- Convenient Continuous Flow Synthesis of N-Methyl Secondary Amines from Alkyl Mesylates and Epoxides
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The first continuous flow process was developed to synthesize N-methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N-methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds or their precursors. Up to 10.6 g (88% yield) of an N-methyl secondary amine was produced in 140 min process time. The amination procedure included an in-line workup, and the starting mesylate material was also produced in continuous flow from the corresponding alcohol. Finally, an in-line process combining the mesylate synthesis and nucleophilic substitution was developed.
- Lebel, Hélène,Mathieu, Gary,Patel, Heena
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p. 2157 - 2168
(2020/11/23)
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- triAZOLOtriAZINE DERIVATIVES AS A2A RECEPTOR ANTAGONISTS
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The present invention provides triazolotriazine derivatives of formula (1) as A2A receptor antagonists. Compounds of formula (1) and pharmaceutical compositions including the compounds can be used for the treatment of disorders related to A2A receptor hyperfunctioning, such as certain types cancers. Compounds of formula (1) and methods of preparing the compounds are disclosed in the invention.
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Page/Page column 49
(2020/01/24)
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- Structure-based drug design, synthesis and biological assays of P. falciparum Atg3–Atg8 protein–protein interaction inhibitors
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The proteins involved in the autophagy (Atg) pathway have recently been considered promising targets for the development of new antimalarial drugs. In particular, inhibitors of the protein–protein interaction (PPI) between Atg3 and Atg8 of Plasmodium falc
- Villa, Stefania,Legnani, Laura,Colombo, Diego,Gelain, Arianna,Lammi, Carmen,Bongiorno, Daniele,Ilboudo, Denise P.,McGee, Kellen E.,Bosch, Jürgen,Grazioso, Giovanni
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p. 473 - 486
(2018/02/06)
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- Pyridine ethyoxyl coumarin plant growth regulator
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The invention discloses a pyridine ethyoxyl coumarin compound with a structure shown as a formula I, and the pyridine ethyoxyl coumarin compound serves as a plant growth regulator. The compound shown as the formula I has excellent effects of promoting germination and rooting, increasing the yield and improving the quality and can be widely used for increasing the yield or improving the survival rate in agriculture or forestry.
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Paragraph 0019; 0020; 0021
(2017/07/19)
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- 2,4,6-trichloro phenylpyridine ethyl ether plant growth regulator
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The invention discloses a 2,4,6-trichloro phenylpyridine ethyl ether compound structurally shown as a formula I. The 2,4,6-trichloro phenylpyridine ethyl ether compound is used as a plant growth regulator. The compound shown as a formula I has the advantages that the plant rooting and sprouting are promoted, the growth and the development are promoted; the obvious yield improving effect is achieved; the structure is simple; the production and use cost is low; the use is safe; the compound can be used for crop and fruit and vegetable yield improvement and quality improvement. The formula I is shown as the accompanying drawing.
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Paragraph 0017; 0018; 0019
(2017/07/20)
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- CXCR4 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00326; 00359; 00401
(2018/04/11)
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- CXCR4 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Page/Page column 00320; 00347
(2018/04/11)
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- BICYCLIC HETEROCYCLIC DERIVATIVES AS BROMODOMAIN INHIBITORS
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The present disclosure provides bicyclic heterocyclic derivatives of formula (I), which may be therapeutically useful, more particularly as bromodomain inhibitors; (I), in which R1, R2, R3, R4, L1, L2, Cy1, Cy2, X, n, and dotted line have the same meaning given in the specification, and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof that are useful in the treatment and prevention of diseases or disorders, in particular their use in diseases or disorders associated as bromodomain inhibitors. The present disclosure also provides preparation of compounds and pharmaceutical formulations comprising at least one of bicyclic heterocyclic derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent, or excipient.
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Paragraph 0193
(2017/04/04)
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- 2,4-DIOXO-QUINAZOLINE-6-SULFONAMIDE DERIVATIVES AS INHIBITORS OF PARG
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The present invention relates to compounds of formula I that function as inhibitors of PARG (Poly ADP-ribose glycohydrolase) enzyme activity wherein R1a, R1b, R1c, R1d, R1e, W, X1, X2, X3, X4, X5, X6, X7, c are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which PARG activity is implicated.
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Paragraph 00803
(2016/07/05)
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- BICYCLIC HETEROCYCLIC DERIVATIVES AS BROMODOMAIN INHIBITORS
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The present invention provides bicyclic heterocyclic derivatives of formula (I), which may be therapeutically useful, more particularly as bromodomain inhibitors; (I), in which R1, R2, R3, R4, L1, L2, Cy1, Cy2, X, n and dotted line are have the same meaning given in the specification, and pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder associated as bromodomain inhibitors. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of bicyclic heterocyclic derivatives of formula (I), together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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Page/Page column 40; 41
(2015/07/23)
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- Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6- methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d ]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor
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We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3- yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl} -3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.
