- Preparation method and medical application of benzisothiazole and benzothiophene
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The invention discloses a preparation method and medical application of benzisothiazole and benzothiophene, and telates to the field of pharmaceutical chemistry. According to the invention, benzisothiazole and benzothiophene are the first type of HIF-2 agonists; compared with a compound M1001 found by the applicant in the earlier stage, the invention has better HIF-2 agonist activity, and has remarkable enhancement activity on expression of mRNA and protein of EPO, VGEF, Glut1, NDRG1 and the like at the downstream of HIF-2, so that the invention can be used for preparing drugs for treating and/or preventing chronic kidney diseases/chronic renal anemia, dyslipidemia and high cholesterol caused by abnormal expression of HIF-2; and the method has a good industrialization prospect.
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Paragraph 0166; 0170; 0171; 0209; 0213; 0214
(2021/08/19)
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- INHIBITORS OF THE YAP/TAZ-TEAD INTERACTION AND THEIR USE IN THE TREATMENT OF CANCER
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The invention relates to compounds of formula (I): wherein R1; R2, R3, R4, R5 and are as defined in the description. The compounds of formula (I) are inhibitors of the YAP/TAZ-TEAD interaction and thu
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Paragraph 0096; 0098; 0106; 0108
(2020/04/21)
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- O-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity
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Leishmania (L.) infantum causes visceral, cutaneous, and mucosal leishmaniasis in humans and canine leishmaniasis in dogs. Herein, we describe that O-alkyl hydroxamate derivatives displayed potent and selective in vitro activity against the amastigote stage of L. infantum while no activity was observed against promastigotes. Compound 5 showed potent in vivo activity against L. infantum. Moreover, the combination of compound 5 supported on gold nanoparticles and meglumine antimoniate was also effective in vivo and improved the activity of these compounds compared to that of the individual treatment. Docking studies showed that compound 5 did not reach highly conserved pocket C and established interactions with the semiconserved residues V44, A45, R242, and E243 in pocket A of LiSIR2rp1. The surface space determined by these four amino acids is not conserved in human sirtuins. Compound 5 represents a new class of selective ligands with antileishmanial activity.
- Corpas-López, Victoriano,Tabraue-Chávez, Mavys,Sixto-López, Yudibeth,Panadero-Fajardo, Sonia,Alves De Lima Franco, Fernando,Domínguez-Seglar, José F.,Morillas-Márquez, Francisco,Franco-Montalbán, Francisco,Díaz-Gavilán, Mónica,Correa-Basurto, José,López-Viota, Julián,López-Viota, Margarita,Pérez Del Palacio, José,De La Cruz, Mercedes,De Pedro, Nuria,Martín-Sánchez, Joaquina,Gómez-Vidal, José A.
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supporting information
p. 5734 - 5751
(2020/07/14)
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- A scaffold replacement approach towards new sirtuin 2 inhibitors
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Sirtuins (SIRT1–SIRT7) are an evolutionary conserved family of NAD+-dependent protein deacylases regulating the acylation state of ε-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.
- Seifert, Tina,Malo, Marcus,Kokkola, Tarja,Stéen, E. Johanna L.,Meinander, Kristian,Wallén, Erik A.A.,Jarho, Elina M.,Luthman, Kristina
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- Novel compounds that are inhibitors of YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma
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These compounds are useful as inhibitors of the YAP/TAZ-TEAD interaction.
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- Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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Paragraph 1267
(2015/09/22)
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- SUBSTITUTED HETEROCYCLIC ACETAMIDES AS KAPPA OPIOID RECEPTOR (KOR) AGONISTS
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The present invention relates to a series of substituted compounds having the general formula (I), including their ste reoisomers and/or their pharmaceutically acceptable salts, wherein R1, R2, R3. R4, R5, and R6 are as defined herein. This invention also relates to methods of making these compounds including intermediates. The compounds of this invention are effective at the kappa (κ) opioid receptor (KOR) site. Therefore, the compounds of this invention are useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of central nervous system disorders (CNS), including but not limited to acute and chronic pain, and associated disorders, particularly functioning peripherally at the CNS.
