determinants for the in vivo efficacy were demonstrated to be the 5-fluoro group on the benzothiophene ring and the 4-imidazolyl moiety. Superimposition of 9k and 17 alpha-hydroxypregnenolone demonstrated their structural similarity and enabled rationalization of the pharmacological results. In addition, selected compounds were also identified to be potent inhibitors of human enzyme with IC(50) values of 20-30 nM.
- Matsunaga, Nobuyuki,Kaku, Tomohiro,Itoh, Fumio,Tanaka, Toshimasa,Hara, Takahito,Miki, Hiroshi,Iwasaki, Masahiko,Aono, Tetsuya,Yamaoka, Masuo,Kusaka, Masami,Tasaka, Akihiro
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p. 2251 - 2273
(2007/10/03)
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- Indole derivatives for the treatment of depression and anxiety
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The present invention provides compounds of formula (I): which are useful for treating depression, anxiety, and alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine.
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Page/Page column 57
(2010/02/05)
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- Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 2. 6,6-dimethylbicyclo[3.1.1]heptane derivatives
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In an earlier paper, we reported that novel prostaglandin D2 (PGD2) receptor antagonists having the bicyclo[2.2.1]heptane ring system as a prostaglandin skeleton were a potent new class of antiallergic agents and suppressed various allergic inflammatory responses such as those observed in conjunctivitis and asthma models. In the present study, we synthesized PGD2 receptor antagonists having the 6,6-dimethylbicyclo [3.1.1]heptane ring system. These derivatives have the amide moiety, in contrast to those with the bicyclo[2.2.1]heptane ring system, which have the sulfonamide group. The derivatives having the 6,6-dimethylbicyclo[3.1.1]heptane ring also exhibited strong activity in PGD2 receptor binding and cAMP formation assays. In in vivo assays such as allergic rhinitis, conjunctivitis, and asthma models, these series of derivatives showed excellent pharmacological profiles. In particular, compound 45 also effectively suppressed eosinophil infiltration in allergic rhinitis and asthma models. This compound (45, S-5751) is now being developed as a promising alternative antiallergic drug candidate.
- Mitsumori, Susumu,Tsuri, Tatsuo,Honma, Tsunetoshi,Hiramatsu, Yoshiharu,Okada, Toshihiko,Hashizume, Hiroshi,Inagaki, Masanao,Arimura, Akinori,Yasui, Kiyoshi,Asanuma, Fujio,Kishino, Junji,Ohtani, Mitsuaki
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p. 2446 - 2455
(2007/10/03)
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- Direct gas-phase synthesis of 4-fluorothiophenol and bis(4-fluorophenyl) sulfide
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The gas-phase reaction of 4-chlorofluorobenzene with a 4-fold excess of hydrogen sulfide at 700°C allows simultaneous one-stage synthesis of 4-fluothiorophenol and bis(4-fluorophenyl) sulfide. The low yield of the reaction products is compensated for by the facility of their synthesis and isolation.
- Deryagina,Sukhomazova,Levanova,Papernaya,Dolenko
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- Benzothienopyrazinedione compounds and their preparation and use
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Novel [1]benzothieno[2,3-b]pyrazine-2,3(1H,4H)-diones or tautomeric forms thereof of the general formula (I) STR1 wherein R 1, R 2, R 3 and R 4 independently represent hydrogen, halogen, alkyl, alkoxy or trifluoromethyl.The compounds are useful for treating a central nervous system ailment associated with the NMDA receptor-associated glycine site.
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