- Nucleophilic Aromatic Substitutions of 2-Halo-5-(sulfamoyl)benzoic Acids and N, O-Bis-alkylation via Phase Transfer Catalysis: Synthesis of RoRγInverse Agonist GSK2981278A
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GSK2981278A (1) is a RORγinverse agonist used as a potential topical nonsteroidal therapy for psoriasis. New synthesis of 1 was developed based on a SNAr reaction of (tetrahydro-2H-pyran-4-yl)methanol with an aryl halide intermediate, prepared from 2-halobenzoic acids. The dianion underwent in situ N,O-bis-isobutylation, followed by a reduction to provide 1. The new route eliminated a genotoxic tosylate of (tetrahydro-2H-pyran-4-yl)methanol and a difficult reductive amination from the original synthesis starting from methyl salicylate. A primary version of the route has been scaled up to deliver 125 kg of 1. However, the heating of a strong base in DMSO for an extended period during the bis-alkylation was found to be a safety concern for manufacturing. A safer and greener process was then developed utilizing a facile N,O-bis-alkylation, which was conducted under phase transfer conditions with mild bases such as potassium carbonate and in green solvents such as water. The concise four stage sequence from 2-halobenzoic acids to GSK2981278A (1) had an overall yield of 41%.
- Barcan, Gregg A.,Conde, Jose J.,Mokhallalati, Mohamed K.,Nilson, Mark G.,Xie, Shiping,Allen, C. Liana,Andemichael, Yemane W.,Calandra, Nicholas A.,Leitch, David C.,Li, Ling,Morris, Michael J.
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p. 1396 - 1406
(2019/07/04)
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- Bitopertin synthetic method and intermediate
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The present invention discloses a new synthesis method and intermediates of Bitopertin. According to the Bitopertin synthesis method, 5-methylsulfonyl-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzoic acid is adopted as a raw material, and continuous multi-step operations such as chlorination, acylation, deprotection, condensation and re-crystallization are subjected to performed to obtain the Bitopertin, wherein the intermediates in each step do not require further purification, and the total yield can achieve more than or equal to 80%.
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Paragraph 0066-0068
(2018/03/26)
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- Synthesis of sulfamoylbenzamide derivatives as HBV capsid assembly effector
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The synthesis of novel series of sulfamoylbenzamides as HBV capsid assembly effector is reported. The structure was divided into five parts which were independently modified as part of our lead optimization. All synthesized compounds were evaluated for their anti-HBV activity and toxicity in human hepatocytes, lymphocytes and other cells. Additionally, we assessed their effect on HBV cccDNA formation in an HBeAg reporter cell-based assay. Among the 27 compounds reported, several analogs exhibited submicromolar activities and significant reduction of HBeAg secretion. Selected compounds were studied under negative-stain electron microscopy for their ability to disrupt the HBV capsid formation. Structures were modeled into a binding site recently identified in the HBV capsid protein for similar molecules to rationalize the structure-activity relationships for this family of compounds.
- Sari, Ozkan,Boucle, Sebastien,Cox, Bryan D.,Ozturk, Tugba,Russell, Olivia Ollinger,Bassit, Leda,Amblard, Franck,Schinazi, Raymond F.
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p. 407 - 421
(2017/07/10)
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- Small Molecule Microarray Based Discovery of PARP14 Inhibitors
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Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1. Co-crystallization of the PARP14/H10 complex indicated H10 bound to both the nicotinamide and the adenine subsites. Further structure–activity relationship studies identified important binding elements in the adenine subsite. In tumor cells, H10 was able to chemically knockdown endogenous PARP14 activities.
- Peng, Bo,Thorsell, Ann-Gerd,Karlberg, Tobias,Schüler, Herwig,Yao, Shao Q.
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supporting information
p. 248 - 253
(2016/12/30)
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- ELIMINATION OF HEPATITIS B VIRUS WITH ANTIVIRAL AGENTS
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The present invention is directed to compounds, compositions and methods for preventing, treating or curing Hepatitis B (HBV) infection in human subjects or other animal hosts. The compounds are as also pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof as pharmaceutical compositions and methods for treatment, prevention or eradication of HBV infection.