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- COMPOSITIONS FOR TREATMENT OF CYSTIC FIBROSIS AND OTHER CHRONIC DISEASES
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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- DERIVATIVES OF BENZOTHIAZINES, PREPARATION THEREOF AND APPLICATION THEREOF AS DRUGS
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The object of the present invention is benzothiazine derivatives having the capability of inhibiting 11β-HSD1 not only at an enzymatic level but also at a cell level. The compounds of the present invention are of general formula (I). Wherein notably R1 represents a hydrogen or OR1 represents an ester or an ether. R2 represents a naphthyl or a 1, 2, 3, 4-tetrahydro-naphthalene or a biphenyl or phenyl pyridine or a substituted phenyl. R3 represents a methyl or ethyl; R4 and R'4 represent a hydrogen.
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- Modulators of ATP-binding cassette transporters
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Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.
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Page/Page column 410
(2008/06/13)
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- Oxidative cyclization of N-alkyl-o-methyl-arenesulfonamides to biologically important saccharin derivatives
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Various biologically important saccharin skeletons and their N-alkyl derivatives have been efficiently prepared by chromium(VI) oxide catalyzed H5IO6 oxidation of N-alkyl-o-methyl-arenesulfonamides in acetonitrile. N-tert-Butyl saccharin skeletons were easily prepared by H5IO6-CrO3 oxidation of N-tert-butyl-o-methyl arenesulfonamides in the presence of acetic anhydride. The method that furnished the novel fluoro and trifluoromethyl substituted saccharin skeletons is characterized by two steps, a simple work-up procedure, a single purification and good overall yields from substituted toluene derivatives.
- Xu, Liang,Shu, Hong,Liu, Ying,Zhang, Suhong,Trudell, Mark L.
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p. 7902 - 7910
(2007/10/03)
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- Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: Synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives
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In a previous study, we described the structure-activity relationships (SARs) for a series of thiazolidenebenzenesulfonamide derivatives. These compounds were found to be highly potent inhibitors of the wild type (WT) and Y181C mutant reverse transcriptas
- Masuda, Naoyuki,Yamamoto, Osamu,Fujii, Masahiro,Ohgami, Tetsuro,Fujiyasu, Jiro,Kontani, Toru,Moritomo, Ayako,Orita, Masaya,Kurihara, Hiroyuki,Koga, Hironobu,Kageyama, Shunji,Ohta, Mitsuaki,Inoue, Hiroshi,Hatta, Toshifumi,Shintani, Masafumi,Suzuki, Hiroshi,Sudo, Kenji,Shimizu, Yasuaki,Kodama, Eiichi,Matsuoka, Masao,Fujiwara, Masatoshi,Yokota, Tomoyuki,Shigeta, Shiro,Baba, Masanori
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p. 949 - 961
(2007/10/03)
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- Some new 1,2-benzothiazine derivatives with analgesic and anti-inflammatory activities
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Twenty-three new 7-halo-4-hydroxy-2H(or alkyl)-N-(3-aralkyl-2-thio-l-hydantoinyl)-2H- 1,2-benzothiazine-3-carboxamide 1,1-dioxide derivatives were synthesized through the condensation of 7-halo-4-hydroxy-2H(or alkyl)-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxides with 1-amino-2-thio-3-aralkyl-imidazolidine-4-one. The analgesic and anti-inflammatory activities of the synthesized compounds were investigated by acetic acid-induced writhing syndrome and carrageenan rat paw edema tests. In analgesic activities most compounds exhibited higher activities than acetylsalicylic acid, but in antiinflammatory activities most compounds except compounds 24, 36, 39 showed lower activities than indometacin.
- Kwon, Soon-Kyoung,Park, Myung-Sook
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p. 966 - 971
(2007/10/03)
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