- Miwa, Kazuhiro,Hitaka, Takenori,Imada, Takashi,Sasaki, Satoshi,Yoshimatsu, Mie,Kusaka, Masami,Tanaka, Akira,Nakata, Daisuke,Furuya, Shuichi,Endo, Satoshi,Hamamura, Kazumasa,Kitazaki, Tomoyuki
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experimental part
p. 4998 - 5012
(2011/09/19)
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- Indol-3-ylcycloalkyl ketones: Effects of N1 substituted indole side chain variations on CB2 cannabinoid receptor activity
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Several 3-acylindoles with high affinity for the CB2 cannabinoid receptor and selectivity over the CB1 receptor have been prepared. A variety of 3-acyl substituents were investigated, and the tetramethylcyclopropyl group was found to lead to high affinity CB2 agonists (5, 16). Substitution at the N1-indole position was then examined. A series of aminoalkylindoles was prepared and several substituted aminoethyl derivatives were active (23-27, 5) at the CB2 receptor.Astudy of N1 nonaromatic side chain variants provided potent agonists at the CB2 receptor (16, 35-41, 44-47, 49-54, and 57-58). Several polar side chains (alcohols, oxazolidinone) were well-tolerated for CB2 receptor activity (41, 50), while others (amide, acid) led to weaker or inactive compounds (55 and 56). N1 aromatic side chains also afforded several high affinity CB2 receptor agonists (61, 63, 65, and 69) but were generally less potent in an in vitro CB2 functional assay than were nonaromatic side chain analogues.
- Frost, Jennifer M.,Dart, Michael J.,Tietje, Karin R.,Garrison, Tiffany R.,Grayson, George K.,Daza, Anthony V.,El-Kouhen, Odile F.,Yao, Betty B.,Hsieh, Gin C.,Pai, Madhavi,Zhu, Chang Z.,Chandran, Prasant,Meyer, Michael D.
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experimental part
p. 295 - 315
(2010/06/11)
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- Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family
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Adenine derivatives bearing substituents in the 2-, N6-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [3H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N 6-acetyladenine (25, Ki rat: 2.85 μM; Ki human: 0.515 μM) and 8-aminoadenine (33, Ki rat: 6.51 μM; Ki human: 0.0341 μM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family. 2009 American Chemical Society.
- Borrmann, Thomas,Abdelrahman, Aliaa,Volpini, Rosaria,Lambertucci, Catia,Alksnis, Edgars,Gorzalka, Simone,Knospe, Melanie,Schiedel, Anke C.,Cristalli, Gloria,Müller, Christa E.
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experimental part
p. 5974 - 5989
(2010/03/24)
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- Concise synthesis of vinylheterocycles through β-elimination under solventless phase transfer catalysis conditions
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Various vinylheterocycles compounds have been prepared in excellent yields through β-elimination of the corresponding sulfonate esters with 50% aq NaOH under phase transfer catalysis conditions without organic solvent. The new approach provides an economic and environmentally friendly solution to removal of hazardous bases as well as toxic and expensive dipolar aprotic solvents.
- Albanese, Domenico,Ghidoli, Cristina,Zenoni, Maurizio
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p. 736 - 739
(2013/01/03)
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- In vitro SAR of pyrrolidine-containing histamine H3 receptor antagonists: Trends across multiple chemical series
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Structure-activity relationships (SAR) were analyzed within a library of diverse yet simple compounds prepared as histamine H3 antagonists. The libraries were constructed with a variety of low molecular weight pyrrolidines, selected from (R)-2-methylpyrrolidine, (S)-2-methylpyrrolidine, and pyrrolidine.
- Nersesian, Diana L.,Black, Lawrence A.,Miller, Thomas R.,Vortherms, Timothy A.,Esbenshade, Timothy A.,Hancock, Arthur A.,Cowart, Marlon D.
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p. 355 - 359
(2008/04/03)
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- CHEMICAL COMPOUNDS 428
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Compounds of formula (I): wherein variable groups are defined within; their use in the inhibition of 11βHSD1, processes for making them and pharmaceutical compositions comprising them are described.
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Page/Page column 36
(2010/11/30)
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- 3-CYCLOALKYLCARBONYL INDOLES AS CANNABINOID RECEPTOR LIGANDS
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The present invention provides novel compounds of Formula (I), which are CB2 selective ligands useful for the treatment of pain.
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Page/Page column 35
(2008/06/13)
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- N-SUBSTITUTED BENZENE SULFONAMIDES
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Disclosed are N-substituted benzenesulfonamides for use intreating in treating or preventing cognitive disorders, such as Alzheimer′s Disease. Formula (I) In formula (I), R1, R2, R3, R4, R3’, R10
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Page/Page column 92
(2008/06/13)
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- A total synthesis of Manzamine C and its geometrical isomer
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Manzamine C (1) has been synthesized from silyloxyacetylene (3) along the line: 4→5→8→18→1. The overall yield is 21%. The β-carboline segment (11) was obtained by the Bischler-Napieralski reaction of 14 followed by dehydrogenation. By the similar procedur
- Torisawa,Hashimoto,Nakagawa,Seki,Hara,Hino
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p. 8067 - 8078
(2007/10/02)
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