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Page/Page column 84; 85
(2017/09/27)
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- 2-Substituted-phenyl-oxy-5-methylsulfonyl piperazine acidamide analogue and preparation method and application thereof
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The invention discloses 2-substituted-phenyl-oxy-5-methylsulfonyl piperazine acidamide analogue and a preparation method and application thereof, and particularly, relates to 2-substituted-phenyl-oxy-5-methylsulfonyl piperazine acidamide analogue with a formula (I) compound and a preparation method and application thereof, wherein substitutions in the formula (I) compound are defined as in the description. This serial compound can inhibit the activity of glycine transport protein-1 (GlyT1), is useful in treating related diseases in central nerve and psychological fields, for example, schizophrenia (including positive symptoms, negative symptoms and cognitive symptoms), senile dementia, Parkinson's disease and other related psychological diseases, is widely applicable to the drugs for preventing and treating central nerve and psychological diseases, and is expected to be developed into new-generation GlyT1 inhibitors.
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Paragraph 0346; 0347; 0348
(2016/10/08)
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- HEPATITIS B ANTIVIRAL AGENTS
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The present invention includes a method of inhibiting, suppressing or preventing HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of at least one compound of the invention.
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Page/Page column 224
(2013/07/05)
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- Selective GlyT1 inhibitors: Discovery of [4-(3-fluoro-5- trifluoromethylpyridin-2-yl)piperazin-1-yl][5-methanesulfonyl-2-((S)-2,2, 2-trifluoro-1-methylethoxy)phenyl]methanone (RG1678), a promising novel medicine to treat schizophrenia
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The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.
- Pinard, Emmanuel,Alanine, Alexander,Alberati, Daniela,Bender, Markus,Borroni, Edilio,Bourdeaux, Patrick,Brom, Virginie,Burner, Serge,Fischer, Holger,Hainzl, Dominik,Halm, Remy,Hauser, Nicole,Jolidon, Synese,Lengyel, Judith,Marty, Hans-Peter,Meyer, Thierry,Moreau, Jean-Luc,Mory, Roland,Narquizian, Robert,Nettekoven, Mathias,Norcross, Roger D.,Puellmann, Bernd,Schmid, Philipp,Schmitt, Sebastien,Stalder, Henri,Wermuth, Roger,Wettstein, Joseph G.,Zimmerli, Daniel
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experimental part
p. 4603 - 4614
(2010/09/17)
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- SYNTHESIS OF GLYT-1 INHIBITORS
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The present invention relates to a process for preparation of a compound of formula I wherein Het, R1, R2, R3, and n are as defined herein and pharmaceutically acceptable acid addition salts thereof, which comprises reacting a compound of formula 21 with a compound of formula 8 to obtain a compound of formula 11 and coupling the compound of formula 11 in the presence of a coupling reagent or the corresponding acid halogenide with a compound of formula 15 to obtain a compound of formula I.
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Page/Page column 4-5
(2008/12/08)
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- IL-8 RECEPTOR ANTAGONISTS
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This invention relates to novel compounds, compositions and combinations thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).
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Page/Page column 22-23
(2008/12/06)
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- THERAPEUTIC COMPOUNDS
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The present invention provides novel compounds that function as potentiators of glutamate receptors, methods for their preparation, pharmaceutical compositions containing them, and methods of their use in therapy.
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- Process for preparation of pyrazolo[4,3-d]pyrimidin-7-ones and intermediates thereof
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A process is provided for the preparation of a compound of formulae (IA) (sidenafil) and (IB) comprising reacting a compound of formula (IIA) and (IIB) respectively in the presence of—OR, wherein R in the case of formation of compound (IA) is CH2CH3and R in the case of formation of compound (IB) is CH2CH2CH3, where X is a leaving group:
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- Sulfamylbenzoic acids
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Certain mono- and disubstituted-5-sulfamylbenzoic acids, many of which are novel, and their use in lowering blood lipid levels in mammals.
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